"This transcript has not been edited or corrected, but rather appears as received from the commercial transcribing service. Accordingly, the President's Council on Bioethics makes no representation as to its accuracy."

FIFTH MEETING

CHAIRMAN KASS: Let's come to order. It's, if I may so, a special pleasure and privilege for me to welcome Dr. Friedmann to this meeting of the President's Council. We go back a long way, but we don't see much of each other. And in looking through the bibliography, I just checked to make sure I was right on the date. I had it right.

We met long ago in relation to what became a paper called Gene Therapy for Human Genetic Disease?, Science 1972, co-authored with Dick Roblin, who is the Scientific Director of the Counsel. These are old colleagues and friends. Dick here, and Ted has been a man of science and a physician who, before it was fashionable is not the right word. Before it was even conceivable was giving an immense amount of attention to the large ethical issues related to biomedical advance.

Ted is Professor of Pediatrics at the University of California - San Diego Medical School, and also the Whitehill Professor of Biomedical Ethics at the same medical school. He's the Chairman of the Recombinant DNA Advisory Committee, and a member of the Medicine, Health and Research Committee of the World Anti-Doping Agency. Also, has been the Chair of the AAAS Committee on Germ Line Modification, and a member of the California Commission on Human Cloning. We could use you, and we're very grateful to have you with us this afternoon to take us our next step in our discussion of questions of enhancement.

We've had a couple of meetings ?- we've had one meeting on this before. For some of us, we are even more interested in what these new powers are to be used for, than where they come from, which is part of the reason that this is a specially interesting topic. And I'm looking for the title of this. I lost my agenda. I don't want to get it wrong. I'll leave the title to you. It's on the use of ?- potential use of genetics for the enhancement of athletic performance, or something close to that.

DR. FRIEDMANN: Something like it.

CHAIRMAN KASS: Very good to have you here.

DR. FRIEDMANN: Thank you very much, Leon. It's really a very great pleasure to be here. I'm grateful for the opportunity, and to see so many familiar faces, it's great to have the chance to talk with you.

First of all, I should give a caveat. I do not sit here sort of in an official capacity as Chairman of the RAC. I may let some RAC kinds of things slip by, but please don't take that as policy from the RAC. What you'll hear is my own opinion.

Much of what I'd like to cover briefly has already been presented to you in your background paper, Number 7, I guess, that you've had a chance to look at over the past ?- and I will reiterate some of the points there, and make a few additional points. And then at the end, I hope leave you with some questions that I think may be germane to the function of this Council.

I should allow apologize in advance for some of the Power Point features. This is the first Power Point presentation that I've prepared, and you'll see titles flying in, up and down, and I apologize for that. If any of you get motion sick, it's not my fault.

All right. So let me start by posing three questions that I'll come back to toward the end of my presentation, and that has to do with these questions. Is genetic enhancement feasible, and is it likely, and is it desirable under some conditions? Two, what have we learned from the world of gene therapy that may instruct us about the potential for genetic enhancement? And three, does sport and athletics represent a kind of scenario which might be a useful springboard for discussing the opportunities for genetic enhancement. Is it, in fact, feasible in sport? Is it likely, and under some conditions is it maybe even considered desirable? So I come to these issues from three backgrounds, and I'll try to be a little bit personal about some of this if it's all right with the Council.

These come from three interests that I've had for a very long time. One, obviously in genetics and gene therapy, which is my day job. Biomedical ethics, which is kind of my afternoon and early evening job, and then a background in sport, which I don't have personally, but which comes to me through my family. So this is my family connection. These are medals that my father won as an athlete in sort of Central European athletics pre-war. And it was in the context of this kind of view of sport and all its beauty, and all of its sort of effort that I grew up thinking that sport was a beautiful and lovely endeavor, and one that ought to be protected.

The other part of the background that I bring to these issues is an experience that comes from my early sort of post-doctoral time. After a stint at the NIH, I went to the Salk Institute, ostensibly for a year to learn something about viruses and virus vectors, and came under the influence of Jacob Bronowski, who was there at the time as the head of the Council for Biology and Human Affairs. And the Council was interested in directions that science was going, the directions that genetics, molecular biology was going at the time.

You'll recognize from the years that that was before the era of Recombinant DNA technology, but the people at the Salk were wise enough to know that it was coming, and Jacob Bronowski asked me and one of my colleagues to look into the issue of where molecular biology was likely to take medicine in the near future. And that was based on the presumption, on the intuition that the approach to genetic disease at the time was flawed.

Now I won't be able to point at anything, but this is kind of a scheme of genetic disease, and the ?- well, it does point. Okay. A scheme of genetic disease and directions from which one might approach treatment and understanding of genetic disease. And you can see here, so there is the DNA with the X indicating a mutation response for disease. That gene, that mutant gene is responsible for making this gene product, and that gene product has the role of driving a metabolic step here. If that metabolic step is defective, then one induces a state of disease by either producing too little of a gene, of a metabolic product, or accumulation here of Product B. And it suggests a number of ways in which disease can be understood and treated. And you'll recognize that this is the scheme - for those of you who are interested in medical history and the history of science - this is the scheme that comes directly to us from Sir Archibald Garrett at the beginning of the 20th Century and his rediscovery of Mendel's Principles in 1900.

You'll notice that, and I think if you think about this scheme, and you think about what it implies about therapy, you'll recognize that everything that happened essentially during most of the 20th Century in terms of therapy, is aimed at sites of this pathogenesis scheme everywhere except where the defect is. The defect is here in the gene at X, here in the DNA, and all therapies have been aimed, from time zero have been aimed everywhere other than for the site of the defect. And it became clear in the late 60s or so from work from many places, that the opportunity was going to arise in the reasonably near future to begin an attack on the mutant gene itself as an approach to treatment, so that takes the form of this cartoon.

The cartoon says, "You fix what's broken." On the left side is a broken dam, representing a mutuant gene. That results in a metabolic flood downstream and a mess, and all therapy until sort of the end of the 20th Century took the form of cleaning up the mess, and it began to be apparent to a number of people, sort of in the mid-60s, early 70s, that the opportunity would come to fix the dam, to fix the gene.

So here is the paper that Leon kindly referred to, and you'll recognize two things about it, three things about it. One, the date, 1972. Two, that one of the authors of this is Richard Roblin, who's your Science Director, I guess his title is. And three, there's a question mark at the end of the title, which meant that we really didn't know what we were saying, but we thought it was all going to come true, and so we published this in size at the behest of the Council for Biology in Human Affairs, and Jacob Bronowski's invitation to prepare this initially as a white paper for the council.

And what Dick Roblin and I sort of envisioned at the time was not only is this an option for treatment of genetic disease, but it really is a requirement finally for designing rational therapy of human genetic disease. It was a necessary new step, a necessary next step in the treatment of disease.

We envisioned that the approach would be to introduce functional therapeutic genes into cells to correct genetic defects, to correct mutations. And then we envisioned the use of viruses to do this. We did that because we were working, both of us, in a laboratory of virology with Renato Dulbecco, who had just established the mechanisms by which viruses cause cells to become cancer cells. And we thought well, if a virus can cause a cancer by introducing its own gene into cells, maybe we could fool the virus, use it as a trojan horse to carry therapeutic genes into defective cells, so we liked the idea of viruses. They were efficient and they did the right thing.

We thought that in order to move ahead with such a procedure, one needed a very profound understanding of pathogenesis. We were worried a little bit that this field would lend itself to premature use, and to the use of immature technology in the name of therapy. And were concerned about when and if this would really move to human clinical application.

We saw a number of ethical and policy dilemmas, including the potential for germ line modification, and the use of gene transferring to modify traits that were not obvious to everybody, obvious disease traits, but rather traits that were other sorts of human capability. That, of course, is the subject for today. And we thought that all this was so important, and so likely to be a difficult area of the confluence of technology and policy, that there was going to be a very ?- a need for heavy local and federal review and regulation of the technology, including FDA and local hospital committees.

The paper appeared at a time, first of all, before recombinant DNA was available, and also before any vectors were available to move genes around, but those virus vectors became available over the next decade or so. And the details of this aren't important, but simply indicate two approaches to introducing genes into humans.

Here is a patient with a human genetic disease, a woman at six o'clock. She might be treated genetically in one of two ways. She might donate some cells to a tissue culture plate, which would then receive a virus, or some other gene transfer vector in vitro. Those cells would then be genetically modified and returned to her to compliment some genetic defect that she had. That's call the ex vivo approach to gene therapy. In contrast to that, of course, is the in vivo approach, and with this virus vector here on the left side of the picture, is introduced directly into the patient to correct the defect, so that's the in vivo approach.

I hope this doesn't make you dizzy. This now ?- the elaboration of this concept really came first in a most clear fashion from LeRoy Walters some time later, who developed this matrix for understanding gene therapy, and it took the form shown here. So the initial approach was obviously to use somatic cell modification to correct a disease phenotype, so for real therapy of a disease trait.

LeRoy was concerned also about eventual use of a germ cell as the target for genetic modification, and envisioned that that could also be used for therapy, for prevention of disease or for therapy, but he also assumed sooner or later that somatic cells would be targets for the introduction of genes designed to enhance traits, rather than correct disease phenotypes. And the same thing to be done at the level of germ cells, so he had this four-way matrix, somatic cell, germ cell, therapy, enhancement, as four areas in which gene transfer was likely to become feasible in the human being.

In terms of disease targets, very early the initial disease targets tended to be in-born errors of metabolism, single gene defects because they had a single gene missing, rather easy genetics to try to sort out. And in principle, all one had to do was to put the gene into the right cell at the right time, and you've got a cure.

Not too long after that, of course, it became clear to many people that other kinds of diseases ought to represent targets for genetic modification. Complex diseases in which many genes talk to each other. Cancer is a gene in which many genes are ?- a disease in which many genes are involved. Neurological disease, psychiatric disease, cardiovascular, all those things became very popular targets for gene transfer kinds of studies. Even infectious disease, so non-in-born errors, non-genetic diseases, but diseases which had available genetic targets that one could manipulate to modify the disease process.

And I won't go through the history of the 80s, late 70s, 80s, and early 90s, only to show you that all these concepts grew very rapidly at the beginning of 1990s, the last year or so of the 80s, `89/90, and the concept was that all you need is a gene, a target cell, and that therapy would be rather straightforward and rather easy.

In 1989 was the first clinical study, human gene transfer study. 1991 was the first potentially therapeutic study, and you can see what happened over the next some years. Many proof of principle studies have been done in animal systems. Those animal systems look very promising, and by 1990, I can't see the date, `98/99, there was an enormous amount of optimism ?- well, by 1995 there was an enormous amount of optimism that this job would be really quite easy.

In `95, you can see a little dip there from 44 to 28. In 1995, a series of papers appeared which showed for the first time that the job was going to be more difficult than we thought. There were a number of rigorous studies which, for the first time, showed failure, rather than this sort of exaggerated over, hyper-expectant field that had come to develop, which we thought things were going to move very quickly. In `95, things obviously became much more difficult. And the field of gene therapy kind of began to be more introspective, and to emphasize more rigorous hard basic science. But that also began to grow, and by 1991 ?- sorry, by 1998/99 things were growing again.

And then, of course, in 1991 came the disaster in Philadelphia with Jessie Gelsinger's death, and another pall was cast on the field, indicating again that there were many surprises, and many unexpected reversals that we should be on the look-out for. That field was, in fact, going to be far more difficult than we had anticipated, and that it was filled with traps, and with potential pitfalls that only careful clinical experimentation would eventually clear up for us.

However, what's happened since 1999, and since Jessie Gelsinger, is rather impressive. You can see now by March of this year, there are more than 500 clinical studies being carried out in many countries in the world, most of them in the U.S., but many studies in Europe, and Sweden, and Japan, China and others. Most of those studies are for cancer for a number of reasons. A number of diseases are, in fact, common genetically complex diseases, cardiovascular, neurodegenerative disease, arthritis.

The first clinical success after 30 years after the Roblin-Friedmann paper, finally after all that promise and all that expectation, came what looks to be a real success over the past two years, a study in France carried out by Dr. Alain Fischer in Paris, showing, I think quite convincingly, and only time will tell if it's a cure or not, but quite convincingly, a phenotypic cure of children with an immunodeficiency disease, X-linked SCID. That's now been repeated in another form of immunodeficiency, and it looks as if we've turned the corner now. The field exists, it's a reality, it's a clinical reality, and poised to move into other clinical situations.

At the same time, there's been no overt enhancement studies reviewed or approved by the local or federal regulatory review process. So again, June of this year, very impressive apparent success by Alain Fischer in Paris. The ADA SCID model, which is a similar disease, seems now to have been cured. The paper last week in Science indicates a very similar approach, with similar results.

Interesting, and probably real results are being obtained now with coronary artery disease with injections of agents designed to induce new blood vessel formation in the heart, and also in peripheral tissues. There is a continuing slowly advancing number of studies in cancer showing some response of some cancers in some patients, and a very promising approach now with Factor IX Hemophilia, which seems to be poised on the edge of showing some clinical efficacy.

So what do we conclude from all that? That the field is real. That it's beginning to show clinical effect. However, we know better than ever that the field is faced with many unknown, and many known dangers and problems. We learned that in spades from the Philadelphia study. The gene therapy studies have to be considered clinical research in the strictest form of that word, and therefore, require all the local and national regulatory review processes that clinical research needs. That the wish to do good, of course, is not on its own enough, to undertake studies, and that the studies have to be designed properly, a result that also came from the disasters in Philadelphia and a number of other places in which clinical design was possibly not as rigorous as it ought to have been. And that any applications of gene transferring outside of this realm of review and regulation recognizing the hazards and difficulties, and problems would be inappropriate, hazardous to the patients and to the participants in the study, and therefore, probably unethical for reasons, at least, based on safety.

All right. So we get to the point we're back to LeRoy Walters' matrix. Therapy of somatic cells, treatment of somatic cells with foreign genes for the purpose of therapy seems now to be a reality, and that takes us then in the next step to the potential for using exactly the same methods to modify traits that are not disease traits, but at least farther out on this disease/non-disease spectrum, and begin thinking about enhancement.

That doesn't come as a surprise to us because we already accept and seek enhancement in our society in many ways. And that was, of course, also reviewed very well in your document number 7, and I won't repeat all of that. Just simply to say that cosmetic surgery is with us, and we accept it, we seek it out. Recreational drug use is with us, and we accept it and seek it out. Psychopharmacology, an exploding area, a very important area which obviously comes initially from the need to treat psychiatric disease, but also to treat the rest of our neuroses and behavioral deviations. And, of course, the use of anti-depressants, tranquilizers and serotonin reuptake inhibitors, things of that sort, are ubiquitous and universal in our society, and we hardly question their use any longer.

Attention deficit, hyperactivity disorder, a very popular and very important potential area. I don't know what the figure is now, but it must be 30 percent of children in this country on Ritalin, requiring 50 percent of the teachers to go on Prozac, I guess. But it's a situation that we accept, and we know, and we don't question it very much at a societal level. The area of aging offers major new areas of socially acceptable enhancement. Again, that was covered in your document number 7.

There was a very interesting review in the New York Times last week on the use of anti-depressants to sort of underscore what I've just said, and indicating that social phobias and generalized anxiety, premenstrual distress and many other behavioral issues are targets, and probably legitimate targets for drug therapy. And in that article, a quotation as given below, "Psychiatrists argue that such conditions are real illnesses, but others say the impression is often conveyed by commercials."

It's clear, almost everybody could benefit from them. Symptomatology is so broad and vague that any one of us could say yeah, that's for me. And we all know that. We watch the commercials and we think maybe that would help me.

Well, if we accept enhancement, how far are we from accepting ?- if we accept pharmacology-based enhancement, how far are we from accepting genetically-based enhancement? The pressures for that come from, obviously, from the general acceptance of enhancement, in general from drugs. The indistinct line between disease and non-disease, what is one person's Alzheimer-based memory deficit is another person's desire for a slightly sharper memory, to memorize a role that he needs to enact on a stage, or learn a piece of music, or something of that sort.

The Genome Project, and other advances in genetics, is dumping into our lap all kinds of genes involved in personality and cognition traits. You all remember probably the early days of the century, again the work of Archibald Garrett at the Cold Spring Harbor Genetics Record Office, in which everything was considered to be genetically determined, including love of the sea, thalassophilia, slovenliness and things of that sort. Those kinds of traits were based ?- were presumed on the basis of poor science to be genetic, at least partly genetic in origin, but those days of genetics are no longer with us. But we're now, of course, coming to realize that genes do play an important role in personality and cognition. And those genes are coming to be identified slowly but surely. And will, therefore, eventually be targets for manipulation. And, of course, the increasing pace of clinical efficacy in gene therapy is providing tools which are likely to be useful in an enhancement setting.

All right. So if that's true, then on might begin to wonder about what kinds of approaches in the therapeutic sense may open doors inadvertently to enhancement. And I would like to just remind you of a number of studies, protocols that have been reviewed by the federal regulatory agencies, by the RAC, which are therapeutic in intent, but which have implications for non-therapeutic use for enhancement kind of applications. So these are a series of studies that have been proposed to the RAC for therapy.

The first one here is the use of IGF-1, insulin-like growth factor for treating a muscle wasting disease in a peripheral nerve entrapment syndrome. It's called the Cubital Tunnel Syndrome in which a nerve gets entrapped, leads to muscle wasting. The proposal reviewed by RAC was that a non-viral vector of plasmid would be injected into the muscle around this blockage to stimulate nerve regeneration, muscle re-innervation. That would be directly injected in the muscle. And because the vector in this case is not a virus, but rather just a piece of DNA, its affect would be transient, but it would stimulate local muscle repair and maybe nerve regeneration, as well. Clearly, this is therapeutic in intent, but again clearly, the injection of IGF-1 into muscle has other implications. We'll get to that in a moment.

Another study proposed to RAC in 2000 had to do with the production of Erythropoietin, to increase hematocrit levels in patients with chronic renal disease. These patients have difficulty with maintaining adequate blood production, and one way to treat that, other than for injections of Erythropoietin, is to introduce the Erythropoietin gene into the smooth muscle cells of these patients in vitro in the laboratory, and then use those genetically modified cells that are now producing EPO to line an artery-vein dialysis graft that these patients have implanted. Those cells would sit down on the graft, and produce a constant supply of EPO, which would then increase the blood production in these patients.

Still another study reviewed earlier this year by the RAC, a very important study, suggested the use of growth hormone as an approach to treating Cachexia in cancer patients, have this terrible wasting syndrome very often, and one doesn't know what that's due to, but one potential approach to treating it is to introduce growth hormone, or things that will produce growth hormone into those patients. And this study, in fact, proposes exactly to do that, to use a hormone called "Growth Hormone Releasing Hormone" to stimulate the pituitary of a patient with cancer to produce its own growth hormone. That would then ?- to increase body weight, and to prevent parts of this Cachexia Syndrome from developing. The amount of growth hormone could be regulated in this system by the administration or removal of an oral drug, in this case, RU-486, which has the property of turning on or off the gene in this case.

Again, it's not a therapy for cancer, but it's the therapy for something that comes with the cancer, and that's the Cachexia. This has the implications, of course, of developing methods for introducing something that will turn on or off growth hormone in a conditional sort of way, and has applications that we can get to in a moment, as well.

You can't see that very well. Two weeks ago at the RAC meeting, we reviewed still another proposal, which is therapeutic in intent, but which also begins to sound potentially enhancement-related. This is a proposal from Dr. Melman in New York, to treat erectile dysfunction, not with drugs but rather with genes, introduced directly into the corpus cavernosum. This is a potassium channel gene that has the property of modifying blood flow in and out, and therefore ?- and that gene becomes active only during sexual stimulation. And therefore, in animal studies, has shown to produce reasonable results. And like Viagra, of course, has the potential for treating a real problem in some men, but also to go the direction of some Viagra use, and that is an enhancement sort of use.

Well, okay. So if we accept enhancement, is sport an area in which enhancement is likely to find a home? You won't recognize this person here, but that man is Arne Ljungqvist, who is the Chairman of the ?- who was President of the Swedish Cancer Society, but in this era, he was Olympic high-jumper for Sweden in the 1952 Olympics. And he's the Chairman of the World Anti-Doping Agency Committee on Health Science and Research.

So the question is what, of course, determines performance in sport. At least three things do. One, talent and drive. Those tend to be not terribly manipulable, but are innate and learned, and partially genetically determined. Of course, there's training, manipulable kinds of training, what equipment you use, what opportunities you have to train. And, of course, then physiological manipulation, performance-enhancing drugs, environmental changes. You train at altitude if you're going to be an endurance athlete. And now the question of new genetic functions becomes pertinent.

It won't surprise you to learn that doping is extremely common sport, in some sports more than others. I won't reiterate all that, just simply again to remind you that it happens, and the sport profession considers it a problem. Some people do, at least. There was a question in the L.A. Times several days ago by Jerome Holtzman, who is the major league baseball historian, and his attitude was I don't care if guys are taking steroids or not. If they're taking these drugs, and if they want to risk their bodies so they can hit 20 homers a year, that's their decision, so that's kind of the official statement from baseball.

You all know from the tests that U.S. screening agencies have had sort of a love/hate relationship with screening, and in screening for Olympic athletes, the U.S. committees have not always been as effective as they would like to be.

You all know, of course, the response of the U.S. population to Mark McGwire's homerun hitting feat some years ago. That was not met with universal disdain or disapproval. It was really quite welcomed by most sports fans in the country. And, of course, the recent revelation of baseball use of ?? probably much more ubiquitous baseball use of steroids and the response that that's had. So sports organizations look down officially on the use of these kinds of agents. There's a list of banned substances. That list is evolving all the time, but tends ?- but includes things like Erythropoietin as drugs, not as genes, as drugs, growth hormones to improve strength, anabolic steroids, stimulants and narcotics are banned. Diuretics and plasma expanders are used commonly to hide the use of other drugs by athletes, and those are also banned. Beta blocks are banned.

Medical exceptions are permitted under some conditions by the sports authorities. And recently, a revision of some of these lists of banned substances has begun to exclude things like caffeine and marijuana, which are universally used. Alcohol, which are universally used, but which have not been shown to be sports enhancing, and therefore, they no longer sit on lists of enhancing drugs.

The sports world tests for drugs and screening in a number of ways. The International Olympic Committee and other international bodies have had screening methods in place for some time. National Athletic Associations similarly.

In 1991, the IOC and the member nations established the World Anti-Doping Agency, the World Anti-Doping Association, funded by IOC, which has a three-part program to screen both in and out of competition, to educate athletes, and to do research on detection and screening. And then the member nations have their own versions of the same kind of agency, in this case, the U.S. Anti-Doping Agency.

So why does one think that genetic approaches to athletic enhancement are inevitable? First of all, athletes are risk-takers. They're young healthy athletes who think nothing is ever going to happen to them. And they are known to accept all sorts of risks. Polls have been taken of young athletes asking if I were to guarantee you a gold medal in the next Olympics at the risk of losing 20 years of your life would you do it? And universally, they say yes. They will take that risk for the reward of gold medals.

There are enormous financial pressures and national pressures to push athletes to perform and to win. We know that they use pharmacological approaches to enhancement. WE know that they're aware of gene transfer technology, and we know that that technology is still immature, but it's advancing rapidly. And we know that many of the studies in gene transfer technology, in fact, use the genes that are of particular interest to athletes, Erythropoietin, growth hormones and other relevant genes.

There's a general perception among the athletic communities that these manipulations genetically would be less detectable than pharmacological intervention. That's not at all clear, but that's what the athletes seem to think. So how does one enhance athletic performance genetically? One can increase oxygen carrying capacity with Erythropoietin. One might enhance skeletal and cardiac muscle function growth hormone, IGF-1, and other forms of growth hormone. One might imagine increasing blood flow to a particularly stressed muscle with agents designed, as in the cardiovascular therapeutic setting, to increase blood vessel production to that organ. One might imagine altering energy utilization by the tissue to raise pain threshold of injury, and to prevent injury, or to accelerate healing by genetic means.

So let me give you now several examples of the way in which preclinical, therapeutic preclinical studies have used relevant genes to convince people that use in athletes is possible, and probably inevitable.

The gene in this case is Erythropoietin, and it's been transferred into Baboons with this vascular graft approach that I described before. In this case, cells from the Baboon are injected with a virus that expresses Erythropoietin. Those cells then are used to line this vascular graft. And here you see the affect on the blood production of the Baboon over more than a year. The top closed circle curves represent the levels of red blood cells in this Baboon after a single injection, a single introduction of the smooth muscle cells into the graft. The lower curves represent the control animals, and you can see that the manipulated animals develop hematocrit levels, red blood cell levels well over normal, and up to the 70 percent level. That can be good, or it can be bad. And obviously, it's very dangerous if it goes too high because that predisposes to strokes, and to other cardiovascular disasters.

Here's the use of another cell line to introduce Erythropoietin into animals, again the same affect. In this case, carried out over a shorter period of time. But again, you can see a prolonged elevation of Erythropoietin using a muscle cell to deliver the gene. Here's a different virus, an adenovirus vector. Adenovirus is used commonly in gene therapy studies, and on the right panel you can see a very prolonged elevation of hematocrit levels in, I guess in what animal? This is Baboons, as well. Prolonged increase of hematocrit levels after a single injection of a virus into the muscle of these animals.

Here again is the single injection of a different virus into non-human primates. The lower right curves show you the persistence of increased hematocrit levels in these animals, despite the fact that the serum Erythropoietin levels in the very far lower right curve drops after a while, the hematocrit level stays up for more than a year.

So a single injection of a vector carrying the Erythropoietin gene works. It increases hematocrit levels. And in some other of these, this can be turned up and down at-will, so you can take this animal and treat it with a small drug orally that will turn off this affect. The hematocrit level comes back down to normal. You can then turn it back on at-will, and you can bounce back and forth many, many times to modify and to titrate the amount of red blood cells that you want.

With respect to muscle, very impressive studies by a number of workers, Sweeney in Philadelphia, and Goldspink in London have taken IGF-1, this insulin-like growth factor, and similar muscle growth factors, injected them into mice. Those mice then develop much bigger muscles, stronger muscles. If you tie little weights to their tails and force them to climb up a little pole, the injected ?- the mice with injected muscles climb higher, and faster, and carry more weight than the controlled mice, so it works. The muscles get stronger, they get bigger, and they also show improved muscle repair properties.

I'll just skip that. That's more of the same. One might even, in fact, look upon this as a preventive procedure. Here is a study by people interested in preventing or treating joint injury, again with IGF-1, with insulin-like growth factor. In this case, cells from a joint were treated with a virus carrying IGF-1, and then put back into the joint. And on the left, you can see the thickness of the synovial membrane, the membrane in the joint that protects the joint from injury on the left, and on the right. The same cells now treated with a virus producing IGF-1, you can see the thickness of this synovial system, synovial tissue is much greater, and this joint is less likely to be injured, and is more likely to recover more quickly.

So is application of these experimental kinds of approaches feasible in sport? To remind us all again, some of the properties, the lessons that we learned from gene therapy, so gene therapy is feasible in humans. It can be therapeutic. It can correct and treat disease. All present approaches to gene transfer must be considered experimental. The current methods are still immature, and many unknown dangers, and known dangers. Methods for gene transfer into humans all must, at the moment, go through this process of local and federal review. And I would suggest that rogue use, or illicit use in athletics or any other area, which circumvents that process, that is, the gene transfer into humans for other purposes, whether it's therapeutic or whether it's enhancement, which circumvents the review and regulatory process is dangerous to the subject, as unacceptable. And, therefore, I would posit, is unethical.

Well, you can say that, but that may or may not convince athletes, and enormous pressures exist in athletics which make this kind of direction very likely, and inevitable. And the reasons are the following, the athletes, and their handlers, and federations know about gene therapy. They know vaguely what's happening, and they know that the field now thinks that it's turned this corner of efficacy. What they don't know, and what they don't appreciate is the safety concerns and the dangers lurking behind every corner.

If this application to athletics is to be done, it probably will be done in a private setting, and private setting studies do not require review by the RAC. They do need to go through FDA, but certainly don't require RAC review. And that private and governmental funds are available to accumulate the kind of molecular expertise that would be required to make these vectors, to solve the rather trivial problems of delivery to the appropriate tissue, and simply to take the published data from gene therapy world and apply it in an enhancement setting in athletics.

Regulatory structures largely are silent on the issue of enhancement, and that might be, in fact, a question that this Council might like to pose. Is continued silence on the issue of enhancement a wise thing to tolerate?

We come back to the caveat that Dick Roblin and I sensed in our initial paper; and that is, the likelihood that immature science is going to be used before it's ready for real application. It happened in gene therapy. It's likely to happen in athletics. So faced with that issue, a number of agencies have tried to provide a shot across the bow of those who might want to circumvent these concerns. In 2000, a couple of years ago, the World Anti-Doping Agency incorporated into its Medicine, Health and Research Committee an effort to identify the potential for gene therapy as an approach to ?- for gene transfer as an approach to doping.

Last year, the International Olympic Committee, taking that cue from WADA, had a one-day meeting in Lizon (phonetic), which began to identify the potential dangers to sport, and this year, several months ago, that the World Anti-Doping Agency sponsored a meeting at Cold Spring Harbor, a three-day meeting which was designed really to look in some detail into the potential for genetic modification in athletics.

That meeting urged a number of things. It urged the publication of the proceedings for general promulgation to the scientific and sports community. It also called for dialog in the public sector, position statements from professional societies such as the American Society of Gene Therapy, to look at the issue and examine whether this is a real concern and what, in fact, one might do to head it off.

Also, this spring the American Society of Gene Therapy held a symposium at its annual meeting on potential applications of gene transfer in sport, and next year AAAS is going to have a similar symposium.

So back to the original questions that I posed, and I am going to wind up now, back to the original questions: Do advances in human gene therapy affect the potential for genetic enhancement? I think the answer to that is a clear yes. Is genetic enhancement feasible, likely, and desirable? I think it is certainly feasible and likely. Questions of its being defensible and desirable is something that deserves your careful consideration.

Finally, is the enhancement of athletic performance feasible, likely, and desirable? I think it is certainly feasible. Attempts will be made soon, and its desirability again is not clear.

So let me leave you, then, finally, with some questions that might be interesting for your Council to consider. These questions are difficult, and we certainly have not been able to answer them even in the context of the World Anti-Doping Agency.

So one question is, of course, what is sport and what is it that we are trying to protect in identifying genetic approaches to modification? There is a classical view of sport I call the romantic view of sport, the kind that I grew up with at home, that says it is the effort and the triumph over adversity that makes sports so beautiful. We know that sport is more than that. Sport is entertainment. Now it is an economic force. Therefore, it is a different beast from what it was some years ago.

As an undergraduate I studied a little bit and took a course with a man named Paul Schrecker at Penn, who had developed a principle of work and history looking at the features that make a society. He identified six major areas that define societies: development of the state, science, religion, the aesthetic province, economy, and language. He did not include sport. Sport, to whatever extent he discussed it, was included the aesthetic province. But it may be that sport represents something more aboriginal than that and very basic human instinct, and may, in fact, represent a completely different province of society.

Sport is a technology which is manipulable in terms of material science. We make better swimsuits. We make better skis, more flexible pole jump poles. But it also represents now an area of biotechnology and bioengineering. It is not quite as clear to me and the WADA Committee whether that is a good thing or a bad thing. You might want to ponder that.

Does sport offer a useful arena for ?? I guess I shouldn't have used the word "arena" there ?? does sport offer a useful area in which to examine this intersection of technology, in this case genetic technology, with public policy? Where do they clash? Finally, if we accept, as a society accept, enhancement in general, what is it that makes sport different, if anything, and why?

On no particular subject, I just wanted to make one plea to your Council based on things that I heard this morning. There's no question that this march of technology, both in therapy and in enhancement, is going to continue and accelerate. You need and we need an enlightened public policy, an enlightened discourse.

It seems to me a terrible thing that the U.S. has relied on very few stable bodies to continue a discussion of technology and public policy. The OTA was one such body, but we don't have that any longer. All the previous bioethics councils have come and gone. They have been too transient to keep up institutional memory and a momentum.

I would certainly hope that this body, in whatever way it can, can make the point that it is an ethical issue, a bioethical issue, to have a national body to continue to advise our policymakers on what is coming next and how to prepare for it.

So let me stop there and thank you very much for your attention. I would be more than happy to try to expand on any of this, if you would like.

CHAIRMAN KASS: Thank you very much.

Could we have some lights and this machine turned off?

I think the presentation makes very clear how developments intended for therapeutic purpose can acquire a life of their own and are used for things that are beyond therapy, not necessarily making them either undesirable or wrong, as really beautifully documented here. Other people may want to weigh in with different questions.

Granted that you and colleagues have concerns for the area of genetics, and therefore the uses of genetic technology. The question of a genetic means of delivering performance enhancement would be an obvious new question for you. But I guess, could you help on this question: Why in a world of steroids and epo available by injection and orally ?? what if someone said, look, this is really rather precious and very highly sophisticated, but how is this different, or is it different, and why is this likely to be a much larger problem than the one that is now faced, if it is a problem?

What about the genetic angle makes this special? That is the less interesting question, I guess, as to what we should think about this, and if we should think ill of it, how to proceed. But just on the narrow, technical question, why is the fact that this is genetically-delivered enhancement special?

DR. FRIEDMANN: I am not sure that it raises any new issues. It raises issues ?? the interest in this area seems to come from the general perception in the athletic community that this can be done more surreptitiously, and, therefore, less likely to be detectable, if in fact you can do it with a one-shot administration of something, turn it on and off at will ??

CHAIRMAN KASS: With small molecules?

DR. FRIEDMANN: And, therefore, not so easily subject to out-of-competition testing. I think that is a misperception because what is detectable, of course, is the physiological effect of the introduced gene, and that is going to be presumably as detectable as if you had injected yourself with the protein itself, rather than the gene.

So I don't think that there is a new kind of ethical issue that separates genetic doping from pharmacological doping. It is a challenge more, I think, to the athletic community because they are going to have to devise different kinds of methods of screening and detection. It is also a challenge, I think, to the gene therapy community because the applications in athletics, when they come, if and when they come, will come outside of the realm of current standard review and regulation. It seems to me that that is clear.

How, in fact, to be on the alert for that and how, in fact, along the lines of this shot across the bow, how do we warn people, athletes, first and foremost, because they are the ones who are in most danger of being injured by such a manipulation, which is, after all, maybe less easy, less redeemable, and less easy to reverse than simply stopping taking a drug.

The genetic manipulation is probably going to be less forgiving, maybe less manipulable and less titratable, but also less easy, more difficult to reverse. That increases the danger to athletes. That danger is not being advertised by the sort of between-the-lines support that one is beginning to see in these rogue athletic communities for this approach.

So I think the fairest answer is there's nothing ethically new here, except from the gene therapy point of view, and the insistence that, if and when these kinds of manipulations are done, they must be done in the context of clinical research and not in the context of sort of East German approach to swimming as of some years ago.

We need to be sure that the athletes are aware of that and know that, if they are being attracted by promises of surreptitious and less detectable approaches to doping, that they need a high level of suspicion. So the work of the Vardon, and you saw at the moment, is in fact to provide that shot across the bow.

CHAIRMAN KASS: Robby?

PROF. GEORGE: Thank you, Dr. Friedmann, for that wonderful presentation. I wanted to ask a couple of questions by way of clarification, and then I have a more substantive question.

On clarification, one of your slides identified a list of stimulants that have become socially acceptable, and they included caffeine and marijuana and LSD.

DR. FRIEDMANN: I don't think I had LSD on there. I hope I didn't.

PROF. GEORGE: Okay, I'm sorry.

CHAIRMAN KASS: No, he didn't have that, either; just caffeine and marijuana, unless you were taking something.

(Laughter.)

PROF. GEORGE: By socially acceptable, you simply, I take it, mean that it is widespread in its use?

DR. FRIEDMANN: Widespread, and those agents have been on the list of proscribed drugs in the past, but a recent list developed by WADA now has removed them because they have not been shown to be performance-enhancing. They are lifestyle kinds of drugs, lifestyle agents, that are common, but which the athletic community no longer sees, or may no longer see itself in the need to proscribe because they are not performance-enhancing.

PROF. GEORGE: Okay. I was wondering if socially acceptable there refers to accepted in the broader ??

DR. FRIEDMANN: In the broader sense, sure.

PROF. GEORGE: In the broader society?

DR. FRIEDMANN: Wider used; therefore, a lot of people accept it.

PROF. GEORGE: But while it would seem to me caffeine is socially acceptable, cocaine and even marijuana is in a sense not, if we consider that we are now more than 30 years into a pretty aggressive campaign to legalize marijuana, and the national public polling, public opinion polling, seems to show that it hasn't really moved public opinion on that issue very much at all, although there are significant regional and even local differences. I bring this up only to say that, as we are thinking about this, maybe we are keeping in mind that, even where there is widespread abuse, some taboos along these lines, but not others but some, have been maintained, and in part reinforced, by countervailing social pressures.

DR. FRIEDMANN: I tried to finesse that a little bit by putting "acceptable" in quotes. I hope that it was still there.

PROF. GEORGE: I did notice that.

DR. FRIEDMANN: But, also, I hope I didn't have cocaine. But the point is that widespread use indicates something.

PROF. GEORGE: I agree.

DR. FRIEDMANN: And ours, of course, is not the only society that's faced the use of those agents, and others have been more willing to buy into them. So "acceptable" in this case means widely used, but heavily debated still, and probably on their way to wider use.

PROF. GEORGE: Well, I stay with the point because I think an interesting dimension of the problem is the question of inevitability, which was raised at various points in your presentation. Obviously, if something is inevitable, then thinking about how it can be restrained is a waste of time, although it might be that you can think about how its use can be channeled in certain ways or maybe even limited in certain ways. But that is why I was interested in that problem.

Similarly, and I guess the answer is going to be the same thing, on a couple of occasions you used the term "universal," and I think I interpret what you meant by that as, again, being widespread, the universal use of drugs or the universal opinion among athletes that it would be worth giving up a certain number of years of life ??

DR. FRIEDMANN: I used that word it was wrong, about universal.

PROF. GEORGE: Now to the substantive matter, am I thinking about this correctly? We have the health sets of issues when it comes to possible attempts at enhancement; that is, the attempts themselves could end up damaging the health of people who undergo the enhancement techniques.

Then separated analytically from that is the question of the ethics of people, even if they are safe ?? so laying aside their safety ?? the ethics of undergoing these enhancements or availing oneself of these enhancements to be better athletes or to perform at a higher level. Am I right to think that the ethics of that depends on the concept of sport that is in play, on the, I think what you referred to, if I remember correctly, as the old romantic version or concept that you grew up with, you really do have an ethical problem, because the enhancements have driven out what seems to be central on the romantic understanding, which is drive, effort, perhaps natural talent in some sense.

But then on a different conception that puts the focus on, say, entertainment, rather than the romantic conception, it doesn't seem to be undergoing ?? the enhancements techniques doesn't seem to be an issue because the goal is to entertain the public. Mark McGwire, or whoever, hits 70 home runs; the public likes that. Nobody has done anything ethically wrong. Am I right so far?

DR. FRIEDMANN: I agree, yes.

PROF. GEORGE: Okay. Then I guess we get to this interesting question ?? I remember the quotation you had up there from the basically baseball historian who said, "Well, look, if somebody wants to give up their certain number of years of their lives or damage their health to hit 20 home runs, that's a private individual decision."

I think something in most of us wants to agree with that, that that is a private individual decision, but I wonder if we ought not to agree with that, not only the health question, but because it is not a private individual decision what sport is going to mean in a culture. The question whether the sport will have some substantial element of the old romantic notion or be entertainment will itself, in a certain sense, be the product of a lot of individual choices, but it is going to be a social reality, for better or worse, a social good, if you will, that all of us, whether we like it or not as individuals, are going to live with. Is that right, too?

DR. FRIEDMANN: So far you're perfect.

PROF. GEORGE: Okay. Well, that's all I wanted, the only ??

DR. FRIEDMANN: I mean, that is why I raised the question at the end. I am not so sure any longer what sport is. What is sport, and, again, the question of, what are we trying to protect from people's individual choice to use performance-enhancing anything? It is not fair for me to insist on my view of sport to the point where I say that it is improper for Mark McGwire to use what he uses. I have a view of sport; he and many other millions of Americans have a different view of sport.

But to the point where it begins to suggest the ways in which areas of our society move from one realm to another and become entertainment or become technology, if sport is going to move to the position of being bioengineering ??

PROF. GEORGE: This is what I find interesting.

DR. FRIEDMANN: -- then it is a different world, and you may say, well, that's too bad; goodbye sport and hello bioengineering. I would find that sad, but I am not so sure on what basis I rail against it.

PROF. GEORGE: Let's, just for the sake of argument, say that human life is enhanced, where the romantic conception of sport prevails, just for the sake of it. Let's say you did believe that we could, then, explore what the argument would be for that, but let's just say that that is a good thing, and therefore, it would be reasonable for me to want that to be available to my children.

DR. FRIEDMANN: As athletes or as spectators?

PROF. GEORGE: Well, both. Both. I want them to live in a world where the benefits to them as athletes and spectators, of participating and viewing that kind of human achievement, that kind of activity, are available to them.

It looks to me like that gives me at least a reasonable basis for rejecting the kind of strong individualism or ethic of choice in these matters that would line up with what the baseball historian is quoted as saying in your presentation: that it's really nobody's business if this one guy, or every single individual athlete, decides that he would rather have 20 home runs than another three years of life. Because that set of decisions is robbing everybody else of the opportunity to make available to their children, let's say, probably starting all the way down in Little League, this conception of sport, since it turns out that sport is itself a kind of social reality. And if it is a good thing, if there is a conception of it that it is a good thing, it is a social good.

DR. FRIEDMANN: I think one has to have faith in one's idols. When I was growing up, I lived down the street from the Philadelphia Phillies player who was one of the neighbors and just another person. I admired him. He was an athlete, but he was another one of us.

I must say that in watching the Wimbledon tournament recently and watching baseball games, I no longer know what I am seeing. In a way, I feel a little bit robbed by not really have faith, not as much faith as I had in my old idol of the reality that I am now seeing bioengineering more than I am, and pharmacology more than I am sport. Maybe that's inevitable. I use that word again, but sport is not what it was, and it may be that we simply have to recognize that nothing is what it was.

PROF. GEORGE: You have a couple of children. When they were small, you probably would have directed them or encouraged them into sport or not into sport, depending on what it was that was being offered in sport, right, whether the future was, if they wanted to get serious about it, enhancements, whether pharmacological or genetic or not?

DR. FRIEDMANN: Well, one of them went into sport because he loved the effort.

PROF. GEORGE: On the romantic conception?

CHAIRMAN KASS: I have Janet. There is something of a queue, and if it begins to wander in every which direction, I am going to try to maybe stick to some topic, but please, Janet, and then Gil.

DR. ROWLEY: Well, I am going to wander in a direction, but I am going to take up on your last point of the last slide, which is enhancement in other areas. This is a topic that we have talked about off and on here in this Council, using examples like one which is germane to just what you have been talking about. If somebody wants to have a child with the skills of Michael Jordan, then you can start doing germ-line therapy for enhancement for that child, or beauty or intelligence.

I guess I would like your opinion, because it has seemed to me that these areas of enhancement involve complex genetic interactions about which we are pretty ignorant, and that at least at the present time those kinds of enhancements for overall athletic ability or intelligence or beauty are not likely to be immediately a concern. But I would very much appreciate your comments.

DR. FRIEDMANN: Let me make sure I understand the question. So the question is genetic sort of germ-line modification for enhancement purposes?

DR. ROWLEY: Yes, and have a superintelligent child. So is this something that we are going to be able to do germ-line treatment for in the next 5 years, 10 years, 20 years? I mean, enhancement for sports is one aspect, but I think many members of the Council are concerned about these other areas of enhancement. So what does your crystal ball say?

DR. FRIEDMANN: I think nobody knows better than this group the difficulties in even imagining how one's going to do that. All the factors that go into defining one's intelligence and sportability and everything else, they are imponderable at the moment. We know they are genetic to some extent. We know there are non-genetic and environmental and upbringing issues. We all know that one is not going to get a Michael Jordan or a Beethoven or a Michelangelo who's going to care a wit for what his genetic destiny might seem to suggest.

I mean, you make a Michael Jordan and he will probably hate sport. He may be very tall, but he may turn out to not have the opportunities to have learned basketball, not have the coordination which comes from conversations among lots of other genes. I think that is a non-starter at the moment because we are far too ignorant. There is just no question about that.

This nonsense, I must say, about Ted Williams, of course, another destruction of one's image of romantic sport, the nonsense of Ted Williams being frozen so one can sell his DNA, so that one can produce lots of other Ted Williams, it is absolutely "klatsch," as the Germans would say. It doesn't make sense, but, of course, that is not going to happen. There is no scientific defensibility for that. I think that is a non-starter.

CHAIRMAN KASS: Gil Meilaender?

PROF. MEILAENDER: Yes, as someone who could tell you what the Chicago radio stations that do sports talk all day are, I think you are too quick to assume a certain kind of tacit acceptance on the part ??

DR. FRIEDMANN: I'm sorry?

PROF. MEILAENDER: -- to assume some kind of tacit acceptance on the part of the public of, well, most recently, the steroids in baseball, for instance. I think it is pretty far from that.

I wonder if I can get you to just try to help me think a little farther than your presentation, which was very good and helpful. There are certain kinds of things, certain kinds of advances we make in sport. You pointed to them. So we start to use better tennis rackets, for instance, or bigger baseball gloves, or something like that. Maybe for a little while, if I have a better tennis racket and you have an old wooden one, it advantages me, but then pretty soon nobody uses wooden tennis rackets any longer, and all is well.

There is a sense, I suppose, in which you could say the same might be true with some of these possible, in-the-future ways of genetically enhancing performance. For a little while, if I have had access to it and you haven't, you know, it is unfair, but then it evens out.

So if the issue is simply kind of a level field of play and competition, if that is the issue, then probably, although there may be difficulties in the short run, in the long run it might not be a big issue.

So what I want to know is, if that's not the reason that people, just intuitively, seem to be concerned, and maybe they're wrong, maybe their intuitions are just wrong, can we think a little bit more about it? Because I don't think it is just the issue of health. Indeed, if it were just the issue of health, I might actually be with Jerome Holtzman; you know, if you want to give up 20 years of your life in order to be a star, God bless you, sort of.

But is there any difference between using genetic-altering approaches to enhancing my performance and using a bigger baseball glove or a graphite squash racket or something like that? You know, these could all be thought of as accomplishing the same thing in some ways, but do you think about them all in the same way or do you distinguish between them?

DR. FRIEDMANN: I think they are the same if your endpoint is, how far can you hit a baseball or how fast can you come down a ski slope, and how fast you can run 100 meters. If that is the endpoint, just sort of the measure, the quantitation, then you could say there's no difference. On the other hand, if you are saying that there is a difference between modifying the equipment and modifying the user of the equipment, then I think there certainly could be a difference, that it is engineering, sort of materials engineering versus bioengineering.

PROF. MEILAENDER: Well, I mean I understand that, but your sentence was that there's no difference if you are only interested in how far you can hit a baseball, but who is the "you"? See, when you went on to your second distinction, the issue was precisely who the "you" is in a way, you know, a bioengineered you or not.

So the sentence, "There is no difference if you're only interested in how far you can hit a baseball" is systematically ambiguous, I mean, because it cloaks the crucial question, doesn't it?

DR. FRIEDMANN: I don't know if I see that as a crucial question. Maybe I don't understand it too well. If the only measure of the manipulation, a wooden bat or a fiberglass pole, or whatever, if the only measure is the end result, then you can say there is no difference. But if you are looking at the way you got to that point, if it is because the athlete himself has changed in fundamental engineering sorts of ways, then having hit a ball 500 feet is one thing. If he's got there by using a far better designed bat, then that is something quite different.

The problem with Holtzman's analysis, Holtzman's comment, it seems to me, is that that certainly is true, if the athlete, or if people, subjects, whether athletes or not, are provided with full and complete information on what is likely to happen. If their information, if the available information is inadequate or is obfuscated or is not clear, and yet they are being offered, just in the case of the East German swimmers, offered long periods of pharmacological intervention based on the promise that they are going to have athletic success, and yet at the risk of their health, you can say to them, it doesn't matter what they choose. If they choose to win over protect their health, that is up to them. But it is only up to them legitimately if they've got correct information, if they have been educated, if they know what the options are, what true options are for them.

In this case, I think the option is that genetic modification is too immature a technology to assure the subjects that they will not be harmed, that the issues are far too immature and the techniques are far too immature, technology is too young, to know, in fact, what is going to happen in 20, 30 years. That is a level of ignorance that you have to be aware of if they, in fact, according to Holtzman, decide that they would accept that risk.

PROF. MEILAENDER: May I continue for one minute or not?

CHAIRMAN KASS: Well, I was going to come to you, if I might.

PROF. MEILAENDER: Okay.

CHAIRMAN KASS: Because I think I might clarify this. I take it your question is really not about the safety question or the health risks. Your question is whether there is somehow a fundamental difference between alterations, like I say, in one's equipment and alterations in, which I guess is the debated question, in yourself, and if that is a difference, whether we should care about it, I take it is where you're going.

Let me try something with you, because in the article that was distributed, Malcolm Gladwell's essay from The New Yorker ?? I won't get it right exactly ?? but, in effect, he is suggesting that some of these performance-enhancing drugs might, in fact, be a way of correcting for the accidents of natural endowment, and that if the romantic view of sport is based upon striving and effort, rather than on the basis of some ideal of excellence as such, then it seems to me, why wouldn't you want to say, "Look, what really counts is what you make of your talents and you can't take credit for your talents because those are gifts."?

Then why say, "Look, what you really want to do to have real sport is to equalize talent and then what you really want to see is, what are each of us going to make, what is everybody going to make of the talents, on the basis of who you really are, which is not the gifts that you were given, but your discipline, your effort, your aspiration."?

Why wouldn't you then want to say, "Look, body engineering is the possibility of really leveling the field in terms of gifts, so that we can then find out who's who when it comes to what's in the salt."?

PROF. MEILAENDER: There are some complicated questions there. Remember, I began with a question. I wasn't making an assertion.

But why do you think that who I am has only to do with the soul and not the body? Why do you think that who I am has nothing to do with the body that I have and the natural endowments, and so forth?

Well, just, you know, hang in there. Is it not, therefore, possible that we can conceive of certain kinds of alterations of the body that seem to alter the who I am? I mean that is the issue. And I don't have an answer here, but I am not just prepared to accept the disjunction.

CHAIRMAN KASS: But then your view of sport is that it is not ?? then the excellence isn't just in the striving.

PROF. MEILAENDER: Why, no. I coached kids, baseball teams, for years, and I never told one kid that it didn't matter whether you won or lost. I wouldn't tell a kid that at all.

DR. FRIEDMANN: I'm not so sure I buy the issue that you quote in the article about sort of leveling the playing field to make up for people's innate differences, innate differences in talent or ability, because that assumes that there is kind of a finite and defined normal for that. We all know, of course, that that, like everything else, sits along a very long wide spectrum of human capability, human traits.

People at the low far end of the normal curve are going to have very different traits from people at the high far end of the normal spectrum. So is that fair? Is that just, that they have got to compete with each other? So why not, in fact, imagine getting everybody to precisely the same level and have no curve, have just sort of a single point which is acceptable? That's not going to happen. So the level playing field concept, get everybody to the same level of capability and then see who runs the fastest, I think that is not going to be feasible.

CHAIRMAN KASS: Frank, Charles, Michael, and Paul are in the queue. Frank?

PROF. FUKUYAMA: Two separate points. With Gil, I think the health ?? I mean, I just find it hard to believe that health is the only ethical issue. I am wondering if there is actually any empirical polling data about why people oppose doping.

DR. FRIEDMANN: Why they oppose?

PROF. FUKUYAMA: Yes. You know, at the beginning of "The Prime of Miss Jane Brodie," she is a school teacher and she sees a sign on her wall that says, "Safety first," and she rips it down and she says, "No, honor, virtue, courage first. Safety second." That's the choice. Like Gil, I'm with the athletes, but that is just one issue.

But the second one is, I wonder if you could speculate a little bit with me. Supposing that you moved sport from the romantic version completely and made it more like auto racing, where it is a team effort of a bunch of doctors and medical people, to enhance the abilities of the athletes, that we kind of accepted that that is the ground of the competition, like the America's Cup or something, and it is a kind of open-ended competition.

What would happen in that kind of world over time? Would you move asymptotically simply to a kind of natural limit and just get there quicker than you would by normal training and the kinds of things that have traditionally been done in athletics or would it lead to a world, basically, where you would have, for example, an increasingly freakish number of body types?

I mean, already it is the case where football players and Sumo wrestlers and basketball players are look physically quite different, but you could imagine that, with the kinds of biomedical technologies that we're going to have in the next generation, you could push those somatic types in really, really far so that, instead of slam dunks, you would basically have basketball players that are dropping basketballs downwards into hoops.

But what does that world look like? Have you given any thought to ?- I mean, do all athletes become Sumo wrestlers, kind of grotesque Sumo wrestlers, in a sense, or is it just a kind of convergence on a natural limit that ??

DR. FRIEDMANN: I must say I haven't given it more thought than your very perceptive question indicates. You have the same intuition that I have, that the second option isn't very pretty. If one wants to go there, then I keep thinking again of Schrecker, what does that make of sport? What is an athlete at the end of all that, if not just simply another byproduct of a piece of engineering?

It is not sport, I presume. I am not an athlete, and I am new to the anti-doping world. But I have had trouble, as you have, understanding ?? and that is why I put it on one of the slides ?? what it is that we are so worried about. What are we protecting sport, for its own best interests, or are we protecting sport because we have the view of sport as we remember it growing up that we would like to see never change?

I don't like looking at a sports competition wondering what I am looking at. If I am looking at the highly-engineered body, then that is one thing, but if I am looking at an athlete, I would like to see something else.

That is my problem, I think. It is not the athlete's problem. It is not the society's problem.

CHAIRMAN KASS: Charles?

DR. KRAUTHAMMER: Let me try to address the problem, the question that you just raised, what are we worried about and why are we concerned about this? I don't think our concern is about sport. We are not a commission on sport; we are a Council on Ethics. Sport is very useful. Your presentation was very enlightening because it is such a clear sort of pure culture of the question. Things can be measured. We know that enhancement is possible. We know that enhancement has already occurred. So it allows us to look at the larger issue through a window that we can understand.

But I am not sure that the aesthetics of sports is the critical issue. I think the real critical issue is, why does enhancement somehow bother us? As I look at it, I think there are three possible reasons: safety, fairness, and character. Safety is obvious, and that is sort of a given. We are a society that protects people from themselves and the use of drugs or other areas; it would carry over into here. I don't think it is a very interesting question.

The more interesting issue, I think, is the issue of fairness. Gil raised it. I think he gave one explanation, which is that we ought not be that worried about the fairness because, as in the mechanical technology, as in tennis rackets, in the end if all the competitors are using the same enhancement, the fairness is retained. What's unfair now is that you've got doping being illegal; some know how to cheat and some don't. If you lived in a world in which it were either completely abandoned and enforced perfectly or allowed and universally used, you would end up in a situation where everybody is using the better tennis racket or the better body. The fairness issue, I think, would not be the major issue.

The other aspect of the fairness issue was raised by Leon. In a sense, I think he is right; the enhancement can be seen as a corrective for the unfairness of natural endowment. It is not quite clear why we honor people with great talent. It is useful in a competitive society, but why it is honored, if the talent, in and of itself, is innate is an interesting question. If enhancement is a way to level the field, I am not sure it offends our sense of fairness.

In the end, I think the reason that we object to this enhancement, or at least have some initial ?? why we recoil from it initially has to do with character. I think it is a sense that that is not the way to get from A to B. I mean, the ultimate enhancer was Rosie Ruiz. Do you remember Rosie Ruiz? She won the New York Marathon one year by riding the subway for the 18 miles in the middle. She started the race, got on the subway, waited a while ?? that was smart ?? and then rejoined it for the last mile. Her crown was only temporarily held.

(Laughter.)

But it offends us because that's not how you do it. In the end, I think when we discuss enhancement and make recommendations, or at least raise issues about it, not in sport but in life, because I think that is really what is important, is going to be this issue of character, that it is a cheap way to achieve what ought to be achieved by other means.

I am not sure how defensible that objection is, but I think in the end it is what underlies our objection. It is not safety. I am not sure in the end it is fairness. In a sense, it is character, I would say.

CHAIRMAN KASS: Michael?

PROF. SANDEL: Well, I think Charles has advanced the discussion. He has partly stolen some of what I was going to say, but I think that this is onto something important to separate safety and the fairness considerations from some other objection that we have, but find difficult to articulate.

During the last Olympics I was speaking to someone. He works in the biotech. industry. He said he wasn't watching the Olympics. I asked him why, and he said, well, he didn't really know what it was for, what it was about. Here were these people lifting huge weights, and there was all this discussion about enforcing anti-doping regulations, but if the purpose of the competition was to press the limits of human achievement to see what the people could do with the human body, then the logical thing to do would be to allow people to use whatever enhancements were available because that would be the way of pressing the limits of human achievement: how much weight could be lifted, how fast a hundred meters could be run.

But, given the inconsistency about the forms of enhancement, rigorous training regimes, okay, but pharmacological or genetic interventions, not okay, given that inconsistency, there was an incoherence introduced into the nature of the sport. Therefore, he didn't watch it.

I thought this was a bizarre reaction, a bizarre view, but I think he was onto something, just as I think Charles is onto something. I don't think it is true that the classic or romantic idea of sport is based on striving or effort. That misdescribes it.

In fact, I think there are two ideals that coexist uneasily in the classic conception of sport. One of them has to do with effort and striving, but the other has to do with achievement and excellence. Different people, maybe as a matter of temperament, admire more the one or more the other.

People who greatly prize and honor effort and striving will say that Pete Rose was the greatest baseball player who ever lived. He wasn't blessed with great natural gifts, but he was gritty and determined and, through sheer expenditure of effort and will, managed to be a great baseball player.

Whereas, others are drawn more to Joe DiMaggio, who was blessed with great gifts and grace, and part of what people admired about his play was precisely its effortlessness and the grace that went with those gifts.

So the second ideal, the one that's in tension with striving and effort, has to do with gifts, the great gifts that we admire when, of course, they are properly cultivated and displayed by great athletes. We saw the tension between these two stances, these two dimensions, of the ideal of sport in the celebration of Ted Williams. They told the story time and time again about how he practiced hitting until his hands bled. That was effort. That was striving.

But, at the same time, he was celebrated and valorized for having such terrific eyesight, 20/10 eyesight. They said again and again, that he could read the signature of the League President on the ball as it came forward. That had nothing to do with striving or effort. It had to do with a gift, but the gift and the way it was deployed in the excellence is something that we admire wholly independent of the striving. But that raises the question, because now we have laser eye surgery that many athletes go in for, Tiger Woods famously among them, that can change and correct and improve the eyesight that sports figures have.

So if we have, then, these two ideals and tension in sport, the question, an interesting question going back to the technological intervention, the enhancement, is, what exactly is threatened? What dimension of the ideal of sport is threatened insofar as we are uneasy, for reasons that go beyond safety and fairness in the case of sport?

Our first instinct, I think, is to think it is effort and striving. Because of someone goes and gets a technological edge or takes a drug, then they are doing something that they really don't have to strive for and train for. It's training on the cheap.

But I don't think that is really what bothers us about the biotech. enhancement. It is more deeply a threat to the second, not the first. Because what it displaces or confuses in what we honor and admire in sports is the appreciation of the gift, the gift of the great athlete which, when cultivated and deployed, leads to an excellence that we admire.

In fact, the intervention, the enhancement of genetic or pharmacological enhancement is in some ways a ratcheting-up of the element of will, the first thing. It is carrying the idea of will to a kind of logical extreme, and so it threatens to crowd out the sense of gift, the great athlete a gifted. There it seems to me it is in crowding out the sense of gift that this deep, independent, morally-troubling threat consists.

Now it is a further question, and Charles raised it very well, why we are so interested in using sports as a metaphor or as an analogy for trying to understand objections we might have to enhancement in the wider society. I think that is a question we need to think about, but here's just one speculation:

Sports has become increasingly a metaphor for life, as the allocation of rewards and honors in our society, as we search for a rationale. We like to think of ourselves as a meritocracy, but a meritocracy is at odds with the idea of honoring or rewarding gifts or giftedness. So we tend to describe the system of social rewards as it is rewarding effort; if you try hard, you have an equal opportunity, you can get ahead and be rewarded. That is what we honor.

So, if anything, we have kind of refashioned ?? and we saw it in the discussion here ?? we have refashioned the ideal of sport to fit the image of the society, that we have this meritocratic one based on effort, and yet we know with another part of ourselves, I think, that the distribution of honors and rewards in our society can't wholly be made sense of in terms of effort alone. That makes us uneasy, and it may get all the more complicated when we imagine a kind of genetic or pharmacological arms race, not only in sports, but also overlaid on a meritocracy, where we are not quite sure to what extent we are honoring effort or honoring achievement and gifts for which we can claim no credit.

CHAIRMAN KASS: Thank you.

DR. McHUGH: I always come after Michael, and I am so impressed by what he said, I have lost my track a little bit. I want to simply go along exactly with what Charles and Michael have been alluding to, but to make some simpler points along the way. I think, Dr. Friedmann, you have made some of them as well.

But, fundamentally, what we are all concerned about is that which we are going to permit is going to have to be required eventually. I had a dear friend of mine who is a wonderful psychiatrist, who is a wonderful person, and he was involved with the professional football team in San Diego. He discovered that all of the defensive players were on amphetamines, and he wanted to get them off of the amphetamines. They all said to him, "Doc, can you imagine what it's like me going out into that field with those guys who are drooling with their amphetamines? You've got to help me to get through."

The problem for my dear friend, and he is a wonderfully gifted person, is that he tried to help them, and help them reduce their amphetamines, and at the same time kind of keep them in play, and eventually hurt himself in the process, very much hurt his reputation. But that was the first example to me of what is permitted will eventually all be required.

I agree also with what is being said, that one advantage of looking at sport ?? I mean we are not here to talk about sport, but sport does give us a little opportunity to look at what could happen in other arenas. One of the things that is being left out of discussion here is just the plain word "cheating," you know. Doesn't cheating perhaps apply here, just to get to the groundrules?

Now take another game that takes very little athletics ??

DR. FRIEDMANN: But you can have that and have achievement at the same time.

DR. McHUGH: Yes, that's right, and I want to talk about exactly that. There's a game that we know in America, and we know what constitutes learning about the odds and playing it well and folding when you ought to. We also know that if somebody spends a lot of time learning how to slip cards up his sleeve and play that way, that we shoot those guys because that's wrong. It takes away the whole idea of the game and what it is.

I very much, with you, believe that the thing that has gone wrong for lots of people is that we have an immature science that we are telling them, nobody can get ?? everybody is going to have to join up. What's given is required. Yet, the science is so poor, we can't tell them exactly what's going to be lost in their health.

But, ultimately, it does come down, well, for me, and I suppose I do have a romantic view of sport; I certainly spent an awful lot of hours in my life talking about sport. When Ted Williams died, I burned up the phones spending dollars talking to many people all around the country about what a terribly sad day it was and how I saw him hit the Eephus pitch and all of this. Because I thought, and still think, that part of the thing that sports gives to us is that it enhances our capacity to appreciate excellence in others and their character as they use what God gave them to achieve all the things that they have achieved.

If we permit all this genetic enhancement to go, that there will be not only a loss in physical things, but we will lose the sense that there is a place where character counts. If we lose that, then in the boardrooms of the country and lots of other places, where character ought to count again, it will be lost there, too.

PROF. SANDEL: Of course, cheating is what we are against.

DR. McHUGH: Yes.

PROF. SANDEL: But isn't the issue raised here, what counts is cheating? For example, if we go to the wider society, apart from sports, when kids who can afford it take courses to prepare them for the SATs, is that cheating?

DR. McHUGH: Well, as I am saying, I am not sure exactly where cheating ends and where cheating begins, but I know it when I see it.

(Laughter.)

Consider poker. That's one of the reasons I wanted to talk about that.

PROF. SANDEL: I didn't know what game you were referring to, so I'm glad you named it.

DR. McHUGH: Yes, you were wondering, I'm sure. But you can consider games of that sort.

No, I agree with you that there are ways in which you might wonder that we are not a completely equal society in lots of ways. Some people can have, just the case of baseball, some people can offer their kids a batting cage and a batting machine, a pitching machine with which to play early on, and they don't have to do like Ted did, go out into the dusty fields of San Diego and get somebody to pitch to them. I appreciate that.

On the other hand, I think that we should be able to say at some point that certain forms of enhancement just go beyond what is, and I think lots of things that are happening in genetics go beyond there. Although there are gray areas, there are still areas of black and white.

CHAIRMAN KASS: We are going to wind up shortly. I have Bill and then Frank, and I want to give Ted a final comment. Then we will stop. Bill Hurlbut.

DR. HURLBUT: So cueing off of what Michael said, I want to suggest that we institute a third kind of Olympics. We have the normal Olympics and the Special Olympics. Maybe now we need the Bio Olympics.

DR. FRIEDMANN: That is not as facetious as you may imply. There is already talk for sort of an enhanced weight-lifting set of events.

DR. HURLBUT: Well, I, for one, will be much more interested in watching the normal Olympics, if they do it, as I am now more interested in watching Little League than professional baseball.

I think when you mentioned the ?? I have to confess I am a romantic on all this, but I think that might not be so cultural as it is more deeply universal, picking up on what Robby said earlier. I teach at Stanford. We have a lot of Olympic athletes, and I have had them in my classes. It seems to me that there's something important going on here that we've kind of touched on, but maybe not quite completely.

Obviously, there's something entertaining about watching eccentricity and novelty and extreme, but this is kind of ?? I don't know, I see this as almost a societal auto-digestion, where we are deriving entertainment from things that are destructive, a kind of nourishment from our own destructive deformation, rather than what I think sports is about, which is something that has to do with something profound and noble and moral, quintessentially moral.

It is not health that strikes me. I think about, what would you approve using enhancing drugs for or even entering into territory of danger for? I think, for example, about a hand surgeon, I mean an eye surgeon doing an operation on a child. You wouldn't mind him using beta blockers to calm his hands for that, even if it was a little bit of a health risk to him. We send people out into space with NASA, and we don't mind the health risk of that. It seems to me it has something to do with serious purpose.

Even with my students, I talk to them about all this. When it comes to things like cosmetic surgery, they feel okay moving kids with deformities up to the norm, but when you start moving beyond that mean, they are uncomfortable with it. They feel like something has changed.

When it comes to sports ??

DR. FRIEDMANN: Is it the mean or ??

DR. HURLBUT: Or the norm.

DR. FRIEDMANN: Yes.

DR. HURLBUT: I mean whatever you call it, in the middle. They are okay if you move a kid with cleft palate up to looking normal, and they are okay even with taking a person with ears that stick out or a recessed chin or something, but when it starts to become a competitive action, they feel like it is no longer medicine, that it is somehow strangely moved into the realm not of social coherence, but of competition.

It seems to me that that is what is going on in sports enhancement that bothers me personally. Maybe this is more universal than me; I think so. Sports is a kind of symbolic combat, but it seems to be a moral combat fundamentally. You spoke of an aboriginal impulse.

If you go back and you look at Murdoch's human relations files ?? do you know about those? They did these ethnic studies across all cultures, and every culture has something in the way of a sports ritual. Often they are tied in with the rites of passage.

I wonder if maybe at this particular age group that sports involves, primarily this risk notion has something to do with confronting the real world as it is, confronting danger, confronting infantile impulses and all the persuasions of pleasure, and in the constellation of that we gain control over ourselves.

In that sense, when I watch an athletic event and I see somebody manifesting self-mastery, that seems to me to have a moral element to it that is quintessentially the essence of morality in the first place; that human beings exist in a world of striving and struggle within their open possibilities and indeterminacies, and they move in a moral direction when they move for serious purposes against the natural quality of giving in to the easy or the obvious.

In that sense, it is not just effort that we care about. Ultimately, it is what is done. That is why to me all the things that we are talking about in terms of enhancement seem like they might be more okay at least, and maybe okay, when done for serious purposes. But the problem with sports is, instead of being a communal matter, it becomes a purely individual competitive matter then. It changes its character from being a place where we come together as a society to being a place where we lose the essence of what it is to be moral.

Does that make any sense?

DR. FRIEDMANN: I think that's a good analysis, but it flies in the face of the analysis of sport having multiple characters. One is striving and effort; the other is achievement. If achievement, in fact, is achievement and excellence or, in fact, the calculus by which sport is measured in a society, then it seems to me you don't have much of a leg to stand on.

DR. HURLBUT: Doesn't it become boring when it is just about achievement?

DR. FRIEDMANN: Well, of course, it's boring, but we presume that, to some extent, effort and striving ?? or at least how do I get to Carnegie Hall? Practice, practice, practice. No one ever said, take something to help you get there. In fact, most violinists probably take beta blockers to keep the quiver down.

So I think that the question really, again, is, what is sport and what are the goals of sport? I don't mean in any way to say that this is the moral problem of our time, but I think it is an opening to the issue of what do we take for being normal; what do we take for being acceptable? And those things that we want improved, what is it that enhancement is designed to do for us? What kind of enhancement do we want, and what kind of enhancement is morally repugnant to us?

That, of course, all depends on what we think sport is. If it is a paradigm, that is one thing. But the issue of enhancement outside of sport is still a major concern.

CHAIRMAN KASS: Frank, absolutely the last; I've kept everybody after school.

PROF. FUKUYAMA: Okay, well, very briefly, I thought Michael's distinction between gifts and effort was a very good one, but it does seem to me that the concept of gift and reveling in the excellence of that gift has to be related to some concept of what it means to be a human being. It is a human gift.

What you find remarkable is that a human being can do this in a human way. If you're born as a freak, you know, nine feet tall and you can play great basketball, I don't think ?? and then, similarly, we don't revel in cheetahs because they can run faster; they can run the mile faster than human beings because that's what cheetahs do. So there does have to be, I think, a specific notion of what it is to be a human being, and the gift is in relation to our expectations of that.

CHAIRMAN KASS: The hour is late. I usually teach in the afternoon, when I used to teach ?? it is a life for which one longs ?? from 2:30 to 4:30. I taught at 2:30 to 4:30 because, if I wanted to run over, nobody wanted the room.

I have done it to you again. I promised an early start, but, Ted, you have provided the foundation for what is in some ways, I think, one of the most interesting conversations that we have had here as a group. For the illumination and the stimulus, we are in your debt and thank you very, very much.

We will meet tomorrow morning at 8:30 for the discussion of the Richard Selzer story. I have good news for the wonderful people who have sat with us through this day. Whether you come back tomorrow or not, if you do, you will have a chance ?? the text of the story we are going to discuss is out there. So you can take it home, read it, and at least be in on the conversation. That is the gift of our appreciation for your endurance here and participation. We thank you also. Thanks to Council members, and the meeting is adjourned.