CHAIRMAN KASS: Thank you.

There will be a very brief public comment session after this. We have one person who has asked to speak, and we'll have that simply follow on this session without a break.

I want to express special gratitude to Gerry Schatten for agreeing to come. This is an appearance on very short notice, and it was prompted by the fact that reviewing what we understood Francis Collins was going to be presenting to this group by way of the influence of genomic knowledge on the possibilities for enhancement or any kind of intervention, most of what he had to say pointed in the direction of pre-implantation genetic diagnosis, a topic which has sort of come on our radar screen once or twice before, but which we haven't taken up thematically.

And what we thought would be necessary in order to evaluate this whole area of the uses of genomic knowledge for possibilities of enhancement, we needed to know something about pre-implantation genetic diagnosis itself, present and projected, how it works, who uses it, for what purposes, what its likely future disease and non-disease related prospects might be, and in particular, what this technology might look like were it to be wedded to the new screening possibilities that the Human Genome Project is making available.

And I think this is literally on a week to ten days' notice that we asked Dr. Schatten to come, and he graciously consented, and we are delighted to have you here and look forward to the presentation.

DR. SCHATTEN: Thank you, Leon.

And it's a privilege for me to be able to speak to this august body. And first I want to thank you all for the hard work that you're doing.

The bioethical issues surrounding assisted reproduction, reproductive genetics are issues that perhaps we should have been debating 25 years ago. Perhaps we should have had scholarly, learned, thoughtful, faithful people discussing before there were a million of these beloved souls on earth.

But it's wonderful now that we are having these conversations, and I'm grateful to be able to speak about where ART is going in the future.

What I'd like to do today is speak about reproductive medicine and pre-implantation genetic diagnoses, but I'll break my talk into what occurs clinically in the category of reproductive medicine, and then, secondly, what happens in the category of the molecular biology of development, and that is the fundamental science.

One of the problems that I think many of us get into is the crossover or the concerns of crossover between what is firmly on a laboratory bench and won't move to a clinic maybe in any of our lifetimes versus things that are already occurring in a clinic or could potentially go across there.

As you heard from Francis, pre-implantation genetic diagnosis requires assisted reproduction obviously because you need the embryo in a dish. The overall goal is strictly to help prospective parents realize their own dreams of having a disease free legacy, and I think it's important to remember that PGD is a method helping couples try to have children that will be healthy.

Many of these couples have lost children to spontaneous recurrent miscarriages. Others have learned that through prenatal testing their children were carrying devastating genetics, and they went through the agony of contemplating termination.

The PGD right now is useful with autosomal and X or Y-linked chromosomal diseases, chromosome rearrangements, and I'll speak first about in vitro fertilization, but later will come to a technique known as ICSI, intracytoplasmic sperm injection.

Finally we'll talk about reproductive aging, especially aging in women, and techniques that take a step beyond pre-implantation genetic diagnostics that are referred to either as aneuploidy screening or pre-implantation genetic screening.

Now, the way that these techniques have come to pass is first in vitro fertilization bypassed a blockage in the typically woman's reproductive tract where eggs could be removed from her ovary, put into a culture dish were a number of sperm were introduced, and the sperm entered the egg through the natural process, a process that we fully don't quite understand, but there are mechanisms that select one particular sperm to go through the outer coat of the egg and then to enter the egg through the plasma membrane.

Just about ten years ago a newer technique was developed known as intracytoplasmic sperm injection or ICSI. ICSI is a technique in which a single sperm is selected and injected into the egg cytoplasm.

Ironically, ICSI was discovered in humans and had to be discovered in humans. Animal models for ICSI are only now being perfected. It's a technique that works astonishingly well with humans, and in a sense, this is an example of translational research, but it's research from the bedside back to the bench.

Now, ICSI in mice and domestic species is working, but it turns out that humans were the easiest system to develop that in, and in fact, it happened on Brussels by Johnny Palermo in an almost accidental way.

He was trying to inject a sperm into the space underneath the zona pellucida. It's known as SUZI, subzonal injection, and the micro needle went into the egg. The sperm entered the egg, and surprisingly the egg and embryo developed very well.

And so I think while we may all want to plan for the future, we might also need to be open to the fact that accidents happen, and the accidents aren't always negative.

I'll talk a little bit about the fact that in vitro culture may have consequences on eggs, but we're talking today about pre-implantation genetic diagnosis where you take one cell, one blastomere and do genetic testing on that.

This is a slide from Andre Van Steirteghem at the Free University in Brussels, and here you can see human oocytes, where you can see the sperm and egg nuclei together, and the nuclei line up. First division, second division.

The stage that's called morula. It looks like a mulberry, which is what the Greek term means, and later that mulberry-like cell squishes down to become a compacted morula, and this is the blastocyst that I think you probably all know and love now.

The outer cells of the blastocyst become the placenta. It's some of those inner cells right here that are the inner cell mass cells that can form into the fetus. Maybe only a few of them form into the fetus, and those are the cells from which you derive embryonic stem cells.

An interesting feature that is being deciphered by people like Richard Gardner and Roger Pedersen in the U.K. is the intrinsic polarity in mammalian oocytes, and let me just say that there are thoughts now that the axis at which the first and second polar body come off of the egg actually determines our dorsal-ventral axis, and the site at which the sperm enters determines our left-right axis.

And the reason that becomes important is that even though we may say that there's no -- the oocyte or the embryo is completely plastic and there's no problem in removing one or two cells, the actual information on that is still unknown.

Okay. The way blastomere biopsy occurs is simply a fine needle is used to aspirate a single cell. As you can see, if there are fewer than six cells, typically one cell is taken. If there are more than six cells in Europe, two blastomeres are taken. The eggshell, zona pellucida, is dissolved either with a bit of acid or with a laser, and here you can see those two individual blastomeres.

And you need to understand that this technically is extremely demanding because you have one cell or two cells, and the embryo is now growing in your dish. If you're going to do a blastomere biopsy on day three, you need to transfer the selected embryos by day five. So you have 48 hours with which to do the genetic diagnosis, reassure yourself that the diagnosis is correct, and then have the physician speak with the patients so that they can analyze the results.

Time is of the essence here, and there is not much leverage. In the context of PGD, it was performed many years ago in the late '60s. Richard Gardner and Bob Edwards performed it with rabbits, and interestingly they noted that one of the offspring was acephalic.

The work that most of us -- PGD was pioneered in humans by Lord Robert Winston and Alan Handyside, and Alan Handyside at the University of Leeds was gracious enough to loan me a number of these slides. This is the first report of using PCR to look at a Y specific screening so that you could assure yourself of only having girls so that you wouldn't end up with X-linked disorders in boys.

This is adrenal leukodystrophy. This is Bob Winston here and Alan Handyside with a happy couple, and you realize that the thorny issues of sex selection in part come out because of the development of techniques to assure that X-linked or Y-linked diseases are not passed on.

The way the technique works, and I think it's important to have a reality check on this, is that there are a certain number of oocytes that are collected from a woman who undergoes hormonal stimulation. There is a finite number of eggs. A dozen eggs is a credible yield. Here is ten, and only a fraction of them will fertilize. In the Brussels clinic they fertilize all by ICSI, and even in their skillful hands, only 80 percent of the embryos develop.

Then you go through the analysis, and as you go through the analysis because you're looking at only one or two cells, sometimes the results are ambiguous or there's no result. Sometimes you have the mutation present, for example, in the case of cystic fibrosis or sickle cell disease and you wouldn't transfer those.

Ultimately what you're hoping for are healthy embryos that are developing well, and so while you may think that the ability to screen for all of the traits that I manifest, that is to say, you know, going for blond hair, blue eyed, you know, tall people, would be admirable, the reality is that there are typically too few eggs, too few embryos to really screen for a zillion traits.

Here is one example of the use of fluorescence in situ hybridization, or FISH, and you can see the three chromosomes in this one blastomere Trisomy 21, and this is the work of Santiago Munne at St. Barnabas Clinic.

Here is Trisomy 15. Work from Alan Handyside speaks to the use of multi-colored FISH sequentially so that now even nine different chromosomes can be identified in the very same interfaced cells.

Francis Collins is the pioneer of the genetic basis of cystic fibrosis, and now it's possible to determine which embryos will carry cystic fibrosis versus -- which embryos will have cystic fibrosis versus which ones will carry them, and you might notice that some cells have no diagnosis because of technical difficulties.

Myotonic dystrophy, Huntington's disease, there are a whole host of diseases that can be screened right now using pre-implantation genetic diagnosis, and I'll come to those in a second.

Another technique that is emerging is comparative genomic hybridization, often called CGH, and these slides were loaned to me by Deegan Wells (phonetic) also at St. Barnabas, and it's an extraordinary technique where you can use the embryo's DNA referenced against normal DNA to ask whether you have the right mix of chromosomes, one too many or one too few, and the ratio between the green color and the red color gives you that indication of a normal trisomy or monosomy, and one example of this looking at a first polar body is over here where you can see this chromosome has a reddish tinge, and you can see over here that that's shown quantitatively by measuring the red versus yellow.

And when you come back later, and the light is a little bit too high for you to see that, but there are, indeed, three dots demonstrating that there are three copies of this chromosome in this polar body.

And CGH is a semi-automated way, but it still is incredibly demanding. CGH can be used with chromosome paints so that you can actually see not just whole chromosomes that are present, but also chromosome rearrangements.

The European Society for Human Reproduction and Embryology recently started a PGD consortium, and this includes quite a number of clinics, nearly 30 clinics around the world, and you can see that this comprehensive registry is finding use in a number of autosomal dominant diseases.

Now, you need to remember that an autosomal dominant disease will be one in which 50 percent of the embryos will be affected. There are recessive diseases where one out or four embryos will be affected. X-linked will, of course, be -- the boys will be affected, and the various chromosome anomalies.

And I want to impress on you that the numbers are growing. There are areas in the technique. Some of these involve allele dropout, as well as overlapping signals, but the error rate is good and getting much better.

I did want to say a word or two about the genetics of infertility, and especially the genetics of male infertility since we're so close to the Capitol and the White House. It's important to remember that the father of our country, in fact, was no father at all. George Washington did not have children. Martha did from her first marriage. He never adopted her children, though he did adopt her grand children. And historians have written about whether George Washington's mumps as a teenager might have been the cause of his infertility and whether a monarchy might have been more attractive to him had he had an offspring, but moving right along.

(Laughter.)

DR. SCHATTEN: I mean it is funny that we can talk about the genetics of male infertility. You know, there's a joke that if your grandparents don't have children and your parents don't have children, then the likelihood is that you won't have children.

(Laughter.)

DR. SCHATTEN: But you know, we're now in this strange scenario where we know through the extraordinary work of people like David Paige and Sherman Silver and Pasqualle Patricio that there are micro deletions in the Y chromosome that render certain men infertile, and that you can collect their sperm, inject them into an oocyte, and their daughters appear to be normal, but their sons are carrying this same Y chromosome micro deletion.

And this all involves the technique of ICSI, and what I have here is a slide from the latest CDC SAR data of the prevalence of assisted reproduction and ICSI in the United States, and you can see that sine '95 the number of ART cycles is growing, and there are predictions in our country that it will soon be above one percent of all births.

In some countries in Western Europe up to five percent of all births are by ART.

You can see that multiple gestations continue to be a problem, but I'd like especially to focus on this technique of ICSI, intercytoplasmic sperm injection. It's a technique that could not have been discovered in animals. It doesn't work well in animals, and it's remarkably successful in humans, and it's growing, and we don't know everything about it.

Here is a slide in humans from Andre Van Steirteghem where you can see a single sperm is aspirated into a fine needle. That sperm is then taken to an unfertilized egg which is held by a polished needle.

This is a polar body right here. The sperm is injected into the egg, and then the needle is withdrawn. And it's a remarkably successful technique. There are some clinics that report up to 90 percent fertilization.

It's amazingly important for certain genetic tests because if there are too many sperm around the egg, the genetic testing will fail.

There are some differences in the choreography of fertilization by ICSI versus the fertilization by IVF, and this is the work of Laura Hewettson and Cal Simerly (phonetic) in rhesus monkeys where you can see there's a collar around the sperm nucleus that's brought into the egg, and the X or Y chromosome actually remain up at that edge.

This is the egg nucleus and the sperm nucleus, and I won't belabor this, except to say that there are differences in the way in which the sperm nucleus decondenses after this form of ART, and this is the work of Sherman Silber and Santiago Munne showing that severe oligospermia or severe azoospermia.

That is, there are certain men who produce no sperm in their ejaculates. There are techniques where you can use testicular sperm aspiration or epididymal sperm aspirations, and even though there's no sperm that's released by the man, sperm can be collected through this procedure, but even doing that ends up with embryos that turn out to have chaotic chromosomes as analyzed by spectral karyotyping.

For example, here you can see that there's mosaicism and chaotic chromosome separation with a variety of trisomies in that embryo, and another use of PGD has come up because of ICSI, because of the importance of asking whether the men who might carry chromosome anomalies that render them infertile are now making sperm that might carry those same chromosome anomalies.

Here's an animation where the sperm is brought into the micro needle, injected into the human egg, and so a second use of pre-implantation genetic diagnosis has been to screen for chromosome anomalies after male infertility treatments, especially after ICSI.

And you can imagine the heartbreak for a couple to go through all of the noninvasive, expensive procedures of ART, to have a baby with male factor infertility, only later to do prenatal diagnostics and have to grapple with whether or not they want to choose -- whether or not there's a chromosomal error and they might have to terminate.

Okay. I want to now move to the issue of female factor infertility, and the women in the group will know that your biological clocks tick far faster than men's biological clocks. No one of us knows exactly the reason, but you can see here that the rate of implantation drops with age, as does the rate of aneuploidy and one of the reasons that women over 35 typically choose to have Down's Syndrome screening is because of this rate of trisomy.

Recently a new technique has been pioneered in the United States and in Europe that's referred to either as aneuploidy screening or pre-implantation genetic screening.

Excuse me. Yeah, let me go to that, and then I'll come back to this. Nope, I'm going to go back.

Aneuploidy screening is a technique where you're looking at a variety of chromosomes in the pre-implantation embryo and only transferring embryos that have the correct number of chromosomes. And the argument is that rather than transferring embryos that might have abnormal chromosome numbers, by doing pre-implantation genetic screening, you can transfer only those embryos that have the correct number of chromosomes, and I'll come back to some controversy on that.

There's a technique that involves looking at the first polar body that Yuri Valensky has pioneered in our country in Chicago, and this is an interesting technique because it's a technique that falls into the category of gamete selection rather than embryo selection.

So the polar body, which contains the maternal DNA, can be removed from the egg and it contains the chromosomes that are in the egg, and you can do genetic testing on it.

Now, it won't address issues of paternal or fertilization anomalies in genetics, but it will address maternal issues.

Recently there's been a lot of discussion about another technique that attempts to in a sense turn back the biological clock of eggs, that is, eggs from women after about the age of 40 have great difficulty in implanting, and the clinic led by Jacques Cohen at St. Barnabas has used a technique known as cytoplasmic transfer whereby cytoplasm typically from a younger donated egg is injected into an oocyte from a couple that is experiencing repeated IVF failures, and it's done with an injection of the sperm along with the cytoplasm.

As I think this group already knows, we inherit our DNA from both parents in terms of our nuclear DNA, but all of our mitochondria come from our mother, and so this technique of cytoplasmic transfer has the unrecognized, unappreciated risk of bringing in extra mitochondria. So you could end up with an egg or an embryo and now offspring that in a sense derive their mitochondria from two maternal sources.

And that brings me to a brief discussion of nuclear versus nonnuclear, extra nuclear inheritance. I think all of us think of our DNA as coming half from our dad and half from our mom, and until Dolly, each and every one of us had exactly precisely one mom and exactly precisely one dad.

One of the extraordinary things about Dolly and how it surprised so many of us is that suddenly with somatic cell nuclear transfer you had an offspring in a mammal that didn't have exactly those two parents.

Some of you may know about issues of genomic imprinting or of parent of origin imprints, and unlike non-mammals, in a sense we have a special code in our genome, almost a fifth nucleotide that is linked to our DNA that tells our cells who our dad was and who our mom was. So that there's a memory of the paternal DNA different from the maternal DNA.

And that memory is very important. It's referred to as genomic imprinting. There are certain diseases, like Angelman Syndrome or Beckwith-Wiedemann Syndrome, where there are errors not in the number of chromosome, but in the inheritance of precisely an equal number of chromosomes from a dad and a mom.

And it may well be that there will be new tests on genomic imprints, and furthermore, Alan Hoage and Tracy Prosen at Magee Women's have been looking at skewed X chromosome inactivation, and the women have only one X chromosome that's active, and it turns out there's a group of women who suffer from recurrent spontaneous abortion. They lose their male fetuses in utero. They tend to give birth to daughters, and those daughters also have skewed X chromosome inactivation so that they also give birth to daughters, but they tend to lose their male fetuses in utero.

And this is a weird transgenerational imprinting transmission. It's sometimes referred to as a miscarriage gene, but it's not because there's an error in the number of X chromosome or X or Y chromosomes, but rather, there's an error in the way that they're imprinted.

Mitochondrial DNA is also inherited in a non-nuclear fashion as might other structures in the cell, and these may well serve as the basis for future genetic tests.

Now, a major point that I want to make, and it may not be obvious to this group is that nature has a quality control strategy. Nature has a quality control strategy whereby there's an abundance of gametes for conception, and then unseen by us, there is embryonic withering in vivo. The best estimates are that maybe only one out of every four conceptions naturally results in an offspring.

Now, an irony of assisted reproduction is that the unwitnessed loss of these embryos in vivo can now be witnessed in the culture dish because ART now permits the witnessing of all of those failed fertilization attempts.

So that you can see how the arrested embryos. You can see the defective embryos. You can see all of those embryos that a woman wouldn't have even known about. She wouldn't have even missed a monthly cycle, but now because of test tube fertilization, you now see them in a dish.

And in addition, ovarian stimulations produce additional eggs rather than just that one per month, which also leads to witnessing some of this quality control as well as the thorny decisions of which embryos to transfer and what are the fates of those other embryos.

There's a lot of evidence for aneuploidy in human development, and this is the work of Terry Hassold and Pat Hunt at Case Western, where it appears as if maybe three to four percent of sperm are aneuploid. Oocytes are far greater in aneuploidy, and it may well be that one of the strategies that nature uses for making those six or seven million oocytes in the fetal ovary but only having maybe 400 of them ovulate in the course f a oman's life is to select for the ones that have the correct chromosome numbers.

These estimates of the numbers of pre-implantation and post implantation losses are, indeed, estimates, but it's clear that there is a great deal of loss that occurs naturally, and in many ways I think we can be grateful for this because this natural quality control system assures that the vast majority of babies born have the correct number of chromosomes and are all healthy.

And you may remember that there's only rare cases of trisomies. There are no cases of monosomies. So that there is an in-built method to assure that most all chromosomes have the right or most all offspring have the right numbers.

Here, again, is a diagram of that, and it comes from a combination of both looking at the losses in the first trimester versus PGD, and you can see that there's a great number of monosomies seen in the pre-implantation embryos from the work of Santiago Munne, but those don't even show up as implantation attempts.

There are a great number of facts that are needed for assisted reproductive technologies. Sadly, maybe 20 percent of our population is infertile, and the American public doesn't really know whether these techniques are as safe and as effective as is humanly possible, and it would be ideal not only to reduce the risks, but also to be able to weigh the risk-benefit ratios.

We don't know about the outcomes of ART. We don't know about the children or the grandchildren, and it may be years before we get that information, though we should be garnering that information now.

We don't know about the consequences of our first environment, and as Francis Collins said, identical twins are not identical in their behaviors or their health, which is to say that the environment does play a role.

There are problems in garnering this evidence. Some of the problems is that there are differences among the various ART practices worldwide and especially in our country, and all of these practices are outside of the purview of federal funding.

There are variations in the way that the data is collected, and the innovations occur so quickly that frequently the innovations are introduced clinically and one doesn't even know whether they're optimized or meritorious.

Also, different programs vary in their technical expertise, and so consequently you frequently see that statistics vary from one program to another, and the innovations are abandoned quickly and then replaced with newer ones, and therefore, even trying to get retrospective information is challenging.

And finally, and perhaps most importantly, infertile couples just can't wait years and years for full data to be compiled because their biological clocks are ticking. Even getting information is important, but disseminating it is problematic because there is natural competition among the ART programs.

There are technological issues. There's proprietary issues, and I don't need to belabor that.

And so let me now switch to the science behind some of these techniques and acknowledge to many of you that I am, indeed, a monkey's uncle. My niece hates that. This is the first ICSI monkey made. We've made a number of these animals.

And I want to distinguish at this segue that reproductive medicine is a different field, but it's related to a field of developmental molecular biology. Reproductive medicine is helping prospective parents realize their own dreams for a disease free legacy.

Developmental biology though is understanding the molecular basis of healthy development and the root causes of illnesses. And so when you hear about the human genome and you hear about genetic enhancement, much of that comes from extrapolations of what occurs in a laboratory bench working with mice, and it's important to talk about where this field can go and especially to talk about that zone of concern that Francis Collins spoke about.

But I think it's also important to focus our energies on what might occur within the next 25 or 50 years and not to lose too much time to issues that probably won't be within that time frame.

Designer babies do not exist, nor are the technologies available. Humans have not been cloned. Monkeys have not been cloned through somatic cell nuclear transfer.

There are too few embryos available for nontherapeutic selection, and let me remind you that even therapeutic selection costs a fortune. And so I think while ART raises many important issues, and I commend this panel, the engineering of humans is very speculative right now.

By studying ICSI we've recently shown that the sperm can be a conduit for foreign DNA, and in this case we used a DNA molecule that carries the green fluorescent protein, and you can see here in monkey ICSI, you can see that there's a red sperm that when introduced into a monkey embryo can give you the marker gene expression, and this is the green fluorescent protein. It just tells us that this foreign gene was brought into the primate embryo.

This is a primate blastocyst where you can see the inner cell mass cells, and this began the very first step towards genetic engineering in a non-human primate.

Now, I should remind you that the techniques that we used to make a genetically engineered monkey were techniques that were reported already in 1971 by Rudy Jaenish and John Gurdon and Frank Ruddle, and if an infertility specialist was, indeed, a rogue who wanted to make genetically modified people, already they could have been doing genetic modifications in humans when they were making the first test tube babies a quarter century ago.

There was no reason for doing it then. There is no reason for doing it now.

I will present to you how we did it in this case last year where we basically used the methods of gene therapy for bringing a foreign piece of DNA into the egg of a Rhesus monkey, and here you can see the viral vector which brings in single stranded RNA, which once it's within the unfertilized monkey egg is reverse transcribed first into single stranded DNA and then into double stranded DNA.

The strategy that we use only enters chromosomes as they are decondensing from a miotic or a mitotic stage to interphase, and so because we introduced this into an unfertilized egg, we knew the egg's chromosomes were already arrested at second miotic metaphase. So the foreign DNA entered the blueprint of the maternal chromosomes.

We later fertilized this egg by ICSI, and you can see here the sperm enters the egg by this injection technique, and the eggs developed well, and they carried the marker gene in them, and they implanted it roughly at the same rate as control Rhesus offspring.

And you might ask the question: why perform experiments in adding a gene to a non-human primate, and as Francis mentioned, mice are extraordinary models for blazing the trails on human disease mechanisms, and indeed, there are mice that carry cystic fibrosis, and there are mice that carry muscular dystrophy and Alzheimer's proteins and a whole mess of other human genes.

And in fact, one of the reasons for sequencing the human genome is to make mouse models to understand the behavior of those human genes in a mouse. But there may be diseases, for example, like autism or maybe schizophrenia, where a primate intermediary, a small number of primates would fill a gap between mice and patients.

And so we are exploring that technology, but not for the purpose of genetic enhancement in people. There is a confluence though of what can occur in the reproductive laboratory and the reproductive clinic. For example, one method is a method that we used two years ago to dissociate primate embryos into individual cells, and of course, this is part of the pre-implantation genetic diagnosis technique where we then later made artificial twins and artificial quadruplets, and this is one artificial quadruplet.

This work also leads to discussions about nuclear transfer, and this is a somatic cell nuclear transfer in a monkey egg, and I can tell you from work in our lab that monkey cloning is far, far harder to achieve than mouse or sheep cloning, and the reports that you read about in non-peer reviewed journals are not worthy of consideration. Primate cloning, including human cloning will not be in our lifetimes.

And let me just end here by asking your panel to consider the important work that needs to occur regarding the bioethical issues associated with ART. You all know of the history of Asilomar, and I almost wonder if the country needs something that might be like an Asilomar meeting, but would be focused around ART. The term "ART - silomar" may be the wrong term, but I think you know where I'm going with this.

And part of the reason is that there are these discussions about stem cells and cloning and germline transmission and genetic enhancement, and a consensus meeting with knowledgeable stakeholders and maybe as an ongoing forum, I think, would be commendable both for the biomedical community, but also for the public at large.

Ironically the ELSI funding that went into the Human Genome Project does not support studies on assisted reproductive technologies and reproductive genetics, and part of that involves the thorniness of human reproductive issues at a national level.

I think having ELSI sponsorship for reproductive genetics is important, especially to define what is feasible and to articulate reasons for going forward or not.

We, as your committee came up with, we all have a real problem even with nomenclature. It's important to safeguard ART and determine what clinical approaches are widely accepted versus which ones are probably not warranted, and maybe equally important is to have wide public conversations about what's feasible and what is truly science fiction.

And I think this committee could help by fostering an ongoing conversation with the public at large. In a certain way, I think what you're grappling with with reproductive genetics embryo selection may rise to the level of the Human Genome Project. It might even be something equivalent to a Manhattan Project where for the first time you will be looking at the behavior of genes in a cell with profound societal implications because really where the DNA expresses itself is in the egg cytoplasm, and it has among the most profound of implications.

And I've heard some people talk about thinking of a Manhattan Project but with one difference. A Manhattan Project brought a number of brilliant people together. It brought standardized resources and ethical issues together, but the Manhattan Project was performed with complete secrecy.

I think in many ways this field of ART reproductive genetics needs to be different from a Manhattan Project because it needs to have complete transparency.

The public, I think, is concerned about what is going on with stem cells, what is going on with embryo selection, and I think your panel could help allay may of those suspicions.

The oldest children from aneuploidy screening, from ICSI have not even entered preschool. This is the right time to be fostering ongoing studies on the outcomes of some of the techniques, and here you can see a cartoon of a little alien and one mom speaks to her friend and says, "You know, Jeffrey was a surprise," and God knows none of us wants to have surprises from any of these techniques.

And let me, you know, again, thank the many people who helped me put this talk together, including Alan Handyside, Andre Van Steirteghem, Santiago Munne, Sherman Silber, Kathy Hudson.

And, by the way, that scene from Gattaca was prepared by Glen McGee, who comes from Penn's Center for Bioethics, and so the reason the Gattaca scene was done so well was it was actually written by a bioethicist.

Thank you for your attention.

(Applause.)

CHAIRMAN KASS: Thank you very much. A very interesting talk.

Can we get the lights?

And Michael Sandel.

PROF. SANDEL: Thank you very much.

I have a question about the purpose and the practice of ART. When I came in untutored, I assumed that the purpose of assisted reproduction was to help infertile couples have children, and so I was taken aback to learn from the mission statement that you put up a couple of times that the purpose of reproductive medicine is to help prospective parents realize their dreams for a disease free legacy.

In fact, it almost had kind of Gattaca-like chilling overtones, that formulation. I hadn't thought that a disease free legacy was the purpose of the assisted reproduction, though it occurred to me that some people might go in for it for that reason.

So my question is partly about the mission, but also about the current practice. Of the people now who use it, are most of them people who have infertility or are there people who go in for it who are not infertile but who go into it for reasons of genetic screening?

DR. SCHATTEN: Let me clarify that. That term was mine that I came up with early this morning for you because the combination of PGD with ART is the search for a baby that wouldn't have cystic fibrosis. So that's why I spoke about the disease free legacy.

Now, ART has its origins in treatment for infertile couples, and with a combination of pre-implantation genetic testing, now couples have the ability to screen before implantation. And so I meant it strictly in the category of couples who might carry, for example, Huntington's disease or some of these other inherited diseases.

PROF. SANDEL: But of the people who actually use it, are they all infertile?

DR. SCHATTEN: No, no. And, in fact, that's a very interesting issue because many of them may be infertile and carry a disease, but there is and I would guess it's roughly a third of people who choose PGD are otherwise fertile, but may have had children that have cystic fibrosis or muscular dystrophy or they may have had previous terminations, and they for a variety of reasons are unwilling to go through that again.

Embryo biopsy is a complicated technique, and it's a very expensive technique, and it's not clear that it is completely innocuous. So you would not go into embryo biopsy unless there were compelling reasons for actually going through all of the costs and expense and heroics of ART.

Thank you.

CHAIRMAN KASS: Michael, are you okay?

Rebecca Dresser and then Frank and then Janet.

PROF. DRESSER: Thank you for being willing to exercise scrutiny over your practices. I think maybe you've got some negative responses from some of your colleagues. So I really am grateful for your willingness to raise some of these questions.

I was wondering if you had given thought to what a responsible system of research should look like for these new procedure. Do you think it should be modeled on what's required for new drugs and devices or, you know, with the animal research in certain species and then different phases of human studies, or do you see something else being appropriate?

DR. SCHATTEN: Thank you for your comment.

And, by the way, I think the reproductive medicine community shares the view that ART is, indeed, a gift for the couples who enjoy success. It's safe and it's effective, and certainly future research will make it even safer and more effective.

In shaping public policy or science policy on this, I don't have a single simple answer. Certainly if there were broader coverage for ART, maybe 75 percent of the couples who are unable to afford it would be able to afford it, and therefore, there would be equal access, and an irony would be by performing more ART cycles, not only would more people be treated, but the field would benefit from the increased knowledge that would be garnered both clinically and more fundamentally.

There's also an irony in our federal funding system, and you'll know this better than I will, but we know that not a single penny of federal dollars ever goes to support a single abortion. There is, you know, clear mechanisms to insure that that will never happen.

And yet within the research community that pathological, that discarded material can be investigated. Ironically, the field of infertility research has additional barriers on it so that not only does not a nickel of federal money go into supporting ART itself, its clinical practice, but further, no research on the pathological discarded material is permitted.

And I know this gets into the issue of what's appropriate for federal sponsorship and what is not, but the public is left with inadequate answers in our country about what are the best practices. And you know, you asked a good question. Should these be treated as if they are drugs where the FDA would regulate them as if they were, you know, new compounds that would be tested first in vitro and then in mouse models and working its way up?

And as you see, this field moves very swiftly. New methods are introduced almost every couple of years, and some of those methods are developed in the United States. Others are developed in Europe or in Asia, and somehow it would be commendable if the United States could play a responsible but proactive rather than reactive role in grappling with the ART innovations.

Let me just end this by saying who among us a quarter century ago could have predicted that IVF would have given us a million children. I mean these are the most beloved children on earth, maybe after my own. Who among us could have predicted that ICSI would have been so marvelously successful in treating male infertility?

Who among us could have predicted even five years ago that this committee would be debating human embryonic stem cells?

And of course, you need to remember that none of those human embryos were made with federal funds. Indeed, none of the human embryonic stem cells were made with federal funds.

And so when we grapple with where the field is going, and we need to be grappling with these things, I think we also need to acknowledge that we're on a journey together and no one of our crystal balls is clearer than the other, and that we just need to foster the conversation and maintain it in an ongoing way.

CHAIRMAN KASS: Please, Rebecca, go ahead.

PROF. DRESSER: I guess I just hear some inconsistency, and I thought that the rest of some of your writings and your statements here was that some of these techniques are being widely used without sufficient information about risks to the children, as well as information that you would want to have so that the couples could make informed decisions about whether to go through the procedures.

So it seems to me to say that, on the one hand, I mean, it seems to me then you would have to favor some more cautious approach at the front end rather than just saying insurance should cover it and more people should go through it.

DR. SCHATTEN: I do have a degree of inconsistency, and part of it comes from being a basic scientist and recognizing what the evidence is to get a paper published in a peer reviewed journal is versus also having been infertile myself for a number of years and knowing about the heartache of yearning for your children.

You know, there's a reality. On the one hand, some of us might say, "Look. We don't understand the molecular genetics of miotic errors in yeast yet, and so we need 35 years and many millions of dollars to study that, and it's inappropriate to transfer these technologies to people until we understand miotic aberrations.

And, on the other hand, if a couple is experiencing infertility, they can't wait 35 years. And, in fact, they're paying to have things done to alleviate their own infertility, you know, for their own therapy.

And there is a dynamic here where reproductive medicine and molecular biology are intersecting, but there isn't a perfect union, and I think it would be devastating to say that, you know, infertility treatments need to be dialed back because all of the information isn't out there yet.

I think instead what we need to be doing is garnering the information while we're also allowing people to have the families as they themselves define it with their doctors.

CHAIRMAN KASS: But let me just press Rebecca's point further. We have embarked now on the practice of pre-implantation genetic diagnosis, the desires that the parents acknowledged. Is there even a prospective study in place to study the effects of this procedure on the children who, of course, it is on their backs that the satisfaction of legitimate parental desire is going to be worked out?

I mean, to take two-eighths of an eight cell embryo and to proceed on this without being -- granted maybe you couldn't do it in other species first, and even the animal studies won't give you the security you need about being confident that this is absolutely safe in humans.

Wouldn't you think on the front end before one encourages the demand for this practice that one takes some kind of steps to make sure that this isn't really actually harming these children? And what is being done on that?

DR. SCHATTEN: First off, there are careful, comprehensive studies being done on the outcomes of PGD, not in the United States, but in the European countries, and I think it would be a great step forward if the United States could participate more proactively in learning if, you know, admittedly these experiments are having unintended outcomes.

So I agree with you that research does need to be going forward, and I also agree with you that we should have a forum, a mechanism to articulate, debate, and evaluate which future treatments should be accelerated or investigated.

But in our country because all infertility practices are private, there is this disconnect between other aspects of medicine. For example, with other aspects of medicine the NIH can sponsor it. You can get careful studies performed. When insurance companies cover it, there's additional scrutiny about the efficacy of the treatment.

You know, certainly ART in our country and around the world is regulated. It's regulated by various professional societies. It's regulated by the CDC. It's regulated by every hospital and Institutional Review Board. But we do have a strange gap where infertility clinics are performing clinical research and clinical practice, and then others are performing very fundamental research, often with mice, and the NIH which normally fosters the important translational and clinical connection between the fundamental and the clinical practice is not as actively engaged for reasons that you all will understand better than I do.

CHAIRMAN KASS: Well, Rebecca did mention, I think, the Food and Drug Administration, which did a few years ago claim authority over human cloning. Whether that's a statutory proper interpretation of the statute we're going to actually have someone come talk to us about this in the future.

But, I mean, there are lots of things that are developed in the private sector that have the questions of safety and efficacy attached to them, and that we have a mechanism for review.

DR. SCHATTEN: And I think the FDA is doing a fine job with that. I hear from my reproductive physician colleagues that the FDA is not charged with regulating medicine, and I think there is a conversation that gets testy at times between what is the appropriate role of the FDA and what is the authority granted to physicians for practicing medicine.

CHAIRMAN KASS: I guess the gentle way of putting the question is: if this is a branch of medicine and responsible medicine in which one is not only dealing with the infertility of the adults, but is bringing into the world children who may be at risk from the procedures used to bring them into being, it would seem to me that the responsible practice of medicine by that profession would see to it that not because it's imposed upon them, but would somehow see to it that all kinds of proper scrutiny is given to that practice and not dependent upon whether the government, in fact, has taken that role.

And the question is: is this an area where as you say yourself the innovations come fast and furious and they replace one another before anybody has had even a chance to study their effects?

And what really is the professional self-regulation in this area and the proper scrutiny of what all of this is doing?

That's --

DR. SCHATTEN: Leon, I must say those are excellent questions, and I think very few of us really would like the government to be under the sheets in our bedroom. You know, one could argue perhaps that women of child bearing age should be tested for drugs so that, you know, compounds that could affect the offspring, fetal alcohol, whatever, you know, shouldn't affect the next generation.

And these are thorny issues, and I don't pretend to have the answers, but having been infertile myself, I know that there are issues involving procreation that I prefer to sort out in a way with my own doctor and not necessarily have folks from the government here to help me.

CHAIRMAN KASS: Frank.

PROF. FUKUYAMA: Well, actually I had two questions, but the last round asked the first one. Basically I was going to ask about the politics of how people -- maybe I could just do a little bit more specific thing.

Is there a difference between the clinical practice and the scientific research community? I mean is one more hostile to this kind of oversight than the other, or is it pretty much across the board? That's my first subset of the questions that Rebecca and Leon were raising.

The second one is completely different. In terms of boosting the enhancement potential for PGD, the big limitation is the number of eggs. I mean, we saw from beginning with Francis Collins' presentation.

Lee Silver, when he talks about this talks about all sorts of strategies for boosting the number of eggs so that you'd have a greater degree of selection including, you know, harvesting them from, you know, fetal eggs from female fetuses.

Do you regard all of that in the realm of science fiction or which of those practices do you think are realistic?

DR. SCHATTEN: I have to say I love science fiction as much as the next guy or woman, but I think it's important that we don't lose our concentration on things that are truly fiction. Isolating oocytes from female fetuses is way, way, way science fiction. It doesn't even work from mouse fetal ovaries except in perhaps one or two hands.

As you pointed out, the issue of the number of high quality embryos produced in an infertility clinic is the major issue, but it's not just the number. It's also the difficulty of getting those embryos. So very few people can afford it. Very few people would be motivated to do it. You would need truly a very strong rationale to do this.

And further, you won't find many infertility clinics or maybe you won't find any infertility clinics that would consider even doing sex selection for family balancing. So to talk about having a limitless number of embryos from which you can screen for a certain number of inherited traits to give you genetic enhancement I think really is science fiction.

PROF. FUKUYAMA: The first question was about whether there are differences in the resistance to oversight.

DR. SCHATTEN: Yeah. I don't think there are. There are discussions that go on between the very basic scientists and the clinical community, and I've heard it stated most historically in the context of why is it whenever the NIH funds anything on ART it only funds research that raises concerns. It never funds research that is improving the approaches.

And I think in a certain way that's a legitimate criticism, though ART hasn't been studied with the vigor and depth that it deserves. I think the biomedical fundamental community and the clinical community agree that all evidence supports the fact that ART is quite safe. The rate of congenital malformations is not significantly different from the general population.

There are studies that come out and every one of those studies is scrutinized, and it's hard to know whether or not the study itself has some errors or bias. For example, next month there will be a paper out by Andy Feinberg at Johns Hopkins that report on an increase in a genomic imprinting issue of Beckwith-Wiedemann Syndrome after ART.

One doesn't know whether the voluntary registry might have been skewed because couples that can afford to use ART might participate in this Web based registry more than the general population. Perhaps there are, indeed, some consequences of the in vitro environment that we don't yet understand.

One of the challenges I think for the public is that you hear alarming reports that are rarely put into the proper context, and I think for infertile couples they tend to be so motivated in having their biological children that an increase perhaps from, you know, one in every 100,000 births to now, say, six in every 100,000 births or whatever the ratio is probably isn't at the level of concern for those motivated individuals.

And also, you need to remember that the infertile patients, you know, have some underlying issue, and so perhaps you wouldn't expect their offspring to be absolutely level with the general population because there is a genetic basis to infertility.

CHAIRMAN KASS: Okay. There are a couple of our members who have a plane to catch, and I would like to thank them and wish them a happy holidays and excuse them. If there's one of those who has to leave, I'd give you the privilege of jumping the queue and asking your question if that's the case.

All right. Then let's proceed in order. I have Robby George, and then Janet.

PROF. GEORGE: I'm happy to defer to Dan. Oh, you don't have a question?

Dr. Schatten, my first question is really just a yes/no question. I want to make sure I understood you. Were you telling us that no human or even monkey embryo has been created by SCNT or will be in our lifetimes?

DR. SCHATTEN: Yes and no.

(Laughter.)

PROF. GEORGE: Oh, both answers then.

DR. SCHATTEN: No offspring have been produced in monkeys and I don't believe any of these extravagant claims of people who claim that they have human SCNT gestations that should come to term.

I think, you know, one of the dangers of human SCNT offspring is that it captures so much of the media's attention that, you know, this nonsense is being discussed as if it were reality.

Now, let me switch to your other question, and, yes, SCNT has been attempted by us in monkey eggs and also by Don Wolf's group, and those don't develop.

Also, as we know from advanced cell technology, human eggs were reported to have been used for SCNT in that report that you folks grappled with. So, no, no offspring; yes, in vitro attempts, failed attempts.

PROF. GEORGE: Failed to produce an embryo or failed to produce an embryo that could sustain further development?

DR. SCHATTEN: Failed to produce an embryo that could sustain further development, and this is an important point, and that is many embryos, human, primate alike, will spontaneously activate or will activate after a cell is introduced to them, and they'll divide from one cell to two and maybe two to three and four and five.

And for the life of you, you'd look down the microscope and say, "Well, that looks like a viable embryo."

But when you come back and count chromosomes, those embryos have no reproductive future.

PROF. GEORGE: Back to just the practice of assisted reproduction, what protocols are used or are there a set of protocols across the -- if I could say "industry" that might not be right -- but the practice for decisions as to retention or discarding of embryos created for assisted reproductive purposes?

Now, you might want to separate that from the question of prediagnosis screening, but just for assisted reproduction outside the screening, the screening for disease context.

DR. SCHATTEN: Those two questions are very good. The American Society for Reproductive Medicine in our country, ESHRE, the Human Fertilization and Embryo Authority in the U.K. have guidelines or restrictions. You may know that there has been a worrying increase in the rate of multiple births, especially triplets and higher order, and this has occurred because of multiple embryo transfers after ART with the hope of a couple having the family they're seeking from the infertility clinic.

As a result of that, there are strict rules now on trying to limit the number of embryos that are transferred. Most programs will transfer maybe just two, depending on age maybe three.

An irony of this fast moving field is that since techniques for growing blastocysts out to day five have been optimized, there's a greater time when you can do pre-implantation genetic testing and many clinics have moved to day five transfers. The irony that there's now an increase in monozygotic twinning, in identical twins, in these day five transfers, you know, it's so ironic that a clinic would have decided to only transfer later stage embryos to reduce multiples, and yet nature sort of slams you in the head, and you end up with identical twins even though you put in just one or two embryos.

So from the perspective of trying to reduce the number of multiple pregnancies while still having a singleton, there is a dynamic in every country of trying to reduce the number.

Now, in the issue of which embryos are chosen after PGD, I think it's universally the decision of the parents. That is to say that I think the laboratory people and the clinicians view themselves as informing the couple of what the results are, and the couple then makes their decision.

PROF. GEORGE: Leon, I have one more question. Should I defer and see if we have enough time for other people?

CHAIRMAN KASS: Let's do that Robby.

PROF. GEORGE: yeah.

CHAIRMAN KASS: Janet Rowley, please.

DR. ROWLEY: I have a couple of questions, and one of them was going to be on multiple offspring, and the impression that I've had is that at least in the United States, because the parents are paying for each time that the procedure is done, if you did only one or possibly two embryos and it was unsuccessful, the parents then have to pay again for the procedure even if embryos have been stored from the first attempt at pregnancy. Parents have to pay again to do this.

So that our health system, if you will, encourages individuals to seek multiple embryos to be implanted.

DR. SCHATTEN: That's correct. Now, the cost of transferring a frozen embryo is far less than the cost of collecting the eggs, doing the fertilization, et cetera, but there still is a cost, and it's interesting to compare the United States with Australia.

Australia became alarmed about the societal cost of triplets and higher multiple births, and as I understand it, they now cover repeated cycles of single embryo transfer so that there is not an incentive for a couple to seek a very large family because they know that they'll have many more chances to have a singleton.

DR. ROWLEY: Right, or pressure on the physician who wants at least a success to do the same thing.

DR. SCHATTEN: Correct.

DR. ROWLEY: Now, I'd like to go back. In terms of ELSI for ART, what institute funds any research on ART? You sort of implied that the federal government is not giving any money. So ELSI being a component, at least the one I'm most familiar with, of the Genome Institute as part of that institute, if there's no institute funding ART, then you can say there's no institute that has a vested interest in making sure that ethical issues are being considered in the research that that institute is funding.

DR. SCHATTEN: I think that's a correct comment. IVF came to our country in the late '70s, early '80s, and of course, this was long before the Human Genome Institute was founded, and while one or another institute could have considered the ethical, legal, and social implications, the thorniness of federal funding for in vitro fertilization, I think, discouraged the NIH from stepping into those muddy waters.

I can understand the reasons the Human Genome Institute would prefer not to have to grapple with these difficult issues, and yet it is very important, it was very important for our country to be having the serious, thoughtful conversations like the conversations that are occurring here today. You know, these conversations could have taken place 20 years ago already, and somehow the congressional ban, the Dickey amendment, I think, may have been either over interpreted or just was too worrying for NIH Directors concerned about their congressional appropriations to step up to this plate.

DR. ROWLEY: Okay, and the last question I wanted to ask, you recommended to us that we consider developing an Asilomar or encouraging the formation of an Asilomar type of conference where these issues could be discussed amongst the community. And I was particularly struck by the fact that you said knowledgeable stakeholders should be included because this is certainly the way Asilomar was done.

The individuals who knew most and who had the most experience were included in Asilomar. There's been concern from some members of this Council that if you have knowledgeable individuals on such a panel, that they are going to influence and maybe distort the outcome of such a conference because they have a vested interest in that, and I'd appreciate your comments.

DR. SCHATTEN: You remind me of years ago in Berkeley when the city bought the electric company. they were afraid of having, you know, the capitalists running their electricity. So they wouldn't hire anybody who had any knowledge of generating electricity, and this created a problem.

So, you know, when I say "knowledgeable stakeholders," I mean just that, and I don't mean to say just people who earn their living through ART. There are many of us who are knowledgeable stakeholders, but I also think that like with Asilomar, one needs to have some learned, scholarly discussion.

Now, I don't want to imply that the times are going to be right to replicate Asilomar. You know, the recombinant DNA community was very small back then. You did not have intellectual property and commercialization, and almost everybody was in a university with federal funding. This is a much more complicated issue, but as Francis said, just because it's complicated doesn't mean that we shouldn't try to jump into it and reach consensus where we can and continue to move forward.

DR. ROWLEY: Thank you.

CHAIRMAN KASS: Thank you.

Mary Ann Glendon.

PROF. GLENDON: I think this is just a quick question. I was really struck by your statement that about 20 percent of the population is infertile, and I wondered if that -- it seems to me it's hardly possible that that's a constant across time and populations. So it sounds like an epidemic, and if it is, I'd be curious to know if we know what the cause of it is.

DR. SCHATTEN: That's a good question. I mean, the 20 percent is of the child bearing population, and infertility has always been around. I mean, you can go back to the Bible and see infertility there.

I mean, I think one of the reasons that "The Honeymooners" was so poignant was that they were also infertile. I mean, there was always this element there.

Infertility has always been in our society. There are --

PROF. GLENDON: In that proportion?

DR. SCHATTEN: Perhaps not at that proportion, no. This is highly debated. There was a Senator who a few years ago spoke about how he is half the man that his grandfather was, and that was predicated on sperm counts dropping since the '30s.

The data is not completely solid, but there are reasons to think that estrogen disrupters, that other societal environmental issues can be increasing the rate of infertility.

I think in a certain way until infertility clinics were around, people suffered from infertility quietly. I mean, I don't want to focus too much on Senator Dole, but until Viagra was around, he probably wouldn't have shared his intimate details.

PROF. GEORGE: Gil Meilaender, Bill Hurlbut, Alfonso, and then we'll stop.

PROF. MEILAENDER: These are just two points probably too large to really take up, but I'm not content not to at least mention them because it seems to me there are two just assumptions built into your presentation that I myself was somewhere between puzzled and astonished at. The one is that it's somehow our responsibility to safeguard ART when you yourself acknowledge that it hasn't been studied with the depth it deserves.

And it would seem to me that -- I naively think that a scientific mindset wouldn't think that it was anybody's responsibility to safeguard it unless we had the data that we seem to need. So that's one sort of puzzlement that I have.

And the other is that there's a very deep assumption, partly in the presentation, even more in your responses to questions, that the desire for a child somehow constitutes an entitlement, and that, it seems to me, needs exploration. After all, many people don't just desire a child. They desire a child of a certain sort, a boy or a girl, a child with certain abilities, a child lacking certain diseases, and it seems to me that if we simply buy the assumption that the desire is an entitlement, we are simply privatizing eugenic choices in certain ways.

I mean, I realize that they're both too big a question for you to deal adequately with, but they seem to me to be just assumptions buried there, and they need to be unearthed and at least recognized that they're at work.

DR. SCHATTEN: I appreciate the questions. You know, the issue of whether infertility is a disease or a nuisance is one that the society debates, and different states have different rules about whether infertility treatments and which infertility treatments are covered.

For those of us who have wanted to have children and had difficulties, we would argue it's far more than a nuisance, but I think there is room for debate. You know, does infertility rise to the same level as, say, juvenile diabetes or schizophrenia? I might say yes. Others would disagree with me.

And so you know, this issue of an entitlement, I think, is a little bit more complicated because treating ones infertility as a disease is one thing. You rephrased it in terms of the child of one's dream or one's hope, you know, which implied sort of a selection or an enhancement or something beyond just having a child.

And, by the way, I think most people don't want to just have a child. They want to have a healthy child. And that leads me to answer your first question, and that is, "Well, why should we as a society be safeguarding ART?"

I think both because it's the right thing to do for the hundreds of thousands of children that are in our country. I mean, you know, we would want to know whether the future children are being subjected to any risk that we don't yet know about, and we'd want to minimize that both as a society because the health care of all of these children become all of our responsibilities, and also like in other aspects of medicine, you'd want to make sure that the very best is being brought to people who are seeking treatment. The same thing like with liver transplants.

PROF. GEORGE: I think there's a disconnect here.

CHAIRMAN KASS: Do you want to follow up just briefly?

PROF. MEILAENDER: Yes. I took you to mean by safeguarding meaning making the world safe or keeping the practice around, and it seemed it was just puzzling to me that you would want to safeguard it while at the same -- that is to say keep the practice alive and well -- while at the same time acknowledging at least from the scientific angle that it wasn't well studied and we didn't know very much about it. That was what I thought was puzzling.

DR. ROWLEY: But I think it's important to say here that it's not well studied because we have prevented the study of this. So that it's a societal or a political decision.

CHAIRMAN KASS: Janet, I'm sorry. People can study things without government money if they're so inclined.

DR. ROWLEY: You get very little of it, and it is under such a cloud that no credible researcher is going to go into the field.

DR. SCHATTEN: Yeah, I also disagree with you, Leon, on that.

CHAIRMAN KASS: I was simply making an operative point that there are things that people can do if they're sufficiently interested that doesn't require a government grant, and the industry itself might be rather interested in finding out the safety of its own procedures by its own self-study if it, in fact, provides itself on professional self-regulation. You don't need a handout from Uncle Sam to find out whether what you're doing is good.

PROF. MEILAENDER: And if I wanted to safeguard a practice over against potential critics, I would, in fact, if I were involved in the industry, I would, in fact, want to study it in those ways precisely to head off potential critics.

DR. SCHATTEN: Well, I mean, if you extended that to areas of mental health or cancer or diabetes, you could say, "Well, why is the National Cancer Institute or why is, you know, NIDDK, studying the diseases? Couldn't the doctors who were treating those people also study it?"

I mean we may just want to leave this as a debatable point, but clearly there aren't the resources; there aren't the -- you know, it takes time; it takes equipment; it takes money. And ultimately what you would do by that is forcing ART patients to pay a tremendous amount more because they would end up paying for the future research, and so even fewer would be able to do it.

DR. ROWLEY: I think we're very fortunate that there are other countries in the world who actually have a much different view, and their subsidizing of this kind of research for which we and patients in the United States will benefit, but it's really a disgrace that we're not doing it ourselves.

CHAIRMAN KASS: I have Bill Hurlbut and then Alfonso.

DR. HURLBUT: The first time I met Francis Collins was over a decade ago, and I asked him because I knew he had discovered the gene for cystic fibrosis and was also a clinical physician, and I asked him, "Francis, have you ever taken care of a patient with CF who said that they wished they'd never been born?"

And he said that he had not, and that struck me as a very heavy statement on what was just coming at that time, PGD.

Now, I raise that in another context. You can humanly sympathize with this a lot, but I wonder in your thinking if you say that this is a legitimate sifting of embryos, obviously not because nature does it, because nature would do it anyway in most cases, but for some kind of quality control of product.

Then do you operate with a certain sense of the natural as overriding the decision?

You said two things that struck me as difficult to reconcile. One was that you thought the private choices in the bedroom should be left to the individual, but you then said that clinics will not do certain things, like sex selection and so forth.

Here's my kind of complicated twist on that. So obviously there are questions whether individuals should have a right to select for things that wouldn't be called normative health like deafness or achondroplasia, and there are cases of this. Some people think sex selection is a social disease giving a family proportion. There are now HLA typings that are complicated.

But I want to ask you about a really complicated one that relates to our Ritalin discussion yesterday. There was a recent paper in Science, I think, about a study of child abuse in which case a certain gene -- I think it was MAOA -- do you know this story?

And here the case was interesting because there was a genetic disposition if the child was subject to abuse during childhood, but if not, that genetic disposition did not express itself.

Now, can you just give us some general sense of how you're approaching the decisions on what to do here?

And then I have a follow-up question.

DR. SCHATTEN: I hope that was a yes or no question.

Look. You put a lot into that question, and I'm not authorized and I'm not trained to be the arbiter of these decisions. My guess is if you ask the parents who have come back from a grave site where they buried their CF child if they had had the choice to have a healthy child you would have gotten a different answer.

And you know, for those of us who have lost children these are very, very difficult issues. Maybe let me just leave that there.

On the issue of a trait that is detrimental if there's a certain environmental influence, I can't advise you about whether that would be one that you would screen for or not screen for. I think the reality of what's happening right now in the clinics is that couples that show up for PGD are appearing because they have had devastating losses or they've had affected children, and all they're asking their doctor to do is to increase their chances of having a healthy child.

DR. HURLBUT: I don't want to be unsympathetic. I have a handicapped child myself, but I'm trying to get at a more fundamental question under this. What is our referent here?

If you say it's toward health, then one has to take into account the fact that, for one thing, we're propagating infertility to a small degree maybe, but there's some of that. You admit that.

Second, we are taking unknown risks. I mean, when you add in the effects of hyperstimulation which would be affecting the eggs because some people think there's more aneuploidy; the media in which it's cultured, you will admit that's changed over the years and affects things. The blastomere loss with taking out the few and the lower rate of implantation success. It looks like it's equal because you're taking a normal embryo and reimplanting it. It comes out it's probably half a success. You're killing normal embryos, if you will, in the process because when compared with a normal rate of implantation, which includes many aneuploidies, you -- do you see what I mean?

DR. SCHATTEN: Well, I don't think you're killing them. You're witnessing the natural arrest of fertilization and embryogenesis that occurs in a woman's body, but you would normally not be able to see it.

DR. HURLBUT: No. My point is that if you do PGD, put back in and say you have a 30 percent rate, and you say, "Oh, that's the same as the normal IVF transfer rate," there's no attrition of embryos.

But if you looked at the normal and then you saw -- well, actually we can't see. It's below the radar screen, but half of them are aneuploidies. Then actually you may be killing many more normal embryos.

Well, that's a fine point.

CHAIRMAN KASS: That's a side point. Why don't you --

DR. HURLBUT: Yeah, let me -- my point is this: that there's a lot of intervention going on here, and I agree that I saw in my own medical training how profound the sorrow of infertility is, but there's something going on here that mixes the metaphors, if you will.

We're trying to cure disease, and yet we're at the same time extending disease and maybe causing disease. And I know that's a statistical question, but here's what I really want to know. And that is: are we heading for a situation where notwithstanding all of these potential dangers, we may arrive at the other side where we can definitively say that assisted reproductive technology is actually safer, produces a better quality control, and just a better final product so that we really do enter a post sexual reproductive society?

DR. SCHATTEN: No.

DR. HURLBUT: You're sure?

DR. SCHATTEN: Oh, come on. I mean, it's cheaper and it's more fun. I mean, people don't go to ART clinics for recreation. You know, I think extending ART to the point where people will choose it rather than the old fashioned way is unlikely.

And I have to say I appreciate your questions because, yes, we are learning that we're propagating infertility genes, and the men who have these Y chromosome micro deletions are counseled on that and understand it.

You know, there is a difficult question of, you know, who is the patient at an infertility clinic.

DR. HURLBUT: That's right.

DR. SCHATTEN: I mean, is it solely the infertile couple?

You know, your verb about killing embryos is one that I wouldn't have used because I think in some ways PGD helps couples avoid the terrible decision of an abortion, and so in a certain way being able to avoid an abortion I think is a real godsend.

But I know all of this is charged, and I certainly don't have, you know, a clear vision of what is stark, what is jet black, and where the grays change.

CHAIRMAN KASS: Alfonso, and then we will have the public comment, and we'll stop.

DR. GÓMEZ-LOBO:: This may be very brief. You gave us a figure of the cases of success in ART. Now, do we know how many frozen embryos there are and how many embryos were discarded in the process of achieving this success?

DR. SCHATTEN: I'm sure the sort registry for the CDC have those numbers. Alfonso, as I mentioned, the estimates are that maybe 25 percent of natural conceptions result in a baby, and so one can envision that in vitro 25 percent might go on and develop normally, and that would mean that you would end up with 75 percent of the inseminated eggs, you know, arresting in some aspect of development.

DR. GÓMEZ-LOBO:: No, but I didn't mean the ones that sort of naturally died. My concern is this. I see a noble goal, but I'm not sure about the means, and I have deep concerns about cryopreservation of embryos.

Now, I have heard estimates going from 300,000 to one million. I just want to know whether that --

DR. SCHATTEN: I'm sure that's wrong.

DR. GÓMEZ-LOBO:: Okay.

DR. SCHATTEN: I'm sure that's wrong, way, way too high.

Now, as Janet mentioned, couples can freeze high quality embryos so that if they have a child, they could have another child from the same event who would then be, you know, the equivalent of, you know, not a twin by any means, not an identical twin.

And so there are frozen embryos that are stored that way. I don't know the final number, but I had heard that the ASRM with the CDC was looking at that number, and I think there are frozen embryos, but I thought it was something like less than 10,000. It's a far smaller number than you are suggesting.

But these embryos are there for patients to preserve their fertility options.

DR. GÓMEZ-LOBO:: Okay. The 300,000 figure I obtained from one of my colleagues at Georgetown who's very knowledgeable -- that's why I mentioned it.

DR. HURLBUT: Of frozen embryos, the number of frozen embryos?

DR. GÓMEZ-LOBO:: Yes.

DR. HURLBUT: Well, there's 60,000 in Australia alone.

DR. SCHATTEN: Oh, I'm sorry.

DR. HURLBUT: And worldwide they estimate there are a million.

DR. SCHATTEN: You may have better knowledge than I do.

CHAIRMAN KASS: Look. Let me bring this to an end, and with one comment. I think one might sort of downplay the likely magnitude of the combination of ART with genetic screening, pre-implantation genetic diagnosis were it not for the fact that we have the estimate in Europe of up to five percent of all births are now with the aid of assisted reproduction. In the United State you said is approaching one percent.

And if this infertility rate of 20 percent is accurate, and it certainly is rising, I mean, the estimates. It's hard to get the correct estimate, but there are a number of people who at least claim that this is rising.

One might expect to see considerable increase in the use of ART initially for infertility, but if one is going through the procedure and if the PGD becomes safe and if there are lots of things to screen for, then while many people who can and would prefer to have children the natural way will have the opportunity, in fact, not only to have the benefit of ART, but to have the benefit of the screening.

And that, it seems to me, means that even if this is a minority practice, it could be a very sizable minority practice, depending in part on the safety of the technique, the expense, and what it is to screen for.

So from what I've heard in the presentation, the fact that right now we've got 6,000 cases worldwide of PGD, and how long has it been practiced? Three, four years?

DR. SCHATTEN: Oh, no.

CHAIRMAN KASS: On humans.

DR. SCHATTEN: Well, longer than a dozen years.

CHAIRMAN KASS: In humans?

DR. SCHATTEN: In humans.

CHAIRMAN KASS: Well, I mean, one doesn't know what the future is going to look like, but I wouldn't be surprised if this turned out to be a practice of significant magnitude and one worth our attention.

I see Kathy Hudson here in the room, and their group is, in fact, paying special attention to this, and we look forward to finding out what goes on there.