Arthur F. Haney, M.D.
Department of Reproductive Endocrinology and Infertility
Duke Medical Center
CHAIRMAN KASS: 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
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
DR. HANEY: Can everyone hear me?
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
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
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
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
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
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
In vitro fertilization, simply taking the
selected sperm that you have and placing them in the dish with the
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
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
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
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
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
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
So that's the strategy between intrauterine
insemination. You simply have to wash them so seminal plasma is not
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
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
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
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
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
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
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
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
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
DR. HANEY: You're going to stress me
CHAIRMAN KASS: Well, roughly. What's
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
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
The floor is open for discussion. Mike
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
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
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
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
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
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
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
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 --
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
DR. HANEY: I'm sorry?
PROF. MEILAENDER: You engage in client
DR. HANEY: Define "client selection"
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
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
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,
DR. HANEY: It's just a matter of having a
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
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
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,
PROF. SANDEL: But the thing that works is the
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
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
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
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
And what's the practice at Duke? Just
continuing to accumulate these, or do you have a time after which you
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
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
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
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.
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
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
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
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
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
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
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
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
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
PROF. GEORGE: How about a borderline case like
DR. HANEY: I'm color blind.
DR. HANEY: And I don't think that's --
it's probably not fair to ask me.
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
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
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
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
DR. HANEY: Oh, I don't think that's
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
DR. HURLBUT: Pardon me?
DR. HANEY: We're treating disease,
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
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
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
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
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
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
(Whereupon, the foregoing matter went off the
record at 10:44 a.m. and went back on the record at 10:57 a.m.)