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Hotel Monaco
Paul McHugh, M.D.
CHAIRMAN KASS: Well, welcome to Council
members, guests, members of the public to this, the seventh meeting of
the President's Council on Bioethics.
I note the presence of Dean Clancy, the
designated federal officer whose presence makes this a legal meeting.
I would like to announce that we have at long
last added a lawyer to our staff. Carter Snead from Ropes & Gray
will be joining us starting in two weeks. He will be at the meeting
tomorrow. I will introduce him at that time.
I would also like to announce that we now have
at headquarters a members' office so that should you find yourself in
town and need a place to sit and work and also to interact with our
lively staff, there is a special office set aside fully equipped for
your use.
Our cloning report in final version has been
produced by the Government Printing Office and Public Affairs has
produced the commercial version, copies of which are at your seats.
We have discussions of the report set up in the
months ahead, and I know others of you are talking to Diane about
arranging things on your campuses.
There will be a book forum at the American
Enterprise Institute on the 29th of this month; a session in Baltimore
sponsored by the law school of the University of Maryland and Johns
Hopkins University on the 21st of November; and there are conversations
underway at Georgetown, Princeton, and Chicago for further meetings.
Our next meeting is December 12 and 13 where we
will have what's definite for that meeting is a presentation on the
use of Ritalin and other stimulants in children; a couple of
presentations on aging and longevity research; and Francis Collins of
the Human Genome Project will be talking about uses of genetic
technologies and the prospects for enhancement.
I would also, since as everybody knows this
Council is charged with the monitoring of stem cell research, I would
at least like at this point to make a very brief presentation, an
update on the subject of the monitoring.
As I think everybody knows, since August 9th of
2001, federal funding has been available for research on embryonic stem
cells subject to the particular restrictions announced by the President
at that time. The implementation of that policy which has fallen to
NIH has yielded the following information for us.
There is a registry of cell derivations that
meet the original criteria and the NIH has identified – 78 cell
derivations that meet the original criteria.
The NIH has reviewed 13 grant applications
involving human embryonic stem cells at its May 2000 Advisory Council
session and 19 grant applications for its October 2002 Advisory Council
sessions, and continues to receive applications each receipt date.
The NIH has also made available infrastructure
grants to help developers defray the costs of providing cell lines,
administrative supplements to encourage expansion of existing projects
to produce preliminary data of human cells, and investigator initiated
grant awards.
And so far the NIH has granted seven, 37, and
eight awards in these respective categories.
Also, six of the NIH intramural labs are
conducting research on human embryonic stem cells, and cumulatively
there are over 45 researchers representing over 40 different research
institutions receiving federal funds for research on human embryonic
stem cells.
The NIH has also finalized four material
transfer agreements with the commercial companies that have developed
these lines. They are Y Cell, the ESL International, BresaGen,
Inc., and the University of California, San Francisco,
associated with Geron.
Data on how many of these lines are presently
available to be shipped is, however, not easy to get. At present three
developers have lines available for shipment totaling five different
cell lines.
Finally, I'd like to mention one recent
development that I think is pertinent to our ongoing deliberations.
Since the last meeting, researchers at the National University of
Singapore funded by ESL have announced the successful culture of human
cells on human feeder cell lines.
This is a newly derived cell line, and
therefore under current policy, federal funding could not be used to do
research with it. All of the lines that are in the NIH registry were
supported on animal feeder cells so that should human trials be
required, these cells would at least at the moment not be available for
use under the xenotransplantation regulations.
This new development, I think, will probably be
important for us as the pressure might mount for work on these new
lines that are potentially usable in clinical trials.
That just by way of an update. Staff is
working ahead on the monitoring of stem cells, and after the beginning
of next year, we will have more to do with that at our regular
meetings.
Questions or comments on that?
(No response.)
CHAIRMAN KASS: Well, the two sessions that
we have planned for this morning are on the topic of choosing the sex
of children, the discussion of current technology and practice, and
then a look at the demographics.
Our interest in the topic of sex selection is
in part a continuation of questions that we touched on in the cloning
report, namely opportunities to select in advance some of the genetic
traits of children.
It also represents at least in part a use of
biomedical technologies not for therapy, but for the satisfaction of
client or patient desires.
This is also an interesting case in which the
aggregated effects of choices that might be innocent in themselves
might produce results such that even the people who use the technique
might be unhappy with the result as a result of its being used by
everybody.
And it is also an interesting case for us
because there are international implications of biomedical technology
where techniques developed for one purpose and one use and one country,
say, in the United States, will be used for other purposes and in
different ways abroad with consequences that may, in fact, come back to
have an influence here at home.
We're very pleased to have with us this
morning Dr. Arthur "Cap" Haney, who is the Roy T. Parker
PROF. of Obstetrics and Gynecology and Director of the Division of
Reproductive Endocrinology and Infertility in the Department of
Obstetrics and Gynecology at the Duke University Medical Center.
Dr. Haney is a past President of the American
Society for Reproductive Medicine, a researcher, and a leading
authority in this area, and I'm very delighted that you could be
with us, and especially after all of the travels that were required to
make it possible.
We're in your debt, and we look forward to
your presentation.
Thank you.
DR. HANEY: Can everyone hear me?
PARTICIPANTS: Yes.
DR. HANEY: Okay. I appreciate the opportunity
to be here. I'm actually a stand-in for Sandy Carson [President ASRM] who
couldn't be here. She's attending our meeting, and hopefully I
can give you something similar to what she would present.
I think I reviewed your briefing booklet, and
it has virtually everything I'm going to talk about in it, and so
I'll try to do this relatively quickly and then respond to any
questions that you have.
So I choose -- and this is all personal -- I
choose to separate two terms: sex selection from sex determination,
and you'll see as we go through this what I mean by that.
Now, by way of indications currently one would
define two, a medical and a nonmedical. There are probably 350 or plus
diseases known to be linked to an X chromosome, either autosomal
dominant or recessive or X-linked dominant or recessive. But
an X chromosome as a potential carrier of disease.
The Y chromosome to my knowledge -- and I'm
not a geneticist, so I apologize if there are some others that are
around -- the AFG mutations creating severe oligospermia have been well –
documented now. With many of the X-linked recessive diseases, the
families who had these children or they're in the families would
like to avoid having another child born, and hence, having a female
with two X chromosomes and screening -- by definition the father
doesn't have it -- would lead to that outcome.
The Y-linked diseases, we've actually been
able to, using ICSI, intracytoplasmic sperm injection, have these very
severely oligospermic men father children, but they will automatically
pass on to any male offspring, which is going to be 50 percent, the same
mutation that created their oligospermia.
And there's two responses to that. One is
I'd like to avoid that and have daughters, and the other response
is that if we were successful in 2002, that meant by the time my son is
27 and wants to have children, he'll be that much more successful
in 2029.
But in any event, that would be a medical
indication for sex selection.
Now, the nonmedical ones, I choose to break
into two categories: primary gender selection, that is to say, the
first conception, and the second one would be family or gender
balancing, which tries to equilibrate to the social desires of the
family, the opposite gender from preceding children.
Now, I don't need to go through the
glossary in great detail, but we're all in our business acronym –
related.
IUI means intrauterine insemination with washed
sperm, getting rid of the seminal plasma, which contains lots of
prostaglandins and being able to put the sperm themselves in the
uterine cavity without reaction.
COH is stimulation with -- it's supposed to
be -- I'm a little off on the right-hand side over here --
gonadotropins, but controlled ovarian hyperstimulation, that is to say,
inducing multiple ovulatory events in a single cycle.
IVF, pretty traditional, in vitro fertilization
and embryo transfer.
ICSI, or intracytoplasmic sperm injection used
to inject single sperm into oocytes to create embryos.
Blastomere biopsy, typically done at day three
post – fertilization, which is removal of blastomere, typically an eight –
cell embryo for some sort of DNA analysis.
Fluorescence – activated flow cytometry, or FACS,
which is prominent in this arena here that we are discussing today.
Discontinuous density gradient centrifugation,
and this is essentially layering the sperm or the seminal plasma on a
gradient and centrifuging the sperm through it trying to separate the
weight, subtle weight difference between X and Y bearing sperm to
separate them.
DNA analysis, I'm not a geneticist, but
there's tremendous numbers of these opportunities, which there will
be more. The ones that are most frequent for us are typical PCR or
whole chromosome amplification or FISH, fluorescent in situ
hybridization, and those are simply techniques to identify unique DNA,
whether it's an X chromosome or a specific gene mutation.
Amniocentesis, removing the cells around a
fetus which have the fluid in it and the cells from the fetus are
present there. You then culture them and do genetic analysis on those,
and that's typically done by 15 to 18 weeks of gestation.
Chorionic villus sampling is a similar
technique, but actually biopsying the trophoblast much earlier in
gestation, much more rapidly growing cells. They are proliferating
trophoblast cells. So in 48 hours you can have information or even
shorter time.
And then traditional karyotype, just looking at
the actual chromosomes.
Now, this is not a new phenomenon, the attempt
to control the gender of offspring. There have been for basically
eternity people attempting this in one way or the other.
There are clearly very unsuccessful methods.
Coital timing, trying to be close to ovulation, there's a whole
literature on that.
Changing the environment in the vagina where
ejaculation would occur.
Electrophoresis, looking for trying to
distinguish the X and Y sperm based on electric charge.
Transferring embryos with the most blastomeres
because it's been the observation that the male embryos,
genetically male embryos, proliferate. The blastomeres proliferate a
slightly bit faster than the female ones do.
And then density gradients, which I sort of
listed as unsuccessful, but it's still practiced and many people in
the United States use it, and you have a variety of materials:
albumen, Percoll, Ficoll, Sephadex, et cetera, that you could use to
do the separation.
Now, possible methods -- and I stress the word
at the moment "possible" because in the absence of clear
randomized clinical trials demonstrating efficacy, I really cannot tell
you there is a method that effectively works, but at least these are a
step above what was on the preceding slide.
And if you try to do this before fertilization,
that focuses on selected sperm, and this is a relatively new
phenomenon. The technology was pioneered by someone in the Department
of Agriculture named Johnson, and that's been applied in animal
husbandry in a variety of species and simply adapted in the
mid-'90s to try to do this to human sperm, and we'll talk a
little bit more about what it means.
But when you preselect sperm, you have several
options to use them. You can use them in intrauterine insemination,
simply in a natural spontaneous cycle timed reasonably proximate to the
ovulatory event.
You can stimulate the patient with
gonadotropins to increase the efficiency so that the likelihood of
conception goes up, but there is also some hazard of multiple
gestation.
In vitro fertilization, simply taking the
selected sperm that you have and placing them in the dish with the
collected oocyte.
And then trying to preselect the sperm and
actually inject it into the oocyte directly with ICSI, and these all
basically are the same philosophy with different efficiencies.
And then preimplantation would be not using
selected sperm, but simply doing IVF, having embryos developed, and
then doing blastomere biopsy and identifying the genes of the embryos
to be transferred.
Now, sex determination is certainly not new,
and that's a very old technology, and when ultrasound became more
sophisticated and the resolution improved sufficiently, then one can
identify the gender of a fetus simply by the anatomy of its genitals in
utero, and that's probably about 15 weeks to 16 weeks of gestation
that can be done.
And then chorionic villus sampling, as I
mentioned, is biopsying the trophoblast, and that will be typically
done between 11 and 13 weeks of gestation.
And then amniocentesis, which collects the
fetal cells, and that would be done closer to 16 to 18 weeks of
gestation.
Now, the human sex chromosomes are different
than many other animals in that the difference between the amount of
DNA is relatively small in the total genome. So it's 2.8 percent
between the X and the Y sperm, and that does leave the possibility at
least theoretically of trying to separate it by a centrifugation.
As I alluded, that has not been
demonstrated to be effective, but I'll continue to discuss it a
bit because it's being currently used.
And then the X and Y sperm can be
differentiated to a degree by the amount of binding of fluorescent dye
which allows their separation in a FACS, or fluorescent activated cell
sorter. A difference of 2.8 percent would then bind a greater amount
of dye in a Y chromosome.
Now, the typical albumen or the Ericsson
method, which has been used for many, many years, or at least propagated
for many, many years, is albumen density gradient centrifugation, and
it's discontinuous, and this is the various concentrations of human
albumen, et cetera, have been more empirically defined, but the method
has never been demonstrated to be effective.
And despite claims to the contrary, when
objective observers have used it, they cannot see any difference in the
offspring resulting.
Now, fluorescence activated flow cytometry is
the current one, and it's licensed. I'm not sure exactly who
owns the patent, but it's licensed to Genetics and IVF Institute
and under the trade name MicroSort, and essentially sperm are mildly
sonicated, stained with a Hoechst vital dye, which reversibly and as
best one knows does not alter the DNA, and then this dye fluoresces at
359 nanometer of ultraviolet light, and one can then be using the
difference in the amount of dye bound to the two gender specific
sperm. They can be separated by fluorescence activated sorting and
trying to simply enrich the fractions of X and Y bearing sperm for
subsequent use.
So that's basically the principal involved,
and this is just an illustration to show you the stained sperm coming
through and then deviated left and right with X and Y.
And there's actually in practicality --
they are mostly done not simultaneously, but sorted for X or sorted for
Y. So don't sort them all together for both.
And this is what the proof as has been proposed
for the efficiency of that process, and that is that when you extract
-- this isn't done in the actual treatment procedure, but to
demonstrate that they are accurately doing that, they then use FISH,
fluorescent in situ hybridization, and look for probes for either X or
Y, and this is in an XSort, and you'll see that there's a --
it's not so clear here, but these are pink, and that one's
green, showing you that there's a substantial shift toward X
bearing sperm, and they estimate, based on their FISH numbers with some
data that it is 80 to 90 percent effective in separating the two sperm
haplotypes.
The FISH analysis with the Y sort is similar,
and you see they have the sperm. An X is marked in red, and the other
is green. This is a little less effective. Somewhere between 60 and
70 percent shifted to Y bearing sperm with this technology.
And then a case report was forthcoming for the
first initial case of a birth that occurred after this procedure in
1996 and consistently the reports have been, except for one, related to
female selection. And this was, I believe, -- I believe this is an
X-linked hydrocephalus problem in the family. I'm not sure exactly
what it is, but it is a medical problem that this child -- they opted
for a female offspring.
Now, there are several utilizations or there
are several ways of utilizing the sperm that you get, and the number
and quality of the sperm selected in this process determines how they
can be used.
Now, you have to make the assumption that if
you use them, that the selection process did not harm sperm function,
how it actually works, and we can't really test sperm function
other than the fact that fertilization and embryo development occurs.
So you can look at the number of sperm and
accrued semenalysis or a swim-up sample and look for a variety of
surrogate markers, capacitation, et cetera, in the sample to see if it
had an impact, but function is still difficult.
So if you get what appears to be after your
whatever the procedure of sorting that you get normal qualitative and
quantitative parameters for this washed sample, then you have the
potential for putting it in the uterus, and if you do that in a natural
cycle, it turns out to be about an eight percent cycle fecundity, that
is, term delivery after one treated cycle.
And the human fecundity at max is probably 20
percent, and people argue between 12 and 18. That is to say one in
every five to six cycles turns into pregnancy. That's clearly age
related, mostly maternal age.
If the selected sample is not in the normal
range, but there's more than a million hyper modal sperm, and by
that I mean when they're layered in media and allowed to swim out
of the pellet with centrifugation. Those are the most actively modal
sperm and the highest quality fraction.
If that is greater than a million, but
you're not in the normal range, then you have the option of doing
an IUI with stimulation. Now, that increases your cycle fecundity
slightly, and the reason that's probably true has to do with the
estrogen stimulation of the female with higher numbers of oocytes and
follicles, and the estrogen in the female genital track facilitates
sperm transport into the distal tube where fertilization occurs.
You run the risk of multiple gestation with
that.
In vitro fertilization significantly increases
your cycle fecundity, but at much significant cost, and we'll talk
a little bit about cost at the end, but depending on the circumstances
and the quality of sperm, age of the mother, et cetera, you would sort
of currently go between 15 and 35, maybe up to a 40 in women below
30 for a per cycle delivery rate.
The conception rate, that is to say, missed
period and clinical pregnancy rate, would be slightly higher, but you
would see some spontaneous abortions.
And then if the sample is noticeably lower in
quality and the motility in addition may well be abnormal, then
instead of traditional IVF where the sperm are simply placed in with
the retrieved oocyte, one typically microinjects the sperm or the egg
with the sperm, ICSI, and that offers per embryo, which you generally
can get the same number of embryos you would if you put healthy sperm in
with the standard egg retrieval. You get the same success rate.
So ICSI, even though it's just a little
more manipulation, turns out to be virtually identical to IVF for
oligospermic either samples or males.
Now, intrauterine insemination is simply, just
to illustrate what we're doing, after you separate the liquid from
the sperm and get rid of all of the prostaglandins and the seminal
plasma which normally stay in the vagina and never enter the uterus,
only the modal sperm actually enter the uterus. If you can separate
the two, you will lose a few sperm in the process, but you then place a
small catheter into the uterine cavity and deliver the sperm there.
And the attrition that normally occurs in the
vagina to the uterus is on the order of 100-fold loss. One percent
actually get there, maybe two percent. So tremendous attrition.
So placing them higher, even if you lose a few,
will increase the numbers of sperm in the distal tube where
fertilization occurs.
So that's the strategy between intrauterine
insemination. You simply have to wash them so seminal plasma is not
transferred.
Controlled ovarian hyperstimulation is a more
complicated scheme where one injects LH and FSH, the human
gonadotropins that are normally made in the pituitary. Humans are
monotocous, that is, we release one oocyte even though a crop of
follicles matures every cycle. Polytocous animals don't have the
selection that goes from a crop to a single ovulation that we do.
So the difference between a monotocous species
like us and a polytocous species is not the number of follicles you
move forward each reproductive cycle, but the selection process to
release one.
That's clearly involved with gonadotropins,
and when you simply overdose the patient, if you will, with
gonadotropins, you can get a larger proportion of that crop to mature
and hence you can stimulate more than the single ovulation in a given
cycle.
All those follicles appear functionally equal
in genetic quality, et cetera. It's just in monotocous species the
metabolic demands of the mother are such that you should have one offspring
most of the time.
But that's the way it's done and simply
has daily injections in the follicular phase in the first half of the
cycle until ovulation.
And this is what it looks like and how it's
controlled. One stimulates the patient, and then you do standard
transvaginal ultrasound exams, and you can very accurately with the
technology today measure follicular diameter.
And the stimulation is maturing the follicles
and typically human ovulation occurs about 22 millimeters. We can
trigger with HCG ovulation about 18 millimeters, and from a lot of
other information with IVF, we get healthy oocytes and mature
pre-ovulatory oocytes when you do that.
So this stimulation is then by injection. We
teach husbands how to do it. They do the shots. We do the monitoring,
and you can measure with the estrogen because each of these follicles
makes estrogen as well.
So a combination between ultrasound and
estrogen gives you the follicle number and the timing for triggering
release of those follicles.
Now, IVF with ICSI using selected sperm, you do
the same stimulation with the injectable gonadotropin. You do the same
ultrasound, but at the appropriate -- we block the LH surge, blocking
the pituitary so the patient cannot mount the terminal 36 hours of that
maturation of the oocyte and release of the egg. We block that so that
we're in control of it.
We then do a transvaginal ultrasound guided
oocyte retrieval. It sounds kind of gruesome, but it's very
efficient, and it's not very uncomfortable. We just use
contrasedation and retrieve the oocyte, and it's age – related how
many you'll get per patient.
And then you have the oocytes in vitro, which
you then inject with whichever of the two sperm that you had selected.
The embryos are then transferred via the cervix
into the uterine cavity and implantation and all subsequent pregnancy
events.
This is what it looks like. This actually
isn't a needle, but this is very accurate. It's the same
picture you saw before, and we simply take our ultrasound probe and put
a guide on it and slide the needle through, and you can literally
puncture each of these follicles in succession and with minimal suction
aspirate the contents, and about 90 percent of the time an oocyte will
come with the follicle, the follicular fluid that you've aspirated.
So that's basically the process. You
stimulate with gonadotropins and then do an egg retrieval rather than
allow ovulation to occur by itself.
Now, ICSI then to inject the sperm, this is
done with micromanipulators in vitro. There's a cumulus mass. I
should have shown you that, but a cumulus mass is normally present, the
zona pellucida. We strip the cumulus mass, and then with very low
pressure fix the oocyte up against a pipette. This is done with
micromanipulators. So it's not by hand, and then a drawn glass
pipette has become very small.
You can crimp a sperm tail and get a single
sperm in the pipette, puncture the zona pellucida and the plasma
membrane of the egg, inject the sperm, and then withdraw the pipette,
and both the plasma membrane and the egg and the zona pellucida seem to
tolerate this reasonably, and fertilization then occurs at the same
rate as the normal sperm would penetrate in vitro and have
fertilization occur.
So that's used both for oligospermic men,
and it was simply adapted here to be able to take sorted sperm and do
the same thing.
Now, host fertilization pre-implantation
selection is a different phenomenon. The preceding slide showed you
that you injected selected sperm of the gender that you were looking
for. With this process, in vitro fertilization is performed with just
the routine semen sample available in the same series of events, except
there's no ICSI. It's standard fertilization in vitro.
And then at about three days, blastomere is
removed for determination by one of these analytic methods, FISH, PCR,
whatever, to determine the presence of an X or Y, and then one has a
series of embryos which are kept in each of their own wells, and
you've identified their genetics.
And this is exactly the same technique you
would use for pre-implantation genetic diagnosis, except there you do
PCR first, with a specific probe for gene defect you're looking
for. Here they're looking for a gender differentiation.
There's a biopsy. You can pull out of a
blastomere and then do some sort of DNA analysis. This is actually on
leukocytes, but it looks the same. FISH is identified with colored
probes. You can do whole chromosomes. You can do whatever the most
efficient analytic technique you have and identify the gender.
Now, here's the clinical data that has been
presented for fluorescent activated cell sorting to date, and this is
the initial paper in Human Reproduction in 1998, and all of it except
for this one little bit here for the YSort, which I'll tell you
about, was last week at ASRM, was on X, selecting for Xes.
And so they did 208 cycles, and they did a
variety of things. Two hundred and eight cycles of IUI, intrauterine
insemination, where they simply got samples and then placed them in the
uterine cavity of the wife at the appropriate time.
They had a ten percent cycle fecundity with
that. They then did either IVF or IVF with ICSI, and they did 36 cycles
in 27 couples and had an improved success rate, though it's not as
high as one typically sees with just straightforward ICSI for
oligospermia.
And of those, they ended up with 29
pregnancies. They had seven losses, one ectopic, nine deliveries, and
at the time of the report, 12 ongoing clinical pregnancies, and they
have never gone back and validated in the literature what those turned
out to be.
But they then claimed that they had 15 of 18,
or 88 percent, of fetuses with known gender, and some of these
presumably were ultrasonically identified, were of the gender of
choice, female, for the selection they had.
Now, that's what existed up until Tuesday,
this past Tuesday, as best I can tell in all of the literature, and if
you think of all the activity that has gone into this up until Tuesday,
it's based on this, and there isn't a single male paper out
there demonstrating an equivalent YSort to show that you could actually
increase the likelihood of male delivery.
And a comment was made without data in an
abstract at ASRM that they thought that the babies born were 78 percent
when they did YSorts and 92 percent when they did XSorts, and that
didn't have numbers associated with it. It was just a sentence in
the abstract which was actually done for a different reason. It was
there to show that there was no abnormality in the offspring that were
generated.
And I tried to deduce based on some issues they
had for abortion, spontaneous abortion with that. They were assessing,
and you'll see in a minute, the number of losses that might have
occurred and was that different than normal?
And I think I could deduce 304 total
pregnancies in the group, and out of 1,900 sorting procedures. So
that's as best trying to extract from them what's published as
to what's actually going to validate that this works.
Now, their current usage, and by that I mean
request usage, this is an abstract, two abstracts the group presented,
245 ICSI cycles. They had roughly two thirds were looking for Xes to
select for females and one third for males, and they did note that the
goal is to be able to send samples frozen through the mail, get them
sorted and send them back, and then do ICSI with them.
And they did note that when they did that, they
had a reduced fertilization and cleavage rate, which isn't terribly
surprising with the trauma of cryopreservation. When it works, it
works, but the efficiency is going to be declined.
And the other abstract that I mentioned that
had 1,900 separation procedures, they separated them without the
numbers in each category as family balancing and medical indications
and found the same spontaneous loss rate and then noted a 2.5 percent
major anomaly rate, which is favorably compared to the three to four
percent in the general population.
And importantly, if you look at those sorts of
anomalies, there is no pattern. They're all random and different.
But, again, the fleshing it out to the actual
numbers wasn't in the abstract. It's a little hard to do.
Now, the current availability, if you will,
there is no comprehensive place. ASRM or any other doesn't compile
any programs that offer sex selection, and basically this is an
Internet advertised offering.
And I could find six sites, although I'm
sure there are more, but there are many locations. Some of these
programs have locations in different states and advertise them in
different countries, and the technologies that they advertise -- and
sometimes it's very difficult even in the Internet site to figure
out what they're doing for sex selection. So you can't tell if
they're doing the Ericsson method of density gradient
centrifugation or actually doing the fluorescent activated cell sorting
or even PGD.
And some of the sites separate them and say you
can do PGD where it's extremely accurate, where you've actually
pulled out the blastomere and know the genes to the extent that PCR or
FISH would do.
Others -- and the couple that would choose that
can pick whichever level of security they want for increasing costs to
do them.
So they're all over the place, but it's
basically an Internet business that's being advertised, and this is
the sort of ad that one sees. This is one of the franchised MicroSort
centers, and complete with a full debate about whether it's
appropriate or not.
And then if you're really interested, click
this button and go further.
These are roughly what the costs are, and they
will vary a lot. New York City is very different than Durham, for
example, in IVF costs. IUI is, with the preparation and insemination,
about four to $600; COH, about 2,500, including the drugs and the
ultrasound monitoring. IVF in our institution is ten. Other places,
in more expensive markets, 15, 14, $15,000.
ICSI will be an additional fee with the IVF.
So this fee is the entire thing. It's a couple thousand dollars
more than you traditionally do with IVF.
Most of the others are not done often enough in
enough places to get a good idea what the costs are, but these are
estimates for a blastomere biopsy equivalent to ICSI, $1,500 for a
manipulation, the same basic sort of technology.
PCR I've seen in several places around
$3,000; FISH, a little bit less. The MicroSort varies, and depending
on the franchise place for it, between 2,500 and 5,000.
Ultrasound is relatively inexpensive. When you
look at the three determination as opposed to selection technologies,
they're relatively cheap. Ultrasound exam is very simple, $300,
and amino with the karyotype is probably between 1,500 and 2,000, and
then a chorionic villus sampling, slightly higher.
And that would be a rough idea, but there is
some variation from institution to institution and locale to locale.
Now, the questions that immediately come to
mind with fluorescent activating cell sorting, which is the most
heavily advertised version, is the relatively small number of reported
clinical outcomes, and this is particularly true since the success of
the technology is not validated by anyone other than the people who own
it, if you will, or who are franchised for it. So it's not
independently done.
It has not been a technology that has been
validated by anyone else. So very small numbers, and I think you have
seen what is in the literature. I could have missed something
somewhere, but I scanned everybody's name, whoever was on the
MEDLINE and any of those papers and tried to find their name on
anything, and that's the only thing I came up with.
So there could be an abstract somewhere else
that isn't in MedLine, but other than that, I think that's it.
This is the dye utilized to Hoechst 33342 dye,
bisbenzimide, and that's the binding to the sperm that's
reversibly binding. But the question is: what is the true impact? Is
there any subtle impact in altering the DNA?
And similarly, we're using the wavelength
of ultraviolet light to cause it to fluoresce. So you have the marker
to separate the light. I think there certainly have always been some
concerns about the exposure of sperm to that and DNA to that.
And then the relatively small recovery of sperm
after you do this process makes the efficiency of doing it with
insemination much lower. So you then, to make it an efficient process
after cell sorting, is you see as time has gone on the reports that
occur, always focus on doing ICSI and IVF, and certainly those carry
their own concerns as well.
Now, future technologies -- and this is more
free association, and believe me, as you well know, smart people will
do things I haven't possibly dreamed of, but future technologies
for sex selection would be selective elimination of an X or Y bearing
sperm on the basis of something on the cell surface biochemically or
immunologically, and that's been talked about a lot, but has never
come to fruition.
But you can think of it very similar to an
assay using complete mediated cell lysis where you lysed sperm of the
sort you wanted to remove, and then selection of sperm by some
noninjurious DNA analysis rather than simply the density of binding of
the fluorescent, something that specifically bound the sperm.
Now, the limitation to date, as you can
appreciate, is the sperm is a very condensed DNA package. It's
basically a DNA packet with a tail, and it's very hard to get any
probe into this condensed DNA where you could determine anything, but I
won't say that isn't possible at some point.
Preimplantation you can potentially look for a
gender specific gene expression within an intact embryo analogous to
the Fisher dye staining. So you could potentially without -- if you
could do it in a noninjurious way, without doing a biopsy, you can
potentially look for any genetic trait within an embryo if you can get
to the point of not being able to injure an embryo.
You can look in the media and see if
there's a differential uptake of one precursor or another. I
don't think that's terribly likely to be profitable just given
the undifferentiated state of the early embryos we have, but I
can't exclude that.
And then you can do a FISH analysis similar to
something like that on cells that remain after you've hatched, an
embryo is hatched. And we've seen something like that happen. We've
transferred just when you get to blastocyst cultures, some of these are
beginning to hatch, and you're going to see some cells that are
just going to fall away from the embryo and you potentially have those
to use as well.
So there's a lot of options, and there are
going to be more that come along.
Now, sex determination, that is, having a
clinical pregnancy and determining what the gender is, just so that you
know if you haven't seen these things before, this is an ultrasound
showing a tear shaped uterus with a gestational sac and a fetus in a
yoke sac, and the amniotic fluid.
And so one then at a much later stage of
gestation can aspirate the fluid from the amniotic or aspirate the
amniotic fluid in fetal cells that are in the amniotic fluid, are then
available for cell culture. They use fetal fibroblast and slow to
grow. So it take a long time to culture them. It's a laborious
and difficult process.
The chorionic villus. sampling where you're
getting trophoblasts, they're proliferating very actively. So
it's extremely rapid, and you basically place a needle and remove a
bit of trophoblast.
And then the fetus itself, you can -- I'm
sorry. The red isn't really clear -- but you can begin to look at
the characteristics of the fetus, such as its yoke sac and other
things, by ultra sound and begin to look at gender differentiation.
So the future for sex determination as opposed
to sex selection is going to be a variety of things: a collection of
exfoliated trophoblasts which may be present in the vagina. The
membranes of the fetus, there may well be very small numbers of cells
shed into the endocervical canal and virtually equivalent to a Pap
smear, you could extract those, determine that they were fetal, not
maternal, and then have a genome to look at.
Detection of factors in the maternal
circulation responsible for gender differentiation in the fetus, and
these are primarily related to the duct systems of the two sexes, the
Mullerian duct or Musophen [sp?] ducts and Wolffian ducts, and there's
some very, very specific hormones involved in female differentiation
and male differentiation, and potentially small amounts of those will
cross the placenta and be detectable in blood.
There's a phenomenon called 4D ultrasound.
It's 3D with a time element for the fourth, and they're getting
extremely sophisticated with high resolution, ten, 12, 11 megahertz to
be able to see much more details in the fetus, and that's for a lot
of prenatal diagnosis.
And then fetal red blood cells. Once the fetus
begins to make them, they are nucleated so they show up. And they do
show up in very small numbers in the maternal circulation, and you can
try to filter them out, and people have for years been trying to find
ways of doing that. It would save you doing an amniocentesis if you
could efficiently retrieve them because they have the nucleus, and you
could then do a DNA analysis on the fetus by fetal nucleated cells.
CHAIRMAN KASS: Sorry. Could I ask? Could
you give the rough age of gestation when these things might be
possible?
DR. HANEY: You're going to stress me
there.
CHAIRMAN KASS: Well, roughly. What's
the earliest?
DR. HANEY: I don't honestly know. I would
hesitate to say.
Sandy [Carson] and Joe Leigh [Simpson] can probably tell you better than I can, but I'm sure it's no
earlier than 14 weeks. I think it's minimum then, but I honestly
don't know the exact week.
And then ultrasound guided amnios
transvaginally, we aspirate many, many things we never dreamed possible
before down to four and five millimeters. So easily one may well see
transvaginal much earlier amniocentesis for fetal material as you saw
in the picture.
And just two slides, and I don't want to
steal the thunder of the subsequent speaker, but to show you the impact
of the sex determination and all of these gender differences, I would
tell you are probably related to sex determination, not sex selection,
and ultrasound showed up somewhere in the early to mid-'80s that
was then capable, sophisticated and with high enough resolution to
actually begin to look at genital differentiation in utero, and you
began to see that's when the largest change in disparity of male to
female ratio by birth occurred.
But this would be both. Whatever gender
selection might have been going on, but I'm going to bet it's
all sex selection, but I'll bet it's all sex determination, and
this would be for people in this category because they're all
parities. It would be people who selected primarily to get the fetus
as opposed to people who had three children of one sex and wanted
another.
And then if you look at the impact of gender
determination for balancing, that is, in subsequent pregnancies, you
can see it's very dramatic; that the further they go in the number
of pregnancies, the greater the desire to balance the offspring.
And I think I'll stop at that.
CHAIRMAN KASS: Dr. Haney, thank you very
much.
The floor is open for discussion. Mike
Gazzaniga.
DR. GAZZANIGA:: I'm just curious to know
how many cases, if we call it, an event where there's a desire for
sex selection or sex determination; how many in the United States per
year are seeking this sort of service?
DR. HANEY: I don't think there's any
way whatsoever to determine that. There's not a record kept anywhere,
and the best you have, I think, is an estimate of the total number that
are reported in the abstract you saw there, but there's absolutely
no way of knowing.
DR. GAZZANIGA:: So say within your own center.
What percent of births do you think would be governed or guided by this
technology?
DR. HANEY: We don't do it at all. We
wouldn't do it.
DR. GAZZANIGA:: Oh, you don't do it?
DR. HANEY: No, no.
CHAIRMAN KASS: Bill May.
DR. MAY: You used the word
"franchise." Are you talking about the ownership of
technique and then franchising locations? Is that what you mean by
franchising?
DR. HANEY: Maybe that's a loose -- I
don't know all of the financial arrangements of their program, but
they do have the label on MicroSort and various programs around the
United States, and they have programs hither and yon. So that's
just a loose way of me describing.
They must be related to Genetics and IVF
Institute in some fashion.
CHAIRMAN KASS: Bill.
DR. HURLBUT: I want to ask you about a couple
of the scientific sides of this. When they use the dye that
interpolates into the DNA, is there a way of washing it out before the
gametes are mixed with the oocytes?
DR. HANEY: As best you can read the
technology, it's not actually washed out, other than the amount
that's washed out in the processing that would occur subsequent to
the sorting before you put it in, and it's thought to be
noninjurious, and it will begin to -- if you wait an interval of time,
you get less and less fluorescence. So the dye is constantly being
disassociated with the DNA.
DR. HURLBUT: What I'm thinking of in
asking that is we're coming to appreciate more and more how
transcription is affected by large scale operations on the centrosome
and around the histones and so forth so that something that interfered,
even if it seems to be innocently intercalating, might actually be
affecting something.
DR. HANEY: I think that's the concern.
That's I think what prompted the abstract with the 300 offspring
and looking for anomalies, but they're all young and you don't
know what's going to be there over time.
DR. HURLBUT: Other questions on this line. I
know that at least I think it's established that there are often
events within a normal embryo where aneuploid cells are produced, for
example, or even cells without nucleus in a given eight, ten cell
embryo. There may be a couple of cells that are abnormal.
They normally gravitate into the trophoblast
apparently and don't actually make their way into the embryo. So
this isn't a matter of sex selection primarily, but you could have
instances in post – implantation or pre-implantation diagnosis where you
are actually getting a misimpression from looking at one cell over
another, right?
DR. HANEY: There's no question that when
you do pre-implantation genetic diagnosis for anything, you're
going to have a limit to the technology because of heterologous, if you
will, or heterozygosity of this, the particular agent, and particularly
if you have some error in one cell doesn't contain that.
They don't use polar bodies that much for
that reason. Polar bodies could be used, too, for the maternal
mutations, and they are less reliable than blastomeres, and you're
talking about blastomeres that aren't all the same. But these are
not chimeras. So it's some other technical abnormality that would
have to be there.
But I think that's known inherent with the
technique.
DR. HURLBUT: And finally, the recent evidence
seemed to suggest that there is already polarity even in the early
embryo, and that there is asymmetric cell division with regard to
cytoplasm, which may contain certain determinant factors in the
ultimate outcome of the embryo.
This is a rather abstract question, but does it
worry you at all that even if you produce a normal, apparently normal
pregnancy out of this process that you're actually altering the
outcome of the individual life?
DR. HANEY: By what?
DR. HURLBUT: By taking --
DR. HANEY: Blastomere biopsies?
DR. HURLBUT: -- a blastomere out of the
developing embryo.
DR. HANEY: At an eight – cell stage, I mean, the
blastocyst is five to six days, and you have a blastocoll cavity and
innercell mass, and then the trophectoderm on the outside. And
that's clearly -- I don't know if polarity is the right word,
but it's clearly differentiated into those compartments.
At the eight cell stage and based on animal
models, one would not anticipate that you would alter that blastocyst
development by any methodology I'm aware of. I can never say it
couldn't be there, and the more subtle you look, the more reassured
you are, but as best I know, when you biopsy that early when there are
undifferentiated cells, before that and at an eight cell stage you
don't see polarity. They're just eight cells.
So I think you have to get another day or two
out to be able to see that, but I cannot tell you there's some, but
not biochemical polarity occurring, if you will, in that process. And
all you can ultimately do is look at the offspring that are born, and
hopefully in an animal model under experimental conditions, and
determine that as you move forward.
DR. HURLBUT: There was an article in Nature
magazine about four months ago. Its titled "Your Destiny from Day
One," and it tracked the asymmetric cell divisions and certain
cytoplasmic factors that were disproportionately assigned between the
cells of the embryo, showing that there is a predicted cell fate even
at that early stage with disproportions of cytoplasmic factors.
So theoretically at least you might be getting
a different outcome than you would. The only reason I raise this is
because in the thinking about this issue, is the general assumption in
the community that you're taking one or two blastomeres out at the
six to ten cell stage is not affecting the outcome in any way, or is it
accepted that you're affecting the outcome in some way, but not
adversely in an abstract sense?
DR. HANEY: I think that the general, if I had
to characterize it, it would be that you're risking that the embryo
will not survive, but you're not risking that you're going to
have an anomalous embryo.
DR. HURLBUT: What percent increase of failure
to survive do you think you're affecting the embryo with by doing
this?
DR. HANEY: If you looked at IVF success, and I
won't say that this is good enough data, but I would guess that
you're at least cutting the success rate if you looked at standard
IVF without a biopsy at let's just say 35 percent and you do a
biopsy, it's probably 20.
DR. HURLBUT: Thank you.
CHAIRMAN KASS: Gil and then Michael Sandel.
PROF. MEILAENDER: I understood you to say you
don't do this at your clinic; is that right?
DR. HANEY: My institution, that's correct.
PROF. MEILAENDER: Why not?
DR. HANEY: I wasn't going to talk about
ethics and that sort of thing.
CHAIRMAN KASS: You're free to. You can
take the Fifth if you'd like.
DR. HANEY: No, we would --
(Laughter.)
DR. HANEY: We don't philosophically agree
with gender selection.
PROF. MEILAENDER: I mean obviously you
don't have to talk about anything you don't want to, but
I'd be interested if there's a short version of the philosophy
and if you're willing to say a word or two about why you don't
agree with it.
DR. HANEY: I'm fully supportive of
pre-implantation genetic diagnosis for medical indications, for medical
diseases. We just don't believe that gender -- influencing gender
birth by medical manipulation at my institution personally for my
division, and all three of us who work there, we're gynecologists.
We think women are good people, too.
PROF. MEILAENDER: So you engage in client
selection?
DR. HANEY: I'm sorry?
PROF. MEILAENDER: You engage in client
selection.
DR. HANEY: Define "client selection"
for me.
PROF. MEILAENDER: Well, the purposes for which
one wants --
DR. HANEY: Okay. Medical indication.
PROF. MEILAENDER: -- medical indication.
DR. HANEY: Correct. In that sense, yes.
CHAIRMAN KASS: Technically speaking, by the
way, it is -- I think you might agree with me in the suggestion that
what you're doing when you're doing pre-implantation and
genetic diagnosis that involves the gender of the offspring, as in the
cases of the X-linked diseases, if there were a way of finding the
presence or absence of that disease marker, you wouldn't be doing
sex selection at all. You would be looking for the marker.
So this is sort of incidentally sex selection
as a way of making sure that you do not produce the afflicted child. I
mean, it belongs really with pre-implantation genetic diagnosis for
diseases, and it happens that the quick way to screen for the
possibility of the disease is to screen for X-Y.
DR. HANEY: You're exactly right. If you
looked at the -- you have two Xes. One is affected; one is not. And
if you could not only look for the X, but you could look for the
specific mutation on the X, then you'd be doing exactly the same
thing as any other autosome.
And I think it's just an efficiency, quick
and dirty, simple.
CHAIRMAN KASS: Right.
DR. HANEY: It's much easier to screen for
the X chromosome than it is to be looking for the specific gene
mutation.
CHAIRMAN KASS: Right. So that technically
speaking, I don't think -- this is a kind of accidental sex
selection as it were. The intention really is disease prevention.
DR. HANEY: Correct.
CHAIRMAN KASS: Could I, Michael, before?
Just to clarify, to see if I can sum up, and I think this is what Mike
Gazzaniga's first question was getting at, just sum up where we are
technically speaking here.
There is certainly no cheap way of doing this.
There's no do-it-yourself way of selecting in advance. The best
figures right now from MicroSort are if someone were interested, for
example, in producing a male child, they could get 70 percent instead
of 50, roughly speaking.
So that at the present time it doesn't look
like that there is anything that is likely to be used on a wide scale
in the way of selecting the sex of children.
Would that be --
DR. HANEY: I'm even hesitant to say
it's effective until I see randomized clinical trials showing me
data.
CHAIRMAN KASS: Okay. Then second, on the
pre-implantation genetic diagnosis, there the diagnosis is pretty
accurate. There's some questions about the safety of --
DR. HANEY: An estimate would probably be 90
percent. You'd be 90 percent accurate with a prenatal --
pre-implantation genetic diagnosis using PCR or something like that.
CHAIRMAN KASS: Only 90 percent?
DR. HANEY: Un-huh.
CHAIRMAN KASS: Now, if this technology were
used for screening for diseases on an increasingly large scale, in
other words, if the future holds much more pre-implantation genetic
diagnosis, wouldn't it be -- will it be just as easy to
simultaneously do the screening for X and Y? Get the information
whether you want it or not?
DR. HANEY: Not if you're doing specific
gene probes. So if you're looking for Huntington's, you're
screening for Huntington's, and you're not doing anything to
look at the --
CHAIRMAN KASS: Okay.
DR. HANEY: -- gender determining chromosome.
CHAIRMAN KASS: So there's no necessary
-- if someone were to say, "Look. If we have a lot more PGD
coming, then it will become a lot easier for people who are using PGD
also to engage in nonmedical sex selection."
DR. HANEY: I think you can argue that the
better you get a PGD, the less gender you care about. that's what
you were alluding to before, and you're going to use probes --
CHAIRMAN KASS: No, I --
DR. HANEY: -- that are specific for the
mutation, and you'd have to do something additional.
Now, if the lab is working, sure. I mean, and
you had another probe for something on an X or a Y. If your lab is
functioning, that's true, but the more specific you get, the
actually less concerned you are about the --
CHAIRMAN KASS: Well, you're looking for
the disease, but I'm thinking now in terms of the client. The
client says, "Look. I'm going to have PGD anyhow. By the
way, I would like a girl," or, "By the way, I would like a
boy. Can you do it for me, Doc?"
DR. HANEY: I think it's exactly the same
argument that you had if you did it just without a disease.
CHAIRMAN KASS: Technically, I mean,
it's --
DR. HANEY: It's just a matter of having a
functional system.
CHAIRMAN KASS: Right.
DR. HANEY: And if you're good at it and
you have a lab doing it well and you're looking for a lot of
different mutations, I mean, no center is probably going to do
everything. You're going to have some centers that do cystic
fibrosis more and Duchenne's muscular dystrophy and all the various
ones, and there's going to be some centers that like to do a lot
more of it, and they're just good at it, and they have a system
that's very efficient.
And so if you said, "Fine. We had one of
those other probes," yes, it will be easier, but it's actually
going to be less important from the geneticist's point of view.
CHAIRMAN KASS: Yeah. Let me try one last
time. Sorry. I don't think I'm -- what I'm trying to
figure out is whether this is a problem we should worry about in the
United States or not.
DR. HANEY: Okay.
CHAIRMAN KASS: And that was in a way Mike
Gazzaniga's question.
DR. HANEY: One of the most interesting parts
about the numbers is you have no idea of where the country are that
they came from.
CHAIRMAN KASS: I'm sorry?
DR. HANEY: You have no idea where the
countries are that they came from. The data they presented because it
isn't even listed in the abstracts as happening in the United
States. So I have absolutely no idea what it is. It's a very
small number.
CHAIRMAN KASS: Well, it would seem to me
that it would not be -- I mean, people who want to do sonography and
abortion can do that. I mean, people who want to try to find some way
of selecting in advance, either this MicroSorting technique is going to
have to be perfected or you're going to find surface specific
antigens that will differentiate X and Y carrying sperm and so on,
stuff that we don't yet have, or those particular people who offer
-- there are apparently some 30 or 40 or 50 clinics in the United
States that already are offering sex selection. If more and more
people are using PGD for other purposes and they don't have your
scruples about doing this for nonmedical reasons, the question is:
could this get to be a sizable phenomenon simply by piggybacking on an
increased rate of PGD?
That was the point of the question, and Ó-
DR. HANEY: There's no question more PGD
you do, the more things you can screen for.
CHAIRMAN KASS: Yeah. I'm sorry for
holding you back, Michael.
PROF. SANDEL: I have a general question, but
this exchange leads me first to a specific one for Dr. Haney.
Did I understand that the thing that you
haven't seen, the kind of trials that would persuade you that it
works, that's the pre-fertilization sex selection?
DR. HANEY: I mean, if you're at the FDA,
you do a randomized trial. You're looking for an outcome, and you
wouldn't accept something that didn't have that.
PROF. SANDEL: Right.
DR. HANEY: And I don't care if you're
a surgeon or -- it's sometimes harder to do, but you need to look
at a more substantial database to be able to do it.
And the disconnect is when you look at FISH
related semen or you were talking about 70 percent of the sort being
male. That's not going to translate to 70 percent males born.
It's going to be less than that.
So that it's a fairly inefficient system.
So before I would accept that it's really going to work, if I was
simply looking at it, I would want more rigorous testing, and certainly
by a variety of different participants, not just the franchisee.
PROF. SANDEL: So that's the sorting.
DR. HANEY: That's the sorting business,
right.
PROF. SANDEL: But the thing that works is the
pre-implantation.
DR. HANEY: The PGD works much more -- it would
be much more highly accurate because you're taking the actual
blastomere from the genetics of the embryo you have created and
screening for it, and there's very simple whole gene amplification
and looking for other epitopes that you could identify, satellites,
alpha satellites, and whatnot that you can clearly identify.
So far more expensive, far less efficient, but
much more accurate.
PROF. SANDEL: Well, thank you.
This has been a fascinating account of really
what's out there, especially for those of us who are not
knowledgeable about this field. It's of enormous interest.
The general question I had really was for Leon
and for the group, and it's a question of what we do with this
fascinating overview of the technology. We could kind of probe Dr.
Haney to see, well, just what's the risk of harm and so on and at
what stage is this done and what are the technologies that involve
destruction of embryos and which ones not and how prevalent.
But is there an opportunity -- and maybe this
isn't the session for us to take up this question -- to address the
underlying ethical question itself if there were a way of doing this
without harming, without harm and without killing embryos? Would it be
objectionable and on what grounds?
Are we supposed to shoehorn that into this
discussion or is this discussion just acquainting us with the
technologies so that we can then be in a position to decide whether
later we want to take up that ethical question or not?
CHAIRMAN KASS: Well, I mean, my sense was
that we invited Dr. Haney, as we've been inviting other researchers
in the field, to get us up to speed as to what's possible and even
to -- and I'm very grateful to Dr. Haney also for not shying away
from suggesting what might be possible, thinking ahead to various at
least conceivable techniques so that we have a way of thinking about
this -- but that we amongst ourselves are free now also to discuss the
implications of this and the ethical questions.
The American Society for Reproductive Medicine
has -- and I think these were distributed with the briefing books --
has policy statements both on the use of pre-implantation genetic
diagnosis for nonmedical sex selection and also on the sperm sorting,
and it seems to me perfectly reasonable for us to discuss amongst
ourselves and Dr. Haney insofar as he wishes, I think, to enter into
this discussion.
So before we went there, are there any other
technical or use questions before we went into that area, just so that
we don't leave out?
Janet, did you want to?
DR. ROWLEY: So as I understand it from
particularly one of the slides that you had of oocytes or developing
blastomeres in a Petri dish, that particularly if you have super
ovulation you may have four or five oocytes that you can do for
fertilization.
DR. HANEY: Typically what's done is all
mature oocytes are -- I shouldn't say "all" -- but almost
all. If you also do ICSI, you practically will do eight or ten
or 12. If you had 15 embryos it gets a little much to do them all, but
you do basically all you can.
And then if you're just in standard IVF,
you're going to put sperm, hypermotile sperm, with all of them
because the fertilization rate probably won't exceed 50, 60 to 65
percent, and then the two pronuclear egg, the pronuclear egg with two
pronuclei won't get to a cleaving blastocyst.
So if you started with ten oocytes, you'll
probably have six or seven that are fertilized and probably no more
than four or five that are cleaving embryos in the process. So
it's a matter of trying to get as many in the beginning so that you
can get down to reasonable numbers at the end.
But if you end up with healthy, which
occasionally you do, healthy embryos that you're not going to
transfer, you freeze them.
DR. ROWLEY: Okay. That was actually my
question. So then you have these frozen embryos available either for
the couple if they choose to have a second pregnancy or for whatever
purposes.
DR. HANEY: Correct. In every IVF center in
the United States there's large numbers of frozen embryos.
DR. ROWLEY: Right, because this is one of the
issues that we dealt with earlier on, is that at some point some of
these developing embryos may actually be discarded, and then if
that's the case, what are the acceptable uses of those developing
embryos?
And what's the practice at Duke? Just
continuing to accumulate these, or do you have a time after which you
discard them?
DR. HANEY: Every institution has their own
pragmatic and philosophic way of dealing with this. So you have our
attorneys have worked out an agreement. The patients sign it. They
pay for and store extra embryos, and they're their embryos, and
many of them will come back. If they don't conceive, they'll
be back to get their embryos thawed out, much less expensively
transferred.
If they conceive, I would say 90-plus percent
will be back a year or two later for another transfer. If you can get
both pregnancies out of a single embryo or a single oocyte retrieval,
it's much more efficient.
There are people who will get a set of twins
and deliver their babies and say, "That was our family size
expectation and I have three extra embryos that are still in the
incubator or still in the freezer," and then we have legal issues
that they have to go through, what to do with those.
I don't know what the actual numbers are,
but most of them go through a legal adoption process and put their
embryos up for adoption for couples that have no sperm and no oocytes,
cancer patients, premature renal failure patients, Turner's
Syndrome, people who have no oocytes at all, and they'll adopt
embryos.
In our state, we have no embryo adoption law,
but we go through an adoption process with an attorney that basically
the couple that's going to receive the embryos, before they get
them, goes through an adoption process, and the couple that's
giving them up goes through a very legal process as if, virtually
identical to what they would do if they had a living child doing the
same thing.
And then some couples will say, "I want
the embryos destroyed."
We haven't destroyed any embryos. So even
the couples that say, "We don't want them," we
haven't yet destroyed them. Our lawyer keeps telling us sooner or
later we have to destroy them if the couple says, you know -- we
haven't had people tell us they want them destroyed. They have
just left them in the freezer, and we're not going to destroy them.
But our lawyer tells us sooner or later couples
are going to tell us to destroy them, and we have to.
CHAIRMAN KASS: Thank you.
Rebecca.
PROF. DRESSER: These are probably overlapping
facts and ethics questions. I was wondering do you know whether the
FDA has tried to regulate this MicroSort process. It sounded to me as
though you personally are concerned about the objectivity of the data.
And is there concern in the organization about
pushing toward more rigorous testing and about inflated claims that
might be made and advertising similar to the, quote, success rate of
IVF in the past?
DR. HANEY: Yeah, I think I wouldn't
exactly characterize it as objectivity of the information. I just
think it has to be done in a rigorous, scientific design. And it's
not a scientific design that's currently in the literature.
That's number one.
Number two, the FDA is going to exert, I'm
sure, regulatory authority over most gamete tissues in the lab
comparable to blood banking, and the ASRM has spent some time trying to
help educate them.
For example, they wanted us to do the kind of
testing we do for semen samples to oocytes, for oocyte donation, and
for semen you can freeze a sperm. You can double check the donor six
months later for all of the diseases. You can take an aliquot of the
sample and test it if you choose. You have a lot of opportunity to do
that.
With an oocyte you don't have that
opportunity. You either use it or it's gone. So they wanted us to
freeze oocytes as their preliminary to do donor oocytes, and that just
isn't possible. You might as well ban the procedure because
it's not going to be functional.
So they needed some education, and they got
it. I think they're going to be reasonable about what they do and
be rational and do it the same way. They just need a little scientific
updating because they're used to blood banking and other kinds of
tissue things.
And there are some other issues that they just
needed education on, and I think it can be ultimately anything that
bothers programs. We all now have certified CAP, College of American
Pathology, or whatever certified programs, and I think that's just
going to be one more layer.
PROF. DRESSER: So you think they probably will
start looking at safety and efficacy of this MicroSort procedure?
DR. HANEY: I suspect they will.
PROF. DRESSER: The other question I had was I
was a member of the ASRM Ethics Committee during a lot of the years
when these two statements came out, and I was wondering whether your
program's position was at all influenced by those statements.
Because one of the problems is when we think
about trying to formulate professional standards or, you know, ethical
recommendations and so forth, if they don't have any legal effect
or there are no professional consequences to not following them, you
know, in terms of the organization perhaps suspending a member or
something, how much influence do they really have?
So I wondered whether you all paid any
attention to them or you've just reached your own program's
position based on --
DR. HANEY: I would simply say it's a work
in progress. It's becoming much more influential than it was in
the past. Programs now in SART [Society for Assisted Reproductive Technology], they're going to very seriously
look at the average number of embryos you transfer and things like
that, that there were ethical comments, and in practice those are
translated into practice guidelines.
And you're going to have very specific
criteria that you should work under for maternal age related
influences in the number of embryos you transfer, et cetera.
I mean all of that, I think is becoming much
more codified, but it started with absolutely nothing, and it has taken
some time to get there.
And in the absence of being able to do NIH
research on any of this because of no funding, you know, it's
difficult.
PROF. DRESSER: Thanks.
CHAIRMAN KASS: Michael, did you want to
raise a particular question on the ethics of this?
PROF. SANDEL: Well, I don't know whether
-- did you want --
CHAIRMAN KASS: Please. I think we should
get started on it in any case. So please.
PROF. SANDEL: Well, rather than advance it, I
think there is a widespread sense, though I don't know how widely
shared, that there is something ethically troubling even apart from the
question of harm and even apart from those technologies that would
involve killing embryos in nonmedical sex selection, but it's one
thing to have that reaction and it's another to try to articulate
the actual reasons and to assess those reasons to see if the initial
reaction is correct.
And it seems to me that independent of the harm
consideration there are at least two different kinds of reasons that
might be operating to explain this and to ground the unease, and this
is really just by way of inviting reactions. It's not a worked out
view certainly on my part.
But one kind of ethical worry has to do with
the way in which this practice, were it to become widespread, might
change the norms that inform the practices of procreation, childbearing
and child rearing by changing the relation between the parents and the
children in some of the ways that we worried about when we were talking
about the designer baby objection to cloning, reproductive cloning.
So that would be one set of objections that we
might investigate, and then another set of objections might have to do
with a different worry, which is the disposition or the character of
the desire to control, to choose the sex of one's offspring.
Independent of the effect on social practices
and the effect on childbearing and child rearing, is there something
troubling in the stance? Maybe the short label is the hubris
objection, something objectionable in the stance of the person who has
the desire and acts on the desire to control the sex, to choose the sex
of his or her offspring.
These seem to me different kinds of objections,
though they may overlap, and there may be others, and to further
question how weighty the two are and how we would make them up, this
really would be just by way of inviting discussion on them.
CHAIRMAN KASS: Someone want to join on
this? Sir, Mike.
DR. GAZZANIGA:: It's sort of a prior
question to that.
CHAIRMAN KASS: Please.
DR. GAZZANIGA:: When hearing about sex
selection and seeing the fact that it's sort of being done ad hoc
and without any massive government program or monitoring, it raises the
question, of course, of how American medicine works.
And how American medicine works, my
understanding is that it's sort of monitored locally, monitored by
professional groups, monitored by the sociology of a specialist field,
and that there isn't a grand monitor somewhere in Washington making
sure that all the procedures that go on in a hospital have been given
some stamp of approval or being carefully followed up as to their
efficacy and so forth.
And if I'm wrong, I would like to --
CHAIRMAN KASS: That's absolutely right.
DR. GAZZANIGA:: -- I'd like to have comment
on that so that we all understand that as one thinks about this issue,
because it is a red button issue, and if there was any recommendation
to somehow monitor this from a government point of view, it would be
one of the first because that's not how we do medicine, and I think
that's just worth a comment.
CHAIRMAN KASS: Well, I think the point ties
in with the topic we'll be talking about tomorrow with the help of
our British visitors, where they have official bodies that in some
cases simply advise and in other cases, in fact, regulate.
The question of regulatory activity was part of
both sides in the cloning report and something that this Council wants
to take up in a serious way. So the fact that it's unprecedented,
while true for the time being, might be an invitation to think through
whether we really want that precedent to remain.
But would someone go back and pick up a
response and then Robby and then Bill?
DR. GÓMEZ-LOBO: Yeah. I'd like to
continue along the lines opened by Michael. I thought it was
interesting.
And just to contribute to the conceptualization
of the problem, I honestly think about this as questions. It seems
that there is a goal which has to be questioned first, the goal of
choosing the sex of the child. I think that there are various problems
there.
And then comes the question of the means, and
if I understood correctly, Dr. Haney, there are really two methods:
selection and determination, right?
Now, selection seems to involve the discarding
and destroying of sperm. Now, of course, from a moral point of view
that may not be a problem.
On the other hand, determination which can be
both pre-implantation and post implantation seems to entail the
discarding and destroying of embryos, of human life, human embryos.
And of course, that is very troubling for anyone who tries to think
about it.
Now, a last remark on this. I was very
impressed by those charts about three countries, China, South Korea,
and Singapore. Now, the charts about South Korea were really very,
very impressive. They get to, what is it, 130, 140 males per female?
It would seem to me that's a massive
discrimination and destruction of females either via abortion or even
infanticide. Is that a possibility?
So that would seem to me to be the extreme to
which the acceptance of the goal can take. Again, these are questions.
CHAIRMAN KASS: Someone else. There was
Robby and then Bill, yeah.
PROF. GEORGE: Michael's comment earlier
obliquely raised a different question for me, Michael Gazzaniga's
comment a minute ago, and it brought me back to thinking about Dr.
Haney's comment that his clinic doesn't do this and doesn't
do it on ethical grounds.
When Michael was referring to the way in which
we practice medicine or the way in which medicine is monitored in this
country, it left me with a question. When it comes to sex selection,
Dr. Haney, in thinking about whether your group would do it, is part of
your thinking governed by the question whether this is medicine?
What's your own thinking on it? Let me
just ask. Is sex selection medicine? Whatever else it is, I mean, is
it medicine?
DR. HANEY: I think that's the question
everybody is going to ask themselves. We would probably at my
institution for nonmedical reasons say no.
PROF. GEORGE: And how do you decide the question
of what constitutes medicine and what doesn't, just sort of in a
rough and ready way? I mean, in a borderline case, how do you think
about that?
DR. HANEY: Define a borderline case.
PROF. GEORGE: Well, someone wants to insure that
they don't have a mentally retarded child. Is that medicine?
DR. HANEY: I would think that is.
PROF. GEORGE: Okay.
DR. HANEY: I would view that, if you knew the
process that created the mental deficiency, Tay-Sach's disease,
something, not having a child born with Tay-Sach's disease I think
is a medical decision, just as it is for Down's Syndrome or other
things.
PROF. GEORGE: How about a borderline case like
color blindness?
DR. HANEY: I'm color blind.
(Laughter.)
DR. HANEY: And I don't think that's --
it's probably not fair to ask me.
(Laughter.)
DR. HANEY: I'm only mildly color blind.
CHAIRMAN KASS: Bill?
DR. HURLBUT: When you try to differentiate
this issue of sex selection from what you said was medical, and I
assume you mean therapeutic in the sense of healing something or
preventing something that has a detrimental implication, buried in your
statistics was something that struck me as potentially troubling.
I know this might be pulling too much out of a
very limited sample, but I think it was with MicroSort. One of your
statistics showed a decreased rate of congenital abnormalities. You
said half, roughly a third to half of the rate. It was 2.6.
DR. HANEY: I don't think that's
decreased. In other words, they found in their sample 2.5 percent of
offspring had a major anomaly. The accepted rate in Washington, North
Carolina, wherever, is about three percent. So three to four at the
most, depending a little bit on the definitions and how thorough you
are.
Those are not different numbers. I have no
illusions. That's not a decline. That's just within the range one
would anticipate for a general population.
DR. HURLBUT: Oh, okay. I thought you had
pointed out that it was somewhat lower than the otherwise noted rate.
DR. HANEY: In this particular sample it was
2.5 compared to --
DR. HURLBUT: Okay.
DR. HANEY: -- what most public surveys would
be a little higher.
DR. HURLBUT: Not making too much of that
particular sample, I want to ask you a theoretical question then.
Suppose it turned out that this procedure,
either sex selection by gamete sorting or pre-implantation genetic
diagnosis for something neutral or even IVF just done without some sort
of sex selection, actually had a therapeutic effect in the sense that
it produced better outcomes than the natural way of doing procreation.
Would that then change your view if the procedure that produced this
better outcome actually produced a healthier subset?
Do you see what I'm getting at? I mean
suppose --
DR. HANEY: Are you asking me if Caesarean
section is less traumatic than vaginal delivery would I tell --
DR. HURLBUT: No, no.
DR. HANEY: -- everybody to get sectioned?
DR. HURLBUT: Oh, okay.
DR. HANEY: Is that what you're asking sort
of?
DR. HURLBUT: Maybe. That's not -- that
carried a little different atmospherics, but what I'm kind of
getting at here is are we heading to the realm where as we understand
the biochemistry and then the early development, media into which the
blastocyst is sculptured; are we getting to the point in your opinion
where we might be able to produce a better than natural outcome?
DR. HANEY: I would be highly suspicious
that's not true. I can't fathom that's true, but I'd
have to face that if it actually had some data to bind it.
DR. HURLBUT: Well, isn't it true that the
implantation of blastocysts at blastocyst transfer actually have a
higher success rate than would be statistically implied by normal
sexual intercourse?
DR. HANEY: Oh, I don't think that's
true
DR. HURLBUT: You think 30 percent of
successful blastocyst formations go on to --
DR. HANEY: No, I don't think it's
anywhere that high.
DR. HURLBUT: Isn't that the rough success
rate with blastocyst transfer?
DR. HANEY: Well, all I can tell you is our
experience in 1998. We thought this was blastocyst -- in other words,
the biggest problem with IVF is your inability to pick out healthy
embryos. We don't understand implantation well. Human embryos
implant very nicely in the fallopian tube. They don't need
endometrium to implant.
If they're healthy and at the right point
in time, aggressive -- I think humans are the only species that gets
ectopics. So our embryos evolutionary have learned the ability to
implant themselves at the appropriate time. So they don't really
need endometrium to do it in.
Then we get to IVF where we're putting
embryos a little dissynchronous into the uterus, and we don't know
how to pick the good embryos that are going to potentially be developed
into humans, and so we compensate by adding more embryos for transfer.
In 1998, the notion of -- we were able to then,
by media changes and some understanding better of in vitro culture
technology, were able to keep embryos on the same growth curve that
they would occur in vivo in vitro. So the opportunity then to grow
them further out and do blastocyst transfers and allow developmental
selection to pick the best embryos, that idea finally became possible
to test, and that started in 1998 or '97-'98, and there was a
great enthusiasm for growing embryos out to the point you let the
healthy ones continue to grow and transfer those, and you will cut down
the multiple gestation rate by being able to maintain a relatively high
pregnancy rate with your multiple gestations.
And my reading of the general approach today is
that that didn't work out; that it has not been as successful, and
there are very few programs exclusively doing blastocyst transfer today
and very selected patients who are getting it.
So if anything, I would say it's not, as
you allude, a better implantation rate than in vivo.
DR. HURLBUT: So what you're saying is
nature is better and looks to you like will be better in the long
term. It's better not to intervene in nature is --
DR. HANEY: Well, we're definitely treating
disease.
DR. HURLBUT: Pardon me?
DR. HANEY: We're treating disease,
infertility.
DR. HURLBUT: Yeah.
DR. HANEY: Or we're treating patients who
can't get pregnant or we're treating patients who in this case
if you talk about PGD, of people who have genetic diseases.
But we're not enhancing normality or
improving upon it.
CHAIRMAN KASS: We're going to come up
on the break. I have Gil and then Michael.
PROF. MEILAENDER: I want to try to just think
a little more about the issues that Michael Sandel raised, and if I use
Alfonso's distinction between the goal and the means, I want to try
to think about the kind of means that would be least problematic
presumably, namely, the pre-fertilization, the ones that you don't
think are very successful right now.
But if we just keep it to that, then we're
not raising the kinds of issues that pre-implantation genetic diagnosis
would involve. Though I have to say, by the way, that on another
occasion I'd like to pursue with you the question of exactly in
what sense you're treating disease when you do that. I mean,
I'm not actually persuaded by that.
There's a difference between eliminating
diseased embryos and treating disease, but let's let that go.
I can understand how you might be worried about
problems that would happen with the sex ratio as a result of doing
this, and I can understand simply saying we don't want to use
medical resources that are scarce in this way.
But what I'm interested in is those ASRM
policy statements that we read that Rebecca has claimed some
responsibility for here.
No, the interesting thing is that the way the
issue is couched is that you shouldn't do this in order to choose
nonessential characteristics of human beings, and I'd like to see
us figure out what that means in a way.
In certain contexts I would never describe
being male or female as being nonessential. In fact, I'd describe
it as much closer to what's essential to a human being than lots of
other things.
So I'm not sure what role that language is
playing actually there. I can understand some other things it might
mean, but the longer I think about it, the less clear I find myself
actually, and so I just put it forward.
If the kind of dis – ease that countless people
feel with respect to sex selection is articulated or is to be
articulated, is that the right way to articulate it?
I don't know.
CHAIRMAN KASS: Paul.
DR. MCHUGH: I, like Gil, would like to follow
up on what Michael was saying, that we should be laying out some of the
ideas that are a concern to us, and the one that I think is wrapped up
in the issue that Gil mentioned is sex ratio, but probably needs
another expression. Probably an expression felt by PROF. Haney,
that is, that you know, when we produce our children, we're not
just producing it for our generation. We are producing it for a
community, a community ultimately that goes generation after
generation.
And although one can appreciate perhaps that
you would like one or the other at this time simply for somebody to be
able to use your baseball gloves or somebody to be able to do something
else, there is a higher purpose that we all serve from our families to
the community at large.
And I feel that one of the things that concerns
me about this is that we alter something which is very natural and
which we sense only as we move from one generation to the next.
We saw that very interesting data that you
showed us from South Korea, and you used interestingly the
nonchallenging term "family balancing." It seemed remarkable
that the family balancing all tended towards producing males. So it
seemed to me to the motivation was male specific, and maybe we should
talk about this as a growing male hunger in some cultures because,
after all, you could have three or four children and they could all be
boys, and one would have thought if it was balancing, there would be a
balancing out of those.
So I just wanted to make the point that the
issues that we're talking about have more to do with just the
pleasure of one child or one sex now with all that that relates to the
designing of the relationship and that we deal with a community that
ultimately has a long term ahead of us.
CHAIRMAN KASS: Yeah, the practices in other
countries is the topic of the next talk, and we'll talk about that
then.
I want to intervene briefly in my own
name, too, if I might. It seems to me that however uncertain are the
technologies at the moment, it's also clear that there is an
increasing pressure whether created by the people with the licenses to
have the techniques used or whether there is a growing demand in the
culture for the use of these things. There's a lot more interest
in sex selection now than there was even five or six years ago.
And particularly with PGD there are clinics
that are offering this service for non-medical reasons, even though the
society has discouraged its practice. I mean, there are groups that
are using this, and we understand from our friends in Britain that they
have now to reconsider this question there as well.
So whether we like it or not, it seems to me
it's a question that's going to be coming on the table.
And here it does seem to me that a couple of
things that have been mentioned are worth our attention. One is the
question of what the arguments are both for and against. And I guess I
have to say that I find the arguments in the ASRM documents puzzling,
where, on the one hand, one begins by worrying about contributing to
sex bias as if sex doesn't matter at all; on the other hand,
arguing that it's probably okay for sex balancing, which suggests
that sex matters a great deal, providing that you treat it absolutely
equally, that you don't give additional preferences.
And I'm not sure, Paul, whether one could
say -- I mean, one worries really about what it means not just to pray
for a child of a certain sex, which doesn't necessarily produce the
result because the Good Lord doesn't necessarily give you what you
want, but there's a difference between that and actually having
exercised the control over it and have the parents be responsible to
the child for the choice made, regardless of what the choice is.
That's a new step, but I'm not sure
that we're going to be able to say in this rather libertarian
climate of ours that you can't use it for these and these reasons.
And in the Jewish tradition, orthodox
tradition, there was a great demand for the son because, among other
reasons, there's an obligation that falls on the male child to say
the Kaddish for the dead, an obligation that falls on a male child.
Female children can do it.
And people would describe a male child as
"now I have my Kaddish." Now I have the child who is going
to actually say the prayer when I die.
I'm not sure that one is going to be able
to say to members of those subgroups that's an illegitimate reason
for making use of this technology should it be available.
So, I mean, I think that there are a variety of
reasons why even if this is practiced on a small scale and when
it's practiced on a small scale, by the way, it becomes a question
for people to decide do you want to take advantage of it when it now
becomes offered.
I think that it's much more complicated
than the ethical argumentation that we've seen in those documents
indicated, and I think the pressures on this are going to increase, and
it might mean that if this is to be left for professional
self-regulation, to avert to Rebecca's point earlier, that maybe
the society has to think about ways in not simply saying this should be
encouraged or this should be discouraged, but these are the guidelines
we expect people to follow for these and these kinds of reasons, or
perhaps it is for us to recommend other kinds of bodies for at least
promulgating such recommendations, subject, of course, to review and
reconsideration as time goes by.
DR. MCHUGH: Yes, Leon. I was not when making
my point saying that this should be go to legal issues. I just think
that we're at the point of raising consciousness about what our
problems are or what our difficulties represent when sex selection is
brought forth.
We want to just sense is there anything behind
our feelings other than the "ugh" factor that we've
talked about before.
CHAIRMAN KASS: Right.
DR. MCHUGH: And I'm just saying that one
of the things that lies behind it is a sense that we all have, believe
it or not, even though we never feel it at the time the first child
comes along, that we have a generational and community responsibility
that comes from bringing up our children well, making sure that they
are members of this community, as well as being suitable to go out and
find new mates and add to our world.
CHAIRMAN KASS: let me ask. Since the
general discussion can come back and we've run way over here,
let's take a ten minute break. We'll have the second
discussion, and the general questions will come up after Nick
Eberstadt's presentation.
(Whereupon, the foregoing matter went off the
record at 10:44 a.m. and went back on the record at 10:57 a.m.)
CHAIRMAN KASS: All right. In this second
session on choosing sex of children, we turn to certain demographic
implications of the use of this capacity, and we're very fortunate
to have Nick Eberstadt, who is the holder of the Harry Wendt Chair in
Political Economy at the American Enterprise Institute, to make a
presentation to us this morning.
It was actually a talk that I heard Nick give.
It must be four years ago on this topic that opened my eyes to how
things quietly initiated here in the United States for one reason wind
up having very powerful effects across the globe to which we should pay
attention.
And when this topic came up, I thought it would
be worthwhile for the Council to hear about the uses of sex
determination practices.
And, Nick, thanks very much for joining us. We
look forward to your talk.
DR. EBERSTADT: Leon, thank you very much.
Ladies and gents, it's an honor to be with
you here this morning, and I'm going to start off more or less
exactly where Dr. Haney left off in his excellent presentation.
What I'm going to try to do very quickly is
provide you with some information about the state of conditions in the
world today with respect to the secondary sex ratio, usually called the
sex ratio at birth, and also to offer some speculations about some of
the implications of trends that are now developing.
Demography is a study about three centuries
old, maybe a little bit more than three centuries old at this point.
As soon as students of demography began to look at patterns in human
numbers, one of the first things that they recognized was that there
was quite a regular pattern with respect to births, slightly more boys
born than girls born.
And this was noted and commented upon at the
beginning of the study of demography. I'll read you something that
Johann Sussmilch, who was an early demographer, wrote in 1741. He
said, referring to other early demographers, that "Grant, Durham,
and others have suggested the Creator has reasons for insuring four to
five percent more boys than girls lie in the fact that it compensates
for the higher male losses due to the recklessness of boys, to
exhaustion, to dangerous occupations, to war, to seafaring and
immigration, thus maintaining the balance between the two sexes so that
everyone can find a spouse at the appropriate time for marriage."
Well, as you will appreciate, demographers are
rather more loath today to talk about divine intent, but they do
recognize that there is over time and over space a consistent pattern
of somewhat excess male mortality over female mortality. So that the
early surfeit of boys, if you will, more or less evens out by
marriageable ages so that cohorts are more equal in numbers.
Now, demographers have noted variations in the
secondary sex ratio or the sex ratio at birth associated with a variety
of factors. They have noted variations with respect to ethnicity.
They've noted variations with respect to parity, which is to day
birth order, and with the age of parents.
They've noted some variations with respect
to the nutritional status of parents. Nutritional status may have some
slight influence upon sex ratio. Also various sorts of diseases and
disabilities.
And there is an ongoing question/discussion,
call it a debate, in certain areas of demography about whether there
may be an adaptive response with respect to sex ratio at birth, that is
to say, it's called the operational sex ratio or the sex ratio of
the adult population may have some influence upon the rising
cohort's sex ratios.
I have no opinion about this work. I consider
it an unsettled discussion which continues, and I wouldn't suggest
that there's any conclusive findings that have been found in this
area, but for noting all of these influences upon sex ratios at birth,
I think the overwhelming biological fact about sex ratios at birth in
large and regularly constituted populations is regularity and the
stability of the sorts of numbers one sees produced.
These ratios are almost constant in large
populations over time and over space. Just to give you by way of
background some perspective on this, these are the sex ratios at birth
by ethnicity for the United States from the early 1980s, and you will
see that for the country as a whole, it was about 105 live baby boys
born for every 100 live baby girls. There were differences by
ethnicity, but these were not dramatic, let's say.
By the same token, you can see differences in
sex ratio at birth with respect to birth order, the parity. In general
the sex ratio at birth is somewhat lower at higher parity or higher
birth orders than at lower parity or lower birth orders.
And this result for the United States in 1984
is hardly uncommon. We could have used data from many other countries,
many other times to replicate that.
This was 1984, and we live in 2002 today, and
some things have started to change even in the United States itself.
And one of the things we are beginning to see in the U.S. are sex
ratios for at least certain groups within the population which would be
very hard to explain on the basis of purely random occurrence since
we're dealing with large numbers of people.
The odds against some of these sex ratios at
birth look very forbidding, very imposing. Let me show you here.
These numbers compare sex ratios at birth in
the United states in 1984 and in the year 2000, which is the latest
year for which we have complete birth data, and you'll see that
there's not terribly much difference in the sex ratio at birth for
the total population or for the so-called white population or the
so-called black population.
But when one gets down to Asian Americans, to
the Chinese and Japanese ethnicities in the United States, we're
seeing some very substantial increases in sex ratio at birth, and those
would be very hard to explain on a purely biological basis.
Over the last decade or so, we find, indeed,
that there are many places around the world where these sex ratio at
birth has started unaccountably or seemingly biologically unaccountably
to rise.
Let me show you some data from other
countries. These data were gathered from the United Nations'
statistical office which publishes an annual demographic year book. Of
course, it's never up to date, and of course, when it is compiled,
the data are from earlier years. These are the most recent data that
the U.N. demographic year book has pulled together on live births in
countries and areas where vital registration is nearly complete.
And what I have listed here are simply
countries reporting now a sex ratio at birth of 107 baby boys per 100
baby girls or higher. In ordinarily constituted populations ratios of
103, 104, 105, even slightly over 105 are not things that would look
unusual.
One, oh, six starts to need some explanation,
and 107 just usually doesn't happen, and that's why I chose 107
as the cutoff there.
And you will see here a number of different
regions of the world represented with these unusually high sex ratios
at birth: some Latin American countries, Salvador, Venezuela, most
dramatically Cuba, where we have a phenomenal 118 baby boys per 100
baby girls, some of the Maghreb countries, the North Africa, Tunisia,
and Egypt.
They represented also some of the post
Communist states from the former Soviet Bloc, Belarus, Bulgaria. I
think we have excluded some additional post Communist countries whose
birth numbers were rather lower, but whose sex ratios were very high.
I think Moldova, Estonia, Lithuania could also be added into this
grouping.
And then, of course, we have a grouping of East
Asian countries and regions: Hong Kong, the Republic of Korea being
most prominent there.
One of the problems in tracking changes in sex
ratios at birth around the world is that most of the world's
population is not found in countries that have complete or nearly
complete vital statistical systems, vital registration systems.
By the U.N. Population Division's estimate,
in fact, less than one person in 12 in the low income world lives in a
region that would be described as a country with complete or near
complete vital registration. So that's a big problem in trying to
track trends in sex ratio at birth.
However, we can draw some inferences about
changing patterns of sex ratio at birth by looking at the numbers of
children at young ages reported in national censuses and other sorts of
demographic survey data. And I will show you this imperfect, but
perhaps indicative proxy for a number of other countries.
These data were compiled by the U.S. Census
Bureau's International Programs Center. These are their estimates
for 1998 of sex ratios for children under the age of five and for
particular countries where the ratio was 107 or higher. And you'll
see, again, a representation of an Islamic society in Tunisia.
You'll find some post Communist representation in the form of
Serbia and Macedonia. For the most part what one's seeing there
are East Asian countries: Singapore, Taiwan, China, Hong Kong, and
South Korea.
And the sex ratio in some of those settings for
children seem to be very, very unusually high indeed.
There is another smaller area of the world
whose imbalances I've just become aware of thanks to a colleague at
the Census Bureau. Dennis Donahue kindly supplied me with this table.
But in the Caucasus area of the former Soviet Union, the ratio of
children under one year of age -- these are not live births, but
tabulated infants and through census materials and demographic counts
-- the ratio of children under one year of age has risen very rapidly
and dramatically in Armenia, Azerbaijan, and Georgia.
These Caucasus societies represent a diversity
of religions. Azerbaijan is primarily Islamic. Armenia and Georgia
are not, but as of the year 2001, the sex ratio for infants under one
year of age was approaching 120 in each of these three countries.
Let me turn to East Asia which Dr. Haney
discussed a little earlier. This slide, which is put together by
Daniel Goodkind at the U.S. Census Bureau shows reported sex ratios at
birth for a number of East Asian countries. You'll see that the
sex ratio at birth for Japan, this lower line, falls within the range
that would ordinarily be expected of a large human population.
For all the other countries and regions, for
Singapore Chinese, for Hong Kong, for Taiwan, for South Korea, in
particular for South Korea, some of these ratios have risen really
quite extraordinarily. In the past several years South Korea's sex
ratio at birth had declined, but it has declined only to a degree.
It's still in the range of 110 baby boys per 100 baby girls,
something like that.
The big enchilada is China, which is the most
populous country in the world, and China does not have complete birth
registration statistics. So determining the actual sex ratio at birth
requires quite a bit of inference.
As you'll see, there is a discrepancy in
China between hospital records, which are certainly not complete with
respect to annual births, servicing only a limited fraction of the
population, predominantly the urban fraction, and records from vital
statistics, limited though they may be.
There is a discrepancy there, and this is a
discrepancy which demographers have puzzled over. It has suggested to
some that the imbalance in China may not be as great as some observers
have feared.
I think, however, the weight of evidence from
demographic records leans towards the more pessimistic rather than, if
you will, the more optimistic assessment, and that's a judgment
reinforced by the initial data from the November 2000 Chinese census.
If one attempts to do reconstructions from that
and from previous censuses, one sees a sex ratio at birth that has
risen perhaps from around 108 20 years ago to something like 117 today,
and if one looks at the sex ratio of children under the age of five
from this and previous censuses, one gets even more extreme indications
of increasing imbalance between young boys and young girls.
As Dr. Haney's presentation indicated
previously, the imbalance in these societies is concentrated
disproportionately in higher parity births, although as I think I
already showed you, in ordinary biologically constituted population,
sex ratios at higher birth orders tend actually to decline slightly.
But what we find in many East Asian societies
today is an increasing imbalance, increasing sex ratio at birth with
higher birth order parities. This slide presents data collected by two
doctors in Hong Kong at St. Margaret's Hospital. Hong Kong does
not ordinarily offer comprehensive data on sex ratios by birth order,
although it does have complete vital registration.
St. Margaret's Hospital, I believe, handles
about a sixth of the births in Hong Kong, SAR. So it is by no means
comprehensive, but it is indicative, and as you'll see there, Wong
and Ho show that for births that were second births, there was quite a
significant distinction between sex ratios for parents, for mothers,
whose first birth had been a boy and whose first birth had been a girl,
and the phenomenon is even more extreme for third order births. In the
cases where the two previous births to a mother had been girls, the sex
ratio was 137.
Even with small numbers of births, as in this
sort of situation, the odds against this being a natural occurrence
become quite astronomical.
Dr. Haney already showed a slide indicating
changing sex ratios by birth order. These are data for Taiwan in 1990
and for China in '89, and as you see, when one gets up to birth
order four, fourth births in Taiwan, by 1990 we are talking about sex
ratios of 160 boys per 100 girls.
But it gets better than that. Let me show you
South Korea. In 1992, by the time one is talking about fourth order
births, we are above 200 boys for every 100 girls born, and you can see
there that blue line is South Korea in 1992. The red line is South
Korea only 12 years earlier, in 1980, for the wide dissemination of
technology, making available sex determination and, therefore, sex
selective abortion.
In all of these cases, the inference that one
would draw, I think, is that sex determination has led to sex selective
abortion as a main driver of these biologically unnatural results.
Female infanticide may have played a more pronounced role in China,
especially in the late 1970s and early 1980s, but increasingly, I think
we can draw the reasonable inference that sex determination and sex
selective abortion has been the primary instrument at work here.
Dr. Kass asked me to gather for you some
information on gender preference on the parts of parents, and I had
assumed this was going to be a very easy task for me, very easy part of
my presentation, and was quite surprised to find that it was not.
The reason for the opacity or the difficulty
here is that the ordinary or the regular surveys that are circulated
through much of the world to determine demographic health fertility
patterns, the so-called DHS survey, as a rule now simply do not contain
any information to present to respondents with respect to gender
preference of children. Such information was collected in earlier
rounds of world fertility surveys, but as it happens, for the most part
these are not available now for most low income countries.
It's unfortunate. As you can see, it's
an increasingly unfortunate oversight.
However, one of the countries that does collect
information on gender preference among married women is India, and
it's not an inconsiderable portion of humanity. Roughly one out of
six people in the world today live in India. It's a population of
over a billion.
And this shows you results from the national
family health survey, second round done about three or four years ago.
Almost everyone, almost all mothers asked to have no children, and most
of those who had one child desired more children, and as you'll see
below, when asked whether they preferred a boy or a girl, some said no
preference. Some said leave it to God, but of those who expressed a
preference, there's an overwhelming preponderance of preference for
boys, four to one for the sample overall, and in some cases even higher
ratios.
Let me show you data for a particular state in
India, the State of Punjab. Punjab is a smaller sample, and we have
asterisks there because in some cases there weren't enough
respondents to arrive at statistically significant results, but for the
Punjab as a whole, out of the almost 3,000 married women questioned,
the preference for an additional child being a boy as opposed to a girl
was on the order of ten to one.
Now, let me show you some results from the
latest Indian census. India is another country that has no – that
does not yet have complete vital registration of births and deaths for
the country as a whole. So one has to work with census materials and
other sorts of large counts to do reconstructions or to draw certain
sorts of inferences.
The March 2001 Indian census did account by age
for the country as a whole and its various provinces, and what I'll
show you now is the sex ratio for children under age seven or children
zero to six for different provinces in India.
You will see that there are a number of states
and territories in which the sex ratio for surviving children,
surviving up to the age of seven, falls within the range that we might
call biologically expected, maybe up to about there, but there are a
number of states for the most part in northern India where the ratio is
outside of historical biological norms. Mostly these are states in
northern India.
But I'll point out in particular to you the
results for Punjab. In Punjab today for every four girls under the age
of seven there are over five boys, and it's probably also worth
noting that these newly found differences do not comport with patterns
of tradition or with patterns of traditionally construed under
development.
These heightened abnormal sex ratios at birth
are instead very closely associated with modernization or with some
particular variant of modernization. Punjab, for example, is one of
the most prosperous provinces in all of India. I think we see Delhi.
Delhi at 116 is also one of the most -- is an urbanized area with one
of the highest income levels in India and one of the higher literacy
levels in India.
Thus also Chandigarh, thus also Haryana, and
if we go back and review some of those other data that I showed you, I
think we'd say that this imbalance in sex ratios at birth has
coincided with improved levels of income with higher educational
attainment and with heightened interaction with other cultures and
other economies, with what we would call globalization.
So far from being traditionally driven, these
trends have certainly coincided and comported with some form of
modernization.
I will get to that in a moment.
I think it also mentioned that these heightened
abnormal sex ratios at birth have been associated with fertility
decline, and they're most obviously in low or sub-replacement
fertility populations.
As you saw from the East Asian data, all of the
East Asian countries that we were discussing are currently at or below
replacement levels of overall childbearing, which is to say that if
current childbearing patterns continued indefinitely and there were no
immigration, no net immigration, population would stabilize and
ultimately decline indefinitely.
The phenomenon of choosing higher parity, the
sex of higher parity children seems to be more of a pronounced
phenomenon in the context of declining or sub-replacement fertility,
and it is worth noting that the Punjab area of India has been an area
of rapid fertility decline. It is not the lowest fertility area in
India. There are some sub-replacement areas of southern India that do
not exhibit this extreme imbalance between male and female children,
but Punjab is an area of rapid fertility decline and is now close to
the replacement level.
Dr. Kass asked me if I would draw together some
data on sex preference and sex selection in the Arab-Islamic world. I
think I showed you earlier some indications that Tunisia, which is one
of the few areas in the Arab-Islamic expanse to have hit replacement or
sub-replacement fertility, is now exhibiting unusually high sex ratios
at birth or excuse me. I think it's ratios of children under the
age of five, sex ratios of children under the age of five.
And there is precious little information on
gender preference from survey and demographic data for this great
expanse of humanity, but one of the few surveys that I could find is
actually for the Palestinian authority, and it isn't quite as neat
as I would like something to present to you, but I think it is
indicative nonetheless of what we have here from a demographic survey
conducted in the late 1990s, is the preference expressed by I think it
was a total of 3,000 married women for an additional child or for an
additional son or an additional daughter if one already has a son or
daughter, if one already has four-plus sons or four-plus daughters.
And I hope this presentation isn't too
confusing, but I think you'll see from these numbers a very strong
and pronounced disposition towards son preference across the board
here.
Interestingly enough, the sex ratio at birth
for babies within the Palestinian authority area and for Muslims in
Israel proper is no different. It's not appreciably different from
that of Israeli Jews. Both sex ratios for now are in the vicinity of
105, slightly below 105 baby boys per 100 baby girls.
But what we have not yet seen in Palestinian
areas or in the rest of the Arab-Islamic expanse is the dramatic
dissemination of relatively inexpensive techniques of gender
determination prenatally, and so this is a phenomenon which we may yet
experience, although we have not thus far.
What are the consequences of gender
imbalances? One of the most obvious possible consequences of the sorts
of gender imbalances we have seen developing around different parts of
the world is a later, potentially inevitable, inexorable imbalance in
the marriage market. If there are too many boys to marry off to a
given number of young ladies, the market can't clear.
In the past that has not been too much of a
problem even in areas where boys in any given age group have tended to
outnumber girls in any given age group because for the most part, over
the last century certainly world population has been rising, and that
has meant that each year slightly more girls were being born in any
given birth cohort. So that matching up or pairing simply would entail
an average difference in age at marriage.
You will appreciate, to make a very crude
example, if population were growing, if birth numbers were growing by
about two percent a year and there was a ten percent imbalance between
young men and young women, it would take roughly five years in
difference in average age at marriage to make everything square.
But the arithmetic becomes very much less
forgiving when one is dealing with sub-replacement populations rather
than populations that are at or above replacement level. And as you
will have seen already, the gender imbalances that we have seen
developing are most pronounced in societies that are precisely
sub-replacement or below replacement fertility contexts.
What I wanted to show you here is some
speculative projections for china, and I have to emphasize that these
are speculative. The data on the year 2000 are not really terribly
speculative. We've got those data, but then the question is: what
will China look like, say, 25 years from now?
What I have put together for you here is a
Chinese population structure and age-sex structure based on the
presumption or the assumption that the 117 to 100 imbalance, implied
imbalance, in sex ratio at birth that we've seen from the recent
Chinese census is, in fact, real rather than a statistical artifact,
and that that imbalance continues from 2000 to 2025.
I think even by eyeballing this, you can see
that there are at younger ages an awful lot more greens than blues in
this figure. What does that, what would that hypothetically mean?
Well, let's look at this. The U.S. Census
Bureau takes the cautious and, I think, respectable posture that until
there is overwhelmingly persuasive evidence to the contrary, they will
be projecting China's future population on the basis of an
assumption that the true imbalance, the true sex ratio at birth is 109
to 100 rather than 117 as recently reported.
If one accepts that, by the year 2025, the sex
ratio for young men and young women ages 20 to 35 would have risen from
about 106 reported roughly today to about 109. There'd be a
deficit; there'd be a shortage in this particular cohort of about
13 million women as opposed to men.
Now, China has been a society, a cultural
setting, where near universal marriage has been the expectation. One
takes a look at previous censuses or demographic data on China.
Ninety-six, 97, 98 percent of women report eventually -- report having
been ever married by the time and heads towards older ages.
But that means that three, four percent of
Chinese women do not get married, do not take a husband, and if one
deals very crudely here, that would be suggesting that something like
ten, 11, 12 percent of the Chinese men in the Census Bureau's
projections in this year would have to find wives if they were to find
wives from outside of this cohort.
If one takes an assumed sex ratio of 117 and
projects that forward, the numbers are even more dramatic. We would
end up with a shortage within these given cohorts of about 16 million
potential brides or 16 million excess husbands.
And if one stuck with this same
back-of-the-envelope sort of calculation that two, three, four percent
of women would end up never marrying, we'd be talking about 13, 14,
15 percent of this cohort having to find wives or partners from outside
of this grouping or never marry.
Now, what are the social and economic and
political implications of having a large group of men for whom the
expectation of never marrying is fairly plausible? My impression, my
very unscientific impression from demographic history is that it very,
very much depends.
One can see all sorts of ominous arguments
about unsocialized or unsocializable young men causing social strains
and perhaps even political problems, and you know, prima facie, I think
that argument is inherently plausible.
But it is also true that there have been large
regions of the world in which the expectation of never marrying has
been quite real for large proportions of the population and where
social fabrics have dealt with this in sort of a regular and
non-catastrophic manner.
Pre-industrial Europe, for example, is a
setting that comes to mind, although in Europe west of the Danube today
a very large proportion of women end up eventually marrying, end up
being ever married. A hundred years ago or so that was not at all the
case, and at the end of the 19th Century and earlier, it was not at all
uncommon to find birth cohorts of women and of men in which 15 or 20 or
25 percent total never married.
Now, in the western European context, western
European culture provided for mechanisms to deal with this phenomenon.
There were mercenary armies. There's the Catholic church.
There's respectable spinsterhood and bachelorhood, and all of these
were social conventions which helped to deal with this demographic
phenomenon.
As best I can tell, in East Asian and in
Confucian societies, there is no parallel set of mitigating social
mechanisms, and rather to the contrary, the expectation seems to be
quite strongly to encourage marriage, if possible, in part to continue
the family line and to respect ancestors and all of the rest.
Social conventions, I think, would have to
change very dramatically and very quickly in large portions of East
Asia and perhaps elsewhere to deal with this impending gender
imbalance, and it seems to me a very reasonable question to ask whether
one can expect this to occur in such a very short period of time.
It's all speculative, but it seems a
question worth asking, and I think I'll stop there.
CHAIRMAN KASS: Thank you very much, Nick,
for a very interesting and provocative presentation.
If we could get the lights, we could start our
discussion.
Frank Fukuyama.
PROF. FUKUYAMA: Nick, thanks. I've been
reading your stuff for many years, and it has all been extremely
useful. I've got a series of small factual questions and a larger
one at the end, but maybe you could just answer them serially.
You know, Amartya Sen wrote this famous book
about 100 million missing women, but from your data, it looks like
that's actually a very low figure. Do you know how he got that or
what period corresponds to?
Because it looks like, you know, just China
alone over the next decade is going to --
CHAIRMAN KASS: Would you turn the mic on?
DR. EBERSTADT: From the 1980s. It was based
on U.N. Population Division estimates of total world population.
PROF. FUKUYAMA: Okay, and on Korea, the drop
that occurred from the early '90s to the late '90s, from about
kind of the high teens to, you know, like 110, my understanding is that
sex selection was actually illegal there in that the reason that that
drop happened is that they actually started enforcing their existing
laws.
DR. EBERSTADT: Yes, it had been illegal. New
legislation had come on the books in the 1980s with the widespread
advent of amniocentesis and ultra sound. The laws were, as you can
tell, completely ignored.
Then in the mid to late 1990s, the government
started to pay more attention to these practices. Civil society was
also important there. There were festivals in South Korea held,
"love your daughter" festivals and things like this, and that
started to make some sort of more general impact.
PROF. FUKUYAMA: I understand the ratios also
varied by province quite substantially.
DR. EBERSTADT: Yes, yes. That's right.
PROF. FUKUYAMA: Do we have any historical data
on rates of female infanticide in Asia just as a point of comparison
for the current sex ratios?
DR. EBERSTADT: We can only draw inferences
about infanticide from, as you will, the missing girls in earlier
censuses and very limited registries.
In China, in particular, there's a
longstanding imbalance between males and females at almost every given
age. Life expectancy for men at younger ages quite surprisingly is
higher than life expectancy for women, and that suggested a whole
plethora of discriminatory practices, not only infanticide, but
discriminatory practices after those young ages.
PROF. FUKUYAMA: Okay, and then I guess the
longer question, you know, there was a book published by Marcia
Gutentag and Paul Secord. I guess it was over a decade ago called Too
Many Women, talking about some of the social consequences of, you know,
these unbalanced sex ratios, and I guess while the conventional wisdom
is having too many men is a problem, they make the point that there may
be some compensating advantages, which is that if you have a sex ratio
that's tilted towards men, it actually puts women in the
driver's seat in marriage markets, and that one of the arguments
they made was with the Baby Boom one of the reasons that the sexual
revolution happened when it did was that because of this phenomenon of
men marrying younger women, they had more choice, and in effect that
skewed the sex ratio towards women, which led to, you know, a breakdown
of family life and so forth.
DR. EBERSTADT: Yes.
PROF. FUKUYAMA: And that you could expect the
opposite to happen if you had a sex ratio skewed towards men.
Is that a respectable argument? I mean, what
do you make of that?
DR. EBERSTADT: That's a very reasonable,
Economics 101 sort of argument, I think, but not all parts of the world
proceed under the sorts of premises that we presume to be in place in
an Economics 101 setting. In China already, the increased value of
women, increased scarcity value of women has led anecdotally to
distinctly increased reports of woman stealing, of trafficking, of
virtual enslavement, and that is, I suppose, a less attractive, but
still quite real manifestation of an improved value of women.
DR. FOSTER: Just a brief comment. If I
remember it correctly, about the last week The New York Times, you
know, had an article about single women in the United States, and if I
remember the figure correctly, that above the age of 15, about 48
percent of all women are single.
And I don't know where it is in other
places, but if a wife of a mature man dies in Dallas, instantly he is
assaulted by women who want to have a date or go to dinner or something
of that sort. I mean, there does seem to be in our country a very
large group of the excess women, and I don't know what to make of
that. I'm just commenting on it.
PROF. GEORGE: It depends on what you count as
our country, Daniel.
DR. FOSTER: Well, I believe -- I don't
know, Robby, whether I'm following you or not, but I believe that
Texas did join the Union some time ago.
(Laughter.)
CHAIRMAN KASS: Rebecca.
PROF. DRESSER: These are questions for you to
comment on, but as for the group as well to think about.
I guess one issue this raises for me is how
should we as a Council look at patterns and practices in other
nations. Certainly it would have an impact on U.S. medicine when
people from other cultural backgrounds come here and want particular
interventions that are more popular in other nations, but should we go
beyond that? And how should we think about that?
And then the second is provoked, I guess, a
little bit by Leon's point about orthodox Jewish preferences for
sons. I think we're looking at sex selection as part of our,
quote, enhancement project, I think. Is that right?
CHAIRMAN KASS: Go ahead.
PROF. DRESSER: Maybe it's related to some
other project I don't know about, but anyway, if we're to think
about sex selection as being done for non-health related purposes,
putting aside defining what falls under health related purposes, but if
we're just to say, okay, for other reasons, is it possible to make
arguments that would say certain reasons deserve more weight than
others?
So a religious tradition, a cultural tradition,
family balancing; is it possible to really discriminate or
differentiate between preferences, saying some are unjustified gender
or sex discrimination and others are not, or should they all be treated
equivalently, whether that is to say they're all okay or
they're all not okay?
CHAIRMAN KASS: Nick, do you want a word on
this or not?
Let me say something about the first question.
I mean one could argue that what goes on in other countries with the
use of these technologies is a curiosity and we should pay attention,
but finally not of concern to this body, and that might be closer to
the truth than not.
On the other hand, as has been pointed out in
previous discussions, what goes on in other countries has an impact on
what happens here, either where precedents set elsewhere come to be
argued for here. I mean if the British are doing embryo research, why
shouldn't we, or conversely, they would say, "Look. If the
United States isn't doing sex selection, you know, maybe we
shouldn't either."
But there's also these -- there are sort of
social and political ramifications of these technologies, and Nick, in
his characteristic understatement, just alluded I think. The numbers
are by themselves interesting, but what they actually mean socially and
what they mean internationally in an age of globalization is, it seems
to me, of importance and, at the very least, it might be worth our
while to call attention to what goes on with the use of these
technologies and perhaps even recommend nothing so radical, nothing
more radical than the need to monitor and pay attention to what is
happening and where in ways which we are not at the moment doing.
That would be at least the minimum suggestion
as to why that kind of conversation -- I mean, the material that Nick
has raised is, I think, of importance to us.
And if I might simply respond just to open up
the other question, yeah, there is a question here as to whether or not
-- I mean, whether sex selection is an enhancement or not could be
discussed. That it is a non-medical or nontherapeutic use of medical
technique is part of what makes this of interest.
And I think one of the reasons it's part of
this conversation is that it's one of a whole series of
developments produced for medically related purposes, but which will
yield individuals, unless there are regulations, but will yield the
desire, will support the desire for individuals to use new technical
power to achieve their desires either for self-enhancement or for the
control of their offspring or for the control of behavior of others.
The question is whether if those things are
worrisome, what, if anything, can and should be done about it. I think
that's the context, and what are the reasonable reasons for using
this thing, except for the prevention of disease is, it seems to me,
interesting.
And does one sit in judgment of the people in
Punjab or is this one of those occasions where who are we to judge the
cultural preferences of other people or, for example, the cultural
preferences of American subcultures, the first slide that Nick showed
about beginning to see changes in the United States in the East Asian
populations where the sex ratio begins to approach 110.
DR. EBERSTADT: I think the ones I showed were
107. The Philippine Americans, it's almost 110.
CHAIRMAN KASS: Yeah.
Janet.
DR. ROWLEY: Well, I'd like to go back.
Just some of the techniques that are used to achieve these changing
ratios, and one of them obviously is sex selection before implantation,
and the other is selective abortion, and it's sort of surprising to
me, say, in countries that I assumed had restricted availability of
some of these technologies, that there are changes.
For instance, you had the statistic about
American Indians going from 101 in 1984 to 103.5 in 2000. I'm not
sure whether that's within the range of variation because one
thinks of American Indians as not having access necessarily to fairly
sophisticated technologies.
And then you also quoted countries like El
Salvador with 107, the Philippines, 108.7, Egypt, 108.7, and Pakistan,
110.9. It would seem to me it's a small portion of the population
within those countries that would have access to more sophisticated
technologies.
But the implication of all of this is that
it's really some kind of sophisticated technology and access to it
that is causing these changes because these are birth ratios. These
aren't zero to four where you can think of infanticide.
So what is going on actually in these countries
that may be associated with these changes?
DR. EBERSTADT: I would not myself become at
least yet too alarmed by the data reported there for the American
Indian population even though the reported ratio, sex ratio at birth in
the years that I chose had increased. 103 is still well
within the range of ordinarily reported biological variability.
I think one starts to ask questions to be
arbitrary at about 106, and one starts to have alarm bells go off at
about 107.
With respect to Pakistan, the data there for
Pakistan were from their vital registration system, which I don't
think is complete. I would guess in the case of Pakistan -- I would
have to go back and double check, but I would guess that those are
hospital deliveries, and hospital deliveries are going to have the
enhanced techniques that you asked about.
With the case of El Salvador or Egypt, medical
services are presumably much more limited than for native American
population in the United States. I'm only speculating, and I have
no basis in fact for this, but just to speculate about this, if a
relatively small proportion of parents felt rather strongly about some
preference issues, it would be possible to alter to some degree the
national sex ratio at birth without having comprehensive medical
services and availability, but I don't know. That's a
speculation.
DR. ROWLEY: Well, if I can just follow on with
this, and again, toward the end you also tied this in with more
sophisticated family planning, if you will. So if you only want to
have two or, say, three children and you already have one or two
children of a certain sex and you're going to have just one more
child, then may well pay much more attention, and your data has
suggested if you already had two females and you were going to have
only one more child, it was very important to you that you have a boy.
I happen to have four sons and only four
children. So --
DR. EBERSTADT: And I have three daughters.
DR. ROWLEY: So, you know, years ago I'm
not sure if really effective sex selection had been available whether I
might have taken advantage of it for family balance. It wasn't
available. It's not clear that it is even yet available unless you
to go really extraordinary lengths.
But I think that these are intellectually
interesting issues. Again, the question whether it's a matter for
us to consider and pursue, I think, is the kind of discussion that
Michael was suggesting that we have.
CHAIRMAN KASS: Michael, and then Bill May,
and then Gil.
PROF. SANDEL: Well, these were two such
fascinating presentations, and I'd like to go back to the ethical
questions that they raise.
First, a comment that occurred to me at the end
of our first session, or thought rather. There are lots of reasons to
worry about sex selection, but I think that our greatest contribution
can be to resist the reflect or the tendency to translate what troubles
us into overly familiar terms.
And that comes out if we say, well, it must be
the means. And so people have views one way or the other about
certainly infanticide, about abortion, and for that matter, about
embryos. So there's a tendency to translate it into that aspect
or, on the other hand -- and in this report, Leon, that you referred to
we have in our binder, to translate it to different kind of familiar
terms.
Well, it's going to lead to gender
discrimination. We're familiar in our society arguing about those
two things, about the status of embryos, on the one hand, and about
gender discrimination, on the other.
But what's distinctive about this question
of sex selection -- and this connects to the broader issue of
enhancement -- is that there are reasons to worry that go beyond those
two familiar reasons, which isn't to diminish those familiar ones,
but this question is philosophically interesting and challenging
because not everything that's objectionable about it can be
translated either into worries about embryos, on the one hand, or about
discrimination, on the other.
And that takes us to the goals or the goods or
the ends to reflect on, and looking at the data, the demographic data,
we all shudder at the numbers, but trying to make sense of the
shuddering is what's interesting.
There are worries obviously about the social
consequences, and here we enter into the kind of speculation in the
exchange between Frank and Nick about, you know, will all of those
extra men in China create instability, make China more warlike. Will
it make the situation with women better? Will it make it worse?
There's that set of worries.
But beyond the worries, there's something
also chilling about this, quite apart from speculating about the social
consequences for China or for the world or for war or for instability
or for all of these extra men rattling around there. And that's
what we should try to get at.
Is it chilling? Well, one thing is, oh,
it's chilling because we know lying behind there, you know, is some
infanticide or abortion or the killing of embryos.
But there's another dimension to what makes
it chilling, and that has to do with -- well, I'm not sure, but
here's a speculation or a question just to invite us to direct some
of our energy anyhow in our reflection to this other set of issues.
Is it that we see in those ratios, rising
ratios, is it that we see here's what happens when we have the
technology to actually implement the things that for various reasons we
might desire?
And is the danger -- is what's chilling the
power that the technology give us? And may shrink before the
consequence of that technology when we see it here, or is what's
chilling that the technology being available just reveals to us vividly
desires, things that people want, that themselves -- we think people
shouldn't want that sort of thing.
And suddenly the technology lays bare desires
that we haven't been able to act upon in other times. So
here's one way of testing that independent of the technology.
Is it wrong or not wrong, but is there
something morally troubling or questionable about praying for a boy
rather than a girl? And is the problem with the technology that it
answers the prayer that's independently objectionable or it enables
us to answer the prayer, to perhaps obviate the need for the prayer?
But is that the underlying desire; is it the prayer? Would that be
objectionable?
And if it's not, then we have to look
elsewhere, but if it is, then that leads us to some difficult moral
terrain, but at least it's the kind of terrain that may kind of get
at this issue of enhancement.
CHAIRMAN KASS: Could I as Chair ask members
in the queue if they would waive the queue and address the question?
Because I think it's a nice -- if we could at least response to
Michael's challenge, if people would like to address it rather than
just run away from it?
Gil, do you want to speak to it? Both you and
Bill were in there.
PROF. MEILAENDER: I do want to speak to it.
CHAIRMAN KASS: Please.
PROF. MEILAENDER: Maybe he does.
DR. MAY: But go ahead.
PROF. MEILAENDER: Well, yeah, I want to pick
up on that actually relate to where it was Rebecca who sort of started
us down this road to some degree by thinking about kind of how this fit
with our larger concerns.
And let's assume an unobjectionable means
for the time being, you know, whatever that means. It probably means
different things to different people, but let's assume an
unobjectionable means so that we're talking about just the goal of
getting a child of the desired sex.
I don't myself think there's anything
wrong with the desire, and if somebody said, "I'm praying to
have a boy," that's all right.
If I may just kind of switch issues for a
moment, St. Paul prays to die and be with Christ. He doesn't act
on that, however.
So that, I mean, I don't think there's
necessarily anything wrong with the desire. So that's not -- if
we're looking for kind of a deeper concern, I don't think
that's it, that it reveals to us some desire that's suspect. I
don't think there's anything wrong with wanting a boy or
wanting a girl. I don't think there's anything wrong with not
caring either, but it doesn't matter in that sense.
I think the issue is when desire turns to
action, it's control, and I think to me at least the issue is or
one of the issues anyway is the kind of control of offspring that is
set up there in the sense that means a less than unconditional
affirmation of somebody who turns out to be other than one desired.
That to me would be the problem, not just
having a desire.
I think there's a second kind of issue that
probably moves beyond --
PROF. SANDEL: Could I just add quickly? But
you don't think the desire could ever condition the affirmation?
PROF. MEILAENDER: I think it could, but I
think it's much more likely that the availability of the technology
is what brings the conditions rather than just having the desires.
Because technology turns out not just to free us and give us new
options, but to shape us and constrain us in various ways.
So that, in fact, is what I think generally
happens. Now, if I may make one more point that kind of in a way
relates a little more to where Rebecca had started us, but I think an
additional question here -- I mean I think you're right, Michael
that it's important to ask, you know. Get out the means and
everything. Is there any reason to just object to choosing the sex and
can we articulate what it is?
But relates to the demography stuff is if there
are undesirable larger consequences, one of the issues that we're
raising then is if my desire is innocuous, if there's nothing wrong
with it, whether I have to suffer for the larger good, whether my
desire should be thwarted, whether we should regulate it.
And that is a question I think at least in a
society like ours that also needs to be faced.
CHAIRMAN KASS: Bill, Bill May.
DR. MAY: Partly a response to yours, but also
to return to the issue you were raising. As I listened to you, I
couldn't help but think about how studying comparative information
of this kind accentuates for us the difficulties of anticipating
consequences.
As I think about India, just a passing word.
The fact that towards the third and fourth child, one even more
intensely wanted a boy does relate to economic circumstances there.
The dowry that has to accompany the girl into a marriage, and I know
farmers there who have gone into major debt and wanted a boy.
Terrific pressure on boys later on. If they
don't happen to hold to that system of a dowry and coming to this
country and working on computer work to be able to send money back at
home to help out the father to escape from the economic bag or trap he
was in.
So there are lots of pressures of that kind
that haven't surfaced in this discussion, but at the same time it
was very interesting you mentioned that at Punjab modernization tended
to move us in this direction. I wondered to what degree that related
to the fact that the boys in those provinces or regions, modernization
meant to move to the city, and there is more mobility in the boys and
girls, and so there might be more reason, again.
But all of this traffics in the question of
micro controlling as opposed to macro controlling, and you say the
problem of micro controlling is acute only if it's going to produce
macro problems, and that may be the wrong way of looking at it, and
that I think is what you, Michael, are forcing us to consider.
The deeper problem as it relates to parenting
for me is the whole question of how parenting relates us to the
question of the unbidden and the unelected in life.
I mean, we elect a mate in our kind of culture,
but we pick up with that a lot of things that we haven't elected:
the in-laws, and the genetic load, and so forth. There's a whole
unelected, and the testing out of a relationship very much depends on
our capacity to rise to what has been unbidding and unelected.
And that's certainly also true of
children. In that very delicate issue is it okay to desire something
else because is that going to hamper your ability to be open to what is
unelected is the exchange I see between the two of you.
You happened to mention prayer, and it's a
very interesting issue, intercessory prayer in the setting of the
Christian tradition. Is intercession the way in which we, absent of
technology, look to God to provide us with the deus ex machina
response?
Within the machine we don't have the
technology. So we need this cosmic bellhop who will do certain things
to fulfill our wants and our desires.
And there's another way of looking at
intercessory prayer, is that circumstance under which we now temper our
desires. We express them, but we temper them. "Let this cup pass
from me, but not my will, but thine be done," and suggests a way
in which one hands over into the hands of another, and that other is
not defined as the cosmic bellhop.
But the way in which I am sustained and
supported to be open to the unbidden in life, the unelected in life,
which nevertheless to which I have to rise.
So I see you, Michael, have raised a very
important issue for us in your opening statement here. In addition to
harm and so forth or long range impacts and so forth, what are the
impacts in our whole understanding of the relationship of parents to
children, mates to one another, is the issue to which we return here.
CHAIRMAN KASS: Frank and then Robby. Oh, sorry. Bill and Robby.
PROF. FUKUYAMA: Well, this may not answer
Michael's question of why this is chilling, but I have my own take
on why this is important as an issue, which is that this is a textbook
case of a negative externality where you have a decision based on
medical technology that is individually rational for the parents, but
has a negative social cost and has a population level effect.
This is not a moral. You know, this is, I
think, a good answer to people who say, you know -- use this
libertarian argument that says, "Well, the only thing wrong with
eugenics was that it was state sponsored, and as long as it's
individual parents that are doing it, we don't have to worry
because, you know, they love their children and they know what's
best, and so forth."
And so this just seems to be -- and this may
not be the most important issue, but it does seem to me it's a
model for other decisions that will be possible in the future where you
could have perfectly individual, rational decisions that will lead to
population level effects that will be bad for society as a whole, which
then, you know, I think even for the most libertarian economist, I
mean, you know, is grounds for some kind of social regulation.
Now, the troubling desire, you know, I have
this mental exercise of a different case of this kind of selection that
would be a lot more troubling to a lot of people. Let's say that
there is a gauging or, you know, you can actually in the privacy of
your doctor's office, in effect, select the sexual orientation of
your child and speculate as to what the population level effects of
that kind of power would be
And my private, you know, privately held
opinion is that even the most tolerant, you know, person with plenty of
gay friends, and so forth, in the privacy of their doctor's office
is very likely to, all other things being equal, you know, if they had
that choice available, you know, they would avoid having a child with a
proclivity to gayness, and it doesn't have to be genetic. You
know, it could be just, you know, done through drugs or some other
thing.
If you had that kind of technology cheap and
relatively simple, I would think that you'd get population level
effects, you know, that would seriously affect the number of, you know,
distribution of gays within the society. It could happen, you know,
within a generation.
So the importance is really not the sex
selection issues per se, but just the fact that this does demonstrate
that there are new technologies that can have, you know, larger social
consequences on the basis of individual choice. So that eugenics is
not troublesome simply because it's state sponsored, but can be
quite troublesome as a result of disbursed, decentralized individual
parental choices.
CHAIRMAN KASS: Bill Hurlbut and then Robby, and then I think we'll have to break.
DR. HURLBUT: I want to ask you a quick
question, and then I want to make a comment.
Are there statistics on the gender realities of
abortion in America?
DR. EBERSTADT: Not that I'm aware of.
There may be some data of some sort kept. Dr. Haney, you may know this
better than I, but since the total estimates for the number of
terminated pregnancies or abortions in any given year aren't
exactly fixed, there correspondingly are other sorts of data one might
want to get.
DR. HURLBUT: I mean, it seems apparent if you
add up the huge numbers of lost females in your international
statistics that that must be driving the abortion rate strongly in
certain countries.
I've read statistics concerning India,
certain hospitals where 99 percent of the abortions are female fetuses.
DR. EBERSTADT: I've read the same sorts of
accounts.
DR. HURLBUT: The second question I want to ask
you: is there a correlation with being noted with crime rates as there
are disproportions of males to females?
DR. EBERSTADT: Internationally?
DR. HURLBUT: I know it's a hard one to
weigh.
DR. EBERSTADT: Not that I am aware of.
Everyone has -- in all societies one always has impressions about the
way things worked in the good old days and the way that things are, you
know, falling apart now.
And certainly in most of the places in East
Asia that we describe, they're not seen as high crime settings. I
wouldn't have the data to support that sort of generalization right
now.
DR. HURLBUT: It seems to me that one likely
consequence of this in the regions of the world where there's a
strong disproportion maybe 18 years later is going to be a high rate of
prostitution and maybe increased rates of sexually transmitted
diseases, which may be local to some extent, but has international
implications.
DR. EBERSTADT: I think that's a very good
question to ask.
DR. HURLBUT: What strikes me about this is if
you add some of this up, you might actually say that there could be a
social advantage overall. This is the individual versus the state.
There might be a social advantage by governmentally imposed sex ratio
of the opposite dimension, that at least in our country crime rates
correlate with the number of young males more than they do with
anything else.
They've tried to correlate this with drugs
and post war and so forth. It always comes out that it's the
number of young males, and so you could theoretically hypothesize a
better society by doing something like sex ratio engineering.
That leaves certain questions unanswered like
who's going to marry whom, but I just bring it up because when I
think about Michael's very deep and important questions, it seems
to me that there's something going on under the surface about
nature, and we somehow relate this question of God and prayer and
nature all together as a single unit.
You start out with the interesting and ironic
comment about God's provision for the balancing of the sexes
because of male recklessness and death and war and so forth. And it
was kind of funny; it seemed an anachronism.
Nevertheless, underneath the surface that
assumption seems to be holding in a broader way for both religious and
nonreligious people; that there's something about the way nature
does things that seems to be better, wiser, more balanced. Even if we
could produce a better society by decreasing the number of males,
therefore decreasing crime or something like this, that it wouldn't
be right even then and that, therefore, when we pray for one particular
sex or another, there's the element that Bill May was suggesting,
that there is a humility in our prayer. Whereas in our technologies
the humility seems to be lost.
DR. EBERSTADT: I think that Sussmilch did not
intend his comment about the Creator at all to be ironic. I think he
was completely serious in his description.
It sounds a little antique to some people
today, but I think he was completely serious in his description.
And as for speculating about young males, if
there were a technology which could cryogenically freeze our children
at the beginning of adolescence and unfreeze them at the end of
adolescence, people might pay a lot for that. I don't know what
the ethical implications of that would be.
CHAIRMAN KASS: Robby, and then we'll
break.
PROF. GEORGE: Dr. Eberstadt, a quick question of
clarification, and then I want to discuss the matter that Michael
Sandel raised.
In the charts that gave us information about
the expressed preferences of women in various countries with regard to
additional children or having children or additional children, the
question was put to married women or was it married women of
childbearing age?
DR. EBERSTADT: It was married women of
childbearing age.
PROF. GEORGE: Of childbearing age. Okay.
DR. EBERSTADT: Yes.
PROF. GEORGE: I didn't think that was
indicated. Thanks.
I'm sorry Michael is not here. I thought
Michael was right or is right to warn us not to assimilate concerns we
may have about sex selection entirely to familiar concerns that have
been expressed in other domains, and the two that he mentioned were
discrimination and abortion and infanticide.
But I wonder if that means we need to find that
when we think the thing through we'll find a new set of concerns, a
new set of concerns laying somewhere deep in our consciousness or
whether it might not be yet another familiar concern, but not one of
the two.
And the concern I have in mind, particularly in
listening to Bill and Gil is the concern that Leon expressed many years
ago and influenced some of us. I realize not all of us accept this,
and that is the concern about turning procreation into production or
manufacture.
It was a concern that was voiced by some of us,
including Leon, at the very beginning of our deliberations about human
cloning and, of course, has been expressed by critics of IVF and other
reproductive technologies.
And it does sound to me when I hear Bill and
Gill, and their points sound very persuasive to me, that there is
something about sex selection which seems incompatible with a posture
toward a child, a posture toward the coming to be of a new child that
really does treat that child not as a product of manufacture, but as a
gift to be received.
And I think that if that distinction holds, and
if we can also distinguish, as I think Christians and Jews would want
to do -- and I'm not saying that other religious traditions would
think about this differently, I just don't know enough about them
to say -- but if we would do what Christians and Jews do about
distinguishing prayer from magic so that we're not trying to use
prayer as an efficient means. It's just the best one we happen to
have to this productive end.
Then I think we can begin to understand that
there really is a distinction between praying to have a boy or praying
to have a girl and an act of the will, a choice, the use of a
technology, and in the process willing that we're going to have a
boy or going to have a girl such that the lack of success in that
enterprise would constitute a failure of our effort in a way that a
Christian or Jew would never say our prayers were a failure. They
didn't produce the result that we aimed to produce.
CHAIRMAN KASS: Thank you.
Dr. Haney, Dr. Eberstadt, any final comments
that you'd like to make?
I want to thank you both for a really very
informative and instructive and interesting morning. We've run
over, as is our habit. We were supposed to start at 1:45. It gives
members an hour and 15 minutes for lunch.
(Whereupon, at 12:27 p.m., the meeting was
recessed for lunch, to reconvene at 1:45 p.m., the same day.)
AFTERNOON SESSION
CHAIRMAN KASS: Let me just remind Council
members that we are in the midst of a three month inquiry into various
uses of biomedical technology, present and projected, for purposes that
go beyond the treatment of individuals with known diseases and
disorders or that have uses that could go beyond those purposes, and we
are doing so because we were, by executive order, encouraged to
undertake some fundamental inquiry into the human and ethical
significance of developments in biomedical technology and to contribute
to the public understanding of these questions.
And that meant at least that we have the
opportunity, but also the liberty to step back from some hot button
topics and to try to take a look at the field as a whole and to
discover whether there are certain kinds of questions that cut across
the uses of this or that technology.
And as I suggested in the memo that was
circulated to you before, the prospect of these kinds of uses of
biomedical technology really do raise for us some of the weightiest
questions in bioethics, as we saw this morning, already touching on not
just the means that are to be used, but also the ends that we wish to
pursue and touching very often on certain fundamental features of human
life.
We've been looking at technologies that
affect the body, whether in terms of muscle enhancement or blood doping
for athletics. We will be talking in December about research on aging
and the human life span, and we have been looking now -- this will be
the second of three sessions in which we will be looking at
technologies that offer the possibility of influencing certain features
of the human psyche, mood and affect the last time; next time,
attention and conduct and the discussions of Ritalin and the use of
stimulants; and this time things that affect memory and cognition.
And we are very, very fortunate to have with us
today two of the leading researchers in the field of human memory. Dr.
James McGaugh, since the 1950s, has been a pioneer in the neurobiology
of learning and memory. He's PROF. in the Departments of
Neurology and Behavioral Science, Psychiatry, Pharmacology, the School
of Social Sciences, and the Director of the Center for Neurobiology of
Learning and Memory at the University of California at Irvine.
And we have PROF. Daniel Schacter, who has
written very widely and for a broad, nonspecialist audience wonderful
books on the psychology of memory. He's the William R. Keenan
PROF. and Chair of the Department of Psychology at Harvard.
We're delighted to have both of you with
us, and by prior arrangement Dr. McGaugh will go first. We'll then
take our break after about an hour and a half, and then we'll have
Prof. Schacter's presentation.
But the conversation can flow with all of you
present. Please, Dr. McGaugh, thank you for being with us.
SESSION 3: REMEMBERING AND FORGETTING: DR. MCGAUGH: Well, thank you very much for
inviting me. It's nice to come here and speak about a topic that I
have been interested in for over four decades and which serves as my
current interest, deep current interest, at the present time.
I'm going to talk about memory, and I think
we can all agree that memory is a good thing to have. You'll hear
later on this afternoon that it comes in different forms and provides
different advantages and different disadvantages.
But I'm going to focus on only one aspect
of it, and that is the experimental or other treatments that will make
long lasting memories longer lasting and stronger, and the general
assumption underlying this, which certainly can be questioned, is that
if it's good for us to have memories that enable us to get along
during the day, to remember where we parked our car, to remember our
motor skills, and so on, then maybe it's a good idea to have a
little bit more of that. That's an underlying assumption
that's been made. I'm even going to question that assumption.
Now, there are several reasons for
investigating memory enhancement which I'll start with later.
I'll talk about memory blocking and start with memory enhancement.
First is just the basic research on brain
memory, and that's what drives my research. I use drugs and other
treatments to enhance memory in order to understand how the brain
ordinarily works when memories are made. That's the purpose of it.
If we take drugs, in particular, if we know
something about the mechanism of actions of drugs, let's suppose we
give a drug which is a GABA receptor antagonist, and we find that this
drug does something to memory in a very precise way. Then we can
conclude that GABA receptors located in some places of the brain are
very important in the making of the memory process.
Beyond that, if we focus on those places in the
brain, we can learn much more about not only the receptors of a
particular kind, but a receptor in a particular location.
And out of this is unraveling little by little
more and more understanding of the key neurochemical systems and the
key anatomical systems that are involved in making and preserving
memory. So that's a fundamental line of inquiry that drives this
research, where memory enhancement is a way of inducing the brain to
behave in a different way so that you can learn something about it.
Another more obvious reason is the question for
finding treatments for memory disorders, such as Alzheimer's
disease. I probably shouldn't say "such as Alzheimer's
disease" because the research is almost restricted to that.
There isn't any research on the drug
effects for the mentally retarded or it's just minuscule research.
There isn't any research for drug effects on people who have brain
damage that prevent them from learning and remembering. That's a
nascent field. It really doesn't exist.
The focus has been on progressive disorders of
learning and memory and cognition that are progressive, such as
Alzheimer's disease, because as you know, the incidence is
estimated to be at least 25 percent, if not 30 percent, in people over
the age of 85.
So we're all looking at something that can
happen to us. So it drives our attention.
Now, there are other interests of the
pharmaceutical companies and the biotech companies that overlap, but
differ somewhat from the two categories that I've given you, and
one is looking for treatments for a new disease, which is age related
memory decline.
Now, that's a new disease because drugs can
be found to treat it. It was new to me that it was a disease. I
thought normal aging was normal aging, and we have known for at least a
couple of decades that there is, on average, a slow decline over the
decades starting at the age of 30 in cognitive processing on memory
tasks, in particular, memory tasks that use speed as a criterion.
For example, if you ever watch
"Jeopardy," you don't see many 80 year old people on
"Jeopardy" because of speed of response is such a high
priority, but those of us who are over 50 or well over 50 know that we
curse the television because we know, but we can't respond as
quickly as the folks that are there.
I'm also concerned about that because while
there is age related memory decline, without question, on average there
are plenty of people who show absolutely no age related memory decline,
and there are others who show rapid age related memory decline.
And underlying all of that, by the way, is a
countervailing influence which is an increase in knowledge and wisdom
and ability to deal with the environment, which readily compensates for
the speed driven responses. But that is a new target for drug
development.
Another target for drug development which
sometimes is said explicitly, but most of the time it's implicitly,
is just drug improvement for everybody else, and why not? And why not?
If you look at the health stores or even your
drugstores or your supermarkets, you can find dozens, if not hundreds,
of bottles and packages on the shelf which are entitled something like
"memory boosters" or "brain busters" or something
of that kind, and they're not on the shelves because people want to
fill up the shelves and make them look pretty. They're on the
shelves because they're being sold.
Ginkgo biloba, which is now the latest study
shows has no effect at all in age related memory decline, still sells,
makes millions and millions of euros in Germany and, I suppose,
somewhat less than that here, but nonetheless, I get more questions
about ginkgo biloba than anything else appearing on my E-mail screen.
But that's a target you can see. That is,
as soon as you see there is a market, you can see that there's a
target for it, and so there is a slippery slide from disorders of
memory to the new disease of age related memory decline, which is in
normals, to just having a drug to improve memory in normal subjects.
Now, I have done a nonscientific sample of this
by just asking lots of people I know. I've asked if there were a
drug that was safe and effective and would improve your memory for such
things as where I parked my car yesterday or, you know, things of that
kind. I have yet to find anyone who said, "No, I wouldn't be
interested in it."
And I would have thought that most people would
say, "No, you'd have to convince me to take it." But
even people whose judgment I trust and have trusted and maybe no longer
trust have said, yes, they would take it.
And then I had another question. I said,
"Well, let's ask how eager you are. Would you do it if it was
free? How about a penny a day? How about ten dollars a day? How
about a hundred dollars a day?"
Well, they drop off, of course. Now, the
drop-off doesn't occur for family members of people who have memory
disorders. The drop-off is not really quite so steep because they will
do anything to try to keep their family members more cognitively
competent for a longer period of time.
But what this nonscientific study tells me is
that this is almost a frivolous kind of thing for most people. Yes, if
we're there, and, yes, if it were cheap, and if it would give me a
slight edge, yes, I would do it.
And don't misunderstand. The
pharmaceutical companies and biotech companies are listening to that by
looking at the sales of ginkgo biloba and other ones.
ow, there are other reasons you have to come
that are implicit, unstated. One of them is memory enhancement in
children, that is, school children, just regular school children.
I'm not talking about children with disorders.
I was driving to a concert with a neighbor, and
our families went, and she said, "Oh, Jim, I'd like to have a
drug for my daughter to make her more competitive in school. Could you
give me the name of one?"
It wasn't "do you know anything about
it," "are there any things that are safe and
effective." It was "can you give me the name of one,"
and the model that she had in mind was Ritalin because some of her
children friends take Ritalin. So there must be something else that
her child could take so that she wouldn't have to study very hard,
you know, just to make up the difference.
But I think that that's coming down the
road, and it's something I think appropriate for this group because
that's part of the slippery slope. If there is a drug which is
safe and effective and not too expensive for enhancing memory in normal
adults, why not normal children? After all, they're going to
school, and what's more important than education of the young? And
what would be more important then than to give them a little chemical
edge in getting a better education if it didn't do damage, and so
on?
So I see that that's there.
Now, we also have genetic manipulation, which
I'll talk about perhaps a little bit more later down the line.
Many of you, I'm sure, saw the cover of Time magazine and read the
article after the report of a genetic manipulation which increased the
number of a certain kind of receptors, glutamate receptors in the
brain, and the mice that had that genetic manipulation, those mice were
better at a couple of memory tasks than were other mice.
And so all of a sudden Time magazine began
talking about designer babies, I think, which would fit in with your
topic of discussion this morning. If you think selecting for sex is a
problem, think about selecting for learning or selecting for
intelligence using genetic manipulation, gene transfer or knockouts or
something of that kind. I think that is an incredible morass.
Now, as we consider these latter, however, in
children and even for adults, there's an important confusion to
clear up that was not cleared up by Time magazine, on the contrary, and
that is the distinction between intelligence and memory.
All these things do -- all of these things do,
including all of the drugs that I work with, is make animals and humans
remember a little better information that they have been presented.
That's all they do.
Now, intelligence is quite another matter,
whether you think of it conceptually or whether you think of it the way
it's tested in an intelligence test. Memory is a very small
component and memory tests are small components of intelligence tests.
They have to do with reasoning. They have to do with judgment. They
have to do with all kind of things, and there's no evidence that
inserting a gene or taking a gene away from a mouse imparts it with
greater ability to make better judgment, better reasoning or anything
of that kind.
So I think that these experiments, however
interesting, do not lead to the conclusions that were jumped on by Time
magazine, that all of a sudden we can do genetic engineering, and we
have to be worried about intelligence.
If that is something of concern, then I think
those people who are interested in it have to be better educated about
what it is that memory is and what can be expected from such
manipulations.
And finally on this, there's a huge
caveat. I'm now going to question the assumption that I made at
the very beginning, that if memory is good, then more is better.
Well, more is not better. At the extreme more
is worse. There are two famous cases, one a fictional case of
"Funes de Memorias" by Borges, a short story in which Funes
was capable of memorizing everything that was presented to him, and he
remembered everything that he encountered such that towards the end of
it he said, "Sir, my mind is like a garbage heap. It's all
there."
And over 100 years ago the famous psychologist
William James, in whose hall Dr. Schacter lives, said that to remember
everything is as valuable as to remember nothing because it's all
there and needs to be sorted out.
Now, there's also the case written in
Luria's book, The Mind of a Mnemonist, which you can get at your
local Border's bookstore, a subject that he studied for many, many
years. This was a subject who could memorize very well. He memorized
by using synesthesia, by mixing the senses which enabled him to
remember better, and he could remember very detailed information for 15
years, very precise knowledge of what numbers were given to him in what
order over a 15 year period of time. He had a very unhappy life and
ended up a failure.
I also had a subject. Up popped on my E-mail
one day as the Director of the center, "I have a memory problem.
Would you talk with me?"
And I sent back, "This is not a memory
disorders clinic. I can direct you to one."
"No, I have a kind of a problem you might
be interested in. Would you at least talk with me?"
And this was a young woman who claimed that she
had such a powerful memory that it interfered with her daily life, and
could I at least listen to her and direct her to someone who might help
her, and I had trouble at first understanding what she meant by that.
So I got out the two books that were published
at the millennia about all of the things that happened in the last
hundred years and just randomly opened pages, and I couldn't stump
her. I just randomly opened pages, and several times she said,
"Well, you have the date wrong."
And I said, "No, no, it's written
right here. It's a date line out of a newspaper."
"No, no. That's the date in which
they wrote it. The date of the occurrence was three days before
that," and so on.
And I said, "Well, how did you do in
college?"
She was a C student in college, barely made it
through, and I said, "Well, why couldn't you put this
extraordinary capacity of being able to remember to good use?"
She said she never could because it's
disorganizing. "I'd begin to do something and somebody would
say, 'Well, it's Thursday,' and I'd begin to go
backwards, Thursday last week, the week before, the month before, the
month -- five years before, and it's just like going through a
Rollodex, flip, flip, flip, flip, flip, flip, like that," and she
was distracted from what she was to do because she had such a powerful
memory.
Now, lest you think I'm making this up, we
also have her diaries, which she kept over all these years, and with
the help of an assistant, we are able to check information that she
said that she has by going through her diaries, and we have yet failed
to find any error or any mistake.
Here's a failed person in life who has an
extraordinarily strong memory for events that occurred in her life.
She's unable to use that, and the only way she used it productively
was she worked for a while with a very well known trial attorney, and
she was the assistant standing there or sitting there so that when some
claim was made about something happening on a certain day and it rained
that day and so on, this trial attorney could turn to her and say,
"Did it rain on that day?" And she could say yes or no
without having to go to the records and see. That's all that she
was good for.
So a little, maybe a little is good, but I
don't think any of us would want to have the memory of Mr. S, Mr.
Luria's patient, or Funes, the Memorias, the fictional character,
or the subject that I've worked with.
Now, let me turn a little bit to the research
on drug enhancement of memory, which is my special interest. This was
all started in 1917 by a study by Karl Lashley, a very famous
neuropsychologist, in which he gave a drug, strychnine sulfate, which
many of you know to be a rat poison, to rats each day shortly before
they were trained on a simple, little maze, and he found that they
learned the maze faster.
Now, this was of interest to me many years ago
because we thought we knew something about the mechanisms of
strychnine. So in the mid-'50s, with a colleague I replicated and
extended this study and found that, yes, strychnine did what Lashley
said it did.
But we couldn't draw the conclusions that
we'd like to draw, which has to do with the drug making memory
stronger, because we're confronted immediately with what we know is
a classic learning performance problem. The animals learn better. The
drug influenced the learning, but did it influence the learning because
the animals could smell better, because they were more attentive,
because they were more reluctant to enter alleys and so they were more
selective? All kinds of performance factors.
Now, if one is only interested in having human
performance better, then one doesn't care about this distinction.
That is, if you just want to get humans to perform better, you
don't care whether they remember better, whether they're more
attentive, or whether they're more highly motivated or whatever.
But if you're interested in mechanism,
it's very important. So I introduced the procedure of injecting
drugs not before learning, but immediately after learning, and the
reason I did that is because it had already been established or already
been suggested that when you make a new memory, there's a period of
consolidation in which the formation of the memory is susceptible to
influence.
This was first seen with electroconvulsive
shock so that humans and animals that are given electroconvulsive shock
treatments remember less well those things that happened just before
the treatment, and this and other things led to the view that memories
consolidate over time.
Now, if that's the case, I said it should
be possible to give a drug after the animals are trained and find the
same effect, and, lo and behold, I did.
Now, that led me and many others down a path of
using this post training drug injection procedure to find out which
drugs would enhance memory, which would not, where they acted in the
brain, and what mechanisms they used in acting in the brain to produce
these effects.
And I won't bore you with all of the
details. Suffice to say that we know that there are several brain
regions that are very important, and for those of you who are
interested in neuroanatomy, they include primarily the basolateral amygdala. They include the hippocampus, the entorhinal cortex, and
the medial part of the prefrontal cortex, in particular, but there are
some other regions as well.
We can enhance memory in laboratory animals by
microinfusing microquantities of the same drugs that we would inject
peripherally into specific regions of the brain and get exactly the
same results or we can put antagonists of those drugs directly into
those brain regions and completely block the memory enhancing effects
induced by peripheral drug injections. So this is a way of learning
about the anatomy of memory, the pharmacology of memory, and the
neuromodulatory systems that are involved in memory.
Now, interestingly many of these drugs converge
on promoting the release of noradrenalin, norepinephrine or acting on
the receptors that adrenalin and noradrenalin use because if we use
blockers of those compounds or of those neuromodulatory influences, we
can prevent the memory enhancing effects.
Now, we asked then a number of years ago why is
it that we have a brain that's organized in such a way as to be
labile to influences that happen after learning. Why is it your and my
brain is made that way?
Because I can skip ahead and say some of the
same drugs have been studied in humans. Amphetamine, for example,
given post training to humans will enhance memory just as it does in
laboratory animals. Well, why are our organs organized this way?
We came up with the idea that this might be
part of the selection process that enables us to keep things that are
important to us and not clog up our brain like Mr. S in Funes, the
Memorias with things that don't happen. It's a way of allowing
a period of time for selection.
So you have an experience, and a decision has
to be made. Is this memory to be kept or not?
Well, we ask what is it that ordinarily would
act in the body that does the same things that drugs do? Well, what
happens when you get excited? You release stress hormones to
yourself. We all do that.
When you are aroused, when you are insulted,
when you're frightened, you release adrenalin into the blood stream
from the middle part of the adrenal gland, and you release cortisol
from the outer part of the adrenal gland. They go into the blood
stream. Both of these stress hormones are released.
So we ask the question then: do the stress
hormones do the same things as the drugs? And the short answer is,
yes, they do exactly the same thing, and they work exactly in the same
places in the brain, and they use the same mechanisms that I describe
for the other drugs that work on GABA systems and noradrenurgic
systems, and so on.
So here's a built in system that does the
job, and our conclusion is that what happens with this release is that
a correlation is then created between the significance of an event and
the subsequent remembrance of the event, and I'll come back to that
a little bit later.
Finally, there's a caveat in all of this
research, which is very important to think about whether it's drug
manipulation or whether it's genetic manipulation, and that is if
there is simply a tradeoff between a drug and additional training. We
have found nothing that a drug can do that additional training
won't do.
So it's not as though the drugs turn the
animals into super animals. It just means that they get there a little
faster. That is, it gives them a little edge in how they get to that
point. That's very important to think about because if you're
thinking about outcome, then there's lots of ways to get that
outcome. You don't have to give a drug to get the outcome.
If you have a child that's not learning
well, you don't need to give it a drug. Give it more training to
get to the same outcome. Now, if you want to use a drug as an aid to
get to that outcome, then that's a decision that you have to make,
but it's not going to get you someplace that you otherwise
wouldn't get.
For example, Mr. S could do all of these
marvelous feats of memorizing. Well, we know perfectly ordinary people
who have been trained to memorize a telephone book. You can do that.
I mean if you want to spend your time learning a telephone book, you
can do that. I wouldn't particularly advise that unless you had
some special reason for doing so.
All right. Let me turn now more specifically
for a moment to the effects of drugs used in the treatment of memory
disorders, and here we have a sad story.
Despite many millions and millions and millions
of dollars that have been spent by pharmaceutical companies and biotech
companies, and despite a lot of academic research, we only have one
class of drugs that is useful in treating Alzheimer's disease.
It's all the same class. They're all acetylcholinesterase
inhibitors, which means that they inhibit the enzyme that destroys
acetylcholine when it's released. If you inhibit that enzyme, then
this neurotransmitter, neuromodulator is around at the synapse for a
longer period of time.
And the drug such as Tacrine, Aricept, Exelon,
and so on, they're all "me, too" drugs. They're all
acetylcholinesterase inhibitors, and the further development is to try
to get rid of the gastric distress, all of the cholinergic side effects
that one would not want to have, and they are more or less effective in
doing that, but they are not horrendously effective drugs.
As a matter of fact, they're modestly
effective. The underlying problem is that Alzheimer's disease is a
progressive disease. Subjects are going to get worse and worse and
worse no matter what you do, and all you can do is squeeze a little bit
more effectiveness out of a patient for some period of time. It is no
cure.
And -- and this is a tough one -- no new or
novel drugs have been produced. So there isn't any drug out there
which is a novel drug, which has been found to be effective, and there
have been a lot of them that were this close to being effective and
didn't make it all the way through for one reason or another.
There are lots of them that have been developed
by pharmaceutical companies that are very effective in animal models,
and then they drop out along the way because of side effects. I'll
just give you one odd ball side effect. There was a company that I was
consulting with that had a very powerful memory enhancing drug in
laboratory animals, which means they could learn much faster, not ever
better, but much faster, and it was yanked out because in Phase 1 it
caused nosebleeds in humans. So it was kicked out because of that, and
others have liver damage and they have other things.
They just haven't made it through for
whatever variety of reasons. And I was wrong because a dozen or so
years ago because so much money was being put into it, I bet that
we'd have three or four by this time working on different classes,
that are different classes of drugs working on different systems, but
they don't exist.
What's really needed when you look at it
carefully in disorders such as Alzheimer's disease is not the
palliative types of drugs we're talking about that squeeze a little
bit more out of a deteriorating brain, but we need drugs that will or
some treatments which will prevent the disorder from occurring in the
first place or restoring cellular function through some other means if
that's possible to do so.
And there is an awful lot of effort going on at
the present time, and now I switched my bet, and my bet is that these
are going to pay off. Let's say, in the next ten to 15 years
we'll have some treatments which might -- particularly because so
much more is known about the etiology of Alzheimer's disease that
it's a good bet that something will happen in that area.
All right. Now, let me say a few words about
blocking memory formation. Can we block the formation of memory? The
answer is, yes, we can do that.
I already mentioned that electroconvulsive
shock will do that. That's been known since 1949 approximately,
and it's known both for humans and animals that if you give such a
treatment, there will be a selective forgetting of things that have
just been learned.
But there are also a lot of drugs that are in
common use that are antagonists of memory that impair or block memory,
and I'll mention some of them. Anti-cholinergic drugs will do
that, drugs like atropine and scopolamine will prevent memory
formation. There's not much danger of that happening because
these drugs are not used in high doses ordinarily, and they're not
anything that's subject to abuse, by the way. These drugs have
such unpleasant side effects that you wouldn't find many people
abusing them.
But there are others that are abused.
Benzodiazepines are memory impairing drugs, drugs like Valium, Halcyon,
clonazopam. All of these drugs induce anterograde amnesia, in both
humans and in animals, if these drugs are taken in high doses.
Performance can be reasonably normal without registering the
information acquired while under the drug. This is anterograde
amnesia.
And these drugs certainly will weaken the
formation of memory, and in some cases they will have very powerful
effects, and these are drugs that are commonly taken by many of us.
They were anti-anxiety drugs originally, but we apparently have lots
of anxiety because they are sold in vast amounts throughout the world,
much vaster, I think, than the extent of anxiety.
So benzodiazepines are there, and interestingly
they work in the same place in the brain that I talked about. They
induced their amnesia by acting specifically in the basolateral
amygdala. So there's something about that region of the brain
that's integrating an awful lot of neuromodulatory influences
coming in, including those for the benzodiazepines.
In the last category are the beta blockers,
which are commonly used for the treatment of heart disease, and
I'll say a little bit more about those.
This work came out of the work in my laboratory
with laboratory animals in which we found that a common effect of many
drugs that enhance memory had to do with the activation of the
noradrenergic system within the brain and then this particular region
of the brain and some other regions as well.
So it looked as though with that information
and the information that we had from the stress hormones that it might
be that ordinary emotionally aroused memory, the memory of emotionally
arousing experiences might involve the systems in humans.
So Larry Cahill, a colleague of mine in the
laboratory, set out to do this. We did the following study, which is
now well known in the literature.
He told human subjects a story about a boy, and
it had two versions. One is an emotionally arousing story, and the
other is a boring story. And then he measured the memory in a surprise
memory test three weeks later, and the subjects selectively remembered
better the information presented to them during the exciting part of
the story.
So let me run through it for you. A boy and a
mother leave home and they cross the street and there's a slide.
There are 12 slide that are shown. Cross the street. They see a
damaged -- I'm giving you the boring story -- they see a damaged
automobile. They visit father who works in the hospital. They're
having disaster prepared in the demonstration that day.
They see people with make-up on to make them
look like they've been injured. The mother makes a telephone call
and goes to the bus and goes home, and that's the story.
And you can divide it into three parts. Early
stages, leaving home, in the hospital, and then the denouement at the
end.
On the surprise memory test three weeks later,
the subjects remembered all three parts equally well.
Now, other subjects, exactly like those, were
told a different story, same 12 slides, and the test is on what's
in the slide. Told the same story.
The boy and a mother leave home. They cross
the street. The boy is hit by the car. He's seriously injured.
They rush him to the hospital.
Surgeons work frantically to save his life and
reattach his severed legs. A distraught mother makes a telephone call,
goes to the bus and goes home.
So here it is. Same pictures, and then the
surprise memory test is: tell us what you saw in the picture.
Don't tell us about the story. What was in the pictures?
And there is a significant increase in the
information remembered in the pictures in this subjects that had the
exciting story told.
So then Larry and I did the same experiment,
except we gave the subjects a beta blocker, Propranolol or Endurol, in
clinically used dose, in a clinically used dose, and told them the
story, and then tested them three weeks later, and those subjects were
-- their memory was just like that of subjects that had received the
boring story.
So here's a blocking of emotionally
influenced memory by Propranolol. Now, this turns out to be important,
we think because it has some implications for the etiology of post
traumatic stress disorder, and as you may know, about 25 percent of the
Vietnam veterans had or have post traumatic stress disorder, and any
time there is crisis, traumatic event, there can be a significant
amount of this disorder, which in many cases will never go away.
In some cases it will go away in a few months,
and what Roger Pitman did was to get hold of human subjects that had
been traumatized in an accident or in some way and put them on beta
blockers as quickly as possible afterwards and maintained them on for
several weeks and then looked to see symptoms of PTSD several months
down the line.
And a first study that was just published
showed that there is a significant decrease in the expression of PTSD
several months down the line, and subjects were put on the beta
blockers.
Well, what is the logic of this? After all,
the exciting event is over.
The logic is based on the evidence from studies
of post traumatic patients, that the events will flash into the mind
after they're over the next day and the day afterward, and you
consider each one of these as a rehearsal.
So every time they relive the experience of
being mugged or being raped or being almost killed in a car or
whatever, every time that comes up again, there's the same
emotional reaction again. It's like a rehearsal with the autonomic
concomitance of this, and the effect of the propranolol is to allow
this inadvertent rehearsal, but without the stress hormone consequences
of that, which would lead to a strengthening of the memory.
There's another study in press that shows
the same results. So there now will soon be two studies showing the
effects on PTSD. Whether this will hold up in the long run we
don't know. This is very early in this research.
Now, let me bring up very quickly some issues.
You asked me to, some issues that might be worth discussing, and one is
the blocking memory. I'll start with that because that's where
we just finished discussing, and there is some concern that it might be
a bad thing to reduce the strength of memory for people who have had a
traumatic event for lots of reasons.
Maybe we need to remember trauma in order to
deal with life or maybe we need to remember the trauma in order to
testify in court, and so on.
So one could make an argument that it is
certainly a judgment to be made as to whether if this really does work,
as it appears to, but we're not sure at this point; if it really
does work, then one would have to make a judgment. Is it better to
reduce the probability of development of PTSD and forego a strong
memory, or is it better to save strong memories, complete with the
suffering, and forego the opportunity to decrease the suffering?
That's a judgment call that each individual
would have to make if what I have told you turns out to be validated
and substantiated.
Here's another one that's of deep
concern to me, and this is, by the way -- we've had several
conferences on this topic, including one at the Ciba Foundation in
London a few years ago, and so we've discussed these issues many
times in small conferences.
This one concerns me. Arresting
neurodegeneration, I said that there were likely to be such drugs.
I'm worried about that because I could anticipate a situation in
which Alzheimer's disease was identified, let's say, because a
person is becoming demented. Now there's a drug which will prevent
any further deterioration, and now you have an arrested dementia, which
means that people will be in this arrested state for a longer period of
time.
It is not necessarily the case that you would
want to stop deterioration if the deterioration is far along. Once,
again, that would be a judgment call.
The next one I touched on, drugs for children.
If we go down that slippery slope from Alzheimer's disease to age
related declines in memory to drugs for normal people who would like to
have an edge, well, children can be normal people who would like to
have the edge. They would be on that slope, and so the question would,
in the subjunctive, or will, if things have a certain way, come up;
should drugs be given to children as an ancillary treatment for
learning? Why? Which children? Is this going to be another economic
divide? The rich kids get the pill in the lunch box and the poor kids
don't, if it's readily available.
I mean, I can certainly foresee that
happening. I can't predict that it would happen, but I can foresee
that happening. And is this yet another cost that we're going to
have to bear in society in treating the walking well?
We already spent a lot of money on treating the
walking well. Here's yet another example of it.
And finally, the worst one of this is the
designer baby and what I call the Time magazine issue. Time magazine,
based on this study that was published in a very reputable journal took
unfortunately a word that was used in the paper, both in the abstract
and in the introduction of the paper, "intelligence."
That PET study did not study intelligence.
That study asked does a mouse freeze when you put it in a place where
it had received a shock. Does a mouse swim more rapidly to a platform
where it could escape from cold water?
The genetic manipulation produced mice that
both of those did better than their controls. That's what they
did.
Now, there's nothing in there that 100
other people haven't already done with drugs. Those are the same
studies that have been done literally hundreds of times with drugs,
enhancing memory of this kind. So there's nothing conceptually
new.
What's new is the permanence of it and the
use of molecular genetics to produce it, which leads people to think,
and Time magazine certainly thought that and the author of the paper
implicitly suggested that by using the word "intelligence"
rather than "memory" or "performance," that it
might be possible with right consultation of the right people to have
designer babies in which you insert particular genes which are
guaranteed to make them learn better.
Well, there's no guarantee, but my guess is
that we would have, if they worked, we'd have more Mr. Ses and more
Mr. Funes de Memoriases and not necessarily more thoughtful,
intelligent human beings that will help to make this place a better
world.
Thank you.
CHAIRMAN KASS: Thank you very much.
We should just open the floor for discussion.
Mike Gazzaniga, please.
DR. GAZZANIGA:: Thanks, Jim. That's
terrific.
It might be helpful though for us to have you
distinguish between memory as sort of a unitary event and memory as you
and I know it to be, which is this complex system of information and
coding, retrieval and all of the rest.
The reason I say that is that one of the
benchmark observations in the clinical and neuropsychology is that the
memory quotient score correlates perfectly with the IQ score. And so
when we have these enhancing devices that allow for, quote, increased
memory, probably what we mean by that is increased sort of lexical
entries or something. It isn't enhancing the entire memory system
that allows the intelligent encoding and retrieval of all that
information for use.
And if that pill came along there might well be
an impact, it would seem to me, on these matters. What do you think?
DR. MCGAUGH: Well, starting way back when I
first began working on the drug enhancement, I tried to ask the
question are there limits to the kind of information that, let's
say, post training drug injections will influence. And the answer so
far is no. That is, I found memory enhancement with post training
administration of a variety of drugs in every task that I could think
of that would tap different kinds of information that the animals were
acquiring.
So it appeared to be general over a very broad
range. Now, we're going to hear more about different forms of
memory in the human this afternoon, but as far as different kinds of
things that animals are capable of being taught, I haven't found
any constraint on that, nor has anyone else.
Now, with respect to the memory and the IQ,
however, wouldn't you agree that if the memory test was a perfect
predictor, then you wouldn't need the IQ test, and the IQ test
covers things besides just the memory subtest, correct?
DR. GAZZANIGA:: Oh, yes, yes. The fact is
though that if you take a look of somebody with an IQ of 100 versus an
IQ of 125, the memory subtest goes right up with it.
DR. MCGAUGH: Sure, sure, and it would have to
because that's the way it was built.
DR. GAZZANIGA:: Well, no, in separate, totally
different, independent memory tests, too. But anyway, you know my
point.
But one final point. Beta blockers and
Baghdad. So let's say you're going to send troops into
harm's way. Is in some sense modern neuropharmacology suggesting
in order to prevent post traumatic syndrome you ought to give them a
beta blocker before they go in for their dirty work?
DR. MCGAUGH: Well, first let's assume that
what has been found will be replicated. Let's make that case. I
don't want to make that too strongly because this is an early stage
in the human application.
But once again, that's your tradeoff
question, isn't it. Let's suppose they really were to prevent
or to attenuate the development of post traumatic stress syndrome, and
actually the number from Vietnam, I think was 29 percent of the
veterans of the Vietnam War had post traumatic stress syndrome, from
which many never recovered, and then they filled up the veterans
hospitals. That's just a fact of life.
Would it be worth using pharmacology to prevent
that from happening, if it didn't do anything which would harm the
person? That's the judgment to be made. Somebody would have to
make that.
DR. GAZZANIGA:: That's right.
DR. MCGAUGH: Now, stimulants have been given
to soldiers for years to make them implicitly, and I think explicitly
in some cases, to make them better soldiers. Nicotine is a memory
enhancing compound in laboratory animals. Post training injections of
nicotine enhance memory. It just does. It's been known for many
years.
One doesn't do those studies in humans
because of the taint from the tobacco industry so that one just
wouldn't do that research. You don't want to be tagged as
somebody who's going to increase tobacco sales, but my guess is
it's probably is memory enhancing in humans as well, and caffeine
as well.
Soldiers are routinely given cigarettes, and
that came in with their K rations. Amphetamines were used by the
Germans, given all the time to their soldiers.
So the use of pharmacological enhancement of
human performance is not new to the military. So the question is if
you think that they're going to survive and they have a quarter
percent, a 25 percent chance of being debilitated even if they win,
would you want to do something to prevent that from happening?
That's a judgment that would have to be made.
CHAIRMAN KASS: Gil and then Dan.
PROF. MEILAENDER: I don't know I even know
enough to know how to ask my questions here, but I have two sorts of
questions. One is -- and this is really a naive layman's question
-- but in some of the things you talked about with respect to --
actually it was particularly with respect to sort of blocking memory
formation, which it seemed to involve controlling various kinds of
emotional responses that one might have in various ways.
In what sense is that -- in what sense were you
doing something that specifically touches memory when you do that?
I mean, I don't know. As I say, this may
just be too naive, but is it really memory that one's dealing with
at that point? That's my one question.
Let me just ask my other and you can do what
you want with both of them.
Is it conceivable just in terms of the
mechanisms one's working on that one could go to work on
Alzheimer's, on trying to find ways to stop that kind of
degeneration, that would not also be applicable to, you know, possible
memory enhancement in school children, say, or something like that?
Are these separable categories?
So those are my two questions.
DR. MCGAUGH: Well, those are both very good
questions, but I do think they are completely separable from my
perspective. Let me take the first one.
The answer is no. We're not only affecting
memory. The question is are we affecting memory, and the answer to
that is yes. We can show that it's not due to some other side
effect of it.
We are affecting memory, but we're also
affecting -- I mean, after all, these beta blockers are going to affect
the action of the heart. I mean, that's what -- think of all the
things that adrenalin are required for. They're required for
releasing glucose from the liver and so on.
So that when we give a beta blocker, lots of
systems are going to be affected. The body is going to be changed in
lots of different ways, but we've been able to sort out with our
experiments the question is it specifically, no matter what else
it's doing, is it working on memory, and the answer is, yes,
it's working on memory while it's doing all of these other
things.
Does that answer that part of it?
All right. The second one is that I think that
they're really quite different questions. Let's take the
Alzheimer's disease, and let's assume for the moment that the
cause of it is the anatomical sequelae that lead to these plaques and
tangles in the brain. Let's just assume that for a moment, and
that's still a little contentious in the field.
The kinds of drugs that one would use for that
would be the ones that would interfere with the cellular processes that
lead to that kind of neuronal damage, and they may have no other
effects. They may have no other effects at all. They just may prevent
that sequelae from taking place.
Whereas the drugs that are currently given for
Alzheimer's disease, the acetylcholinesterase inhibitors, make
better use of a declining brain system that uses acetylcholine as part
of its communication mechanism, makes better use of that, but it
doesn't do anything that we know of to stop the degenerative process.
So the degeneration is continuing, and it's
sort of like trying to squeeze a little bit more lemon juice out of the
lemon juice that's been squeezed. You can always find a little bit
more.
It's like the economists who say that we
are never going to run out of oil, and their reason is because there
will always be some oil. Now, we'll never run out of coal because
there will always be some coal.
Well, there will always be some acetylcholine.
Can you make it work better with a declining brain?
But the drugs that are used to make the
acetylcholine work better or whatever neurotransmitter may do nothing
at all to deal with the underlying cause of the disease, whatever that
may be.
So I see them as going in different
mechanisms. To put it in another way, I don't think that
there's any danger that normal human beings will run out and buy
Exelon or Cylert or one of the other Alzheimer's disease to try to
make them a better sales manager. That's not going to happen, and
those drugs are not going to be given to children. I mean, nobody in
their even quasi right mind would think of doing that, nor if there
were drugs that would prevent neurodegeneration would a normal person
take them unless they thought they were at risk for the degeneration,
which brings up another question.
If we were able to make those predictions,
would there be drugs to deal with that?
CHAIRMAN KASS: Dan Foster.
DR. FOSTER: Just a comment and then my
question.
Of course, the Alzheimer syndrome or disease is sad, but the sadness and pity is not so much for the patient, who doesn't remember anything, but for the caregivers. The caregivers are continually stressed and presumably releasing epinephrine and norepinephrine all the time. Maybe that is what keeps them going. It is not a bad disease for the patient when fully developed because memory is gone, but one wants to prevent it if at all possible.
Now, you just made a statement which I was
going to follow up. You said that even if you knew that there was a
drug that was going to be preventive, let's say, of the
Alzheimer's dementia, as an example, would I take it or would you
take it, and the answer might be if that were solely an effect of the
drug that you would not. You don't have a family history of
Alzheimer and so forth.
But one of the things that there's an
increasing interest in in medicine, I believe, is where a drug which is
used for one reason has powerful effects in others. For example,
probably the cheapest and safest chemopreventive drug that you can take
with the rare exception that you're going to bleed is an aspirin.
It's going to cut colon cancer 50 percent, probably going to
diminish, slow down Alzheimer dementia. You know, it's got a
variety of things that are additional.
Now, one of the drugs, and I'd be
interested in your comments, that's been very much of interest
lately in terms of chemoprevention of the Alzheimer dementia are the
statins, the drugs that are used to lower blood cholesterol. I mean, at
least in terms of retrospective studies, if you've ever taken them,
you may be as much as 70 percent in large populations. The veterans
population study is the one I know best.
It also is very helpful, it turns out in odd
ways of preventing osteopenia in women, bone loss, and of course, the
people who really work on cholesterol, we have two guys that are Nobel
Laureates for cholesterol at our place. They believe that, you know,
to take a target of a cholesterol of 100, let's say, even if
you've got diabetes and so forth. The NIH says 130 LDL, the bad
cholesterol.
They clearly show a linear progression back to
the 60s and so forth. In other words, if your LDL is 100, that's
great, but if it's 60, it's better if you want to prevent
atherosclerosis and so forth.
So the question would be: would you have the
same anxiety about a single prevention for something like dementia if
at the same time you could handle -- and this is before they get a
disease. So you're in prevention and not treatment. Would that
change your thought about the approach to this fairly common problem?
I guess I don't know whether I'm saying
this very well, but if you get several effects from a drug that's
relatively cheap and seems to be -- and I don't want to confirm
that it's really stopped. It's not due to the cholesterol.
That's clear. It's not due to the cholesterol even though E4
-- I mean apolipoprotein, E4, E4 is one of the genetic risks for early
Alzheimer's and so forth, and that also gives you lipid disease, as
well.
But if you could do that, would you have the
same concern about it?
DR. MCGAUGH: Well, let me shift diseases to
Huntington's.
DR. FOSTER: Okay.
DR. MCGAUGH: There it's clear. If there
was neuroprotection for Huntington's disease or for
multiplesclerosis, I don't think there would be any question at all
because they're well understood or pretty well understood.
DR. FOSTER: Sure.
DR. MCGAUGH: But at the present time, in the
case of Alzheimer's disease, it's etiology is not well
understood even though we know that there are genetic predictors of it,
and so it's not clear what one should do.
You know, take ten times the amount of Vitamin
E and take more aspirin and all the rest, statins, whatever. If I had
three of the genetic markers for Alzheimer's disease, I probably
would look for all of the above in order to keep that from happening,
just as I would if I were destined to have Huntington's disease do
everything I could to find out how I could be neuroprotected.
Now, let's think about it more broadly,
about the general public where they're not going to have genetic
information about this. Already people are taking Vitamin E. People
are taking aspirin, I mean, much more than they used to. So there are
people who are trying to be neuroprotective just to cover the odds.
Now, let's suppose it costs $100 a day to
be neuroprotected. What do you think would happen to the Vitamin E
sales and the aspirin sales and so on? They'd go down to the floor
because people would say getting that new car today is more important
than what happens to me when I'm 70 years old or 80 or whatever.
So there are huge economic consequences that
have to be factored into this, just as there are economic factors for
dealing with AIDS, for example, or the cost of the medication
influences how well it's point to be accepted and used in different
countries and so on.
So the same thing would apply in the United
States. The cost of these things, even if you knew their
effectiveness, would have a big influence.
DR. FOSTER: I was just really trying to get
to the issue that sometimes there are surfaces, and we've heard a
little bit of it today, that if you do anything to alter the natural
development of nature, that is to say if you -- I'm not talking
about acute disease or, you know, a kid who gets zapped by a sniper or
something like that -- but if you alter it, that that is both -- it
should not be done. The playing God syndrome.
And I just want to be sure that your worry
about the issue of the side effects and so forth of dementia did not
imply in some sense that if scientific investigation could give us
prevention against some of these major things and at a reasonable cost,
which also has to be taken that you -- I just wanted to be sure I
understood your philosophy about that, and you've just answered it,
but I wanted to bring that to the floor.
DR. MCGAUGH: And I think in the case of
neuroprotection that that's likely to happen. I mean, that's
the greatest effort that's being made at the present time on
finding neuroprotection, even some thinking that it might be possible
to make the cells behave better and behave the way they're supposed
to after they have started to degenerate.
So not only protection, but recovery are two
targets that are being actively pursued at the present time.
What I was trying to say though is that this is
quite apart from the other reasons for having drug enhancement of
memory, quite separate.
Thank you.
CHAIRMAN KASS: Could I clarify? I was in
the queue. I've also got Janet and Paul.
I would like to clarify just the bottom line on
what is currently available or likely to be available in terms of
interventions both for enhancement and for blockage.
I think I heard you say that notwithstanding
the huge amount of effort, we have nothing really available with
respect to the already existing degenerations of Alzheimer's
disease.
Nevertheless we do have in animal models
various kinds of things that can enhance memory at least as testified,
the performance of certain kinds of tests, but that the attempt to use
these things in human beings have run afoul because of side effects in
most cases.
Let me add one additional fact that you alluded
to at the beginning, but stayed away from. As I understand it, the
main interest in the biotech companies or the others who are pursuing
this is less Alzheimer's disease, but much more the memory
enhancement --
DR. MCGAUGH: Yes.
CHAIRMAN KASS: -- of -- I can't find
the keys.
DR. MCGAUGH: That's where the market is.
CHAIRMAN KASS: That's where the market
is and enhanced probably further by the market of the people who want
their kids to do better on the SATs or as you have it.
With respect to those things, is there likely
to be something -- if you leave aside the treatment of the
degenerations, but talk about possible things that would be coming in
the area of the potentiation of more or less normal memory or this new
age related; is this 20 years, 30 years or --
DR. MCGAUGH: Well, we always think it's
right around the corner because so much money is being spent doing
exactly that.
I did send in a tape [to the Council Staff] of a BBC program that is about ten years old. It's available from somebody here, and in it I was interviewed, and I said
that my belief was that the real target of this drug development was
not for the memory impaired, but it was for the normal because
that's where the market is, but nobody will say that.
I'll be damned if they didn't find the
Director of Marketing of a major pharmaceutical company that they put
right after my statement who said, "Yeah, that's what
we're going after. That's where the market is."
I mean, he just said what I said that nobody
would say in public. I mean just opening.
Well, their compound failed. They put a lot of
money into a compound, and it just didn't work.
Now, let me back up here and say there are
things that work, but they have no interest because there's no
money in them. Paul Gold has shown that glucose enhances memory, not
only in normal people, but in elderly people and in Alzheimer's
patients. You get a little improvement with glucose, but there's
no money to be made in that.
Amphetamine is a very potent memory enhancing
drug, as I mentioned, both in humans and in animals, and it works even
when injected in humans or given to humans after they've learned
something. It strengthens consolidation.
But there's no money to be made in
amphetamine, and besides that, it's a nasty drug, and people get
dependent on it and they get addicted to amphetamines.
So there are things right now that people could
take that will enhance memory, but pharmaceutical companies are not
very interested.
Now, one major company, Abbott Laboratories,
certainly knew about nicotine. So they decided to modify the nicotine
molecule and, once again, the count was millions of dollars to make a
drug that is like nicotine, but for which they could get a patent, and
it didn't work all the way through Phase 3. So that was a big loss
of financial investment.
Now, nicotine probably works, but it's also
addicting. So there are these side things, the things that might do
something for memory that we know of or that companies have tried to
develop. All have some kind of a restriction. They just --
there's no free memory enhancement that isn't going to do
something else.
It's sort of like looking for a
nonaddicting opiate. You remember in the early part of this -- well,
right at the turn of the last century when heroin was introduced by
Bayer. It was called Heroin because it was
heroic. That's why they called it that, as the nonaddicting opiate
for children, and it was in children's cough medicine for probably
20 years.
And after the discovery of the opiate receptor,
there was a huge increase in looking for nonaddicting opiates. If we
could only take that drug which is analgesic and modify it, you know,
pull off a methyl group here, add another group over there; we'll
find an opiate that is nonaddicting.
Well, the less analgesic it is, the less
addicting it is. So memory enhancing compounds, let's say, our own
memory enhancing compounds are adrenalin and cortisol, and they do all
kinds of things. I mean, you wouldn't want to give adrenalin to a
heart patient, for example, but we know that if we give adrenalin to a
rat or a mouse, we can make it learn a lot faster or if we give a drug
that will activate those receptors it will happen.
But there are always going to be these side
effects, and I don't see them disappearing, but that's what the
pharmaceutical companies are looking for. They're looking for the
pure memory enhancing drug that doesn't do these other nasty
things.
And is that around the corner? Maybe it will
be in the paper tomorrow. I don't know.
CHAIRMAN KASS: On the parallel side now on
the memory blocking, the same answer?
DR. MCGAUGH: Well, that can be done right
now. I don't think --
CHAIRMAN KASS: But also with drugs that
have systemic effects, right?
DR. MCGAUGH: Yes.
CHAIRMAN KASS: I mean blockers are also not
innocent --
DR. MCGAUGH: You pay for it, but let's put
the emphasis. You want to reduce the anxiety, and so you take a
benzodiazepine. Well, the sufferance there is that you are also likely
to induce anterograde amnesia. It was discovered after it was approved
for anxiolytic effect.
So now you take, let's say, benzodiazepine
to produce anterograde amnesia. The payoff is you're going to be
less anxious. I mean, you don't have to remember.
(Laughter.)
DR. MCGAUGH: I mean, the way this -- many of
you here probably know that it was discovered by psychiatrists and
psychologists after the benzodiazepines were introduced. People would
come back after having been on a trip, and they were very anxious about
going, and they would come back in the report, "I don't remember
what happened on this trip," and so that's what stimulated the
research on it.
And then it was discovered in animal models as
well as in humans it's a very strong anterograde amnesia, which of
course is dose dependent. So that you can certainly take a
benzodiazepine and get an anxiolytic effect without having severe
anterograde amnesia, but you can also take a high dose, and you think
you're okay, and then have anterograde amnesia.
CHAIRMAN KASS: Thank you.
I have Janet and then Paul.
DR. ROWLEY: Well, I want to follow up. My
question is in a sense related to what you just said because many, many
individuals are taking beta blockers, particularly older individuals,
and the question then is -- and I don't even know what doses are
generally used for beta blockers, but what is the relationship of the
dose that would be used clinically and that which causes retrograde
amnesia?
DR. MCGAUGH: The clinically used doses,
let's say, propranolol, 20 milligrams, is not going to induce any
retrograde amnesia. What it does in a study so far is simply prevent
the added memory that is induced by emotional arousal. So we have not
found in human subjects any memory impairment in these doses, but we
have found complete blockage of the effect of this emotional arousal on
subsequent memory. So in that sense I don't think there's any
danger.
This, by the way, independently in the same
year, an experiment was done in a very different way by Rob Jenson and
his colleagues in southern Illinois, but in place of emotional arousal
what they -- these were now with elderly people who are on beta
blockers or on other drugs for controlling heart disease, and they
taught them standard psychological verbal material.
And then after that they had them squeeze
what's called the hand dynamometer in which you squeeze it, and you
can see how much pressure is induced by squeezing it, and this is well
known to release catecholamines, including adrenalin. You do this.
And they found that the memory, squeezing this
thing, enhanced memory in the elderly subjects who were on other drugs
for treatment of heart disease, but did not enhance memory in subjects
who were taking beta blockers.
In normal subjects now, Larry Cahill has used
another technique which is standard procedure in cardiology studies,
and that is just thrusting one's hand into a bucket of ice water.
I know that doesn't sound very sophisticated, but it will certainly
get the heart going, and it releases adrenalin massively right at that
time, and Larry Cahill has now found that memory for ordinary verbal
material is significantly enhanced. Subjects learn something and put
their hand in this tub of ice water.
So it doesn't have to be an emotionally
arousing response, but we think in our nature that's probably what
ordinarily controls it because we don't go around putting our hands
in buckets of ice water to release catacholamines. We get
catacholamines release when people say, "You're dumb,
you're ugly, you're stupid. You did a good job. You won the
lottery. You got a Nobel Prize. You're going to be executed.
Things like that tend to get epinephrine or adrenalin released.
CHAIRMAN KASS: Paul McHugh.
DR. MCHUGH: Well, we could talk all afternoon
after that wonderful talk, Dr. McGaugh. I had two comments and then
one question.
The first comment was in your deep wisdom you
reinforced what my father told me when I first went off and recognized
that there were a lot of people in schools that were smarter than I
was. He said, "Don't worry. You can out work them."
DR. MCGAUGH: That's right.
DR. MCHUGH: And it's the truth.
You're backing that up.
DR. MCGAUGH: That's a missed point. My
neighbor, who wanted the drug for her child, I don't think had
asked the child to work a little harder. I think she was just saying
she's not doing well. Let's make up for that..
DR. MCHUGH: That's right. That was my
father's idea. Just work harder. You can do it.
DR. MCGAUGH: Well, he was right.
DR. MCHUGH: He was right in many things.
The other thing was, of course, in relationship
to treatments for the conditions, the deteriorating conditions like
Huntington's disease or Alzheimer's disease and the like, which
are devastating when they occur and which have their beginnings before,
if we understood not just the risk factors, but the mechanisms, it
probably would be that everybody who had those mechanisms in play would
probably take the treatments even no matter what they cost.
The real problem now is not for
Huntington's, but something like Alzheimer's disease. We only
know that there are risk factors that are tied to it.
DR. MCGAUGH: Think of all the people who are
taking Vitamin E and aspirin at the present time.
DR. MCHUGH: Oh, I'm well aware of that.
Aren't you?
DR. MCGAUGH: So that there is at least among
people who pay attention to these things -- we try to reduce our risk.
I mean, if we knew more about it, we could do more selective things to
reduce that risk.
DR. MCHUGH: That's right. So the
mechanisms would help us to know more things.
DR. MCGAUGH: Absolutely.
DR. MCHUGH: I had one real question I wanted
because it was very interesting what you were saying about the effects
of beta blockers on consolidation of memory. But as you know, lots of
people use beta blockers who are performers, particularly artistic
performers.
DR. MCGAUGH: Absolutely.
DR. MCHUGH: Stringed instrument players and
the like, and they discovered in their performance that they can do
much better if their hands aren't trembling and the like.
And I wondered about you making the point that
beta blockers inhibit consolidation. Do they have any effect on
retrieval, on memory retrieval, which would both affect the piano
player who was following the Schuman approach of doing it by memory,
but also might affect us otherwise negatively?
DR. MCGAUGH: I had a whole section on that
that I didn't include because of lack of time, but may I just say
something about that?
First of all, it is the case that beta blockers
are the drug of choice for stage fright, speech fright, and also for
controlling trembling and things of that kind.
But in the case of the violin player who is up
there performing, that is so over rehearsed that the memory is not
going to be affected for that. That's on automatic drive at that
point. So that's not an issue.
But these same hormones that I told you enhance
memory consolidation on other circumstances, on other conditions, will
impair the retrieval of memory, and we have studied that fairly
carefully using cortisol in the human or corticosterone in the rat, and
the experiments are as follows, and we try to make them as parallel as
we could for the two.
The subjects learned something on one day to
some criterion, and then the next day they are tested on it, and then
we check to make sure it's not interfering with their performance
or anything of that kind.
And it turns out that a glucocorticoid, a
cortisol, has an impairing effect for about one hour after it is either
released or after it is injected, and we know that it is the cortisol
because if we give a drug that blocks the release of cortisol, then
there is no memory impairing effect of the treatment or in a rats it
can be a shock, an electric shock to its feet.
And this is an effect that lasts for about an
hour, an impaired retrieval selectively induced by that. So we think
that all of the things that we have learned from our undergraduates
over the year about how they knew the information very well and they
just panicked on a test and couldn't remember it. We now think
that at least some of that may have been honest, that there was an over
excitement and there was a temporary depression of selectivity of
memory retrieval lasting for about an hour, and this we found both in
rats and in human subjects.
And we are now doing experiments at the moment
to find out the involvement of beta receptors, beta adrenergic receptors
in that mechanism. We had experiments in place right now doing that.
So I can't answer the question.
But in everything else I said it had to do with
getting information in and getting it stored. It all had to do with
making a memory, and now we're shifting it. That's why I left
it out of my main talk here. We're shifting to something else and
saying are there things that affect our ability to utilize information
that we have, and stress hormones do affect that.
DR. FOSTER: Just one quick question. Does
epi/norepi also do the same thing, that one hour impairment of
retrieval?
DR. MCGAUGH: No, we haven't examined that
yet.
DR. FOSTER: Because oftentimes they're
almost always up together.
DR. MCGAUGH: Yes.
DR. FOSTER: And you know that cortisol has a
permissive effect on that.
DR. MCGAUGH: And we're looking
specifically once again in the basolateral nucleus of the amygdala
because that was critical for our consolidation effect, and I can say
our first experiments indicate that activation of beta adrenergic
receptors within this same region of the brain plays a role in this
memory retrieval effect that I just described.
But that's not published. That's the
only thing I've told you that's not published yet.
CHAIRMAN KASS: Frank Fukuyama.
PROF. FUKUYAMA: Are you born with a certain
natural memory capacity?
And when you talk about memory enhancement,
you're talking about the ability to move information in and out of
that fixed capacity or can the capacity itself be affected by
environmental factors?
DR. MCGAUGH: You're probably going to hear
a lot of that, something about that from Dan Schacter, but let me just
touch it briefly.
The answer is no because there are lots of ways
in which as we go through life we improve our memory capacities.
Let's say in areas that are your hobbies or things that you deal
with an awful lot, you just get better and better because you have more
information that's related to other information, and it's not
stored as an isolated packet, but it becomes integrated.
So that I have two hobbies. I play jazz
clarinet and saxophone, and I do woodworking. So I have lots of things
that are very easy for me to learn because they are related to that,
but if somebody starts talking to me about their hobby which is
something I don't know anything about, I would have trouble
remembering it just because I don't have the contextual connections
formed to do that.
Now, also, if you take very specific domains,
memory can be trained. So that if you want to be able to memorize
digits, let's say for some reason you have a zip code which is
2,000 numbers long. You could do that. You could do that. And you
would be better then for a while in memorizing of digits. So that this
specific domain can actually be improved.
So you're not born with a capacity. What
we're born with is without any extra effort to get seven digits
plus or minus one, and that's one reason we had seven digit
telephone numbers and the area code was kept separate, because you can
remember seven digits at least long enough to write them down.
That's probably the native thing that most
people have, but you can have a digit span of 15 if you'd like to
have it for some reason. You can get special training to do that.
CHAIRMAN KASS: Bill and then --
DR. MCGAUGH: And, Dan, I hope that you'll
elaborate on that because that's more in your domain.
Excuse me.
CHAIRMAN KASS: Bill.
DR. HURLBUT: I want to ask you about something
you touched on briefly, the engagement of possible memory enhancing
agents in education. If you say that, as you more or less said or at
least implied strongly, that memories related to life significant
issues because the body itself produces through at least the adrenal
gland, and probably in many other ways, agents that modulate memory
retention. It then implies from that that if you enhance one component
of that system artificially that you might be disrupting the
psychophysical unity of your identity or your normal life processes.
In other words, you'd be forcing on your
system memory of things that your other normal process wasn't
encoding.
DR. MCGAUGH: Absolutely.
DR. HURLBUT: So in other words, we have a
therapeutic model of memory enhancement where we think there's a
deficit. That makes sense, and just as it's easier to fix a broken
link in a chain than it is to strengthen the whole chain, we can
comprehend how that might work where there was a problem.
But would you really improve life overall is a
large question I hear going on in the background of what you said. In
fact, you started at the beginning in saying if memory enhancement were
a simple good, then evolution probably would have done it. Didn't
you say something like that?
DR. MCGAUGH: Somebody.
DR. HURLBUT: Okay. Here's my question.
The work that Mike Merzenich is doing with enhancing Ó- going back to
basic neural processing, things like dyslexia and reworking very
fundamental things in the way a person takes information where they
have a learning deficit or, for that matter, any strategy of
approaching life tasks.
He suggests that maybe you could combine what
he's doing now with computers with drug enhancement to reinforce or
make more powerful that basic neural revision. You're familiar
with --
DR. MCGAUGH: Sure.
DR. HURLBUT: Do you think this is something
that is coming? Is it realistic? Would it be profoundly disruptive?
And what do you see as the ethical questions
associated with that?
DR. MCGAUGH: Well, I hope it's not coming
because I think that the ramifications are really very broad.
The reason I hope it's not coming is
because you picked a particular case, but I could pick many others.
Let's just say the school teacher who is teaching the number facts
to the children, and number facts are not very exciting, but you need
to know how to multiply at least 12 times 12 and how to do the
division, and that's not any different than dealing with
dyslexics. You're trying to correct here a disorder.
The disorder is that they don't know the
number facts, and they have to know them or that they have to know the
grammar. And so why not a little chemical aid to do that?
So if you start with something as narrow as
that and say: folks, this is a very special case. We're going to
do this for the dyslexics under this condition because we think we can
give a drug to enhance this particular thing. All right? Then
we'll expand it. What about English literature? You know, how
about the sonnet? You know, memorization of the sonnet is due
tomorrow, or how about language? I have to learn German, as I did in
graduate school in four months in order to pass the exam. Wouldn't
that have been nice?
Well, we did have amphetamine in those days.
So that was helpful. Amphetamine and caffeine, as you know, were not
-- amphetamine was not controlled when I was a graduate student, and it
was commonly taken. Would keep you awake, but probably helped a little
bit.
No, I think that you've given a very
special case, but it's easy to make an argument for a large number
of cases. I don't know how you would constrain it after that. I
mean, that just happens to be his interest in what he's doing, but
other people are interested in other things, and they say, "Fine.
What we need is a little pharmacological help."
And now remember the basic thing I said is that
whether it's hormones, our own pharmacological agents or the ones
that we manipulate, we have never been able to do anything that we
can't do by just more training, never.
Now, in the case of Alzheimer's patient,
that isn't the case. With some subjects, particularly with Exelon,
which appears to be a little bit better than some of the others, they
can get them to do some things that they couldn't otherwise do. So
there's some help for a degenerating brain to make it work a little
better so that it can finally do something that it couldn't do.
That data on that are weak, but that's another case.
So I guess what I was trying to do is present
things here, which were tailor made for this group, and so in this
context I would say this is not immune from my criticism. It falls
into, let's say, my concern. It falls into my bag of concerns
because it is a very short step from there to giving the drug to my
neighbor to give her child because she's not going to tall the
child to work harder, but it's just a little bit easier to do.
It's sort of like taking a valium when
you're anxious rather than to use the anxiety to help cope with the
problem.
DR. HURLBUT: I hear a strong preference, if
not prejudice, for the natural in what you're saying because one
could argue, well, so what if it enhances one thing even at the expense
of the other.
DR. MCGAUGH: No. I'm neutral. I'm
bringing it to your attention. I'm neutral on this.
What I was trying to say is that I don't
think that that special case solves the problem for us. If that works,
then I don't see any reason not to do it for any learning
condition.
I do favor the natural circumstance. I think I
would go back and say how can you become a better teacher to use the
naturally occurring devices that children have rather than to use some
ancillary treatment, which we know we're probably going to have to
do for the deteriorating brain, but that kid has all of the machinery.
The machinery is there. How can you make that machinery work better
would be the first approach that I think should be taken.
DR. HURLBUT: Well, you've convinced me
that I should be scaring my students more. A little more adrenalin
would help them learn better, but really --
DR. MCGAUGH: Let me -- let me -- I don't
think you're entirely wrong in the statement that you just made.
It's nice to be nice to people, but I just had to write something
about my earlier experiences recently, and the two teachers that I
singled out as having the biggest impact on my life were two of the
sternest teachers that I had.
I mean it just didn't dawn on me that until
I've thought about it pretty systematically. These were not
touchy-feely people. These were the most demanding teachers I ever had
in my life. One of them was my band and orchestra instructor whose aim
was to embarrass you in front of everybody else.
And so we knew that at any moment during
rehearsal he would stop it and point at somebody and say, "Play
the next 16 bars. Stand up and play the next 16 bars." At any
moment. Now, that kept our attention. It really did.
So if you want to get learning to take place
and have an impact, I don't think that roughness is necessarily
bad. I mean, it's better if they could do it in a nice way and
say, "Gee, Jim, would you do the next 16 bars? We'd sure love
to hear you do it in a nice way for the group."
You know, that would be helpful, but that's
not the way it was.
CHAIRMAN KASS: Rebecca and then we'll
take a break.
PROF. DRESSER: This is in line with some of
the other comments. I think at one point you said there is no memory
enhancing free lunch or something like that. I mean, the tone of your
presentation seems to me to be a good corrective to the media, kind of
public image about a lot of these prospects, which is there are always
going to be costs, financial costs, adverse effect costs, as well as
your great problem of what if we could arrest neurodegeneration in the
early stages of Alzheimer's disease. Would that be a good thing or
not?
I mean that's a very complicated question
socially. So thank you for the really, I think, balanced point of view
and perspective.
DR. MCGAUGH: Well, let me comment on that. I
do memory enhancement as a living, and that's what I do for a
living. So that's what my research is all about. So I
wouldn't want you to let me get out of here saying that I have
dissed memory enhancement.
But I think there is a role for it, and I think
it has been excessively over-hyped by pharmaceutical companies, biotech
companies, and by the press because it requires the kind of thoughtful
thinking that you people as a group have as your mission in order to
evaluate these things and find out what is the proper place.
I think that there may well be -- just as I
believe some children need Ritalin, all hyperactive children do not
need Ritalin. All right? I think there may be some children who need
memory enhancing drugs because they can't do it. They don't
have the machinery to do it in the same way that the deeply disturbed
hyperactive child does not have the machinery which enables normal
behavior.
So some children's brains will need this,
but once again, I come back to the slippery slope. Which ones do and
which ones don't and under what conditions and so on? And
that's a tough one. That's a tough one.
CHAIRMAN KASS: Let's take a break. the
conversation will continue. Let's take 15 minutes.
(Whereupon, the foregoing matter went off the
record at 3:24 p.m. and went back on the record at 3:44 p.m.)
CHAIRMAN KASS: I'd like to turn this
session over to PROF. Daniel Schacter.
Gentlemen, please.
Professor Schacter, the floor is yours.
DR. SCHACTER: Thank you. Thanks for having me
here today.
CHAIRMAN KASS: Push the button for your
mike.
DR. SCHACTER: Am I on now? Okay, great.
I think a lot of what I'm going to say
today will hopefully amplify some of the points that came up in Jim
McGaugh's interesting presentation.
First, let me just say a few general words
about the perspective that I'm coming from. In the program it
listed my talk as "Remembering and
Forgetting Psychological Aspects," and
that is true, but I substituted a cognitive neuroscience perspective,
which is probably a little bit closer to the general approach that I
take to research, which is one that combines analysis of psychological
aspects of memory with analysis of brain systems underlying those
aspects. It's the kind of approach that Mike Gazzaniga, among
others, has advocated and has, I think, become very influential as a
way of studying memory and many other aspects of cognitive function
recently.
And this interface takes place at a relatively
high level. We're interested in the level of brain systems, how
different regions of the brain interact, how different regions of the
brain together underlie the various manifestations of memory.
So that's the perspective I want to
illustration, although fundamentally I am a psychologist and will focus
more on those aspects.
Second, I want to just pick up on a point that
came up a few times in Jim's talk, which is that memory, and we
refer glibly to memory as if it might be one thing, but as we heard
mentioned a couple of times, it's not. It's much more
complicated than that.
And there are various ways in which we can
divide up memory so that we're clear in our own minds about which
particular kind or form of memory we're talking about.
For example, one way of looking at it is
through the idea that there are fundamentally different memory systems
operating within the brain, and this is an idea that has received a lot
of support in the last 20 years in cognitive neuroscience, and there
are many ways of making these distinctions.
One distinction I think widely accepted would
be between a short term or working memory, the kind of memory
that's capacity limited, as Jim mentioned earlier, holds roughly
seven plus or minus two bits of information, and typically lasts for a
few seconds; the kind of memory that you rely on looking up a phone
number in the phone book and then running to the phone before you lose
that memory.
That sort of memory seems to differ
fundamentally from a longer term memory that is the kind of memory that
Jim focused on. It's the kind of memory that most people are
referring to when they're talking about memory improvement.
That's the kind of memory that we really want to target with drugs
or other approaches.
Other distinctions have mainly been drawn
within the domain of long term memory, and there are many of them
partially overlapping, but just to give an example of what I'm
talking about, one distinction that we have found useful in our work is
between explicit and implicit memory.
So explicit memory is our kind of conscious
recollection of everyday events and facts of our lives, the kind of
thing that we ordinarily think of as memory. When we use the term
"memory," we're talking about our ability to recall our
past, personal episodes and experiences to access general knowledge.
That's all within the realm of explicit memory.
The whole other domain of memory that usually
doesn't come up in these discussions, which we call implicit memory –
others have called nondeclarative memory in opposition to declarative
memory – and this is a type of memory that operates largely outside the
realm of consciousness. It's the kind of memory that might be
involved in acquiring skills, how to ride a bicycle.
And interestingly, and there are many different
manifestations of implicit memory, nondeclarative memory, but
interestingly this type of memory can proceed pretty much independently
of the explicit form.
So one type of patient who people have studied
intensively over the last 20 or 30 years, and I'll talk about a
little bit later in a different context, amnesic patients who have a
devastating inability to acquire new memories, but this seems largely
restricted to new explicit memories. They can learn new skills just
fine and show other manifestations of implicit memory even though they
have no explicit conscious recollection of the experiences that
gave rise to those implicit memories.
So we could do the whole talk just on this
topic, but I just wanted to mention that at the beginning because I
think it's useful to frame one's thinking about what exactly is
it we're trying to improve.
Another way to divide up different aspects of
memory or forms of memory is really the one I'm going to take
today, and that is looking at the various ways in which memory can fail
or various kinds of imperfections in memory.
So when we talk about trying to improve memory
with drugs, what precise aspect of memory is it that we want to
improve? What imperfection in memory is it?
And some of the background readings go into
this, but in a couple of recent articles in a book I published last
year, I've argued that if you look at the wide expanse of
literature on the topic of memory and you ask the question, which to my
surprise few people have really asked, what are the difference ways in
which memory can fail? What are the different kinds of memory
imperfections?
I've proposed that there are seven
fundamental categories of these imperfections, and by analogy to the
seven ancient deadly sins, I've called them the seven sins of
memory.
I'm going to have to apologize if
you're looking at the slides. There is a slight glitch in some of
the Power Point translation from Mac to PC. So I don't ordinarily
use these arcane symbols here on the left in my slides, but somehow
they turn up when you E-mail a Mac Power --
DR. MCGAUGH: The yen.
DR. SCHACTER: Well, maybe that's it.
DR. MCGAUGH: You've used the yen for all
of them.
DR. SCHACTER: Hey, you've given me a new
idea for the next book. That's right. The seven yens.
So there are a few glitches that will appear
from time to time, the result of Mac to PC Power Point Translation.
Well, let's just walk through these
quickly, and then I'm going to focus on a few that I think are
particularly relevant to your concerns. The first three of these
so-called sins are different kinds of forgetting, and it's really
forgetting that we are focused on for the most part in Jim
McGaugh's talk.
So transience I refer to as the decreasing
accessibility of memory over time, the fact that all other things being
equal, memories will tend to fade over time unless reinforced through
rehearsal or other means. This is probably the basic fact of memory,
and I think for most of us when we think of improving memory, we are
really thinking in terms of improving this particular feature of
memory. We want to stop information from fading out of memory.
That's not the only kind of forgetting.
Absent-mindedness refers to lapses of attention that are associated
with forgetting to do things. Here it's not so much a question of
information fading over time as the information either never getting
into the system to begin with, operating on automatic and you put your
keys or glasses down. It's those kinds of everyday episodes that
fall under the rubric of absent-mindedness, or failing to remember to
carry out an action at the time that it needs to be carried out, and
I'll come back to that with some everyday examples in a few
minutes.
Sin number three I call blocking. This refers
to the temporary accessibility of storing information so that
information hasn't faded out of memory. You're paying
attention, but you can't get to the information at the moment you
need it. A slightly different sense of blocking than Jim McGaugh
talked about, and we'll talk about one common manifestation of
this.
The tip of the tongue phenomenon we all know,
and when information is on the tip of our tongue, we can't get at
it, and then it comes to us some time later.
The next three of the sins I think are as
important as the first three, but they all refer to situations in which
memory is present but wrong. It's not forgetting, but rather
memory distortion, which we know is a fascinating and very important
feature of our memories; that when we remember, we don't always
remember accurately.
What I call misattribution occurs when we
remember some aspect of a past event, but we attribute that memory to
the incorrect source. Perhaps we think we really did something when we
only imagined it. We know what that is, but we get the source wrong.
We think we did it. In fact, we only imagined it.
Maybe we hear something from a friend, but we
think we heard it on the radio last week. We misattribute our
knowledge. This can have very important implications that we'll
trace out in a few minutes, sometimes leading to a phenomenon (cut off here
in that unfortunate Mac to PC translation) known as false recognition
that I'll elaborate on.
Suggestibility refers to situations in which
implanted memories arise as a result of leading questions or leading
suggestions, the kind of work associated with Elizabeth Loftus, now a
colleague of Jim's at UC-Irvine, and as we know, this is not only a
theoretically interesting foible of memory, but something that can have
grave consequences in the real world.
We know from the controversies that have
existed over the reality of suggested memories of childhood trauma and
childhood abuse. Paul McHugh has been a voice of reason in that very
emotional debate.
Bias refers to I think an under-appreciated
aspect of memory that we all give lipservice to, but has really only
recently been studied systematically by psychologists, and this refers
to retrospective distortions produced by current knowledge and beliefs,
when what we know, believe and feel in the present skews our
reconstruction of the past.
I won't get into that in much detail today,
but I think it's pervasive in memory. There's some elegant
demonstrations of it. I think it as much as any of these sins
emphasizes the crucial point that memory is not a tape recorder, a
playback, a video recorder, but it's a reconstruction that uses
bits of information from the past and combines that with what we
currently know and believe.
And then the final of the seven sins I call
persistence. This is a little bit different from the other six, and
these refer to unwanted recollections that people can't forget. We
covered this, I think, in Jim's talk under the rubric of PTSD, the
kinds of traumatic experiences that result in repetitive, intrusive
memories that are associated with some of the neurobiology that we
heard about earlier.
So for the purposes of today's talk, what I
want to do is walk through some examples both from the laboratory of
everyday life, primarily of transience, absent-mindedness, and blocking
because when we talk about memory drugs, I think these are the kinds of
things that we're really concerned about, and I also want to talk a
little bit about misattribution because I think there's some
interesting issues there that relate to concerns of a bioethical
nature.
Okay. Let's talk about transience.
Probably the best known experimental finding coming from psychology
that bears on transience goes back 100 years to the German psychologist
Herman Ebbinghaus, and it was Ebbinghaus who for the first time was
able to document quantitatively the fact that memory, all other things
being equal, memory tends to get worse with time, which people of
course know from everyday experience in a casual manner, but what
Ebbinghaus did was to show that the curve of forgetting has a
particular shape.
So he did a sort of unique study. He was his
own subject. He just memorized thousands of nonsense syllables and
would test himself at various times after learning and measure how much
of his earlier learning he was able to save at a later time.
So you could see when tested very soon, within
a third of an hour after learning, he showed 100 percent savings.
Everything that he had learned he had retained shortly thereafter, but
as time goes by, within the first hour there's a very steep
fall-off in forgetting, and then the rate of forgetting slows down as
more time passes.
Now, what's interesting about this curve is
that although it was by today's standards somewhat idiosyncratic,
it would be hard to get a study published when you're the only
subject and you're the experimenter and you have hypotheses and so
on, but this transience curve, as I would call it, the basic properties
turn out basically to hold up across a wide variety of situations. You
get variations in how quick the fall-off is, and so on, but the basic
idea that the rate of forgetting slows down as time passes, I think,
holds over a remarkable variety of situations.
So one way you could think about attempts to
improve memory through drugs or other means would be, you know, moving
people around on this forgetting curve. We start off here. You know,
is there a drug that will keep us there? We don't want to go down
there. At least that's one perspective on it.
Of course the risk is if we stay up here,
we're going to become like those unfortunate souls that Jim talked
about, Funes and the Borges story, Shereshevskii and the patient he
saw, which is perhaps we're going to have access to too much
information, which is a point that applies to each of these
memory's sins. I try to argue, and we may get into a little bit
later, I see them as kind of costs we pay for benefits in memory that
make the system work as well as it does most of the time.
Maybe we don't want to be up here for every
bit of trivial information that we take in for the reasons you heard
about earlier. So you can think about transience with respect -- you
can think about attempts to improve memory with respect to this curve
we're forgetting.
Now, what are the variables that affect where
you are on this curve? Well, we heard about one earlier consolidation. Events that occur after an experience has been encoded can have a very
large effect on whether that experience holds up over time or whether
it's lost.
What I want to focus on, and this picks up on
some of the points that Jim was making in response to questions, has to
do with what goes on in the very first seconds when a new memory is
formed, when a new memory is born, the state of memory process that
psychologists refer to as the encoding stage.
As it turns out, what goes on in the second or
two or three when an experience is encoded through the senses, taken in
related to things you already know, has a surprisingly large impact on
the subsequent durability of that memory, and it has a lot to say about
how quickly you're going to fall down this curve.
Now, to give you an idea what I mean by
encoding and how psychologists have studied it and then more recently
how we've been able to look at it from a cognitive neuroscience
perspective, let me tell you about an old experiment, but I think an
important one, that was published some 25, 27 years ago by Craik and
Tulving, a couple of my old mentors at the University of Toronto, who
were interested in trying to get a handle on how people encode new
experiences and whether the nature of encoding operations, the nature
of the mental operations that transform incoming sensory information
into mental representations, whether and to what extent those
operations have an impact on later memory.
Now, prior to the time of these experiments,
psychologists had not made much headway in this problem. The way they
typically studied memory is they brought people into the laboratory.
They gave them a bunch of words or nonsense syllables or pictures or
other material and said, "Here. Try to remember this," and
they'd give them a test later on.
Now, that kind of an experiment can't
really tell us very much about how encoding processes influence memory
because I have no idea what you're doing with the material. You
could be repeating it. You could be making up images, making up a
story. I have no idea how you're encoding it.
So this is an early attempt to get control over
the encoding operations and to look at their influence on subsequent
memory. To do that people in this experiment didn't know that they
were in a memory experiment. They were just told, "We're
going to ask you some questions about words," and they had no idea
their memory would later be tested.
So at what we call the structural level of
encoding, they're shown a word. It could be in capital or in small
letters. You'd be shown words one at a time, and you'd be
asked the question is the word in capital letters.
So if you saw this word, you'd say yes. If
you saw this word, you'd say no. So now the level of encoding is
focused on the kind of perceptual level. What does this word look
like? That's what you're focusing on. That's what
you're encoding from the word on that particular occasion.
When they wanted to focus people on the
phonemic level, they would ask them a question like does the word rhyme
with "wait." So that's kind of the sound level.
So if I showed you "crate," you'd
say yes, and it wouldn't matter if it's in capital or in small
letters, and if I showed you "market," you'd say no, and
it wouldn't matter if it's in capital or small letters. So now
we've got you encoding at a phonemic, phonological or sound level.
The final level of encoding was what they call
the semantic level. Would the word fit in the following sentence: he
met a, blank, in the street? So if I show you the word
"friend," you'd say, yeah, that fits. It doesn't
matter whether it's upper or lower case. "Cloud,"
you'd say, no, that doesn't fit. In either case, you have to
think about the semantic properties of the word to determine whether it
fits in that sentence frame.
So the subjects are sent away. They come back
at a later time and they say, "Oh, by the way, we didn't tell
you earlier, but we're actually interested in your memory for the
words that you saw earlier. I'm going to show you these words now,
and I want you to tell me was it one of the words that you saw earlier
when you were answering those questions?"
And they'd mix in some words that
hadn't been presented previously in order to keep the subjects
honest.
The question is: does the way that you encode
the information at study have an impact on your later ability to
recognize whether the word occurred earlier in the study list?
And the answer as you might guess is, yeah, it
has a huge effect. So here's the proportion of words recognized on
the memory test as a function of whether they earlier appeared in the
structural, phonemic or semantic condition, and every word appears
equally often in each condition. They're counterbalanced in the
way that psychologists usually do these experiments, and you can see
there's a huge effect on level of encoding.
So if all you did was answer questions about
upper and lower case, you'd hardly remember any of those words
later on. You'd do somewhat better with the words when you thought
about sound, and then it's only with the semantic level that you
really get the robust level of memory.
So this speaks to the point that Jim made
earlier that a lot of what influences memory has to do with
interrelating new information with old information. Here you're
interrelating, in the case of semantic information, the word with lots
of semantic associations, things you know about the word, and that
provides you with a good basis for later memory.
There are more extreme demonstrations of this.
Perhaps you were thinking of this earlier. There's an interesting
study of a college student that was carried out at Carnegie Mellon a
number of years ago in which they were interested in the question of
whether you could increase memory span beyond seven plus or minus two.
So they want to see if you could just do this with practice with an
ordinary person.
So they brought a student into the lab, and
they started giving him strings of digits to remember, and he'd
have to repeat them right away, and most of the time he would just give
back seven plus or minus two, and they kept doing it and doing it.
Nothing much happened for a couple of weeks. He would average seven as
you would expect.
Then he started to show some improvements. He
could do 11 digits. He could do 15. He could do 25. He could do 40.
I don't mean repeated digits. I mean random strings repeated back
right away.
After six months of practice, he could do 80 at
once, and what was going on here? Had they just increased some kind of
memory muscle or increased his memory capacity in some general sense?
The answer is no. Basically he had latched
onto a very effective form of semantic encoding. At the moment that he
started to show this improvement, the student was a runner on the
Carnegie Mellon track team, and he started to devise a semantic
encoding strategy in which he encoded these digit strings with respect
to his semantic knowledge of running, and so if a string came along,
you know, four, one, four, five, he'd think to himself, "Oh,
that would be a pretty good mile if I had the wind at my back,"
and build it, you know, starting very simple things like that.
He'd build a very complex semantic encoding network that he used in
order to achieve this remarkable memory performance.
And, you know, to really prove the point, they
did a test at the time when he was able to do 80 digits from one
hearing. They gave him a test of letter span memory, and for that he
can only do seven plus or minus two because he didn't have this
semantic encoding strategy developed.
So I think that shows (a) the power of this
kind of semantic encoding. You know, I'm not sure that you can get
that much of a boost from, you know, any of the drug agents that we now
know of, and (b) the specificity of it.
Okay. So that's some points about the
psychological aspects of encoding. One of the exciting things now
about being in the field of memory is that we're able to relate
some of these psychological and cognitive processes that have been very
carefully and thoroughly studied by cognitive psychologists over the
past 25 years, such as semantic encoding, to brain activity.
And one of the ways in which we were able to do
this in the case of human beings is by using new neuroimaging
techniques, and there are a couple of these, really one now, that is
pretty much standing alone as the main way of doing these studies:
positron emission tomography, or PET, scanning and functional magnetic
imaging, or FMRI, which is really the technique of choice nowadays.
In both cases basically what we're doing is
measuring hemodynamic or changes in blood flow or blood volume in the
brain, and the basic idea is that when a part of the brain becomes very
active, there's more blood rushing into that area of the brain. So
that if you can measure the blood flow into a particular area of the
brain and localize it very precisely, which both PET and FMRI can do
within a few millimeters, then the inference would be that you could
say something about the neural activity in that region during a
particular cognitive act because that is associated with, related with,
correlated with the blood flow in that region.
So making that assumption that blood flow and
these hemodynamic factors associated with neural activity, a lot of
people now over the past ten years or more have been using imaging
techniques to look at a whole variety of cognitive processes, including
memory and including encoding.
So I just want to give you one example of an
experiment. This is one of several that show a similar result. One I
was involved in a few years ago with Anthony Wagner, Randy Buckner, and
a few other colleagues at Harvard and Mass. General Hospital in which
we adapted the Craik and Tulving type paradigm to neuroimaging.
So people would be in the scanner. They'd
be looking on a screen, and they'd be seeing a long series of
words. They would either make a semantic judgment about the words:
does the word refer to an abstract or concrete concept?
So if it was "democracy," they'd
say abstract. If it was "garden," they'd say concrete.
On some trials there's a semantic encoding trials, and then on
other trials they'd be asked the upper/lower case judgment, the low
level structural judgment.
The question is: what's going on in the
brain in the semantic condition relative to the non-semantic condition?
Can we isolate particular brain regions that are active and related to
these semantic encoding effects that we know have such a big effect on
transience?
And the answer was yes. Here are a couple of
images from that study. Let me just make a couple of points. What
I'm showing you here is a slice of the brain. If you can imagine
that you're taking a slice through the brain, you're looking in
from the top down, and we're going about halfway down and making a
cut, and that's the left side of the brain or actually a little
lower than halfway down. That's the left and that's the right.
And these colors here, as I'm sure some of
you know, are basically a statistical map showing parts of the brain
that are activated in the condition of interest compared to a
controlled condition.
So in this upper strip what we're showing
are brain regions that in the semantic encoding condition, the
abstract/concrete task, plus the non-semantic encoding condition, the
upper case/lower case task, are showing activity relative to a low
level condition where you just fixate on an X and don't do
anything.
The most notable thing here is this huge
activity in the back of the brain. That's the visual cortex
showing a large activation. There's also a big activation here in
part of the frontal lobe on the left, the lower left frontal lobe.
Now, if you move down, this lower strip is the
more interesting slide because now you're comparing directly
activation during that semantic encoding task to the non-semantic
encoding task. So now you're seeing words in both conditions. All
that varies are the mental operations, the encoding operations
they're carrying out.
You'll notice now that big yellow blotch in
the back is gone because that's occurring in both the semantic and
non-semantic conditions, that visual activation. So when you compare
the two together, it cancels out. There's nothing there.
What's left over at this point is something
that's going to tell us something specifically about semantic
processing, and what we see here is that left frontal lobe activation
remains, and there's also an activation at the very front of this
visual activation near a part of the brain known as the hippocampus,
which we know is very important for explicit memory. It's actually
in the parahippocampal gyrus.
Those two regions seem to selectively activate
more for semantic than non-semantic encoding, implying that these
regions are playing some role in, and we don't yet understand
exactly what that role is, in carrying out these semantic encoding
operations that are associated with good subsequent memory.
Now, we and others have pushed this a little
bit further, tried to link up the brain activation and the memory
effect even more strongly and asked the question: suppose I put you in
the scanner right now. All right? You're listening to me, and
presumably if I tested your memory tomorrow, you'll remember some
of the things I said, and you're going to forget others.
Could I tell from your brain activity right
now, could I get any insight into whether you're more or less
likely to remember or forget a particular word or sentence that I say?
And that was basically the question we asked in
a follow-up study to this and more precisely was: would these two
brain regions that we saw activate more for semantic than non-semantic
encoding activate more when you're encoding some information at the
time of study that you're going to remember later on as opposed to
forget?
So in this study they were just shown hundreds
of words, and they made abstract concrete judgments about all the
words. It's semantic encoding for all of them, but we know if I
give you a test later on, you're going to remember some and forget
others. Maybe for some words you can hook it up to what you know about
the word or you get a better image or something of that nature.
So the question is: can I tell now from the
scanning patterns and encoding whether you're going to remember or
forget the word later?
And the answer was yeah, and it turns out to be
the same brain regions again. What I'm showing here is that left
frontal, a few different views of the activation in the left frontal
lobe, the same slice I showed you before, and this is looking in from
the back of the brain.
And down here on these graphs what we're
plotting is the strength of the FMRI signal at encoding for words that
you would later remember. That's in red, and the stronger signal
versus for those you would later forget, and you can see in all three
cases these different regions within the left frontal lobe are showing
a stronger signal at encoding for the words.
It turns out that, you know, a couple of hours
later you would remember compared to those it turns out that you would
forget. So this provides an even nicer link between the brain activity
and the neural activity, and this also shows up in that region near the
hippocampus, the parahippocampal gyrus that I was telling you about,
and those are the only two regions in the brain that show the effect.
It's not just that on the trials where they
forget the subject falls asleep and they close their eyes and
there's no signal in the brain. Other brain regions show equal
signal for words you'd later remember and forget.
So this kind of work and a lot of other work
like it, I think, is starting to give us some clues now into the neural
processes underlying this very fundamental encoding process that I
think is central to any discussion of memory improvement through drugs
or other means.
Okay. Let me move from transience, some
ethical questions I was going to raise that I think we've already
heard a little bit of discussion about and we can get to in discussion
later, and say a couple of words about absent-mindedness, lapses of
attention that involve forgetting to do things.
Let me just give you a couple of everyday
examples and throw out a couple of points for your consideration.
Here's a picture of Yo-Yo Ma, the famous cellist, who a couple of
years ago had a kind of unnerving encounter with memory where he put
his cello in a taxicab, took a ten minute cab ride, got out of the cab,
and then walked away without his cello.
Fortunately for him, this episode of forgetting
was nullified. The New York City police got right on the case, and
later that day here he's shown reunited with his $2.5 million
cello.
Now, this would not appear on the face to be an
example of transience. Presumably the information hadn't faded out
of his memory within minutes that he put the cello in the trunk.
Rather, he wasn't reminded at the time he needed to carry out the
action that he needed some cueing to remind him that the cello was in
the trunk.
Presumably had he said, "Where's your
cello, Yo-Yo?" he would have immediately said, "Oh, it's
in the trunk."
So the forgetting here, I would argue, is based
on totally different mechanisms than is the forgetting in the case of
transience, and one thing we know about this kind of absent-minded
forgetting is that it can take extraordinary forms when people (a) are
operating on automatic and (b) are not cued to carry out an action at
the moment they need to cue. So with memory for doing things in the
future, it doesn't help very much to remind yourself, "Oh,
I've got to pick up" -- or it may not help very much --
"I've got to pick up bread and milk on the way home," if
you're not reminded later on at the moment you need to carry out
the action. And there's a lot of interesting research that backs
up that point.
Just an extreme case with, I think, some
interesting ethical implications, so I couldn't resist talking
about it with you today, briefly was that of a -- and there have been
several cases like that around the country in the last couple of years
-- a woman by the name of Carie Engholm, a high level hospital
administrator who drove her son and her daughter to work one morning,
her seven month old daughter who she put in the back of a van, dropped
the son off as she did every day. She was not accustomed to taking her
daughter; drove on to work, forgot about the existence of her daughter,
and unfortunately the daughter died in the van and was found later that
day.
Now, there's a lot of discussion, you know,
how could Mom forget that baby. How is it possible for someone to
forget something of this nature?
I personally would argue that it's an
extension of the Yo-Yo Ma principle, that without cueing at the moment
you need to carry out an action and operating on automatic, it is
astonishing how far forgetting can do.
Eventually she was found not guilty because
there was the question of is someone responsible for their memory
system. Do you take responsibility for the fact that one of the
foibles of memory is that if you go on automatic and are not cued, you
can forget extraordinary things? Are you, therefore, responsible for
setting things up in advance to make sure something like that never
happens?
The judge eventually decided that she was not
guilty. There were various reasons for that, some having to do with
the exact nature of the charge which required proof that Engholm knew
she left her child in the van when she clearly didn't, but he then
concluded that forgetting is an involuntary process that can't be
knowingly or recklessly done. A person either forgets or remembers.
So I throw that out to you in terms of maybe
another angle on some of the ethics of forgetting. When are we
responsible for our memories?
If I show you a 20 word word list and I give
you a test and you only remember five words, I don't accuse you of
being, you know, a flawed moral agent because you can't remember
them all. Does that logic apply here?
I think that's better for you guys to
decide than me.
Memory sin number three, I want to say just a
little bit about blocking and then conclude with a few words about
misattribution.
Blocking is the kind of memory failure that
occurs when we haven't lost anything from memory and we know the
information is there, and it's not a matter of paying attention.
There's an example of this, again, a flawed Power Point slide of
British Deputy Prime Minister John Prescott, who was at a press
conference a couple of years ago where he was forced to justify the
cost of the Millennium Dome, this extremely expensive stadium that was
built in London. I think it is now being taken down.
And he was asked, "Well, where did the
money for this come from?" in his overrun budget so much.
And he said that money came from the -- you
know, what do they call it? He just couldn't come up with this
word, and then he said, "Oh, was it the raffles? No, it
wasn't the raffles. What was it?" and then finally someone
came up and whispered to him, "the lottery." It was the
lottery.
So that's kind of a classic tip of the
tongue blocking phenomenon. Clearly he knew the word. It hadn't
fallen out of his memory, and this tip of the tongue state is quite
pervasive. It's something that is known in virtually all cultures.
There's an interesting article published by
the psychologist Bennett Schwartz who noted that 88 percent of the
languages that he surveyed used the tongue metaphor to describe this
kind of temporary retrieval block, "on the tip of the
tongue," "on the tongue," "on the top of the
tongue," "on the front of the tongue," my favorite,
"sparkling at the end of the tongue," "in the mouth and
throat," all aspects of the TOT.
One thing we know about the TOT state, this
blocking type of forgetting, is that it's a very active state. One
comes up with incorrect items like raffles. You've got to make
decisions about whether those items are correct or not. Are they just
leading you down the garden path?
William James -- being in William James Hall I
have to have one William James slide for any talk I give, and he always
has something interesting to say about something in psychology --
describes it well. "Suppose we try to recall a forgotten name. The
state of consciousness is peculiar. There's a gap therein, but no
mere gap. It's a gap that's intensely active, a sort of wraith
of the name is in it beckoning us in a given direction, making us at
moments tingle with the sense of our closeness and letting us sink back
without the longed for term. If wrong names are proposed to us, this
singularly definite gap acts immediately as to negate them. They do
not fit its mould."
So that really captures the phenomenology of
the TOT state. It's as if there's some cognitive monitor in
there that knows what we don't know. We're not quite sure how
that works, but, again, we've been starting to get some insight
into some of the brain activity during blocking through neuroimaging
studies.
We recently did an imaging study of blocking,
of tip of the tongue blocking, where we induced TOT states while people
were in the scanner by giving a cue such as War and Peace plus author,
London plus river, Aida plus composer. Those may seem obvious to
some. Can you think of the answers for each one? Obvious to some,
maybe not obvious to others, but about ten to 15 percent of the time
you'll get a TOT state for Tolstoy or for Thames or for Verdi.
So we put them in the scanner. We run hundreds
of these by them, and interestingly what we find is that there are
certain parts of the brain that activate selectively specifically
during the TOT state, and by and large, these are regions that in other
studies have been implicated in kind of cognitive monitoring
processes. They're parts of the brain that get going when
there's conflict, when we've got to make cognitive decisions
between conflicting alternatives.
One was a region of the brain in the middle of
the right frontal lobe, and the other is in an interesting part of the
brain tucked away in the middle of the brain called the anterior
cingulate that gets activated in all kinds of imaging studies and seems
to be related to this monitoring of cognitive conflicts.
And in this study these brain regions were
activated only during the blocking state. They didn't show
significant activation when people knew the answer or didn't know
it.
So there's some initial insights into some
of the neural activity associated with blocking. It's an
interesting question as to whether this kind of blocking is something
that merits attention and attempts at memory improvement. Certainly it
is one of the most common subjective complaints of memory loss as we
get older, is blocking particularly on the name of familiar people.
There are cognitive ways this can be approached, and as far as I know
it's really never been looked at through drugs and, you know, maybe
shouldn't be looked at.
Finally, I just want to say a few words about
misattribution because I think the whole realm of memory distortion,
though it's really not a big issue when it comes to memory
improvement – people are, whether they should be or shouldn't be,
people are generally not looking for ways to make their memory less
distorted. They're looking to remember more, and I think people
often take accuracy for granted when perhaps they shouldn't.
Let's just say a few words about
misattribution. We'll go through those paintings and go directly
to misattribution.
A number of you may remember -- probably all of
you remember -- that when the Oklahoma City bombing occurred back in
1995, there was a search for two suspects, John Doe No. 1 and Joe Doe
No. 2. John Doe No. 1, of course, was Timothy McVeigh. John Doe No. 2
was never found, although there were bulletins issued by the FBI
shortly after the shooting in a search for a person who looked like
this.
Well, it turned out he wasn't found because
he didn't exist. At least he didn't exist as a suspect in the
case. He existed as the figment of the memory of a guy by the name of
Tom Kessinger, who was a mechanic who worked in the body shop where
McVeigh rented the van that he used to carry out the bombing. And he
distinctly remembered McVeigh coming in with this guy.
Well, it turned out he was also there the next
day when somebody, who the FBI later discovered looked like McVeigh,
entered the body shop with a guy who fit this description. He was an
innocent Army private by the name of Todd Bunting.
What had happened here was a classic memory
misattribution error. Kessinger was right. He had seen that face
before, but he misattributed his memory in this case to the wrong
time. He mixed up the time that he had seen the two and thereby
committed this error.
Now, this sort of memory error can have very
serious implications for eyewitness testimony. It is the kind of thing
that is often involved in eyewitness misidentification as, as we know
from studies of people who have been wrongfully convicted and
exonerated on the basis of DNA evidence.
Approximately 90 percent of these individuals
who have been studied were put in prison wrongfully, largely or
entirely on the basis of eyewitness identifications, often involving
this kind of memory misattribution. So it's certainly something
that we need to pay a lot of attention to.
One way psychologists have studied this
recently is through a very simple but effective paradigm that came
originally from the 1950s and then more recently in the 1990s,
rediscovered by Roediger and McDermott where if we had time we could
easily induce this phenomenon in most everybody here.
You present people with a bunch of words that
are related to one another, such as candy, sour, sugar, bitter, good,
taste, tooth, nice, honey, soda, chocolate, heart, cake, eat, pie, and
then you later give them a memory test where you present words that
were on the list like "taste," and most people will correctly
say that "taste" was on the list; unrelated words that
weren't presented like "point"; and then the interesting
case which is associatively related theme words or critical words like
"sweet."
"Sweet" wasn't on that list, but
if you do this experiment, if we had time to do it here, what you find
is that most people swear up and down that they heard the word
"sweet," and Paul knows this because he's had this done
to him.
DR. MCHUGH: Exactly.
DR. SCHACTER: Here's an example from one
study we carried out, Ken Norman and I carried out, a few years ago with
college students and old people who were exposed to a bunch of
associate lists like this, and this shows you that both the young group
and the older group in their 70s about 75, 80 percent of the time are
correctly saying that words like "taste," which were on the
list, really were on the list.
The problem is they're also claiming with
high confidence that words like "sweet" that weren't
there were also there, and as you can see, the older group shows an
increased susceptibility to this. I'm sure that it had nothing to
do with you showing the effect.
(Laughter.)
DR. SCHACTER: And which we thought was an
interesting discovery at the time, and I can't resist just giving
you this quick quote that shows that we were scooped by 100 years by
none other than Mark Twain who said, "When I was younger, I could
remember anything whether it had happened or not, but my faculties are
decaying now, and soon I shall be so I cannot remember any but the
things that have never happened. It's sad to go to pieces like
this, but we all have to do it."
What's going on here is this, again,
illustrates the fact that memory is not just a tape recorder or
computer or whatever; that what we're doing is we're kind of
constructing a mental representation of the general sense or the gist
of that list, and "sweet" really fits in well with everything
you heard.
So later on when you reconstruct what you
heard, that seems to fit so well that you're absolutely sure that
you heard it.
Now, we've been interested in this for a
number of reasons. In part, we've been interested in what is going
on in the brain when people make this sort of memory error.
And through a number of approaches, we've
gathered evidence that the hippocampus, the region of the brain that I
told you about earlier that we know is so important for remembering
things that really did happen, also seems to be involved in this memory
illusion.
For example, patients who have damage to the
hippocampus and music patients that have great difficulty remembering
what really happened also how less of the memory illusion than healthy
people do. They show about half of the memory illusion. They're
not fooled like you and I are.
Why? Because we think the hippocampus has
something to do with it.
We've also done brain imaging studies that
I wanted to get to and conclude on because I think they raise some
issues that might be within the purview of this group, namely, about
the ability to use brain imaging to tell whether someone is reporting
an accurate memory of the past or a false memory.
So this is a study we published last year with
Roberto Cabeza, where we scan people while they were making judgments
about whether words were on the list they heard earlier. They had been
given a whole series of these associate lists, and they false alarmed
to words like "sweet" that really weren't there.
What's interesting here is that you can see
these are the FMRI signals, that there's just as much FMRI signal
for the false words like "sweet" in the hippocampus as there
is for the words that were really there like "true."
There's a nice increase in signal compared to words that had
nothing to do with what were on the list and people easily say no to.
So in both of these cases the hippocampus is
lighting up roughly equally. It's fooled into thinking that
"sweet" was on the list perhaps because it's remembering
the semantic gist of what was there.
But there's another part of the brain in
this study, that parahippocampal region we just talked to posterior to
the hippocampus that shows activity only for the true words, not for
the sweet words. We're not quite sure. We have some hypotheses
about why that occurred, and we've seen similar things in a couple
of other studies.
Now, the interesting -- the broader societal
question here is if you want to know whether someone is remembering
accurately, can you just put them in the FMRI scanner and tell? And
the short answer to that would be no. This is data that comes from a
group study. You have to average across many people in order to get
these effects. If you look at any one individual, you're not going
to see very much, but I think it is a technology about which we'll
be hearing more, the use of these imaging devices for distinguishing
between truth and deception in the context of lie detection, perhaps
between true and false memories, and although we're certainly not
at a stage we're even close to being able to use this for practical
purposes, it is something, I think that at the interface of technology
and memory that you might want to consider.
I'll stop there.
CHAIRMAN KASS: Thank you very much.
Someone gets us the lights. Thank you.
Questions for Prof. Schacter? Robby George.
PROF. GEORGE: Yes, just very quickly,
PROF.. On that false memory with the "sweet" are the
Paul McHughs of the world claiming to remember seeing the word or are
they simply reasoning that it must have been? Have you somehow tested
for that, controlled for that?
DR. SCHACTER:Yes, that's a good
question. There's a lot of data that speak to that and indicate
that they're not just reasoning and guessing that it was there or
just saying, well, probably it was there because it fits with
everything.
There are a number of studies that various
people have done and some of our own work that show how it really is
for whatever reason people are having this subjective experience of
memory.
There's a lot of debate in the literature
about what the mechanism is, but they will claim if you give them a
choice of saying one of the two things, one of the following two
responses: you're saying, yes, this word was in the list because
you have the specific recollection of having seen or heard it,
depending on whether the presentation was auditory or visual, or
you're saying, yeah, it was on the list because you just know it
was there, and you don't have a specific recollection.
And sometimes people will say, "Oh, I just
know it." They give the remember response just as much to these
words as they do to the words that were really there.
So in other words, they say, "No, I have a
specific recollection of it," just as much to the sweet words that
weren't there as to the words that really were there.
If you do an experiment where you have half of
the words presented by a man and half of the words presented by a woman
and you say to people, you say to the subjects, "Okay. Tell me if
you remember the word, and then if you really remember who told you, a
man or a woman, tell me man or woman. If you don't really remember
the source of the word, don't write down anything,"
they'll write down man or woman with high confidence just as often
to these false words as they will to the ones that were there.
So it really seems to be subjectively
they're absolutely convinced that it was there. That's my
reading of the literature.
CHAIRMAN KASS: Charles.
DR. KRAUTHAMMER: I just had a question on intrinsic
and extrinsic memories that you mentioned earlier. Can a Korsakoffian
learn to ride a bicycle?
DR. SCHACTER: We don't know the answer to
that exact question, but by implication the answer would be probably
yes, barring -- yeah, barring any general cognitive deterioration.
They can learn a whole variety of motor skills and laboratory tasks
that, you know, for example, if you have people trace a moving stylus
they get better at keeping time on target with practice, and these
patients will show that same kind of improvement.
We've even done experiments years ago where
we have shown that they're able to learn some basic computer
programming skills. Even though they come back to the lab, they have
no idea that they've done it. They don't realize that
they've ever worked on a computer, but if you get them going on a
test, they'll start to do it, and they're kind of amazed that
they can.
DR. KRAUTHAMMER: And have you studied brain injured
people whose injuries happen to be in the two areas that you identified
with encoding, that left temporal --
DR. SCHACTER: The left frontal and the
temporal lobe.
DR. KRAUTHAMMER: Left frontal, right.
DR. SCHACTER: Parahippocampal. You know,
there's a little bit of literature on the left frontals that
suggest an encoding deficit. It's hard to find people that have a
specific parahippocampal deficit. You just don't see those
patients very often. So I'm not aware of any literature on them.
But that's one of the tasks in this general
area, is to try to map the brain imaging work onto the lesion work, and
they don't always go together. I wish I could say that they did.
They often do, but they don't always.
DR. KRAUTHAMMER: Because if I could just add, because
most of the knowledge and until this new technologies, this stuff I
learned 25 leap years ago from Normal Geshwin was based entirely on
pathology.
DR. SCHACTER: That's right.
DR. KRAUTHAMMER: The patient was missing an area, and
then you deduce what that area was doing. Now you can see it in vivo.
I'm just wondering if they correlate. I mean, there's the
whole entity you'd want to be correlating with now.
DR. SCHACTER: Right.
DR. KRAUTHAMMER: Active areas versus pathology.
DR. SCHACTER: Yeah, they don't always
correlate. They correlate often enough in important ways, I think,
both, you know, to validate the technique and, you know, give us some
confidence that, you know, we're looking at some of the same things
that the earlier neurology types looked at.
But I think they're very different kinds of
evidence, and you probably need them both, and in the sense with bright
imaging we're looking at areas that are active during a task, but
it doesn't tell us that they're necessary. They'd just be
coming along for the ride or they may have something to do with the
subject's reaction to the test where monitoring is in the case of
blocking, whereas the neuropsychological patients tell us, you know,
more what areas are necessary.
So I think, you know, each one adds to the other.
CHAIRMAN KASS: Could I ask about -- this
may be perverse of me to ask about something you chose not to talk
about today, but if I'm remembering rightly, persistence was the
last of the sins --
DR. SCHACTER: Right.
CHAIRMAN KASS: -- is not somehow a fault
either of failure, kind of forgetting, or of distortion, but it's
rather a dismaying accuracy that we remember things we would rather not
remember.
First of all, am I right about that?
DR. SCHACTER: Yeah.
CHAIRMAN KASS: Is that what you meant by
it?
DR. SCHACTER: Yeah, that's what I meant,
and I thought we'd touch on it a little bit earlier on, but
that's exactly right. Persistence, as with the other sins, I
wouldn't see as some fundamental shortcoming in memory. It's
the price we pay for having a memory system that, you know, responds to
emotionally arousing situations in the way that Jim McGaugh described
earlier and in a way that presumably works to our advantage most of the
time, and then it's good to remember, you know, these terrifying
events and, therefore, avoid them in the future.
The down side is, you know, you can be plagued by
such events.
CHAIRMAN KASS: Let me see if I could Ó- and
this would be to invite Jim McGaugh back into the conversation as well
to tie up this discussion with the earlier one.
As I think about the possibilities for altering
memory, the enhancement of memory whether it's as good as just
working harder or not, there are lots of our fellow countrymen who
would want it if it were easily available. It doesn't bother me a
whole lot.
But the thought that you could selectively
block and erase memories and particularly not just for the prevention
of post traumatic stress syndrome, but for what when Paul McHugh's
colleagues finish with the DSM-5 or 6 will include painful memory
disorder, shameful memory disorder, because we can do something about
that, and there will be reimbursement for it, and therefore, it will be
in the book.
And it's not just the really horrible
things, but you know, within the last week I'm sure all of us have
probably some things, you know, embarrassments, sorrows. The
temptation will be to have some kind of amnesia for these things or, as
we were talking about it at the break, amongst the young, one could
lose one's inhibitions for shameful behavior and not have to remember it
afterward. It's a kind of win-win situation.
So I'm wondering --
PARTICIPANT: It's called alcohol.
(Laughter.)
CHAIRMAN KASS: It's called alcohol, but
it comes with disturbance.
In any case, I'm wondering about how you
would sort of talk through that aspect of memory and whether we could,
in principle, distinguish those things that persist which say as a
therapist one would be happy to somehow extirpate if one could from the
temptation that all of us would have to our peril and, in fact, to our
detriment, somehow wipe out the things which we would rather not
remember and make us wince years and year after.
DR. SCHACTER: I think there's one
distinction that needs to be drawn between some of the work that Jim
was talking about with propranolol and alcohol in that in the former
case it's not a question of wiping out the memory because people
can remember what happened. It's taking the sting, the extra
emotional edge off of the memory so that you remember it, but you
don't --
CHAIRMAN KASS: It doesn't bother you.
DR. SCHACTER: You're not overwhelmed by
it, right.
So that line of work as far as I know has not
really gotten into memory erasure, which as he points out, you know, I
guess we already have alcohol and we can make our judgments about the
effectiveness of that strategy.
I'll turn that one over to Jim, but I
don't see that as a new issue that is suddenly being driven by new
drugs or new developments.
DR. MCGAUGH: No. I think I may have
overstated the ease of doing it in the first instance. That is, recall
that the only experiment with humans was not erasure with propranolol,
but it was dampening the development of PTSD so that the subjects could
still remember the event, but they didn't have the emotional
outflow, and it didn't take over their lives.
Now, that takes a long time to do. So it
isn't as though I did something horribly embarrassing yesterday and
I can pop a pill and that's going to be gone. If it was really so
horrible, it's going to flash into my head, recur and recur and
recur so that it begins to take over my life; then that would be a
case, I think, in which a little propranolol, if the studies bear out,
might be of value.
But there's something else that I
didn't emphasize, and I should put in the equation. This thing
works equally well for good things that happen, as well as for bad
things. So I think when we think of the strong memory's
persistence, I'm sure that Nobel Prize winners remember what they
were doing -- well, in the U.S. most of them were sleeping, but where
they were and what they were doing when they got the call of winners
and prizes. Anything as much coveted, you remember birthdays and
weddings and all of these kinds of things; they stand out.
So the pleasant side of this works just as well
as the unpleasant, but there's never a quick fix. It's not as
though -- well, there would be. You walk around with an ECT machine in
your backpack and something terrible happens. Deliver yourself an
ECT. That's the only thing I can think of that would do the job.
Short of that, it's all going to be a
dampening. Would you agree with that?
DR. SCHACTER: Un-huh, yeah, I would agree with
that.
And you know, it's an interesting point to
consider, you know, when you consider some of the adaptive role of
some of these intrusive memories. Actually I was running out of time,
but had it in my last slide in case I had time to get to the
persistence issue a picture of a Holocaust survivor from a real
interesting series of art works that's been done on this topic by
an artist by the name of Jeffrey Wollman, who interviews Holocaust
survivors about their stories and then takes the picture and does it in
interesting ways.
And in this particular slide, if you can read
the small writing about the woman's story, I mean, she talks about
how, however painful it was, however critical it was for them, you
know, to keep that memory alive and, you know, the whole issue from an
adaptive perspective of how, you know, dealing with a memory helps you
adapt to the traumatic event.
And then the question of whether it's
better or worse, you know, to be dealing with it with the sting or less
of the sting, it's hard to address, but I think that's one of
the issues.
DR. MCGAUGH: Yeah, I think the critical case
is that of when it becomes incapacitating.
DR. SCHACTER: Right.
DR. MCGAUGH: That's the issue because
certainly I think in most cases having a very strong memory of a
horrible event has adaptive consequences. You want to stay awake. You
want to be on guard. You want to know what to do, what not to do, and
so on.
And as a matter of fact, they had a hell of a
time getting post traumatic stress syndrome classified as a psychiatric
disorder because it was matched up against malingering. You know,
it's not really true; it's not debilitating. What you want to
do is just take advantage of the VA system and take all of the
benefits, and so on.
And it took a long time for them to get to
recognize that in a certain percentage of the cases, their lives were
really debilitated by it, whereas in most cases it's not. So that
they have now matched cases of people who have severe automobile
accidents. All right? Twelve to 15 percent of those cases, as my
reading of the literature, will develop some PTSD. All right? Some
will have none even though they've had the same experience. They
certainly will remember a lot about it.
Now, what do you do about those 12? Well, in
most of those cases or over half of those cases, those will resolve in
about eight months, and then you're left with a residuum of a very
small number of people whose lives have been damaged over the long
term. Now, that would be the focus group, I think, right there.
CHAIRMAN KASS: Thank you.
I have Bill May, Alfonso, Rebecca, and Mike
Gazzaniga.
DR. MAY: Well, in these last two sessions we
verge ruminatively on topics that in so many ways move beyond the reach
of medicine, but no less interesting for that.
I think about the two responses to the past and
remembering of nostalgia and remorse. I've just gone through a
50th reunion, and so you ride down the moonbeams of nostalgia. There
is a faculty member who is now in his mid-80s who wrote a lovely letter
saying, "Affection grows as memory fades."
Laughter.)
DR. MAY: That's a very nice comment.
Another PROF. on another occasion talked
about the sickness of nostalgia, that living in a lost world.
That's a very interesting human problem, and it's not just
ideological bias in that case. It's a kind of disconnect with the
present that afflicts people in the course of time.
And remorse, your category persistence very
much relates to that. We're not now talking about the medical
danger of eliminating past memories, but in fact, as I recall, the
Catholic Church in its sacrament of penance vividly understood that
remorse is very dangerous because it is that relationship to a past
which stings and you bite yourself all over again in remembering it. So
it's unavailing, and there's no way of moving beyond it and
moving forward into the present.
And perhaps just as dangerous as writing out
memory is the reliving of a past event that is so wincing in memory
that one engages in a kind of suffering all over again, which is
unproductive of a future.
And I guess it remains to us, sir, as to how
any of this relates to the questions before us in bioethics.
Fascinating issues though.
CHAIRMAN KASS: Thank you, Bill.
Alfonso, please.
DR. GÓMEZ-LOBO: This is on a slightly
different topic, I think, but I'm really delighted that I have a
chance to ask you these questions.
The topic of memory, of course, fascinated the
ancients. There's a lot of memory in the Platonic dialogues and in
Aristotle, and I'm thinking about -- and I'm going to formulate
a question -- the following.
When we talk about the blocking of memory, if I
understand it correctly, there is a question of retrieving something,
and if we retrieve it wrongly, if for, say, War and Peace we say
Dostoevski, we can do that because there's something that we have
not forgotten, right? So there is an actual belief held by reference
to which we match whether the memory was correct or not.
Now, this is independent of whether it is
factually correct. So memory seems to entail this matching or making
coherent two beliefs of some sort.
Now, my question, what I'm really intrigued
with is this. In the contemporary study of memory, is there such a
thing as remembering something which we did not first acquire, for
instance, through a sensible experience?
I've noticed that memory and the response
is not restricted to the sensory experience.
Now, the example I have in mind is this. Is it
correct to speak of memory, for instance, in the retrieval of the set
of natural numbers, for instance? We've had no encounter with
that, and yet somehow that seems to be stored in our minds.
DR. MCGAUGH: What was the word? What did you
say? The retrieval of what?
DR. GÓMEZ-LOBO: The series of natural numbers.
DR. MCGAUGH: Yeah.
DR. SCHACTER: Well, I think this partly gets
into the realm of the distortion and false memory, that you could say
we know from experiments that people can be induced to remember
episodes from their past that by all objective accounts did not occur.
College students, you just ask them about it several times, and a
certain proportion of college students will claim to recover a memory
of spilling punch on the groom or bridge at a wedding when they're
five years old, and as far as we can tell, this event never occurred.
So, you know, it doesn't make sense to talk
about that as a false memory. Well, if you define memory or part of
memory as the subjective experience of what occurs at the time of
report or retrieval for whatever reason it's there, then, yeah,
that makes a lot of sense.
If you define it with respect to tying it to an
event that occurred in the past, then it would be an oxymoron of sorts.
DR. GÓMEZ-LOBO: Yeah, I think I was taking
care of that. What I'm curious about is the kind of knowledge that
in philosophy we call a priori knowledge.
In other words, the fact that we can say a lot
and handle a lot of problems in this series of natural numbers, which
we have never learned, and in the standard sense, never stored in our
minds, but maybe this question is a question in epistemology or
metaphysics.
DR. MCGAUGH: Yeah, we wouldn't refer to
that as memory even in the same way that we wouldn't refer to our
extraordinary capacity to learn language as memory. It's a
capacity that we have, but it's not memory until we've learned
something.
CHAIRMAN KASS: Rebecca.
PROF. DRESSER: A couple of comments. With
regard to the ability to reduce the distress associated with an
embarrassing experience or a traumatic experience, obviously as with
many of these things we're discussing the problem is line drawing
because, I mean, we don't want to remove that distress for social
reasons in some circumstances.
For example, I think that's where a lot of
empathy comes from. That is, when we have an embarrassing experience,
we develop empathy for others who have a similar experience.
Also, shame or feeling of responsibility for
consequences, I mean, once you do something stupid or sloppy or, you
know, that's a lot of growing up, development. So we want some of
that sting. So the question is: what is dysfunctional sting?
There probably is some sting that we would
rather not have as individuals, but it's good for the rest of us
that others have it in determining, you know, when sting ought to be
removed. This is, I think, a big problem.
The other point that I thought of in response
to your presentation was I think we've been discussing the use of
these things in situations where individuals might want to use them or
parents might want to use them and other people might have reservations
about whether that should happen.
But here with the question about whether
something is an actual memory, there might be cases where it would be
in the interest of society to force someone to have an FMRI or a PET
scan or some other intervention in order to discover whether it's a
false memory or not.
And the person might say, "Well, I
don't want that." And so there could be a coercive potential
use of that, and we would have to think about how should, you know,
autonomous choice fit into the situation.
DR. SCHACTER: I think you have all of these
same issues that surround lie detection today, you know, from that sort
of issue, but also the whole question of efficacy and just how good the
technique is.
PROF. DRESSER: Right, yes.
DR. SCHACTER: That's why lie detectors are
not admissible. They're just not good enough, and brain imaging
is nowhere near the level even of lie detection.
So I think one would end up revisiting pretty
much the whole range of issues that has come up with lie detection.
DR. MCGAUGH: Could I comment on the first part
of that?
I think that this sort of was the view of the
Veterans Administration on the complaints of the GIs who were suffering
so terribly, you know. "Suck up your guts. Come on. Everybody
has problems."
But there's a difference between the level,
the intensity of this disorder in those people who really present as
opposed to people who just said, "I had a very bad deal in
Vietnam," or on the road the other day or whatever it is.
But there's some point you can draw a line
and say, "You can cope with this and for some reason you
can't." And there is no treatment for long lasting post
traumatic stress disorder. I mean, it just sits there.
While you were talking, I was thinking about
the case of anxiety. It's good for us to be anxious about things.
It's good because it helps us prepare. We have to anticipate the
consequences.
And yet there are people who are so anxious
that they can't anticipate the consequences in an adequate way.
And so benzodiazepines are a drug of choice to deal with that end of
the distribution. People will become incapacitated because of the
anxiety, but they're not drugs, in my opinion, aside from Viagra
that's a most widely used drug. There isn't any rationality
for an ordinary person taking a benzodiazepine just because they think
they might be a little upset.
And yet that is the draw. That's what we
see all the time now on TV stations where they're now advertising
medicines. They're saying there's a pill for everything.
Of course, call your doctor, as though the
doctor is going to be standing by the telephone waiting for your call,
right?
There's a pill for everything, and I think
that -- I don't know what you can do about that with your committee
here, but that to me is a major concern, is the marketing of drugs to
the general public that are really initially developed for and
efficacious for a very small set of the public.
And it's the drugification of the society
as a consequence of that.
CHAIRMAN KASS: I have Mike Gazzaniga.
DR. GAZZANIGA:: I just wanted a point of
information from the two, Jim and Dan here. About a year ago from
Joseph LeDoux Lab there was this report of memory erasure by bringing
up an animal that's reminded of something and then a protein
synthesis inhibitor is injected, and then the memory seems to be Ó-
CHAIRMAN KASS: Mike, could you speak up a
bit?
DR. GAZZANIGA:: -- the memory seems to be
erased, and this was an animal model repeat of the classic ECT work
that Jim was mentioning.
I know that talking to LeDoux that he was
inundated with phone calls from humans, not the rats he studied, who
wanted a pill because they wanted to get rid of certain memories in
their life.
Has that folded? Is there any biotech work on
that? Is that a viable concept still?
DR. SCHACTER: Well, they're continuing
with it in their lab, and I was actually at a conference a few weeks
ago, that Self Conference in New York. I was talking to Karim Nader,
who was one of the authors on that paper, who claimed that there is
some obscure clinical paper published 20 years ago where actually some
form of this was done with people. I haven't seen it yet. He gave
me the --
DR. MCGAUGH: Larry Squire did that.
DR. SCHACTER: Larry Squire tried and
couldn't get the effect.
DR. MCGAUGH: Yeah, he did the --
DR. SCHACTER: With ECT.
DR. MCGAUGH: With ECT, did the right
experiment.
DR. SCHACTER: Right.
DR. MCGAUGH: He gave subjects new material to
learn or material that they learned a long time ago or material they
learned, I think, just the day before, gave them an ECT, and the only
thing that they forgot was material that they had just learned.
And so reactivating, that is, just doesn't
do the job.
DR. SCHACTER: I guess the question would be
it's not clear whether it's this new research that would be
pointing toward a possible new avenue for this, but given now that
there's reawakened interest in this because of what it might tell
us about some of the basic, you know, mechanisms of memory, might that
point the way towards some other way of approaching this than ECT?
You can comment on that.
DR. MCGAUGH: But even then it has
constraints. I was one of the first people to publish on this many
years ago, and it didn't work in 1970. We now have another paper
in which we did the same thing, but to the hippocampus rather than the
amygdala, no effect.
The effect is supposed to be that if you bring
up information, you retrieve information that you know pretty well,
that makes it susceptible to erasure by some treatment, and now I know
of several other studies that have completely failed to do it.
So I think the phenomenon itself is in serious
question. I wouldn't get too upset about its applicability because
in my view it doesn't exist, but we'll just have to wait and
see.
DR. KRAUTHAMMER: But what about application to
immediate erasure?
DR. MCGAUGH: To which?
DR. KRAUTHAMMER: Immediate erasure you say happens --
DR. MCGAUGH: On immediate erasure.
DR. KRAUTHAMMER: Right.
DR. MCGAUGH: We've known about that for 50
years.
DR. KRAUTHAMMER: Right. But the question as I
understood it was other than ECT, are there any other agents that can
do it?
DR. MCGAUGH: Sure.
DR. KRAUTHAMMER: Erasing?
DR. MCGAUGH: Sure. Protease synthesis
inhibitors can do that.
DR. KRAUTHAMMER: And these have been tested in humans?
DR. MCGAUGH: No, but scopolamine can do it and
atropine, and that's been tested in humans.
DR. KRAUTHAMMER: So you have an experience. You get
atropine. The memory is erased.
DR. MCGAUGH: It's not formed. It's
not formed.
DR. KRAUTHAMMER: Right. I mean, right, it never Ó-
DR. MCGAUGH: Yes.
DR. KRAUTHAMMER: -- it never takes.
DR. SCHACTER: It's not fully formed and
consolidated.
DR. MCGAUGH: Yeah.
DR. KRAUTHAMMER: And what's the lag between the
experience and the administration?
DR. MCGAUGH: It would have to be for something
like that probably minutes.
DR. KRAUTHAMMER: So you have a memory for a minute or
two, right? I mean, until it's --
DR. MCGAUGH: No, no. You can have that memory
for a longer period of time because that memory is based on a different
system than the memory that you use the next day.
This is what he talked about in the first
instance, the difference between this immediate memory and the long
term memory. It's not the same brain mechanism at all. Underline
that.
So what's happening with these treatments
that are affecting long term memory is that they're leaving short
term memory alone. You can have that memory for hours, let's say,
and then it will finally disappear, but what's happened is you
haven't made another stage of memory.
Maybe that's something to bear in mind,
that not only are we talking about information for different kinds of
things that are learned, like the motor skills, but we're talking
about information that's in a different temporal domain having a
different substrate.
DR. KRAUTHAMMER: I guess my question is: if I could
just follow up, I mean, is it conceivable that you could market
something that would tell people if you take this immediately after a
terrible experience, you'll wipe it out and you won't suffer
from it?
DR. MCGAUGH: Yes, that's conceivable.
That's more doable than the other side of it.
DR. KRAUTHAMMER: Right, and that would seem to me to
be a rather interesting question as to whether you'd want to market
a drug you carry around in your wallet to be administered upon extreme
shame.
DR. MCGAUGH: Well, let me give you an example
of that from the 1978 PSA crash in San Diego where they made the
horrible mistake of sending out desk people and baggage handlers to
clean up body parts after the crash, and then there was a report in I
believe it was the L.A. Times maybe five years ago, a follow-up, and a
very high percentage of those people were never able to work again.
They had been permanently disabled because of the trauma.
Now, that's PTSD to the nth degree, and it
probably for them, I would make a guess, was worse than a soldier.
These things are happening all the time in the battlefield, but imagine
you as a baggage handler and for the first time you have to pick up
body parts and put them in bags.
Now, there would be a case in which something
like that I think would be of value. I don't think that you could
say, "Well, you know, it's really adaptive to be able to know
how to handle body parts. So it's a good idea to keep that memory
strong because you may have to do that again and know how to cope with
it."
I think that's a low probability. So that
would be a case in which -- a clear-cut case -- in which it would be
nice to say, "Take this. Weaken your memory of that."
DR. KRAUTHAMMER: I would agree with you, and I would
say that this is not just an odd event like a crash of an airplane, but
in Israel they're experiencing that every week, and there's
huge reports of post traumatic stress syndrome. So in a society like
that, you might want people walking around with that in their wallets.
DR. MCGAUGH: Yeah. I just gave the other one
as a, you know, clear-cut stand-alone case.
DR. KRAUTHAMMER: Right.
DR. MCGAUGH: But the situation in Israel and
Palestine are just unbelievable. I mean it's just hard to imagine
living. I mean if we think it's bad enough to worry about whether
we should cross the street in Washington or Maryland or Virginia, where
we should be thinking the odds are very high that we're going to
get hit by a car, the probabilities are just vastly different, the
sniper versus dying of food poisoning, for example.
CHAIRMAN KASS: Frank, we've got a few
people on the list, and then we are going to move to wind up shortly.
Please, Frank, Gil, and the two Bills.
PROF. FUKUYAMA: This is just a question on a
somewhat different subject, but both of you have talked about fairly
low level cognitive processes like, you know, memorizing a seven digit
string of numbers and so forth, but there seems to be another much
higher cognitive level that involves memory that's also quite
socially and politically important, which is that, you know, you
develop a paradigmatic way of understanding the world at a certain
point in your life cycle, and usually that stops happening past -- I
don't know -- the age of 25, 30 or so, and once you've got that
paradigmatic way of looking at the world, you know, no amount of
disconfirmatory experience then can shake you from it, which is why
politics, you know, proceeds in generational cycles.
So if you lived through the Depression, you
know, you think that big government is the solution to, you know, out
of control markets, and you think that you've got to save, you
know, and saving is a great virtue because a rainy day may come back,
and so forth.
Whereas if you grew up, you know, in the
'60s and '70s or through the sexual revolution, I mean, you
have just very -- you know, so you get these cohorts, age cohorts that
have basically imprinted memories on them, and basically until they die
they're never going to be shaken, you know, from these paradigms.
I mean, do we know anything about the
physiology of this kind of, you know, memory at this cognitive level?
Because it seems to me it's actually quite, you know, politically
relevant and important. But it seems to be at such a higher level than
the kinds of issues that you're dealing with.
DR. SCHACTER: I think within the realm of
memory discussions what you're referring to would probably fit
under the rubric of what's called semantic memory at another
subdivision, semantic and episodic. Semantic is kind of general
knowledge of the world. Episodic memory for personal experiences.
And you know, we do know something about
semantic memory, albeit studies in the laboratory context and, you
know, in a more modest way than full flown political beliefs and
whatnot, but we know something about the structure of semantic memory
and some very interesting work on how it may be organized
categorically. You know, you have patients who can lose access to one
category of knowledge and not another, you know, fruits and vegetables
versus living things versus tools, and there's new imaging work on
that.
So there's nothing that I'm aware of
that directly speaks to your point, but there's certainly a lot of
cognitive literature on what I would assume would be the basic building
block processes that would be relevant in your case.
DR. MCGAUGH: Well, I would add that the
assumption that is made in the neuroscience of memory is that the
building blocks may be the same for many kinds of memory, but they
build into different systems, and then they can build into higher order
systems, such as concepts.
There was a very famous book by Donald Hebb
from McGill University, Organization of Behavior, which you dealt
with. How do you get a concept? And his notion was you get a concept
out of individual small units which then interact, interface with each
other, and you get a concept because these things hook up.
Now, once those things are built up from a
neurological point of view, they're all the same. That is, this
one is like this one over there, but the content of it is different.
But one thing is sure. You're never going
to build that for somebody. That is, you're not going to put a
gene in and say, "I believe in globalism," or put a gene in
and something else. These are all slowly developed over a long period
of time.
PROF. FUKUYAMA: But if I could just say, I
mean, but there does seem to be an age related ability to put those
concepts together and then to deconstruct them and replace them with
other concepts that would seem to have to -- I mean that just
intuitively would have to have some genetic basis because, you know,
that ability to reconceptualize things in very fundamental ways does
seem to decline with age.
DR. MCGAUGH: Well, I'm not sure. I'm
not sure. Let's put in the motor skills. All right? You can
learn to ski at any age, at any age, and even if you have been an ice
skater, which is very different motor skills involved, you can still
learn to ski.
So you're not prevented from doing that. I
would make the counter argument that you get comfortable and then avoid
changes. It's not that it's genetically fixed in that
you're going to be stuck here for a while and then stuck here.
I think that rather it's a consequence of
what you're doing, what you're surrounded by, what
opportunities there are that provide that. Because we even see people
shifting political parties and saying, "All the time I was
wrong." And we see Lula in Brazil having an epiphany about world
economics that he didn't have a few weeks before.
So the constraints that are put on one can
cause one to see the world in a different way. And then we use the
same mechanism to make a change.
Another thing that happens, I think, because I
am growing old, is that you can see the stages in your own life. I
grew up in the Depression. So I am one of the people that you talked
about, but you can then as you get more information, you can put that
phase of your life in a very different context.
So I'm not tied to what I learned and did
during the bad old Depression days, but I can use that information in a
flexible way to change my views about what our relations are with
Mexico, for example, and what our relation to Canada and whether
Schroeder is a nut or whether Schroeder is onto something good.
Because we learn more. We incorporate more
information, and I think that's one of the great things about the
human brain is we're not fixed in developmental stages, but rather
we retain a large flexibility. That would be my take on it.
It's just artificially that we get forced
into it and you see we respond to our own stereotypes, and this
certainly is the case in the political arena.
CHAIRMAN KASS: Gil.
PROF. MEILAENDER: This is really just a
factual question though depending on the answer there might be sort of
more to be made of it, and it probably relates to transience.
Different people at least as they age, the
effect of aging on their memory is different, more pronounced in some
than in others, and so forth. What I want to know, if this isn't a
silly question, is do people in the very early years, the early years
of childhood, do some people just form less transient, more vivid
memories than others?
And I ask it because anecdotally, it seems to
me to be the case that they do. In other words, just among my friends
and acquaintances, some people remember a great deal more, claim at
least, seem to remember a great deal more about when they were four
years old than others do.
Are there differences at the beginning of life
the way there are at the end? And if so, do we know anything about
why?
DR. SCHACTER: Yeah, well, presumably, I mean,
there are individual differences in memory though they're quite
poorly understood throughout, you know, life, and you know, for the
early stages I'm not aware of anything that would really speak to
an understanding of (a) the nature of the difference and (b) whether
one can really localize it, as it were, to transience, to the actual
forgetting over time process.
There might be many possible subprocesses that
are responsible for a difference between one individual and another in
memory. Some of those might have to do with basic processes operating
within the memory system or it just might be different contents being
operated on by those processes.
I suspect that a lot of time when people
compare their memories, and you have a good memory for this and I have
a good memory for that, that it's less about the basic process and
more about the particular contents of the memory.
But I'm not aware of anything on the very
early stages that would speak to that.
DR. MCGAUGH: But you also have to be concerned
about confounds in that. How much did the family talk about it? How
many photo albums are there around? How many times were they reminded
of it in various things? And these would play into that.
PROF. MEILAENDER: I even have in mind rather
pronounced differences among siblings in this matter. I mean, I know
of cases like that and so I was just curious.
DR. SCHACTER: I would suspect that post event
rehearsal is probably playing a bigger role there than people realize,
and you know, why it is that one person talks about and thinks about
and is reminded of, you know, an event than another is, for example,
within families where you'll get siblings, you know, one claiming
to have no memory for the same event that the other remembers in detail
is unclear, but I would think of that, you know, in some sense as a
confounder and in come sense as part of what's interesting about
individual differences in memory, just the big role of post event
processes.
CHAIRMAN KASS: I have two people left, and
I ask them to be brief, and we have as a procedural matter, we have one
person who wants to make public comment. So if you'd be willing,
we'll not take a break and go straight to that and we should be
done probably in ten to 15 minutes.
I have Bill Hurlbut and then Bill May. And
then we'll go to the public comment.
Charles?
DR. KRAUTHAMMER: I just want to ask a
question.
CHAIRMAN KASS: Why don't you wait at
the end then. Thank you.
Please, Bill Hurlbut.
DR. HURLBUT: Returning to the question of
forgetting, to Frank's question about the political convictions and
affiliations, there's an interesting relationship between learning,
memory, and our larger sense of place within our affiliations.
There was a flood in Leningrad after Pavlov had
conditioned his dogs, and the dogs were floated up and almost drowned,
and afterwards their learning, their conditioning had been erased. Do
you know about that?
DR. SCHACTER: No.
DR. HURLBUT: And this was picked up on and
used as some of the basis for the Soviet ideas on brainwashing, and I
think this is called transmarginal inhibition. Have I got that right?
Anyway, here's the interesting --
DR. SCHACTER: Outside of my domain.
DR. HURLBUT: Here's the interesting
question. How do we and how does memory relate to the dissolution and
resolidification of the self in these very crucial domains of
affiliation?
And this comes back to William May's
comment that affection grows as memory fades. What I'm really
getting at -- and there's a question in here -- it seems to me at
least looking at animal models that certain types of memory and certain
types of structuring of the self are tied in not just with memory in
the broad sense, but with very specific systems, and here I'm
thinking of things like oxytocin where the memory of the sheep, for example, for its nursing offspring, is with the second offspring
completely erased. It doesn't recognize or acknowledge at least
its first offspring.
And there have been suggestions that maybe
oxytocin plays this same role in solidifying and bonding. It's a
kind of a memory conviction state.
Do you know anything about this? And what
I'm getting at here is are there any systems you know of that
suggest that there might be ways to specifically enhance certain kinds
of memories and, therefore, certain kinds of affectionate structures or
convictions of personal identity?
One of the suggestions, for example, has been
that oxytocin be used in marriage therapy to make the marriage bond
stronger. Do you see what I'm saying?
DR. SCHACTER: I think I see it. I don't
know anything relevant to it. Do you?
DR. MCGAUGH: The only thing that I know is
mother-child attachment is associated with the release of oxytocin by
the mother. That's all I know.
DR. HURLBUT: And this kind of bonds a memory
relationship?
DR. MCGAUGH: It is proposed that it plays a
role in the bonding. What we have is a correlation, but no one has
done any critical experiments on that.
Now, oxytocin has been studied in Holland and
DeWied's laboratory as a memory enhancing drug, if you like,
peptide about 20 years ago, but it faded from fashion. So I don't
know of anyone who's working on it now.
CHAIRMAN KASS: Bill May.
DR. MAY: In thinking about the medical -- the
warrants for use of medicine, I guess an old distinction would be
between existence and developed existence, being and well-being,
survival and flourishing. And in some of your writings there's
some suggestion, well, memory is very important to survival. You know,
we need it to survive, and obviously medical warrants for doing
something for those who are impaired.
We get a little bit more nervous if what it
seems to be used for is economic survival, I mean, to help SAT scores
and so forth. On that level the medical warrants, other than helping
the impaired, the basic argument is no longer survival, but flourishing.
The problem of impoverishment and the
Alzheimer's patient, we've got various social ways of keeping
them going and so forth, but the human impoverishment is huge.
It's the flourishing of the human which is our concern there, and
we see objective warrants for trying to solve that problem it seems to
me.
Now, Frank is now gone, but he worried about
was there any application whatsoever at the level of politics or the
level of flourishing of the society at large, and there it seems to me
we may move beyond medicine and so forth because really we happen into
the arena where we are talking about ritual retrieval of the past and
the retrieval of decisive and defining events.
And that's a dimension of education which
is very important, but gets lost where education is justified simply in
terms of what it will give you by way of economic survival. The
problem of safeguarding the treasures from the past operates at the
level of politics and religion, and through education, the transmission
of tradition.
CHAIRMAN KASS: Thank you.
Charles, do you want a brief comment and then
we will --
DR. KRAUTHAMMER: Well, before your question, I
would like to ask Dr. Schacter. I was intrigued by the hints that you
were giving about possibilities of using these technologies to
distinguish real memory from misattributed memory, and I was just
wondering since we are talking about enhancement and thinking about
whether we should worry about enhancement in this area, if you could
just speculate on what the field would look like in 20 years and
whether there's anything about the direction of the field and the
power it's acquiring that ever troubles you.
DR. SCHACTER: It's an interesting
question. So far I would say I'm not too troubled mainly because
I'm all too familiar with the ins and outs of data and how far away
we are in this realm from really having anything that works at an
individual level.
So as a practical matter right now, I'm not
particularly troubled. You know, where it might be in 20 years
it's not clear. It's interesting to look back on, for example,
lie detection, again, as an example, something that is related to this
even though we're talking about people who were doing their best to
tell the truth in a memory situation. I'm not a careful student of
that literature, but it seems to me that pretty much the issues have
been the same at least as practical legal issues, you know, for the
last 30 years.
We may make faster progress in brain imaging
that will bring these things onto the front burner more quickly than
they have in lie detection, where you know I think if you turn the
clock back 20 or 30 years, I don't think you would have -- I
don't think we've advanced all that much in that amount of
time.
Now, whether, you know, the same applies to
this kind of work is not clear to me. Most people, for example, our
group and others who are doing this are doing this not with any
pragmatic aim in mind. We're interested in basic memory processes,
and so you know, I think from the perspective of the field, people who
are working on this stuff in the field aren't by and large doing it
from a practical viewpoint.
Whether the advances, you know, in the name of
basic science in the next 20 years would be sufficient to where we have
to start worrying, I just don't know. It's just hard to guess.
CHAIRMAN KASS: Well, thank you both very
much.
This is one of those occasions, I think Mike
Gazzaniga commented at the break, this is one of those occasions where
in addition to learning some interesting and wonderful things about
memory, memory research, that a certain kind of reassurance has been
provided with respect to at least the immediate concerns that some
people have, and it's good to be able to report things like that,
as well, and to a culture that's rather nervous about just about
everything that's coming.
If you would kindly stay at your seats while we
have a public comment from the one person who has signed up, it's
Wrye Sententia, who is the Director for the Center of Cognitive Liberty
and Ethics. I believe that's California; is that right?
MS. SENTENTIA: Yes.
CHAIRMAN KASS: And you've come a long
way and most welcome to you. We look forward to your comment.
PUBLIC COMMENT
MS. SENTENTIA: Thank you.
I just have a few brief comments that emphasize
two main points, and I'd like to start by saying that any
discussion of the ethics of treating or manipulating the mind or what
some people are now calling neuroethics must begin by protecting the
interiority of individuals' minds.
So our twofold principles are that, first, no
one should be forced to use drugs or mind technologies against their
will, and second, that no one should be denied access or criminalized
for their use.
The Center for Cognitive Liberty and Ethics is
a nonprofit, education, law, and policy center working in the public
interest to foster cognitive liberty, which we defined as the right of
individuals to think independently and autonomously, to use the full
spectrum of their mind, and to engage in multiple modes of
consciousness.
So in essence, we're working to protect the
full potential of the human intellect.
Cognitive liberty is an essential human right.
The United Nations' universal declaration of human rights and the
U.S. Constitution's Bill of Rights both support a basic human right
to cognitive liberty or freedom of thought.
The complexity of our social fabric conspires
to make any assignation of transcendent values difficult, particularly
when, as in the case of bio or neuroethics, the issues span such
elementary yet malleable values as individual and collective good or
quality of life.
The CCLE recognizes -- that's the Center
for Cognitive Liberty and Ethics -- recognizes, as does the Council,
that the complexity of many of the issues involving brain enhancement
are not easily resolvable.
However, we hope that by introducing the
principle of cognitive liberty into the discussion, the Council will
find useful distinctions in making its recommendations.
To the CCLE and our supporters, the question of
mind enhancement is fundamentally a question of cognitive
self-determination interwoven with an ethics of reciprocal autonomy,
autonomy not as arbitrary legislation created for oneself, but rather
as laws that permit whenever possible successful interaction with
others based on respect and tolerance for each other's core values
and freedoms.
I'd like to read a quote from Laurence
Tribe of Harvard Law School.
"In a society whose whole constitutional
heritage rebels at the thought of giving government the power to
control men's minds, the governing institutions and especially the
courts must not only reject direct attempts to exercise forbidden
domination over mental processes. They must strictly examine as well
oblique intrusions likely to produce or designed to produce the same
result."
Decisions about as intimate a freedom as
cognitive liberty should be allocated to the individual rather than the
government. The CCLE works from the premise that the role of the
state, criminal law, science, and ethics, should be guided by
principles that enhance opportunities for each individual to
self-actualize.
Public policy decisions should be framed by
principles of legal liberalism, not by moralism or paternalism. This
is not to say that morals or safety precautions have no place in
determining appropriate uses of drugs or mind technologies, but that
the role of the state should not be to determine what is or isn't
moral, what are or are not acceptable personal risks.
In our opinion, public policy for psychotropic
drugs and/or brain technologies should stem from our democratic
government's responsibility for preserving individual autonomy and
choice to the maximum extent possible.
While neuroethical issues are complex and often
deeply philosophical, the Center for Cognitive Liberty and Ethics
maintains that a solid starting point for practical discussion begins
with these two fundamental recognitions.
First, as long as their behavior doesn't
endanger others, individuals should not be compelled against their will
to use technologies that directly interact with the brain or be forced
to take certain psychoactive drugs.
Second, as long as they do not subsequently
engage in behavior that harms others, individuals should not be
prohibited from or criminalized for using new mind enhancing drugs or
technologies.
Simply put, the freedom and right to control
one's own consciousness is the necessary foundation on which
virtually every other freedom stands.
Thank you.
My written comments also have been submitted to
the Council which are extended.
CHAIRMAN KASS: Thank you very much.
Is there any other member of the public that
would like to make a comment before we adjourn?
(No response.)
CHAIRMAN KASS: If not, thanks to our guests
for stimulating presentations. Thanks to the Council members for your
attention during the long day.
You should have at your seat the directions for
where we are meeting at dinner, which will be, I believe, at seven
o'clock; is that correct? Let me have it. Six thirty for the
reception, seven o'clock the dinner.
I remind you that tomorrow morning we start at
8:30, and we will be joined by two distinguished guests from the U.K.
to talk about regulation in Britain.
The meeting is adjourned.
(Whereupon, at 5:33 p.m., the meeting in the
above-entitled matter was adjourned, to reconvene at 8:30 a.m., Friday,
October 18, 2002.)
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