Meeting Transcript
June 12, 2003

Wyndham Hotel
1400 M Street, NW
Washington, D.C. 20005

COUNCIL MEMBERS PRESENT

Leon R. Kass, M.D., Ph.D., Chairman
American Enterprise Institute

Rebecca S. Dresser, J.D.
Washington University School of Law

Daniel W. Foster, M.D.
University of Texas, Southwestern Medical School

Francis Fukuyama, Ph.D.
Johns Hopkins University

Michael S. Gazzaniga, Ph.D.
Dartmouth College

Robert P. George, D.Phil., J.D.
Princeton University

Mary Ann Glendon, J.D., L.LM.
Harvard University

Alfonso Gómez-Lobo, Ph.D.
Georgetown University

William B. Hurlbut, M.D.
Stanford University

Charles Krauthammer, M.D.
Syndicated Columnist

William F. May, Ph.D.
Southern Methodist University

Paul McHugh, M.D.
Johns Hopkins Hospital

Gilbert C. Meilaender, Ph.D.
Valparaiso University

Janet D. Rowley, M.D., D.Sc.
The University of Chicago

Michael J. Sandel, D.Phil.
Harvard University

James Q. Wilson, Ph.D.
University of California, Los Angeles

INDEX

• Welcome and Opening Remarks
  
  
• Session 1: Stem Cells and Regenerative Medicine: Overcoming Immune Rejection
  
  
• Session 2: "Medicalization":  Its Nature, Causes, and Consequences
                                              
• Session 3: Biotechnology and Public Policy: Assisted Reproduction and Reproductive Genes
  
  
• Session 4: Biotechnology and Public Policy: Embryo and Related Research

WELCOME AND OPENING REMARKS  

CHAIRMAN KASS:  Good morning, everyone.  Welcome to the members of the President's Counsel on Bioethics to this, our 11th meeting.

A very special welcome to Jim Wilson who rejoins us after successfully completing several months of medical treatment.  He has escaped from the leeches in better shape than before.

(Laughter.)

CHAIRMAN KASS:  Welcome, too, to the members of the public. 

I note the presence of Dean Clancy, the Designated Federal Officer, in whose presence this is a legal meeting.

Jim has asked for a moment to address the Council.

PROF. WILSON:  I simply wanted to apologize for my long absence.  I did not realize during my absence that Leon, in the spirit of kindness to which he is so disposed, had not revealed the reason, but I had to be at home for 90 consecutive days.

Ninety consecutive days are over.  I'm fine, and I'm back to join you as mean-spirited as ever.

Thank you.

(Laughter.)

CHAIRMAN KASS:  That's why I have him close.

The agenda for this meeting, as you  know, the bulk of this meeting will be devoted to biotechnology and public policy and our project to assess the current state of regulation of the technologies that touch the beginnings of human life with panels this afternoon from a variety of stakeholders and their representatives and tomorrow morning with a discussion of the discussion document that the council commissioned the staff to prepare.

The first session this morning is separate and is a continuation of our efforts to fulfill the charge to monitor stem cell research.  The topic of stem cell research will be the heart of the July meeting.  We have commissioned five or six scientific review papers from leading researchers to review the work in stem cell research, embryonic and adult, that has taken place since August of 2001.

We also have commissioned an ethics review paper and a paper that will review relevant legislation, federal and state, that has been enacted since that time.

Today, in advance of that meeting, we are trying to inform ourselves about one crucial challenge to the possible therapeutic uses of stem cells and their derivatives, the problem of immune rejection.  This, as many of you know, is an area of intense research activity, not just of stem cells but across the board in transplantation of solid organs.

And we are very fortunate to have with us as our guest this morning Dr. Sylviu Itescu, who is Associate Professor of Medicine in the Cardiology Division at the Columbia University College of Physicians and Surgeons and also the Director of Transplantation immunology at Columbia Presbyterian hospital of the College of Physicians and Surgeons.

Dr. Itescu's curriculum vitae is at your place, and the paper that he has submitted, I think, was delivered to you at your hotel rooms, and it is, as he acknowledges, a technical paper, but one I think that will, in addition to the discussion that he's now going to lead us through, will help us a lot, I think, in thinking through this particular crucial problem in the area of stem cell research and regenerative medicine.

Dr. Itescu, thank you very much for your paper, for your presence, and we look forward to hearing from you.

Session 1: Stem Cells and Regenerative Medicine:
Overcoming Immune Rejection

PROF. ITESCU:  Dr. Kass and council members, I want to thank you very much for having me at this session.

I would again like to apologize for the technical nature of the paper, but please I would really appreciate if anybody has any questions as we go through even from my slide presentation, just feel free to interrupt and ask questions freely, and I'll be delighted to explain in more detail.

The objectives, I think, are twofold.  Firstly, what I'd like to do is to give you an overview of the current state of knowledge and clinical practice in terms of the basic immunobiology of organ transplantation and methods by which we currently immunosuppress patients and prevent organ transplant rejection.

And secondly, I think the objective is to gain an understanding of those issues as they may relate to the subsequent use of stem cells for organ regeneration or for tissue regeneration, and so that you understand the fundamental issues that will be faced by physicians trying to manipulate or to use stem cells for those type of strategies.

But I think of even more interest, towards the end of the presentation by  understanding the obstacles to accepting a foreign organ, there are some interesting new concepts and data that have arisen regarding the use of stem cells to alleviate some of these issues that I would like to really open up for discussion at the end of the presentation.

I'm not sure how to switch the projector on actually.  It may require a — okay.

What this slide shows is that despite the fact that the number of patients on our transplant waiting lists continue to exponentially grow year by year by year, what you can see is that there continues to be a major limitation in the supply of organs.

In yellow you see the living related donors have remained minimally pretty  much the same over the years and, more important, the cadaveric donors have remained the same.  So we have a real problem in terms of shortage of donors.

And it is the same for the previous levels for renal transplantation, and this slide shows the same for heart transplantation.  Significantly increased numbers of patients were on the transplant waiting lists.

And what this results in is a significant increase or significant rate of mortality of patients who otherwise could be saved if they had an appropriate organ donor.

And what you see for kidney transplant patients who are on the waiting list, the mortality now is fairly low, five percent, despite a very long waiting time, and that is because we have dialysis as a modality to keep patients alive.

In contrast, until the last couple of years, you can see that for the heart transplant patients on that waiting list, mortality was as high as 30 to 31 percent, and that is because we didn't have until very recently any way of keeping patients alive who were waiting for a heart transplant.

More recently, over the past couple of years, there's been quite a significant new development, and that is the development of left ventricular resist devices.  You can see these type of artificial devices that are essentially the equivalent for a patient on a heart transplant waiting list to what is dialysis for a kidney transplant patient.

This is an artificial pump that takes over the function of the left ventricle and keeps the patient alive while we find an organ donor for the patient.  And this has now brought the mortality rate on the transplant waiting list back down to almost zero, quite a major achievement.

Nevertheless, there are few ways by which we can increase the ability to have donors.  One is the use of live donor organs.  The pros of using live donor organs are that they are superior in terms of outcome to cadaveric.  The costs are much less than cadaveric, and there are psychological benefits in terms of donor/recipient issues.

The risks.  There are some small risks to the donor in terms of morbidity and mortality, inconvenience, and obviously the overall decision is a voluntary one for the donor.

The short and long-term risks of a living, related or unrelated and living donor donation for a kidney, there's a very small risk of death primarily related to pulmonary emboli.  There are some major complications that could be seen primarily related to the surgical procedure.  Approximately one to two percent of donors will have some degree of clinical complication.

The long-term risk is pretty low to the donor.  However, the survival of a living related organ transplant is significantly superior to a cadaveric organ donor.  You can see that in a kidney transplant, the living related organ significantly survives for a significantly greater period than cadaveric organ.

And interestingly, even a living unrelated donor, in blue, has a better outcome than a cadaveric donor, and what I wanted to emphasize here is that a living unrelated donor is typically a spouse, where genetically completely disparate between the husband and wife.  Nevertheless, the outcome is almost the same as a partially matched sibling related graft donor.

The reason for this probably is the fact that you can prepare the spouse well in advance.  The whole procedure is done in a convenient way, timed appropriately, with minimal risk to the donor.  But the outcome is significantly superior to cadaveric.  That's really the point of this.

And what you can see, there's a change in distribution in the U.S. in terms of living donors, particularly in terms of spouses who are now providing organs to their spouse in need, as well as actually unrelated donors who are now donating organs to unrelated recipients.

In contrast to that, you can see that family related donation has pretty much remained unchanged of these.

Okay.  I'd like to move on to some of the immunologic issues that primarily a cadaveric or unrelated donor recipient pair will undergo when an organ is transplanted.  The primary difference between individuals is at the level of a certain complex called the HLA complex or the MHC complex.  We're talking about genes that incurred a protein on the surface of all of our cells that are called HLA genes.

HLA genes or HLA molecules, two types, Class I and Class II, and these Class I and Class II molecules you can see in blue are two-chained molecules that serve to present a foreign protein or antigen to our own T cells so that they can be recognized as foreign and rejected or removed from the circulation.

This is the fundamental basis of how our immune system will recognize bacteria or viruses and eliminate them from our circulation, and typically what happens is that if this a virus — consider this to be a virus — taken up by these cells which are called antigen presenting cells, but otherwise known as macrophages, the virus is taken up in a vesicle.  It's then broken down into little pieces or little peptides, and the peptide in yellow is then assembled in the cytoplasm of the cell together with an HLA molecule in blue, and the complex of a piece of the virus plus the HLA molecule is then shuttled up to the cell's surface, and as a complex is presented to this structure over here, which is called the T cell receptor on the surface of the T cell.

Typically this is a CD-4 helper T cell, but the key issue is that this T cell receptor structure recognizes a three dimensional structure between the peptide antigen and the HLA molecule, and the whole thing activates a whole pathway in the T cell that then results in removal of the whole invading antigen or invading virus or bacterium.

And this is a typical immune recognition reaction that occurs throughout life, throughout our blood systems and, you know,  our immune organs.  You can imagine, therefore, if this now becomes a foreign organ, the HLA molecule on the surface of this foreign cell will be viewed as totally different from all of the HLA molecules of a given individual by our own T cell receptor.  It will no longer.  It will no longer be seen as a non-molecule.  It will be seen as foreign.

And the fact that the HLA molecules on a foreign cell, this structure itself is different from the HLA molecules of a given individual always will trigger a reaction as though this whole structure was a foreign structure. 

What I have just outlined to you is actually a very complex immunological phenomenon.  So if anyone has any questions, I'm sure this is not a straightforward issue to understand, but please, just feel free to ask.

Can we just focus that a little bit?

Okay.  So with the notion that if this is now the — consider this to be the foreign cell from the foreign organ that has been transplanted.  Understanding that the MHC or the HLA molecule on the surface of this cell is totally foreign to the recipient, it can trigger two types of an immune response.  It can trigger what's called a direct immune response and an indirect immune response.

The direct immune response is when the foreign HLA molecule as a total structure is seen as foreign by the T cell receptor of the recipient T cell.  So under normal circumstances, as I've mentioned to you, the T cell receptor will recognize a little peptide that should be here, not the HLA, just the peptide.

In this scenario, the T cell receptor recognizes the whole HLA as a foreign piece, and so this is called direct recognition, and it allows the immune system to be activated and attack this cell entirely.

A second process of immune recognition, the indirect process, is one where this HLA molecule is internalized in the cell of origin, and a little piece is secreted, and you see there is the little piece of the foreign HLA molecule, and it's just this little piece that then comes up.

And this cell now is the recipient cell, if you can imagine.  It's the recipient antigen presenting cell.  And so this little yellow piece, which is a component of the original foreign HLA, is now presented as an antigen by our own HLA molecule.

And so this recognition is the more classic form of immune recognition the same as you would recognize a virus or a bacterium.  You not only recognize a little piece of this entire structure, and this is called an indirect allorecognition.  But it's two different types of recognition directed at the foreign HLA molecule of the donor.  Both of them drive the immune response against the donor graft.

This is the basis actually of an immune assay called tissue typing or mixed lymphocyte reaction, which allows us to test how different the HLA molecules of one donor are in terms of recognition by the HLA molecules of the recipient.

And so what we typically do is take cells from a potential, let's say, kidney allograft donor, and this really is done in terms of selecting a potential living related donor.  We want to know really how different is the potential donor to the potential recipient in terms of those HLA molecules.

So we'll take cells, blood cells, from a potential donor.  We'll know the typical type of HLA molecules on the surface.  We mix them with the HLA molecules or with the cells of the potential recipient, and we look for the type of reaction.  We look to see whether the recipient cells proliferate and become activated or don't proliferate and don't become activated.

And essentially the degree of proliferation and activation is a measure of the difference between the HLA types on the surface of the donor and on the surface of the recipient, and what you don't want to be doing is transplanting a potential donor whose cells stimulate very vigorously a proliferative response in the recipient cells.

Okay.  Now, in terms of once you have selected your donor for living related, for example, based on as good a matching as you can get at the HLA locus or for a cadaveric kidney transplant we also do HLA typing.  We try to minimize the differences in HLA molecules between donor recipient.

For cardiac transplant actually we don't have the time to do that.  In fact, for cardiac transplant recipients there is no HLA matching.  We take whatever comes because of the severe shortage of donors.

But essentially once you've actually bitten the bullet and you've accepted a particular donor, there's a variety of types of rejections that can occur, and those are defined based on both the immunobiology  of the type of reaction and the time taken  to induce the rejection process.

And there are at least four types of rejection processes that I'd like to talk about.  One is called hyperacute.  One is accelerated.  One is acute, and one is chronic, and as indicated, hyperacute happens within minutes to hours, and the fundamental issue here is that unbeknownst hopefully to the transplant physician, the recipient had what we call pre-formed anti-donor antibodies in his circulation, and as soon as the organ gets put in these, if you've got this type of a serum, you will reject the organ immediately, within minutes.  It is a horrendous outcome.

So we always try to exclude the possibility that a given recipient has antibodies that might destroy the organ, and we do what's called a donor specific antibody cross-match prior to any organ being transplanted.  This is both for kidneys, hearts, and lungs.

Assuming that this doesn't occur, and I'll show you an example of this in a minute, but assuming that this doesn't occur because you've been diligent and have excluded this risk, the typical type of rejection that would occur in the absence of immunosuppression is an accelerated or an acute process which happens within the first six to seven days primarily.

And this is a result of either reactivation of T cells that have previously been activated by some type of similar HLA, such as blood transfusion or primary activation of T cells, that the natural process by how the  T cells will recognize the foreign HLA, and it will take them about seven days to recognize them, and you will get an acute rejection process.

And we understand that, and this is what we have tried always to prevent by treating with a number of immunosuppressive drugs at the same time.

In addition to this, and while the patient always remains at risk of recurrent episodes of acute rejection, there is another process called chronic rejection of the graft which happens within months to years, and we'll talk about that in more detail, that causes a very complex and unclear, but this really is the major limitation of long-term survival of the graft at this point in time.

Just an example of what I was talking about in terms of the hyper acute form of rejection.  If an individual has pre-formed antibodies against the HLA of that particular donor, as soon as the blood comes into contact with the foreign allograft or the foreign organ, those antibodies will bind to the surface of the organ.  They'll recognize the foreign HLA immediately and activate a whole complex that results in a clot formation in the blood vessel and occlusion of the blood vessels to the organ.

This is what it looks like.  This is a classic hyperacute rejection of the heart, where you can see swelling of the heart, hemorrhage, and then within minutes the heart goes black and you've lost the organ and the patient really is in extremis, and often dies in surgery.

So in this day and age, it's very rare to see that type of hyperacute rejection, and we try to minimize the risk of that by screening and doing a variety of assays.

Assuming that you've gone through that first couple of days, what happens is through those two processes I talked about, indirect; so direct recognition of the foreign HLA and the indirect of the HLA, the CD4 T cell, helper T cell is the orchestrator of the immune response, is activated by the foreign HLA molecules.  The CD4 cells start to divide and proliferate, and they then help these cells called CD8, or cytotoxic T cells, to become activated.  These are the effectors of the rejection process.

They also help B cells make antibodies, and the antibodies provide a second barrage, second attack against the graft.  So these are the two effector arms that cause the rejection process, particular CD8 cytotoxic cells.  But the CD4 cells are the primary cells that recognize the foreign HLA and orchestrate the whole process.

And you might recall that CD4 cells, which are the primary orchestrators of all immune responses, are also the targets of the HIV virus.

This slide is a little complex, but just to show you that the cytotoxic CD8 cells that I mentioned ultimately destroy the graft by secreting a variety of factors that punch holes in the graft and cause it to leak and explode pretty much.

We'll just keep going.

Okay.  So that complexity in terms of cellular activation has defined multiple targets for immunosuppression.  You can inhibit the ability of the CD4 T cell to recognize the HLA molecule directly.  You can inhibit T cell activation and secretion of cytokines, and we'll talk about that in a minute.

The most important cytokine here is IL-2 because IL-2 activates the whole downstream pathway of CD8 cells and other T cells that are important in the rejection process.  You can then try to suppress activation of other T cells and B cells, and then we have drugs at all of these points that synergistically will inhibit the immune response.

The axioms of immunosuppression, three major things to think about.  You want to have an immunosuppressive effect of the drug that you're giving.  You want to minimize the immunodeficient complications obviously, and you want to minimize the non-immune toxicity.

And the best way to do these, to maximize the immunosuppressive effect and minimize these two other issues is by combining drugs that work at different sites of the immune response.

And so you see, for example, if we only treat with one agent, and cyclosporin is our example here, we have a fairly minimal, specific immunomodulatory effect, and a fairly high range of nonspecific or immunosuppressive effects.

But if we now add two drugs working at two different sites of action, we maximize or optimize our immunosuppressive effect at a selective level, while minimizing our undesirable side effects, and that's the rationale for combining immunosuppressive therapies.

In addition to that, you want to use drugs that act on different arms of the immune response and at different time points in a synergistic fashion.  So all patients are routinely treated with glucocorticosteroids, which are essentially nonspecific inhibitors of most arms of the immune response, and they act very early to switch everything off.

Now, what you don't want is to continue to have to be using high doses of steroids because they're associated with lots of side effects, most notably global immunosuppression.  So you want to use steroids early on and be able to switch the steroid usage off.

We also now use cyclosporin or FK506.  These are related agents.  These have made probably the biggest difference in the transplant survival over the past 20 years by acting directly on T cell activation to prevent IL2 and other cytokine production.

And then there's a bunch of other drugs that alone or in combination are  used to prevent the second stage of immune activation, other cells, the recruitment of other cells, the differentiation of other cells, and the prototype of this is azathioprine.  Now the most commonly used drug in this group is MMF, or mycophenolate mofetil.  And then there's a bunch of other experimental approaches to prevent other aspects of the immune response.

What this slide shows you is the impact of cyclosporin on allograft survival here in kidney transplant.  You can see that prior to the early '80s — actually cyclosporine was introduced, I think, around 1978, and you can see the difference in survival of kidney allografts.  This is graft survival as opposed to patient.

Patient survival is not the issue.  If the graft is rejected, it dies, and the patient goes back on dialysis.  So what you see here is in the late '70s, early '80s, our one-year graft survival was as low as about 50 percent for kidney allograft.  It's now much higher than this actually.  It's about 95 percent one year survival, and it's the same for cardiac allografts.

So this drug, when this drug came in, it revolutionized the treatment of solid organ allografts, and the way it works, let me just go very quickly.

Cyclosporine binds a calcium activation factor in the cytoplasm called calcineurin and turns on a whole cascade of events that in the DNA and in the nucleus of the activated T cell inhibits the ability to activate various genes of cytokine production, such as IL-2 and interferon gamma, which regulate immune cell divisions.

If you don't make these cytokines, you do not get immune cell division.  That seems to be a critical component of preventing rejection.

However, despite the fact that we understand this process of immune activation and were able to prophylactically treat patients and prevent acute episodes of rejection, we clearly have improved short-term allograft survival.

Despite all of that, there is a second process that kicks in some time during the course of the recipient's life span, and what you see is that, for example, with cardiac transplants over time, over a five-year course, there's a cumulative loss of as much as 40 percent of the allografts in heart transplant patients.

And with kidney transplants, this curve is pushed forward, but you still have about a 50 percent loss of allografts at ten years.

So the question is:  if we're able to reduce the incidence of acute rejections, why are we still getting a limited long-term survival of the graft itself?

And the reason is this pathologic, unusual lesion that happens in actually just about every graft that's  put in whether the heart or the kidney or the lungs.  You get a lesion like this in the blood vessels of the allograft.  It's very unusual.  It's proliferating the lesion where you can see that the lumen of the blood vessel is almost occluded by these proliferating cells.

And this is in the heart.  This is called accelerative transplant related vasculopathy.  In the kidney, this is, again, a chronic vasculopathy.

And the cause of this is not clear, but it probably is due to — much of that, as I suggested, is due to an ongoing immune response against the foreign HLA antigens, which are expressed here on the luminal side of the blood vessel.

And even though the patient is not experiencing major acute episodes of cellular rejection, there is an ongoing subclinical level of rejection process going on that damages and causes these vessels to close off.

The causes of this process really is multi-factorial, but HLA, attack against the HLA of the donor continues to be the number one cause of this.

And you can see that chronic rejection — this is in our cardiac transplant population at Columbia — chronic rejection accompanies those patients who had many more episodes of acute rejection.  So for every hit that you have, for every acute rejection episode that you have, you'll destroy a little bit more of your heart, and you're more likely to go on to get chronic rejection as opposed to those individuals in blue who have less episodes of acute rejection.

So fulminant episodes of acute rejection, even though you survive them and your graft continues to work well and we can reverse them will predispose to chronic rejection and even in the absence of fulminant episodes of acute rejection, ongoing immune reactivity against the donor HLA will also predispose you to chronic rejection.

As you can see in this slide, these are patients who actually have not had episodes of acute rejection over a number of years, but make antibodies against the foreign HLA.  In yellow are the kidney patients or heart patients.  Antibodies against the HLA antibodies, in yellow the HLA of the donor, have a poorer outcome in terms of developing graft failure.

So even in the absence of acute episodes of rejection, an immune response that results in anti-HLA reactivity causes graft loss, and this shows the same.

So what that means is that we need to be vigilant.  We need to monitor the patients very closely.  We can't just expect that a combination immunosuppressive regimen that is used initially is going to keep all patients in check and all patients quiet.

We have an active immunologic monitoring of particularly our cardiac transplant recipients who are much more prone to having rejection episodes, and we actively on a weekly basis measure antibodies, T cell function.  We identify patients who are at high risk of cellular rejection.  We have a whole algorithm that allows us to study these patients on a weekly basis, and you can see that this algorithm allows us to be very flexible and change the type of therapies that we use so that if at a particular time point certain test number one plus test number two in terms of immune activation become positive, we know that we need to change our immunotherapy.

In contrast, if these assays remain negative or perhaps revert from a positive to a negative, we can reduce the type of biopsies that we do.  Instead of doing a biopsy every 30 to 60 days, we may reduce our biopsy frequency to every 90 days.

And this is the type of dynamic approach that we use to monitor our patients and to modify the type of immunosuppression that's required.  It's not a static process.

And I think what I'm trying to emphasize is that the recipient's immune response continues to be a major obstacle in terms of accepting and long-term survival of the graft.  And so since these issues are so complex and so difficult, the Holy Grail really of transplant immunobiologists has always been to try to induce a state of transplantation tolerance, in other words, a permanent acceptance of the graft that can allow the recipient ideally actually to not require any type of immunosuppression.

And the definition or criteria of transplantation tolerance are outlined here:  specific immunologic unresponsiveness to alloantigens, otherwise known as HLA antigens, of the donor, of the graft, in the absence, total absence of continuous immunosuppression; prevention of acute rejection and promulgation of graft survival; acceptance of a second test graft on the same original donor strain — this is for experimental tolerance in animals — and the specificity is then confirmed because the recipient will reject a third party graft.

In other words, tolerance is defined as being absolutely tolerant only to the organ that you've received or that you've seen, but not tolerant to an unrelated donor.  This type of tolerance has been extremely difficult, if at all possible, to detect or to attain in humans, although many studies have suggested that perhaps a term called microchimerism or chimerism may actually reflect a state of tolerance in organ transplant recipients.

And what chimerism relates to is the presence in your circulating blood of at least five percent of your circulating cells being of donor origin.  Whether that, in fact, really does induce tolerance is really not clear, but the concept is that if five to ten percent of your circulating blood pool comes from the donor, essentially what's happened is that the passenger cells from the graft that was placed into the recipient, the passenger cells left the graft, circulated to the lymphoid organs, particularly the bone marrow and the thymus, engrafted in the bone marrow and the thymus, and then have maintained their own essentially self-renewal capability, and continue to be shed and secreted into the circulation to essentially make the recipient think that cells of that HLA type are the same as oneself.

Again, in experimental models, you need to attain at least five to ten percent of your circulating cells being of donor origin in order to have a so-called chimeric state that may reflect tolerance.

And so what are the mechanisms by which tolerance might be attained?  And again, all of this we're talking about now has not been defined in humans, but is based on experimental models in both small animals and larger primates.

The mechanism includes clonal deletion, clonal anergy, and perhaps development of regulatory cells that change the type of cytokines that are produced.

Clonal deletion refers to the ability of the thymus to regulate the type of T cells that we produce that reject the organ.  In other words, if we know that CD4 T cells in our blood recognize the HLA of the donor, why are they not deleted or why are they not removed by mechanisms in our body that can actually do that to our own T cells that attack our own grafts?

And so the function of the thymus is to actually remove self-reactive T cells that we all have at various time points, and if our thymus can remove our own autoreactive T cells, could we perhaps induce our thymus to remove those T cells that are reactive to the graft?

And so this process of clonal deletion or how do you induce clonal deletion is one mechanism by which tolerance might be attained.

Clonal anergy does not involve the thymus.  Clonal anergy is the same sort of concept:  can you remove those deleterious clones, but this happens in the periphery, in lymph nodes, similar mechanisms but in a different location.

Regulatory cells that change your cytokine profile — let me just go to the next slide — it's well known that the type of cytokines that induce an acute rejection process, Interleukin 2 and interferon gamma, and I've already mentioned that cyclosporin primarily inhibits the production of these cytokines, but these cytokines are made by certain types of T cells called TH-1 cells.  It has been shown that if you can prevent the development of these TH-1 cells and instead skew the immune reactivity towards what's called a TH-2 type of T cell that produces a totally different repertoire of cytokines, this type of T cell preponderance and this type of cytokine preponderance appears to switch off the immune response and allow engraftment and allow a tolerogenic state.

And this switching between a TH-1 and a TH-2 phenotype of cells can be attained, again, by a variety of experimental approaches, but if we can drive to this preponderance of cells, we might be able to prevent allograft rejection.

Other novel experimental approaches include inhibition of co-stimulatory molecules on the surface of the graft.  We know that HLA was — well, HLA is the primary antigen that drives the T cell immune response.  There are other molecules on the graft that help deactivation of the T cell, and these are called CD28 and CD40 ligand at least.  There are many others as well.

If you don't have molecules on the surface of the graft, an HLA, foreign HLA molecule by itself may not necessarily activate the T cell.  So there are ways of perhaps altering the graft so that it doesn't express these co-stimulatory molecules, that may induce a tolerogenic state.

Other approaches include the use of MHC or HLA peptides that can mimic the foreign HLA and bind to the T cell and switch it off, and perhaps also induction of death, artificial induction of death of the T cell that mediates rejection.

Another molecule that's important in this pathway is called Fas ligand that could be over expressed, again, by genetically altering the organ, over expression of Fas ligand to kill the T cell that recognizes Fas ligand instead of allowing it to become activated.

These are all experimental approaches, none of which have yet been proven in men.

Let me just keep going.

This is one approach that I would like to just touch on very briefly.  Amongst the co-stimulatory molecules is the IL-2 receptor, IL-2 to IL-2 receptor, and you can see that if you don't express a functional IL-1 receptor on your T cell, the T cell is not able to then proliferate and become activated.

So we said that cyclosporin is a very active drug by virtue of the fact that IL-2 is inhibited.  However, how about if we can inhibit the IL-2 receptor rather than inhibiting IL-2?

And that has led to a strategy from a number of the large pharmaceutical companies that have developed anti-IL-2 receptor monoclonal antibodies, and here's an example of one where in conjunction with other immunosuppressive agents you can see that it delays the onset of kidney allograft rejection.

However, what's interesting here is that as soon as the antibody treatment is stopped at around day 180, you can see that the rejection process starts to come together again.

In other words, what this tells you is that this type of an approach of an antibody to block a surface receptor that may be considered important for the immune response does not lead to a tolerogenic state.  It simply leads to an inhibition of the immune system.

Because when you stop that treatment, you should continue to have an inability to reject the organ.  Because these rejection rates come together, it means you have an induced tolerance.

And so we get back to what I was just talking about, which is can we artificially allow the thymus to delete cells that would otherwise be alloreactive.  And the way we can do this experimentally is to use a drug called cyclophosphamide.  It is yet another immunosuppressive drug, but what this essentially does is it activates a pathway in the thymus that causes T cells that would reject the organ to explode or die through a process called apoptosis.

And what you see here is that if we actually treat — this is now in patients — if we treat patients with cyclophosphamide to induce apoptosis in the thymus of alloreactive T cells, we inhibit the rejection process very significantly relative to patients who are treated with another combination of drugs.

And so this is a major clue to the fact that the thymus can be manipulated to enable a tolerogenic state to occur.

And that leads to this.  This is really my last slide.  This leads to understanding a phenomenon that was described quite a number of years ago in kidney transplant recipients where blood transfusion that preceded the kidney allograft, and this is blood transfusion of the same donor type infused peripherally prior to actually putting the kidney transplant in, significantly prevented the rejection of the organ.

And this phenomenon has now been known for many years, although it has been poorly explained.  Many variations of this have now taken place in clinical practice, trying to define the cells that most likely prevent allograft rejection.

And we have moved from using whole blood because it's very difficult to know exactly how many cells.  If you actually give too many cells, you can actually induce an immune response.  You can induce an accelerated rejection process.

It seems to be very critically linked to how many blood cells are actually transfused, which means that if we don't understand which cells are doing this effect, you really haven't got a handle on the process.

So now people are looking at other subpopulations, and since the whole field of stem cell transplants and bone marrow transplants have moved along pretty dramatically over the past few years, people have tried to now look at whether cells in the adult bone marrow, particularly stem cells in the adult bone marrow, may have this effect when transfused prior to an organ transplant.

And what I'd like to just quickly do is to sort of shift — that is my last slide — but I'd like to just quickly shift into some aspects of my paper, which I think addressed the current state of knowledge in terms of how cells from the bone marrow or from other sources might actually do this sort of thing, induce a tolerogenic state and prevent organ rejection.

In order to — if we could just switch off the - thank you.

In order to understand the type of tolerance that we're talking about, we need to understand a little bit about the characteristics, particularly the immunogenic characteristics of stem cells, both embryonic and adult stem cells.

Embryonic stem cells have been known for a number of years in murine models and recently in human cell lines, but adult stem cells, a population of adult stem cells has recently been described to be present in the adult bone marrow that has many features and many characteristics that seem to be shared with embryonic stem cells.

So I'd like to sort of combine the discussion in terms of the characteristic of both these cell types because they're fairly similar.

Both embryonic and adult mesenchymal type stem cells do not express HLA Class I and Class II molecules and demonstrate reduced surface expression of co-stimulatory molecules required for T cell activation.

When one transplants either embryonic stem cells or mesenchymal stem cells from the adult, one finds long-term graft survival of the cells despite the fact that these cells to acquire HLA Class II antigens after in vivo differentiation.

A striking recent observation of the mesenchymal stem cell population has recently been noted that they broadly inhibit T cell proliferation and activation by various types of antigenic stimuli, including those from HLA of foreign donors.  Mesenchymal stem cells have been shown to inhibit both naive and memory T cell responses, to affect cell proliferation, and to reduce the number of interferon gamma producing cells.

And we actually know more about mesenchymal stem cells, their ability to escape immune surveillance, than we do about embryonic stem cells at this point in time, but nevertheless, there's some information that both when they're transplanted are able to escape immune surveillance.

Extending the observations of donor derived blood transfusions to induce a tolerogenic state.  Several groups have tried to reproduce this type of an approach using embryonic derived stem cells or mesenchymal stem cells.

The two underlying mechanisms by which creation of a mixed chimeric host results in tolerance as I've mentioned are, one, thymic deletion of potentially donor specific alloreactive T cells and, two, non-thymic peripheral mechanisms as we've mentioned.

The theoretical advantages of either of these cell types is that because they don't express HLA Class I or Class II, they might be able to migrate to the thymus, might be able to reeducate the thymus so that the thymus then thinks that these cells are part of its own normal repertoire, and the thymus will then eliminate potentially those type of T cells that could reject these type of cells.

And, in fact, in experiments where either embryonic or mesenchymal stem cells from the adult have been injected intravenously, we know that long-term acceptance of these cells has been accompanied by the presence of large numbers of these cells in the recipient thymus.

And in a particularly interesting study using rat embryonic stem cells recently, it was demonstrated that intravenous injection of rat embryonic stem cells in the absence of any type of immunosuppression resulted in long-term engraftment, as well as the thymus, and resulted secondarily in the recipient rat being able to accept a cardiac allograft of the exact same HLA type as the embryonic stem cells, but not a cardiac allograft of an unrelated donor, which meets all of the criteria of tolerance induction.

In the only study to date using mesenchymal adult derived stem cells, what we have been able to see is that a similar type of long-term engraftment in the bone marrow in the thymus can be achieved with adult mesenchymal stem cells, and I think it's reasonable to anticipate that a similar experiment would likely also demonstrate, although obviously it still has to be done, that the engraftment in the thymus might lead to long-term tolerance and acceptance of a graft of the same HLA type.

So I think those type of experiments are very exciting and raise the possibility that stem cells might have, by virtue of the fact that they do not express high levels of HLA, and even when they are induced to express HLA molecules, might have very special characteristics that allow them to evade immune surveillance and, even more importantly,  might actually allow them to re-educate the host to accept a different type of donor tissue.

And perhaps the hope would be the induction of tolerance might actually obviate the need for all of the stuff that I just told you about this morning, all of those complexities in terms of immunosuppression.

And I think I'll stop there.

CHAIRMAN KASS:  Thank you very much.

Since my guess is that for at least the non-medical, non-scientific members of the house, this was complicated.  Let me see if I could try to formulate something of the nub of this and ask you to elaborate.

I think the large part, the preliminary part of the talk indicates the enormous complexity of the immune system and the difficulties of getting especially long-term graft survival and also the need for long-term immunosuppressants, which have risks and harms of their own.

And the strategies for inducing tolerance have up until this point tried to attack various parts of the host response, immunological response.

But if I understand the most exciting part of this, the last part of this discussion, the suggestion seems to be that the use of stem cells, mesenchymal or embryonic - this is now the concept and not the data — that such cells, first of all, to begin with lack the HLA provocative antigens so that they are not themselves immediately rejected;

Second, that they can apparently take up residence in the thymus and, if given from the same donor, if given from the individual who is then to serve as the donor of a particular organ, that increases the survival of a solid tissue donation from that person.

Is that correct so far?

PROF. ITESCU:  That would be one potential use of such cells, yes.

CHAIRMAN KASS:  And let me draw out an implication for regenerative medicine using stem cells or their derivatives.  Again, just the concept now, not the evidence.

The concept would be that because these are immunologically unprovocative materials, original stem cells introduced into a patient which presumably would take up residence in the thymus and perhaps, as you suggest, re-educate the immune response even after the HLA antigens appear in those cells; re-educate the immune response to no longer regard those cells as foreign; might make the host now receptive to even the introduction of differentiated cells derived from those stem cell lines.  One could put in heart cells taken from these stem cell lines and have them not seen as foreign.

Am I understanding the concept correctly?

PROF. ITESCU:  Yes, I think that's actually correct.  In fact, it's almost a beneficial aspect.  The stem cell that is initially infused does not express HLA, takes residence in the thymus in the absence of HLA expression, and then is induced to express HLA at that site because it's the actual expression of the HLA molecule that allows a re-education process and tolerance induction to that HLA.

So that if it didn't express HLA at all, at any time point, you would not develop tolerance to that HLA molecule.  So it doesn't get rejected in the first instance because it doesn't express HLA.  It enables engraftment in the thymus long enough to up-regulate its HLA molecule, and then it re-educates the thymus to accept that HLA molecule.

So you can then come along with a differentiated tissue or organ which now does express that same HLA and it will be de-rejected it from the outset.  That's right.

DR. KRAUTHAMMER:  So it essentially causes a change in the immunological identity of the recipient.

PROF. ITESCU:  And that's the concept of chimerism.

CHAIRMAN KASS:  Right.  So it's a magic bullet if it works.  Would be.

PROF. ITESCU:  It would be, yeah.

CHAIRMAN KASS:  Paul McHugh.

DR. McHUGH: That was a splendid presentation with very exciting prospects in the future, and of course, the most exciting prospect to any of us who have followed the transplantation business from the time when — I was an intern at the Brigham in the 1950s.  So I was there in the beginning - is the possibility and the prayer of xenotransplantation.

But you know all about that.  Will this bring to bear the possibility that we'll be able to use animal tissues ultimately for transplantation of these vital organs and the use of animal stem cells and, therefore, animal organs will spare us not only this problem you have here of people in need and the lack of donors, but also much of the ethical problems related to stem cells?

PROF. ITESCU:  Well, my laboratory actually was very heavily involved in trying to understand the rejection processes of disparate xenografts, and we have tried to develop a variety of immunologic strategies to try to overcome that.

At this point in time I actually am much more hopeful that regenerative medicine using adult stem cells is much closer to reality than xenotransplantation for a number of reasons.

Most importantly, I think, is the fact that the differences between animals and humans is a wide array of antigens.  HLA is just one antigen, and the fact that we're all so closely related as humans is simply the fact that the only thing that differentiates us is the HLA structure from individual to individual.

However, between species not only is HLA different, but there are many other structural genes, and I, frankly, am fairly pessimistic actually that those differences are likely to be overcome between species. 

So I would emphasize actually the human stem cell regenerative possibilities rather than xenotransplantation.

CHAIRMAN KASS:  Rebecca Dresser.

PROF. DRESSER:  Two questions.  I was wondering how long it takes for this re-education process of the immune system after the first inducing of the stem cells.

And the other question was exactly where is this in terms of laboratory data theory, human data, animal data.  How much of this is hope and how much of this is demonstrated?

PROF. ITESCU:  Sure.  The chimerism concept all comes from human data.  In other words, for many years people have looked at whether donor cells continue to circulate in the recipient's blood stream or organs, months, years, many years after a transplant.

And so this concept that the recipients who do better are those who have the higher percentage of donor cells circulating has been around for many years, and it is data from humans.

In terms of proving that that has anything to do with tolerance, you have to go back now to the animal models.  The experiments that I've outlined to you are actually recent experiments in the last 12 months primarily using embryonic derived stem cells where those embryonic cells were able to be engrafted from one rat to another rat type, induced chimerism, induced tolerance to those cells, and subsequently were able to induce a state of nonresponsiveness to a heart transplant of the same donor.

Now, the experiments with adult mesenchymal stem cells are also within the past 12 to 24 months, and what we know about adult mesenchymal stem cells is that if they're injected at a time of in utero - the experiments that I was referring to where these cells were injected in utero in developing fetuses — and those cells can then engraft and survive for at least one to two years after birth.  This is human cells actually in an animal model, and those cells survive, are not rejected.  They're found in multiple organ types, including the thymus.

What we also have learned in the last 12 months is that these same adult mesenchymal stem cells which do engraft in vitro are able to actually inhibit immune responses from other human T cells against themselves and also inhibit the immune responses of other T cells against other antigens, including HLA antigens.

So we have a lot of information in vitro that mesenchymal adult stem cells are functional.  We know in vivo they're able to engraft in a similar way to the way that the embryonic stem cells can engraft and not get rejected.

And so the only experiment that's missing is that same other experiment that has been done with the fetal cells, and that is can actually induce a tolerogenic state to allow a solid organ graft to be put in.

PROF. DRESSER:  And how long does it take to induce that state?

PROF. ITESCU:  In small animal models, we are talking about probably weeks.  To translate that to man, you know, is a guess, but I would think weeks to months would be the objective.

CHAIRMAN KASS:  Bill May.

DR. MAY:  You said that adult stem cells from the bone marrow may significantly reduce organ rejection, and later you said adult stem cells have many characteristics shared with embryonic stem cells.

I'm interested in the policy implications of this.  Do you feel that we should simply follow out, play out the line of exploration with adult stem cells and delay explorations with embryonic stem cells, or should we be following both tracks at the same time?

PROF. ITESCU:  I think what we know at this point in time about both cell populations, and again, what one calls a stem cell in the bone marrow differs from experimental group to experimental group.  There are many types of stem cells in the adult bone marrow.

But there are a number of well defined stem cells, and I'd talk about mesenchymal stem cells.  There's another group of perhaps an even earlier progenitor cell type to the mesenchymal stem cell, but what I think most people will agree on is that the stem cells defined in the adult bone marrow have many features that are similar to true embryonic stem cells in terms of surface markers and in terms of the way they behave, but there are some differences as well.

So, in particular, what we know is that at this point in time I think the adult stem cells probably do not have the same range of differentiation capability that an embryonic stem cell does in terms of their ability to become almost any organ in terms of differentiation.

Nonetheless, the differentiation capability of adult stem cells at this point is quite remarkable.

Secondly, the self-regenerating capacity, meaning how many times can the cell continue to divide before it stops dividing, and that's one of the fundamental features of any stem cell.  The more division it can undergo, the more likely it is to then differentiate and become a useful clinical entity.

The self-renewal capacity of most of the adult stem cells that have been defined to date probably it's fair to say are not quite to the same degree as great as the self-renewal capability of an embryonic stem cell.

I would say at this point in time it remains an open question as to whether these differences are at a clinical level, and I think I would support continued research in both cell types to understand (a) whether these differences are relevant; (b) whether the diverse functional capability and range of differentiation exhibited by the adult stem cell is sufficient in many cases.

In the work that we're doing with respect to the cardiovascular system and the heart, we have found that so far there are certain stem cells that are terrific in terms of their ability to improve cardiac function.

So I would view these fields as overlapping and say that at this point it's far too early to decide which field is going to be the right way to go for every type of regeneration strategy that one is looking for.

But I think that there's enough hope in the adult stem cell area that it may be sufficient to go down that path.  I would at this point continue research in both areas.

CHAIRMAN KASS:  Dan Foster.

DR. FOSTER:  I have two questions in regard to possible downstream effects that might be difficult, and the first question, I presume that the injection of the stem cell of one sort or the other to protect against the donor's solid organ transplantation would be that the immune inhibition there would be, the tolerance there would be restricted to the donor.  It would not, in other words, in your view interfere with immune responses to infectious agents or anything else.  I presume that's correct, right?

PROF. ITESCU:  The hope would be twofold.  To call this tolerance, it would have to be a tolerogenic state induced only against the inducing cell and antigen and a continued responsiveness to any other antigen.  That would be the hope of the whole process.  Otherwise you would have global immunosuppression.  That's right.

DR. FOSTER:  The second question is probably unimportant to somebody who needs a heart or something of that sort, but if you're look in simple terms at the immune system, it does two things.  It fights off invaders, as you say, viruses and bacteria and so forth, and it surveys for cancer.  I mean, so that in one sense anybody who gets a cancer has had in some way a failure of the immune system to see the oncogenic antigens and as a consequence not to delete it.

I mean, a lot of people think that all of us are forming cancers all the time, and that the failure is the immune system.

I presume that there is at least a theoretical possibility that since even donor tissues or other tissues might get a malignancy that that might be impaired with the tolerant state that was there so that you might be at risk for malignancy, even early malignancy.

I mean in some ways tumor suppressor genes, you may get very early things.  I think if I needed a heart I wouldn't worry about that, but just in theory that might be something that we would have to worry about even if there was not a defect against the one wing of the immune system that fights off against infection, but might make us vulnerable to the other thing that's devastating.

PROF. ITESCU:  No, I think that's actually an excellent point, and that's right.  So in other words, if a cell is so primordial and so early that it confers some type of protection against itself being rejected, it's also that same cell type that is so plastic that it has the ability to differentiate into so many different lineages that it also has a high rate of becoming cancerous.

Typically the embryonic stem cells obviously have the high risk potential for teratoma formation.  Again, if you then think about the adult mesenchymal stem cell versus the embryonic stem cell, there's a tradeoff between these two.  So the embryonic stem cell is the most pluripotent, has the highest rate of proliferation and cell divisions.  The mesenchymal stem cell has a slightly more differentiated, let's say, than the embryonic stem cell.  So it has a less likelihood of — it has less cell divisions left and maybe a little bit more of a restricted differentiation pattern.

But if you then take these two cell types and if they are both able to induce a state of immune nonresponsiveness, the one that's less likely to induce a neoplastic transformation, I think, would be the adult mesenchymal stem cell.

So from that point of view there would be a preference to that versus the former.

CHAIRMAN KASS:  Could I ask just a technical question?  This so-called re-education process that stem cells might induce in the host thymus, could that process persist even if the mesenchymal cells disappear?

In other words, if the adult cells are not self-perpetuating and, therefore, die out as a population, could a short term residence in the thymus be sufficient to confer a long-term tolerance for a subsequent graft?

PROF. ITESCU:  Yes, I think so.  And examples of that are many experiments in transplant immunobiology where people have directly injected HLA molecules into the thymus using specific HLA molecules of the subsequent donor organ to induce a state of immune nonresponsiveness.

The organ is then transplanted and long-term tolerance has been achieved.  Presumably the injection of the HLA molecules resulted only in a transient expression in the thymus.

CHAIRMAN KASS:  Thank you.

Janet and then Michael Gazzaniga.

DR. ROWLEY:  I wanted to ask several questions.  Going back to the mesenchymal stem cells, I assume that they are a related type to those that we heard about earlier from Catherine Verfaillie.  They may not be quite as primitive as the ones she's been able to identify, but it is the same lineage.

PROF. ITESCU:  That's right.

DR. ROWLEY:  Now, going on into the real world, and let's say it's a kidney transplant, you would then get bone marrow mesenchymal cells from the donor.  So it would be cultured to identify the stem cells.  Those would be injected into the potential recipient, and then at some point later you would take the kidney from the donor and hope that you had induced tolerance.

PROF. ITESCU:  Yes.  I think that's about right.  Now, to be fair, you know, to try to do that in the setting of an acute process, such as, for example, when we have a cardiac transplant donor, we are talking about hours from the moment of identification to actual transplantation.

To be fair, I think in that type of scenario it would be extremely difficult to then isolate bone marrow stem cells, purify, inject, and hope to achieve tolerance all in the same space of time.

I think this type of a strategy and approach is much more amenable to living related transplants and would really increase the survival and success of those type of transplants.

DR. ROWLEY:  Part of the reason for pursuing this is to show that this may be potentially useful in a subset of patients, but as you just said, for cardiac transplants this approach is limited and maybe not even be feasible.

PROF. ITESCU:  Well, let me extend the thought.  If you needed to use — at this point in time, I think, with known technology of how to immunoselect and how to get hold of these cells, I think it would be a little bit impractical in the situation of a cardiac transplant patient.

I think there is the possibility that you could potentially use mesenchymal stem cells of an unrelated donor that could potentially enhance the ability of the thymus to be nonresponsive at the time that a graft was implanted and induce tolerance to that graft through mechanisms other than simply the HLA molecules that the stem cell itself expresses.

Do you see what I'm saying?

DR. ROWLEY:  Okay.  What occurs to me is why don't you then get hyperactive response to those rather than suppression.

PROF. ITESCU:  Well, for reasons that are unclear at this point, stem cells do not seem to induce an active immune response to themselves.  They seem to down-regulate immune responses to —

DR. ROWLEY:  In general.

PROF. ITESCU:  In general.

DR. ROWLEY:  Right.

PROF. ITESCU:  So there may be a possibility of the potential of using unrelated stem cells plus a third party graft and you induce tolerance to that particular graft, but not to another graft because the immune system has seen only that graft in conjunction with the stem cells that were infused.

DR. ROWLEY:  Okay.  Now, but following on with this, I guess in terms of the use of embryonic stem cells, unless it's in this same context of a neutral or an unrelated stem cell affecting, in a sense, general immune unresponsiveness, you're not going to take an organ from the embryonic stem cells and transplant it into a donor as you would with the adult stem cell scenario that we just pursued.

So I guess I'm a little bit confused as to how you foresee embryonic stem cells in the sense of organ transplantation or is it in the example you just gave?

PROF. ITESCU:  Yes.  The ideal scenario would be to have mesenchymal stem cells obtained from the same donor where the organ is coming from.  So I think in that type of combination, the embryonic stem cells would have no role.  I think a second scenario would be where stem cells of whatever source you want could potentially be used as a local immunosuppressive agent for that particular organ that's used at that time point.

And, again, we're talking about a tolerogenic induction to the HLA of that organ.

A third possible use of stem cells in this way might be, again, irrespective of whether you're talking about adult stem cells or embryonic stem cells, to induce a state of tolerance by injection of the cells followed by a more differentiated set of cells for organ regeneration.

So as a strategy to prevent rejection of stem cell derived tissue regeneration.  So, for example, if we wanted to improve cardiac function using adult stem cells and we would take, let's say, adult mesenchymal stem cells, differentiate them in vitro into cardiomyocytes, we would be concerned that if we took those cardiomyocytes now and injected them directly into the heart they might get rejected.

So what we might want to do then is take our source of mesenchymal stem cells from a given individual with heart failure, let's say; take those mesenchymal stem cells, set aside a number of them and try to differentiate into cardiomyocytes, take the first batch of mesenchymal stem cells from the same patient, infuse them back, allow that patient to develop a tolerogenic state, and we're talking about mesenchymal cells from a different donor, not from obviously the same, where we're able to have a larger bank of cells to provide back to the first recipient.

DR. ROWLEY:  Okay, and my final question is:  do you have to worry in this situation about graft versus host disease?

PROF. ITESCU:  That's a very good point.  In fact, that's, again, an advantage of using stem cells for this process.  Whereas whole bone marrow transplantation or whole bone marrow used to try to induce tolerance runs a risk of graft versus host disease.

As you probably know, bone marrow transplants, I think, in general, allogeneic transplants keep something like 20, 25 percent incidence of graft versus host disease.  The animal treatments with to date only embryonic stem cells that has been published has not resulted in any type of GVHD, as you would anticipate that you wouldn't get if these cells, in fact, inhibit rather than activate immune responses.

DR. FOSTER:  But in fairness, in the bone marrow transplantation, a low level of graft versus host disease proves to be advantageous, I think.

DR. ROWLEY:  Well, that's true if you're doing it with leukemia because then you get a graft versus leukemia.

DR. FOSTER:  I'm talking specifically leukemia, yes.

PROF. ITESCU:  But we don't want it to happen if we're trying to induce tolerance.

CHAIRMAN KASS:  Michael Gazzaniga.

DR. GAZZANIGA:  I should remember the answer to this, but is there an interesting variation in tolerance to grafts?  In other words, there's a subpopulation that seems to just take it and all of the tricks in the medical bag don't seem to be that necessary?

PROF. ITESCU:  There's no question there are some patients who do wonderfully well with minimal immunosuppression for many, many, many years, and absolutely I would be the first to say that we have no idea why some people accept the graft so well.

So that clearly a mechanism of tolerance induction in some individuals works beautifully.  I would suspect that it's the same type of mechanisms we're talking about today that take  for whatever reason in some individuals better than others, but it will be the same mechanism.  It won't be different mechanisms, I think.

DR. GAZZANIGA:  Is there any way that you could predict that?

PROF. ITESCU:  Yeah, and what I was alluding to earlier, the type of chimerism approaches.  What people do is using genetic probes or genetic markers, you can look for the amount of donor cells or donor tissue in the blood or in the ingrafted in various organisms, the lymph nodes or bone marrow.

You can do these kind of fancy tests, and you can certainly predict that if there's a high percentage of donor cells that continue to be present two, three years  out, actually two or three years — if the patient has already gone two or three years, you know it has done well, but let's say in the first three to six months which is the highest risk of rejection.

If you see a high rate of persistence of donor cells, you can predict that this patient is going to do better.

DR. GAZZANIGA:  So could you use that as information in maybe jumping the patient ahead on the transplant list because you think there's going to be a —

PROF. ITESCU:  Well, you don't know that until the patient has already been transplanted.

DR. GAZZANIGA:  I was asking if there were predictors.

PROF. ITESCU:  No, there are no predictors prior to a transplant as to who's going to accept the particular donor at a given point in time.  There are no global — what I was trying to emphasize is that the exquisite response, the exquisite specificity of the immune system here dictates that there's going to be a very, very close and tight response between the donor's immune system and the particular genetics of the host.

And those two are so specific that they cannot be predicted globally, and that forms the basis for why we actually monitor each one of our patients very closely and we tailor our therapy on an individual basis.  You just cannot make global decisions like that.

DR. GAZZANIGA:  And one final thing.  Maybe it was on your first graph, but I didn't catch it.  If you were to say what the survival rate, transplantation survival rate in 2003 versus ten years ago was, how much has it changed with all of the new technologies?

PROF. ITESCU:  The most dramatic leap was probably about 20 years ago, as I mentioned, with cyclosporin coming in from 50 percent one year survival to about 80 percent.  We've now gone from about 80 percent ten years ago to I would say 95 to 100 percent one year survival for kidneys and for hearts.

You can't get any better than that at this point in time.  The biggest problem right now still is that five and ten-year survival rates, and those are the issues that I was getting at.  I think still donor-recipient immune activity is the problem, that we cannot induce tolerance.

CHAIRMAN KASS:  Janet.

DR. ROWLEY:  I'm not sure whether people have questions along this line because mine is a different question. 

So coming back to the first slide where you show the great disparity between the number of people who need kidney transplants and the number of potential donors and cadaveric donors, and your data on cadaveric donors would suggest that that's not necessarily an avenue to pursue actively because the results are so much poorer in terms of response.

The question I have, and that we've had minimal discussion on this, is whether we should change the strategy of obtaining donors, and I'm interested in your view on whether there should be a program for paying donors for their organs.

It has been pointed out to us that everybody in the system makes money except for the donor, and the donor is the essential individual in this whole chain of events, and I'm curious as to your perspective on this.

PROF. ITESCU:   Okay.  I think that it's clear that we're not increasing the donor pool.  I would disagree.  I think outcome with cadaveric transplants is excellent.  My only point, that was with living related is even better, but there's nothing wrong with our current outcomes with cadaveric donors.

And I wish that we would be able to increase our cadaveric donor pool.  So if question number one is should the families of cadaveric donors be appropriately looked after, I think the answer should be yes.  I think that the families need to be involved in this whole process.

In terms of the living related and whether there should be issues with reimbursement, I would strongly oppose that.

CHAIRMAN KASS:  We've got time just for a couple of questions.  Michael Sandel, Bill Hurlbut.

PROF. SANDEL:  Why do the cadaveric organs not work as well as living ones?

PROF. ITESCU:  For a number of reasons.  First of all, because the living ones you've got more time to select on the basis of how well the donor-recipient are matched, number one.  I mean, that's the objective.  You find the best match, and that's the one that's going to be the best in your family pool.

And you're already starting out with related individuals who are at least going to be 50 percent identical, you know, because you inherit 50 percent from your mother and 50 percent from your father.  So you will share at least 50 percent of your genes with siblings, et cetera.

So we're starting out with a closer pool, and then you're looking for a perfect match.  That's the number one reason.

But interestingly, as I mentioned, spousal related grafts which are HLA completely unrelated generally also do better than cadaveric.  So the answer is more complex than that.

It's also probably because if you can perfectly plan and coordinate the surgery so that everything goes according to schedule, you've minimized all of the potential risk factors, et cetera.  That obviously impacts on the outcome.  You can, you know, organize your timing and the spouse will be there exactly on time and provide the organ, et cetera.

CHAIRMAN KASS:  There's no chimerism there.

PROF. ITESCU:  You know, that's a very interesting question.  It may very well be some other interesting immunologic issues that may also explain this.

CHAIRMAN KASS:  Yeah.  Bill Hurlbut.

DR. HURLBUT:  Two parts to my question.  First, can you make some comment about the effect of mixing of peoples from diverse geographic regions and how it may be making more complex the search for a compatible donor and increasing the reshuffling of HLA types?

I assume that in a specific population there would have been a greater match.  Whether that's making it more difficult, but softening the immune rejection because people are mushing towards the middle, if you will or if it's diversifying a complex mismatch problem.  That's the first question.

Second, if, in fact, it's possible for the marrow cells, mesenchymal stem cells or the ES cells, to induce a kind of generalized inhibitory response or lack of response that makes tolerance of a completely different third party organ donor, then would it be reasonable to say that it might turn out that you only needed one or a few lines of these, let's say, ES cells for the moment, these ES cells or would you need many that would be a better match for the situation?

Do you get what I'm getting at?

PROF. ITESCU:  Yes, I know.

DR. HURLBUT:  Because the argument will be made that the few stem cell lines that are currently available either might be adequate to that task or that we need many more.

PROF. ITESCU:  No.  So let me address the question number one first.  I think clearly that as you're getting mixing of populations, it's making local identification of appropriate donors much harder.  Actually there's much more diversity.

It's not going to make inhibition of rejection easier because the type of exposure to antigens, that takes generations.  What you're talking about essentially from a practical point of view, it makes selection and identification of a matched donor much harder.  More homogeneous populations have a much easier time of finding matched donors.

DR. HURLBUT:  So we're heading for a worse problem with rejection.

PROF. ITESCU:  Absolutely, yeah.

And in terms of your second question, if we're talking about an unrelated stem cell inducing tolerance to an organ transplant, it's essentially, I think, pretty much irrelevant what the HLA type of the stem cell is.

And so rather than needing a wider pool of stem cells, you probably can get away with a more narrow stem cell population because you're not specifically  trying to induce tolerance to HLA antigens that that stem cell expresses.

It's the ability of that stem cell to switch off the immune response to HLA antigens on the organ that is seen at the same time as the stem cell is present.  So you potentially would not need many cell lines, whether we're talking about embryonic or whether we're talking about adult stem cells.

DR. HURLBUT:  So just to clarify, if, in fact, there are stem cell lines not grown on mouse feeder cells, even just a few of them, that might turn out to be the central resource to effect these ends.

PROF. ITESCU:  Potentially.

CHAIRMAN KASS:  Before we close, I want to be somewhat flat-footed here so that as we hear the presentations in July I know what I'm supposed to think about the immunological aspects or prospects of stem cells for regenerative medicine.

You seem to be suggesting the following, and this was, in fact, the reason for the invitation, to learn what we could from experience with immunological problems in the transplantation of solid organs to anticipate the possible obstacles to the uses of stem cells in regenerative medicine.

We've heard something surprising here in a way, that stem cells, both embryonic and adult might actually hold some promise for making the immunological obstacles to the solid organ transplantation less than they now are.  That would be the first point.

And that second, if this matter of education of recipient T cells by some kind of chimerism works, there may not be as large a problem in the use of stem cells for regenerative medicine as has been anticipated, and in fact, just to make a footnote, it might not be necessary as some people have argued that only by cloning can one get immunologically compatible stem cells for therapy.  Is that correct?

PROF. ITESCU:  I think that would be the natural extension of the argument, although I think at this point in time far too few data are available to be able to make those kind of conclusions, but I think that's right.  The surprising evidence to date, I think, is that even when stem cells of either source are enabled to differentiate sufficiently to up-regulate their HLA molecules, they still seem to be able to engraft, and they still seem to be able to regulate immune responses in a downward fashion.

So potentially what that does suggest is that these cells may be less immunogenic than other cells in our body and might produce to requirement for cloning even when used therapeutically, yeah.

CHAIRMAN KASS:  Thank you very much.

DR. ROWLEY:  Can I just interject though?  You said in your presentation that the data all come from experimental animals, and so this last exchange, in fact, we don't know whether the data from the animals are applicable to the human system.

PROF. ITESCU:  Absolutely.  I agree entirely with that, too.

CHAIRMAN KASS:  Thank you very much, Dr. Itescu, for an interesting and enlightening presentation and discussion.

We'll take a break for 15 minutes.  Come back at ten minutes of 11.

      (Whereupon, the foregoing matter went off the record at 10:36 a.m. and went back on the record at 10:54 a.m.)

Session 2: Medicalization: Its Nature, Causes, and Consequences

CHAIRMAN KASS:  All right.  In this session we move from the scientific and medical to the sociological and philosophic, the question of so-called medicalization, making medical some aspects of human behavior not previously regarded as medical, and the question before us is what is medicalization and why might it be important to our enterprise as the President's Council on Bioethics.

And I'm going to make some semi-coherent, I hope, at least semi-coherent remarks to introduce this, just to indicate why we're talking about it.

We have touched on this topic implicitly in many of our discussions of beyond therapy, whether using biomedical technologies to satisfy personal desires or to achieve some form of behavior control, and we have sometimes tried to get at that question by distinguishing the medical from the nonmedical, say, and the distinction between therapy and enhancement of the use of medical means for nontherapeutic or nonmedical purposes.

The topic also came up in the last meeting in the discussion with Steven Pinker, where the issue was not so much the uses of biomedical technologies as the question of the assignment of guilt and responsibility in a world in which behavior is understood largely biologically.

Some observers of the work of the council have concluded, I think falsely, from random remarks made in these discussions that the council has doubts about the existence of genuine mental illness, such as schizophrenia, depression, bipolar disorder, or that it means by raising these kinds of questions to object to the treatment of these disorders under a medical model using psychotropic drugs.

I think that is a misreading of what we have been doing.

But rather than shy away from this subject, it seems to me that we would do well to try to clarify this matter of medicalization by actually treating it thematically rather than as an adjunct to other matters, to see what it is, what causes it, and whether and why it might be important.

And one of the reasons for doing so is it provides us with at least one look at the larger social, cultural context that shapes almost all of the bioethical issues that we have examined or might examine.  For example, ethical issues raised by preimplantation genetic diagnosis or even prenatal diagnosis are really unintelligible save when seen in the context of the fact that pregnancy and childbirth have already been pretty much completely medicalized, or the ethical issues that would be raised by the uses of psychotropic drugs in children would be unintelligible except if we recognize the degree to which behavioral problems have been medicalized and taken out of the moral realm and brought into the therapeutic, or even any discussion of the regulation of the use of biomedical technologies must begin with the fact that uses of approved remedies are, by and large, left to the practice of medicine and the standards of care.

Now, medicalization is a sociological concept that's been around for some 30, 35 years, and it has been a matter of interest and concern to sociologists for some time, and its scope is much broader than questions just of behavior control or mental diseases.

The background paper written by Peter Conrad that we circulated is a review essay by a person who is one of the first to write on this subject, and he discusses the concept of medicalization and shows how widespread is its reach, beginning with discussions of the medicalization of deviant behavior from alcoholism to compulsive gambling, to child abuse, to the medicalization of natural life processes  of childbirth, child development, and the end of life, and going on to women's issues, from eating disorders, birth control, premenstrual syndrome, menopause; children's issues of learning disabilities, behavior problems.

And as this little clip at your place from the Wall Street Journal from yesterday indicates, now shortness of stature is about to become a medical problem, to old people's issues of, alas, forgetfulness and growing kinds of weaknesses.

And I think that Conrad's essay points out, I think, quite nicely how these are matters partly of conceptualization, partly matters of institutional rearrangements, and also when the doctors are actually involved of direct medical implications for the human relations whenever people bring these matters to the physicians.

And he also points out how the development of effective technologies to intervene in a whole range of areas also increases the tendency to make more and more aspects of human life matters of medical concept and medical approach.  And this is meant to be said simply descriptively.  You know, there's no prejudgment, although some people talk about medicalization with a negative connotation.  We simply mean it at least at this point to be descriptive.

Three things I would like to in my own name sort of put before us that seem to me to be of special significance before introducing the materials that Paul McHugh has especially prepared for us.

First, the matter of surveillance and how many, many more things are now coming under the medical gaze, where the medical view of this, that or the other is now kind of commonplace.  The medical view of marriage and its benefits for health, a recent bit of discussion.

And this medical surveillance, I think, now is something that should concern us especially with the coming of the powers of genetic screening which will, I think, soon be a major issue in which not only will child birth be under the medical gaze, but so, too, the necessary conditions for thinking about what are the criteria sufficient to warrant entry into life.

So the whole question of surveillance is one of the things that's important.

Second, there are economic questions that I think are worthy of our attention, and he points out very nicely, Conrad does, that if the only way to get reimbursement for gaining help with life's problems is through medical insurance, there is a high premium on having all kinds of things declared medical in order to get the help that you need.

And the corollary of that is this, of course, drives up medical costs and places enormous burdens on the health care system as more and more things, whether medical in the narrow sense or in the broad sense, now come to the doors of hospitals and clinics.

Finally, in a most abstract way, this question of medicalization bears really even on the business of bioethics because it finally bears on what constitutes a medical or biological phenomenon and what is an ethical one, as our friend Michael Gazzaniga will be quick to tell us, especially if and when we come to begin to think about ethical sensibilities in terms of their underlying biological basis and substratum.

So that even the very activity that we're engaged in is affected by the rise of the medical and biological model for thinking about behavior, including even ethicizing.

Now, with this as a background and presupposing the Conrad material as read, I want us to turn to the material especially prepared for this meeting.  Although the areas of human life that have been medicalized are many, the area of behavior is, in fact, of special interest, especially as behavior at least as we've always understood it has some kind of biological or natural substrate, but also a human and moral meaning.

And staff has asked Paul to help us think about this larger topic by reflecting on the phenomenon of medicalization in the domain of psychiatry, a subject that has been one of his professional interests really for decades.

And I think before we start that one should simply declare for the record that there should be no mistake about this.  Neither Paul nor I nor the council means in any way to cast doubts on the existence of these mental illnesses or the urgency of caring for the thousands who suffer from them or the families who are also devastated by these illnesses.

There is no hidden agenda here.  We're simply trying to understand this phenomenon and what it might mean for the work of this council.

Paul chose to develop his thoughts in epistolary form, and we decided that it was less work to synthesize his two letters as if they were a seamless document than to allow the things to appear actually as the conversation went between us, and we put those materials before you for discussion.

Paul, do you want to say anything by way of start?

DR. McHUGH:  No, Leon.  I'm very grateful to you for having this epistolary discussion with me.  I enjoyed it.

I would like to — I think the stuff rather speaks for itself.  There is a subtext, I'm sure you see, that is, that Leon asked me to do a little something about medicalization and psychiatry.  I wrote the first letter, disappointing him.  He wrote—

(Laughter.)

DR. McHUGH: — a letter reminding me that I could do better, and I tried harder the second time, and I want you all to know that I'm aware of that subtext and want you to be as well.

(Laughter.)

CHAIRMAN KASS:  If others would like to begin, please do so.  If not, I would in a way put a question to you, Paul, as  away of continuing the conversation.

I'm very excited, as you know, by your attempt to go beyond the merely symptomatic classification of human troubles, to provide what you call the reference classes of diseases, of aberrant behaviors, of what you sometimes call dispositions and sometimes you call — I've lost the other term for it — and then finally the sort of life experiences problems.

And the first of the three is the only class that you see as being somehow on the model of ordinary somatic disease, but all of them legitimately come to the healer of the soul for help.

And I guess the question is:  why isn't that part and parcel, in fact, of the growing medicalization, in fact, of all of those other things even if our approach to them is not exactly the same?

Maybe you could elaborate on the value of these kinds of categories for leaving the things to Caesar that are Caesar's and the things to God that are God's.

DR. McHUGH: Well, it's a long story at one level, and I'll try to make it brief.  What it amounts to is that psychiatry is a discipline of medicine.  It is a medical discipline, but people come into your office just like they come into any doctor's office with complaints and with plenty of psychiatric complaints.  The conditions from which they spring don't necessarily seem directly medical, and a psychiatrist has to decide where they belong.

Prior to DSM-III, the dominant approach to dealing with people's complaints was to try to fit them into an ideological scheme.  In America the dominant one was, of course, Freudian thought and a subdominant one in plenty of institutions was the Skinnerian behavioral one.

The great advantage that the classifications developed by DSM-III were that patients' complaints were subgrouped according to which complaints the patient brought forth and which symptoms could be recognized out of an examination.

The problem with that though is that by classifying things by symptoms and complaints, psychiatry was condemned really to stay at the level that 19th Century medicine was when we classified people according to the fever charts and the characteristics of their pain.

And no director of a department, such as I was, that hoped to achieve a coherent discourse with his group, direct research, and at the same time care for patients could be satisfied with simply that classification.

And so what I have been writing about and I have been proposing for a long time is to see different reference classes of patients just as medicine does.  After all, medicine talks about infectious disorders, neoplastic disorders, congenital disorders, genetic disorders, and the time has come in psychiatry to move towards that kind of classification.

But when you think about psychiatry, it's quite clear that there are plenty of conditions that go beyond because of human kind and the particular features that the human brain brings into play that give other reference classes for disorders.

And so I was interested in my department and in my work to separate the things which are diseases, where everyone could see that these are a breakdown of cerebral faculties, straightforward losses of the capacity to think, to perceive, to remember, to emote appropriately, to have executive control from a second group of classes that are the abnormal behaviors in which what are the rhythms of our ordinary behaviors fall awry sometimes because of injury to the brain, sometimes because of conditioned experiences, the behavior disorders, in other words.

The dimensional disorders in which our psychological characteristics are dimensions of human variations just as our physical characteristics are, and so some people can be in distress not because they have anything broken like a disease would imply, but simply because they are at some extreme along a dimension of human variation, the most obvious one being mental retardation, but others being excessive neuroticism, excessive extroversion or introversion.

And then finally, the conditions or the complaints people bring me or any psychiatrist that fundamentally come out of their life experience, what they've encountered in life and what assumptions they're making about that.

These four reference classes, what I refer to in my books as the four perspectives of psychiatry, obviously interrelate.  They all, of course, depend upon a brain.  You can't have any of this without a brain, but the brain, the human brain does all kinds of interesting things, and a psychiatrist in interacting with such people does different things.

He tries to cure diseases.  He tries to interrupt behaviors, to guide the individuals that are often some extreme in human variation.  He tries to help, essentially rescript assumptions that lead people into encounters with life that will distress anybody.

And when you ask me about how to think about psychiatry in these terms, those were the things; that was my natural place to go.

I think the question that you could ask is:  well, by doing this kind of an approach and, by the way, then generating — let me just spell out briefly that this would mean that any department of psychiatry would have in it individuals, for example, who are skilled at brain imaging and the recognition of certain breakdowns of faculties out of the generation of molecular abnormalities, genetic abnormalities and physiological abnormalities.

The disease model that is clear in medicine should be found in psychiatry departments and representatives of that would be there, but also psychiatry departments should have people who are very interested in the life story of individuals, the narrative and how the narrative reveals sometimes the natural wellsprings of disorder.

And such a broad psychiatry department would be open then not only to the medical departments that surround it in any university, but it would also be open to the public at large that wonders and wants to find not only help for, but some kinds of understandings that could make sense out of current problems, current sets of assumptions and the like.

Your question that started me off on this little preamble was, well, does this make medical everything.  Well, no.  In my opinion, although a psychiatrist is often the person that people come to now at first with a concern, like feeling sad or feeling disrupted in their plans of life or disappointed in what they had hoped for, he or she might come to a psychiatrist first to make sure that the psychiatrist in evaluating the person didn't find something else more fundamental wrong, but the psychiatrist at the end might well say, "Look.  This complaint that you have, this demoralized state, this state of discouragement or depression is, in fact, something that derives from who you are and what you're thinking and lots of people besides me can help you with that, and I want you to be able to turn to those other people to think about what you want to do."

In that way, you see, I feel I would like to move psychiatry where medicine or surgery is today, namely, to the point where the patient can be really on all fours with me in discussing the implications of not only the symptoms that they have, but the treatment that they might accept.

Prior to this or often with simply a categorical diagnostic system, the patient comes to a psychiatrist and then has to say, "Well, you're a person with all of this experience.  You must know better than I do about what counts and the way I ought to live and all of that because you know the secrets."

And this way you'd say, "No, I don't know the secrets.  I think you belong in this kind of problem.  Let's find out who might know better and who might open you and me, by the way, to a better understanding of what you've encountered and how that encounter has shaped your reaction."

I can assure you right now that the problem here is not that you've got some twisted neuron or a twisted molecule.  I'm good at that.  I want to open you to the idea that maybe you have a twisted thought that somebody else as well as me might help you with.

And that's a long answer to your brief question.  I have to say that it has been the story of my life, trying to make this clear to as many people who will be willing to listen.

CHAIRMAN KASS:  Do you want to follow up on this, Frank?  Because I had Gil and then — Gil, then go ahead.  Sorry.

PROF. MEILAENDER:  Yeah, I mean, I am following up on this if that's okay with you.

CHAIRMAN KASS:  Well, sure.  Yeah.

PROF. MEILAENDER:  I just want to try to figure out, Paul, and I have to sort of direct it to you though someone else may have insight.  What difference this really makes, the kind of distinction that you're trying to make.  All right?

And I have in mind a sentence that comes on page 9 of your now published correspondence where you say near the top, "But the claim that alcoholism, narcissistic personality, and stage fright are sicknesses of the same kind as schizophrenia cannot be sustained just because these people walk into our office and we help them."

Okay?  Now, it's evidently okay with you that they continue to walk into your office, people who have stage fright or these obnoxious narcissists.  It's okay that they come in, and you think that on a number of occasions you are able to do something or other that helps them.  It might be pharmacological in some cases.  It might just be conversation on other occasions.

So that in terms of the points that Leon raised before, these can still come under medical surveillance, and they can still find ways to be reimbursed through insurance and so forth for the costs of this.

So what difference does it make that some of these things don't fall into the category of brain disease, but they fall into one of the other categories?

I mean, I understand that, and it certainly makes some difference just in the sense of conceptual clarity, but in terms of the practice of medicine, it doesn't seem to make much difference other than, I guess, the person with the brain disease.  You wouldn't say, "Go talk to your friends about this," but with the narcissist you might say there are some other people, too.

But, you know, it's appropriate that they come into your office.  There are things within your armamentarium that you can use to help them.  So what's the difference finally?

DR. McHUGH: Well, let me say, first of all, Gil, that nobody comes into any doctor's office usually with a diagnosis attached to him.  He doesn't come in and say, "Guess what I have.  An aortic aneurism, and it's causing me pain."

(Laughter.)

DR. McHUGH: He doesn't do that.  He comes in and says, "Listen.  I've got belly pain, and I don't know."

Of course, it could be nowadays when you read the magazines that you could do that, and occasionally I can tell you in psychiatry people come in and tell me they've got adult ADHD and I'm to give them Ritalin and let's get on with it.

But for the most part people don't come in to a doctor's office with that.  They come in with complaints and wonder, appropriately, whether the doctor can help them.

And the difference that we're making here amongst them is to say that there are different sources of these complaints, and psychiatrists have greater or lesser capacities to help them, and by making these differentiations and differentiating things according to their essential differences, I think, not only do we serve that patient well, but we ultimately serve the public well who want to ask us appropriately who and whether the patient should get help from you or from other people, and ask us exactly how we give them help.

So first of all, the differentiation is very helpful to the public, in my opinion, by enhancing the differential, enhancing the discourse on the differences in natures about conditions that cause people to suffer.

Yes, I think that I often tell people with stage fright who come into me and say, "Dr. McHugh, I have stage fright, and guess what.  I saw at the Super Bowl that Paxil is very good for this and you're to give it to me."

And I tell them, "No, I'm not going to give you that.  I don't think we have to go that route.  Why don't you find another way to practice and then come back and tell me whether by helping you practice will help you do better?  Okay?"

So I will ask them to go back to their teachers.  I mean, I get this question of stage fright from high school students, you know, who are working, and I'm telling them, "No, I'm not going to give you a medicine now."

It may well be that when I see a person who has more difficulty, for example, a violinist who has problems with trembling in their hands, I  might and I often do recommend, as a lot of people do, Propanolol to help them from those trembles, help them with the physical condition, but I will debate with all of them what they're doing.

And by showing them the nature of what they're asking, I think I enhance their understanding, my understanding, and the public's understanding of my role.  Okay?  Which is not to be the only arbiter of how life should be led.

CHAIRMAN KASS:  Gil, do you want to follow or not?

PROF. MEILAENDER:  Well, no one else is champing at the bit?

CHAIRMAN KASS:  No.  Well, I mean, if —

PROF. MEILAENDER:  I'll wait.  I'll wait.

CHAIRMAN KASS:  Okay.  I have Frank and Robby George and Michael.

PROF. FUKUYAMA:  Well, I enjoyed the exchange of letters between you and Leon.  I think we ought to do all of our reports henceforth in epistolary form.  I have a question about the underlying biology, which maybe you could help me with it, Michael Gazzaniga or other scientists.

Now, in somatic medicine, as I understand it, there's a fairly clear, you know, model for what a disease should look like.  There's a clear etiology.  There's a causative agent.  So we have this thing calls SARS.  We believe that there is actually something that you've going to find, a virus or whatever that will, you know, cause it.

Now, in the world of psychiatry, I assume that there are diseases in that somatic disease sense, but actually the vast majority of the phenomenon that you deal with is this very large category of things called disorders, all of which have biological correlates.  I mean even the most fleeting thought or emotion is going to have some biological correlate, but that there are degrees of biological causation, and there are certain disorders where the biological determinants, you know, are relatively more important.

I guess what I'm getting at is that it seems to me within this category of disorders what makes it so squishy is that a very large number of them are basically, you know, normally distributed behaviors, and that what you're classifying as a disorder is simply something that's out in the tail of the distribution.

And so the question is:  if your project is to try to move your discipline towards a more, you know, biologically grounded categorization of these different things, you know, your four categories, what are the prospects of doing this in terms of the underlying biology?

For example, is it clear in all cases which of these are simply points on a distribution as opposed to, you know, things that will have a different kind of biological, you know, correlate?

And what are the prospects of, you know, moving the field towards a system of classification that is grounded, you know, more firmly in the underlying biology?

DR. McHUGH: Well, first of all, my aim was not simply to move the field into a more biologically based classification, although I support biologically based opinions about certain disorders.

My effort was to say which ones in which I thought a broken part played the major role, that is, the classical disease concept in which an etiology, a pathology lied underneath an expressed clinical syndrome.

I also wanted to say, as everyone would, that you can't have anything in mental life without a brain.  We're not angels.  We all do that.

On the other hand, I also want to acknowledge that there are things about the human brain which are at least to all of us mysterious as to how the brain itself as mechanism causes the problems that the patients bring.

For example, the issue of jealousy.  You can find jealousy as a symptom of a disease, that is, a disease like schizophrenia or manic depressive disorder or Huntington's disease or Alzheimer's disease.  All of those conditions have been described in some of its classical forms as presenting with a jealousy.

On the other hand, much jealousy comes out of dispositional characteristics of an individual in relationship to a life circumstance that they find themselves in, and that their assumptions coming out of their dispositions and the interactions with that environment produce a jealous response.

I want to be sure that people who want to talk about psychiatry would want to differentiate those and appreciate the place of other forms of therapy than a strictly biological form of therapy for that.  Okay?

And, please, press on.

PROF. FUKUYAMA:  I mean, if I can just follow-up.

DR. McHUGH: Yeah.

PROF. FUKUYAMA:  I mean, I'm not  asking to make these distinctions so that we can then discard everything that doesn't have a very strict biological, you know, cause.  That's not my purpose.

DR. McHUGH: No, that's right.  No, that's right.

PROF. FUKUYAMA:  I accept fully that you also want to treat that vast realm of things where the cause is squishier.

But it does seem to me that — and in a way, this gets to Gil's point about why these differences are important, you know.  If something is simply caused by a virus, you don't expect anybody to do anything about that other than, you know, get treatment for it, right?

DR. McHUGH: Right.

PROF. FUKUYAMA:  On the other hand, there's a whole range of behavioral and mental phenomena where, you know, there may be a biological component to that behavior, but the other component is what we traditionally think of as kind of moral behavior that is the result of self-discipline, education, you know, thinking things through and so forth.

And I think that the thing that troubles me and probably a lot of other people about the progressive medicalization or this expansion of the domain of the therapeutic is that it tries to move things that are within this traditional moral realm into a realm of, you know, biological causation where, you know, you're basically telling the patient, well, you can't do anything about it.  So you know, you just have to take your medicine and the like.

And so even if you can get money for being treated for that, you know, what used to be treated by the priests and counselors and so forth, it's still a helpful distinction to be able to say, "Well, look.  This thing is, you know, 90 percent biological.  You can't do anything about it," whereas another category of disorders actually does have this very large component where individual responsibility and, you know, so forth plays a large role.

And so I guess the question is:  does the state of the science give you any help in trying to make that distinction?

DR. McHUGH: Well, I think it does, and I think the advantage of having separate reference classes or separate perspectives of disorder is to see that with each separate class there is a separate understanding of what constitutes disorder within this class, and I think the science does help us a tremendous amount in this.

Well, let me just talk about, for example, what the science, essentially epidemiological science, did to help us understand psychotherapy, and in this case we're talking about the psychotherapy of people that come to us with things like ordinary grief, demoralization, jealousy.

The epidemiology showed us that in contrast to what was expected at the time of the Freudian dominance, that all of these patients would have similar sources of their problems, namely in their libidinal conflicts.  It turned out that these people had very different sources of their problems.

What was common to the psychotherapy patients is that they all felt over mastered by something in life and were discouraged about being over mastered by that rather than that they had a common sources for their problems.

And so that immediately opened up psychotherapy and psychotherapists tomore individual understanding of lives rather than trying to dig deeper for some problem in infantile or early childhood life in relation to their libidinal problems.

But as well it said, well, since the problem here is feeling over mastered, a psychiatrist can help you maybe, but they're going to help you in the same way as other counselors, friends, people of that sort, priests, and the like have previously helped people and open the door to that.

Now, when you bring in, as you did, as Gil did and you did, this idea that we want to be paid for it, I just want to be paid not necessarily for my treatment.  I just want to be paid, I think, for my time like other people, and I want to be sure that I am offering some kind of help.

Sometimes the help is not therapeutic in the sense of actually correcting a disorder, but it is reassuring to people and things of that sort, the same things that other professional people like lawyers do.

And at some level the work is of that sort.  But just to come back to the main point, to express my reference classes could from one point of view be seen as extending medicine out beyond its boundaries.   On another way of looking at it, it could be, and the way I look at it, it would be by defining these reference classes.  People could look at what places — the medical doctor would be primary in the care, and in such classes lots of other people would be able to be on equal standing in that care, and that, I think, would advance us in all kinds of ways, including, by the way, being able to give parity to the mentally ill for the conditions which are most like medical conditions and not clamor for parity for individuals for whom some aspects of their condition, their over mastery, could be helped by others.

CHAIRMAN KASS:  To this?  Mary Ann  Glendon.

PROF. GLENDON:  I just need a little help understanding the distinction between your Class I and Class II, and maybe I'm just wrong in what I've read in the popular literature, but is there not some scientific support for the idea that, say, alcoholism — that there are some people who are more prone to that through brain characteristics than others?

So that your boundary between one and two doesn't seem to me to be quite clear.

DR. McHUGH: Well, the boundary only relates to what leads to the course, not that there — by the way, again, there are going to be brain things behind everything, including, by the way, behind jealousy.

Your question is a frequently asked question, namely, don't you see that certain people, perhaps because of their make-up, have more temptations to sustain a behavior like alcoholism than others.

For example, oriental people often are sickened by alcohol because of an Antabuse-like reaction that they have.  This is very protective for them from taking up this conditions and carrying it further.

It's also probably true that some people get more aroused by a glass of alcohol than other people do and, therefore, find it more rewarding.

Both of those things are true, but in contrast to a disease like Huntington's disease, you will advance in that condition steadily forward regardless of whether you are able to move about or not.  You cannot advance in alcoholism unless you choose to drink, and that choice is, after all, a matter of deciding one way or the other.

That there is a vulnerability behind that choice does not change the fact that it's still a choice, and ultimately the Alcoholics Anonymous that wants to clamor for the concept of disease here as though it was a broken part ultimately does say that, you know, you have to choose to live a different life and acknowledge.

You know, it doesn't matter whether you acknowledge that Huntington's disease has a power over you or not.  It will carry itself through, but it does make a difference if you acknowledge that you are powerless against alcohol and, therefore, avoid it.

And since there are those elements to it, the therapies change.  The responsibilities change, and ultimately the outcome.

Just as a final thing, I might have mentioned this to you before, Mary Ann.  About once a year I get someone coming to my office and saying to me, "Dr. McHugh, I want you to come to court with me because I've been arrested for driving while intoxicated, and I want you to tell the judge that, of course, I'm an alcoholic and, therefore, should get off."

And I always tell them, "No.  I want you to go and be punished for driving while intoxicated because my friends and my children and everybody else are driving, and I don't want that to happen.  After you are punished, I might be able to help you with this conditions, but I might not be able to help you either, depending upon what you're after.  It seems to me today that what you're after is some license and not the appropriate contrition."

CHAIRMAN KASS:  I have Robby George.

PROF. GEORGE:  Paul, I have two questions.  I think they're only remotely related, and the first one you may have gone far toward answering, but it would just help me to get a little firmer grip on it.

I want to sort of follow up.  What I took Gil's question to be, which is really about when are you as a psychiatrist in and when are you out.

Now, from what you've said in response to Gil and Frank and now Mary Ann, I take it that the situation is a little like the separation of powers, if I can use an analogy from my own field.  There's an old line that says we don't have so much a separation of powers in our government as having separate institutions sharing powers, and I take it from what you're saying what we have when it comes to treatment of certain sorts of things that are problems, but they're not like Huntington's disease, we have a kind of sharing of authority, sharing of roles where the psychiatrist, the priest, the dad, all might be dealing with the same problem, and you wouldn't want to carve things up such that you would have strict boundaries where you say, "Ah, this counts as the psychiatric problem.  This counts as the spiritual problem.  This counts as the moral problem."

Am I right so far?

Okay.  But that leaves us where I think we were left after Gil's question.  There must be some criteria by which you as a psychiatrist and others in the field decide, look, this just isn't appropriate for me to deal with.  If I did that I would be practicing priestcraft without a license.

Let me just try and example or two.  I mean, if a corporate CEO comes to see you and says, "Look.  I've got a great career.  I'm making a ton of money.  My business is going well.  Everything is great, but you know, I find myself getting involved with the secretaries romantically, and this could wreck everything.  Doc, I want you to help me."

Would that be the kind of case in which if you didn't detect some pathology, what you detected is a guy who's prone to this kind of —

DR. McHUGH: Fall in sin, yeah, right.

PROF. GEORGE:  Would you say, "Look.  You've got the wrong place.  I mean this is not something that I as a psychiatrist am qualified to deal with"?

DR. McHUGH: We certainly recognize incontinent behavior and call it just that and say, "You don't have a disease, pal.  You have become incontinent in your sexual behavior, and I can tell you what I think about it, and I can tell you some of the things that might help you stop it, but you need lots of other forms of help in the process."

Because they often come with this and say, you know, "I just can't help it, Doc."

And I say, "Can't means won't, and you won't help it," and I begin to talk about drawing in these other people to help  them.

PROF. GEORGE:  Well, now he said, "Well, Doc, look.  Don't get me wrong.  I'm an enlightened guy.  I don't have any moral problems about what I'm doing.  I just don't want my career — I know that the world is such that my career and my company and my business is at risk here.  I just want a fix so I won't do this.  You know, I'm not religious.  There's no clergyman I can go to.  If I told my pals that this was a particular problem I had, they wouldn't consider that to be a problem.  I need you to fix this."

Now, do you now because you're the only game in town, you're the only person he can go to, do you now say, "Well, look.  This isn't psychiatry.  I'm now functioning as some sort of counselor to you, but I'm going to stick with you and see if we can save your professional life"?

DR. McHUGH: Always the beginning of building up a hypothetical case, you gradually get to the point where you might be imagining pigs with wings, you know, and what are you going to do with this flying pig.

But look.  In my opinion, the kind of case you're drawing, Robby, is not at all unusual for many psychiatrists to say, and they, at least as far as I know have not given up on the idea that this kind of behavior is destructive to the milieu in which the person is living, as well sa the character of the person who is involved.

Some of them will use the word "sin" and "adultery."  Others will say this is corruption and the like, and begin from that position, not from the position that your patient that you've imagined said, that is, "Listen, Doc.  You and I are guys together, you know.  Aren't we having fun?  And I just am afraid that his having so much fun is going to get me into trouble."

If someone said that — no one has ever said such a thing to me — but if they said that, I would say, "No, we aren't guys together.  We are people in this society, and there are certain things not only which are against the law, but which are against our ethical posture towards this."

Now, this is to take in some situations a judgmental stance.  Okay?  And, by the way, in my opinion, because psychiatry is the kind of discipline it is and it moves up through these reference classes or up a hierarchy, ultimately we do make judgments and acknowledge that those judgments are derived from the world in which we live.

DR. KRAUTHAMMER:  If I could just say, Robby, we had a recent case of that, and the attempted intervention was not psychiatry, but impeachment.

CHAIRMAN KASS:  I have Michael Sandel and then Jim Wilson.

PROF. SANDEL:  The question that occurs to me in this discussion, and, Paul, I'm constrained to more general territory and the general question of medicalization, is why we worry about it or if we should worry about it.

Why should we have an impulse to try to limit the scope of the medical?  But what is the source of that impulse and is it justified?

And in listening to the discussion, it seems to me there are two different kinds of reasons to worry about the expansion of the medical.  One of them, the one we tend to focus on for the most part is a worry that the biological will colonize the ethical and crowd it out; that the therapeutic will displace the moral.  That's the worry that comes to the fore when we worry about diminishing the responsibility people have for their own conditions if they come to see those conditions as subject to remedy by a pill or by surgery or some kind of medical intervention.

And so we wrestle with cases like narcissism or child abuse or the drunkenness of the driver or the squirminess of the child in the class, and realizing those kinds of things will crowd out or diminish moral responsibility for one's conduct.  So that seems to be one set of reasons to worry about medicalization.

But it seems to me there's a different set of considerations that have nothing to do with whit worry about the biological displacing the ethical, but instead have to do with the range of cases, Leon, that you mentioned at the beginning having to do with medicalizing shortness or the kind of medicalization that accompanies more and more cosmetic surgery.

And this worry has nothing to do with disputing the biological character of these conditions.  No one disputes that shortness is a biological condition.  No one says, "Well, if we medicalize shortness, then people will no longer take moral responsibility for being so short," as in the other cases.

Or if we medicalize the question of someone who has a prominent nose and wants to have cosmetic surgery, we don't say, "No, that's troubling because we want people to pull themselves up by their bootstraps and deal with this themselves, not to pretend that it's just a medical problem that needs to be taken care of."

So it's not that issue at all.  Here it's not the worry about the displacement of moral responsibility, and yet there is still a worry about medicalization in this other domain, and it comes closer to the enhancement cases we were discussing.

And then I think it has to do with another feature of the medical, the reason we want to cabin or confine the medical, and that has to do not with its concern with the biological, but instead with its orientation to fixing rather than accepting.

And so because it's a feature of the medical that it attends to disease.  The telos of medicine, traditionally understood at least, is to attend to disease, which is to say to attend to things in need of fixing.

And so we worry here in this second domain that we will redescribe conditions like shortness or like having a prominent nose as diseases when they're not properly regarded as diseases, and one way of expressing this worry is to say that medicalizing these kinds of things will stigmatize people who are short, let's say such that beforehand we might not have noticed it as much, but now that it becomes something that's routinely subject to a medical cure we notice and worry more when people are short or when they have prominent noses or when they have teeth that aren't perfectly white and aligned or whatever the case may be.

So it's the fixing part of medicine here that wants us to rein in the scope of application of the medical lest we consider more and more conditions as things to be fixed rather than as things to be accepted or, for that matter even appreciated.

I don't know if that's a helpful distinction.  The one final thought about the second category is we could deal with that problem, the problem of medicalizing conditions like shortness and so on in one of two ways.  We could say, "Well, all right.  We will expand, as implicitly we must, what counts as a disease to include that, but that seems bothersome."

Anther way of dealing with it would be to say, "Well, maybe medicine should be detached from that.  Maybe we need to enlarge the telos of the medical so that we no longer regard it as concerned with curing disease."

What do we call the people who do cosmetic surgery for a living?  Well, they're engaged, we would say, or are they, in a medical practice.  Well, here let's talk about just purely elective, or would we say we should detach the medical from the notion of curing disease so that at least we don't taint all sorts of conditions with disease and just say, "Well, maybe medicine isn't solely about curing diseases.  Maybe it can be for fixing things that people simply want to fix, even if there is no disease."

But that seems also to carry a certain kind of cost or at least there seemed to be reasons.  I think a lot of people would resist.  So enlarging the medical by detaching it from curing or attending to disease, but it seems to me in any case that these are two very different reasons to worry about medicalization.

CHAIRMAN KASS:  Does someone want to join in on this before we move on?

DR. KRAUTHAMMER:  Yes, I would.  I would  like to add a third reason, I think, and it might actually be the reason why society decides that it's going to have to act on it, and that is the economic cost, that apart from the moral cost of expanding the medical, the economic cost would be huge.

There is a sense that we have, and I think it's correct, that if you suffer from a medical condition, society has a kind of obligation to help you in coping, and that if you're poor, you shouldn't have to suffer in a way that a rich person would not, and that's why we have this idea of Medicare-Medicaid and expanding social help.

It's inexorable.  In Europe, of course, it's universal.  Here it's expanding.

Now, as you expand what is legitimately considered medical you will expand the realm in which society is seen as required to contribute to your assistance, and as that area expands, it's going to create a huge social cost, and I think that in the end may be the reason why there are attempts to contract it.

We see the argument acutely in whether or not a psychiatric illness, mental conditions should get the same kind of coverage as so-called physical illnesses.  That's the most obvious and acute example of this, but I think it's going to expand as the range of the medical expands as well.

PROF. SANDEL:  Could I give a quick reply to that?  I don't think that the economic reason is a third reason independent of these two.  To the contrary, I think it's parasitic on one or the other of these two for the following reason.

If it were just a matter — if worries about medicalization were just a matter of society having to bear too great a financial cost, it can't just be that because the reason — suppose the reason that things became very expensive is simply because we got very good at transplants, and so people in need of hearts and kidneys on a much larger scale were able maybe because the immune problem were overcome to have them. 

We wouldn't regard that — it would be an economic challenge, but it wouldn't be a challenge of the kind that we worry about when we object to medicalization because it's not controversial that a heart or a kidney transplant is a medical procedure.

DR. KRAUTHAMMER:  What about orthodontics?

PROF. SANDEL:  What's that?

DR. KRAUTHAMMER:  What about orthodontics?

PROF. SANDEL:  Well, the reason that becomes controversial is it falls into one of the two reasons we have for questioning the scope of the application of the medical.

So the economic issue only arises against the background assumption that we as a society agree that genuinely properly medical needs are covered, and so we worry about medicalization under these two other headings — maybe there are others — because in both of those cases we have reason for questioning whether the scope of the medical isn't being expanded in ways that are objectionable, whether because it crowds out the moral or whether because it tries to fix what should be accepted.

CHAIRMAN KASS:  Gil, did you want a small thing on this, too?

PROF. MEILAENDER:  Yeah.  I think that finally there's not such a large distinction between your two categories, Michael.  I mean there is an obvious on the face of it distinction between your accepting moral responsibility and what medicine ought to do.

But as you yourself recognize, if it turns out that there are some things that people want and that we can do, but that don't seem to constitute fixing in the sense that medicine traditionally fixed things, then we have a couple alternatives.

We could expand the realm of medicine and say doctors didn't used to do this, but now doctors do it, or we could say, "Well, but people still want it done.  So proctors should do it.  Yo u know, they've got a lot of the same skills that doctors do and they should do it."

And if you want to resist that, whether you want to resist the expansion of medicine or you want to resist the notion that kind of somebody else should do this, what you're going to have to say is this is something that should be accepted, that should not just be fixed.

And we're beginning now to do talk that though granted it grew out of a different issue is rather like the moral responsibility talk.  So I don't think that there is finally quite as wide a gap between them, though I agree that the second kind of case you raise grows out of the question of what really constitutes health and what really constitutes disease or medicine, but it finally drives us back to assert what we do or do not take responsibility for.

CHAIRMAN KASS:  Briefly Michael and then .-

PROF. SANDEL:  They're both normative question I agree, but they're different normative questions.  One has to do with what should people be held  morally responsible for, and the other has to do with what do we consider should be accepted rather than fixed.

I agree they're both normative.

PROF. MEILAENDER:  Well, people perhaps should be held morally responsible for learning to accept certain things about life.

CHAIRMAN KASS:  Jim Wilson will now make trouble.

PROF. WILSON:  I think the problem that Paul has addressed under the concept of medicalization is much broader than the problem as he sees it in psychiatry, and my views on this are, in part, an effort to answer Gil's question what difference it makes.

Medicalization to me as a non-real scientist, but a fake political scientist is a synonym for causation.  Now, all behavior is causes, and there is an effort in not only our society, but most societies around the world to extend the concept of cause so that everything is caused in a way that crowds out the moral, as Michael said.

Let me give you the case from criminal justice, if Mary Ann Glendon will overlook the many mistakes I will make in this brief summary.

Somebody shoots another person by firing a gun.  The person is brought to trial, and there are a variety of arguments a person can use.  One is that he is a victim of epilepsy.  Admiring a gun that is part of his collection, he had a seizure and his finger squeezed the trigger and fired a bullet at somebody else.

The next level is he's insane or, to put it bluntly, he is crazy.  He doesn't know the difference between right and wrong and thinks the voices of Satan are directing him to do it.

The next level is duress.  Someone pressed a gun to his temple and said, "If you don't shoot this bullet through this window and hit this person, I will blow your brains out."

The next level up is diminished capacity, which is kind of an adolescent version of insanity.  They're kids.  They're not quite sure what they're doing.  They're 14 years old.

On the next level up is prior abuse or neglect of the sort pled by those two wealthy, young Beverly Hills men who pumped 12 rounds of 00 buckshot into their parents and watched them die because, as their lawyer later claimed, they had been the victim of abuse when they were ten years younger.

And then the next level up are life experiences generally, in which you could put alcoholism.

And then finally at the highest level — I'm skipping several — is pure choice.

Now, defense lawyers will go into court and try to  push the argument back toward causation, and prosecutors will go into the court and try to push the argument back towards pure choice.

Now, in this case, there is a solution to the problem.  That is to say a judge and a jury must make a decision that is either a yes or no decision.  The person is guilty or innocent or possibly not guilty by reason of insanity.

And in making their judgments, they asked the question:  to what extent was the person able to control his behavior?  And the control judged by a contemporary social scientist may not be very large, but though they would probably excuse epilepsy and insanity and perhaps duress from diminished capacity all the way up to pure choice, they tend to collapse it into the category of pure choice.

Now, what evidence do they have to back it up?  I think the evidence they have, which the judges sometime state and sometimes not, is that we can think of people who had the same prior abuse, prior neglect, diminished capacity, alcoholism, et cetera, who didn't shoot anybody, and since people with these conditions can avoid shooting other people, the fact that you chose to shoot somebody else means that whatever your circumstances may be, you made a choice that you didn't have to make.

Now, this is not the problem that society faces because society does not have a judge or a jury, and society increasingly, in my view, over the last half century has begun to say that social controls, society's effort to judge somebody as innocent or guilty, have been profoundly weakened because to judge somebody as guilty, society must use such things as shame or stigma, and increasingly we are told that shame and stigma are a bad idea.

And, indeed, the people who go to Paul and say, "I've got stage fright," or, "I am sexually incontinent," or the other will hear from him a response that says, "This isn't a medical condition. You should be ashamed of this."

And what they're going to do is drop Paul as their psychiatrist and go to somebody else, and they will find other people who will say, "Yes, we certainly mustn't use the word 'shame' and 'stigma.'"

Society does not want to be judgmental.  Being nonjudgmental is a good thing.  So I think the problem that the exchange between Leon and Paul raises should not be limited to the definition of what is medical in the eyes of a medical professional, but rather should be viewed as the general social problem of how we define personal responsibility and the fact that in my opinion, which could be wrong, we have changed profoundly the extent to which we judge people as acting improperly, and we are reluctant to impose social rewards and punishments to induce them to act properly.

PROF. GEORGE:  Leon, could I ask a question of Jim?

CHAIRMAN KASS:  Please.

PROF. GEORGE:  Jim, I followed that, I think, completely, and it certainly sounded right to me, but I just wondered about a statement you made very early on in the presentation and its compatibility with what followed, and that was the statement that all human behavior is caused, unless you mean by that simply that there are empirical conditions of all human behavior, including choices that constrain the options for effective choice.

PROF. WILSON:  Yes.

PROF. GEORGE:  Is that all that that meant?

PROF. WILSON:  Yes, I probably shouldn't have used the phrase, but behavior is caused in the sense that some combination of biological imperatives, cultural traditions, personal choice, and the nature of immediate circumstances leads persons to exercise Option A rather than Option B.

I mean nothing more profound than that, and you can strike the word "cause" if that seems to become a motive.

PROF. GEORGE:  No, in philosophy there's a big literature about the distinction between reasons and causes.

PROF. WILSON:  I understand.

PROF. GEORGE:  And I was just wondering whether you were rejecting the idea that there could be reasons that are something independent of the causes.

PROF. WILSON:  No, no.

PROF. GEORGE:  And I take it you —

PROF. WILSON:  I am not rejecting the notion that all behavior is caused and part of the causes are the reasons people developed to make a point.

PROF. GEORGE:  Yeah.

DR. McHUGH: And if I could just enter, too, into this very interesting comment you've made, Jim, and it's this issue of stigma.  And it is often said that psychiatrists and doctors and all of us should give up on stigma, and that is certainly true for the diseases in psychiatry.  We want to give up on stigma.  In epilepsy we want to give up the stigma on bipolar disorder.

But everyone knows that no one is giving up the stigma on certain behaviors.  Smoking behavior is the most stigmatized behavior right now in our country.  It's stigmatized and not tolerated.

In point of fact, your other statement that if I did stigmatize this to a person — again, we have to remember that we made a pig with wings here with Robby — that he would run away.

In point of fact, that's not my experience.  People who come in with the concern that, gee, my behavior is liable to get me into trouble and hear from me that, yes, it will get you into trouble and it should if you continue it would then ask me and do ask me not only how they can avoid it, but how they might look at it in a different way, stigmatizing it appropriately and thinking about it in its relationship to its effect on others.

And, by the way, most of them stay with me and say, "You know, I never thought of that before," when they give as their cause that they're doing this because their feelings matter and their feelings are driving them, and their feelings are the cause, and they hear from me and from other psychiatrists that, you know, when you grow up your feelings don't matter to most people.  It's just your behavior that does.

And they always say, "That's a very remarkable statement to hear," and stay with me as their behavior gets better.

PROF. WILSON:  People keep coming back to you, Paul, because you have such an engaging personality.

(Laughter.)

PROF. WILSON:  You can stigmatize them without using the word "stigma."

(Laughter.)

DR. McHUGH: Well, that's —

PROF. WILSON:  But I would be willing to bet you that the search for non-stigmatic relief is more widespread than your own office experience would be.

CHAIRMAN KASS:  Alfonso and then Bill May and then Janet and then Bill.

DR. GÓMEZ-LOBO:  This is going to be a very brief and perhaps minor remark.  I'm just trying to think for my own benefit about the more general context, and I tend to think that this is a really particular case of something much deeper and much more pervasive in Western culture and Western history. 

What I have in mind is something like this.  I would bet that 30 years ago most people made financial decisions on their own, you know, whether they were going to buy stocks or bonds, et cetera.

Nowadays, I think most people would deeply hesitate to do this before consulting an advisor, financial advisor, or I found this out some time ago.  People who are going to send their kids to college now can go to a college choice counselor.

Now, what does this mean?  It means that socially we have tended to parcel reality and to assume that there are people that within a domain have something close to an algorithm to make the decision.

The reason why we go to a physician is because we trust that the physician is going to have symptoms, et cetera, in front of her and then come to the conclusion, oh, you have pneumonia, and then the solution is going to come.

So I'm not surprised at all about the medicalization, this tendency to reduce things to treatment that can be controlled because this tendency in our culture is a tendency to find areas of control, and naturally enough to displace the prudential approach to those fields, which I think is what Paul is alluding to, and also the moral deliberation, the moral reasoning about those fields.

If a field is dominated by a specialist, of course, we can withdraw and say, "Well, that's where the responsibility lies."

So what I'm just suggesting is that we really immerse in a much broader thrust of our culture to control certain areas of behavior by handing them over to people  who would know how to decide.

CHAIRMAN KASS:  Bill May.

DR. MAY:  Well, it's very interesting hearing you, Alfonso, talk like Ivan Ilyich, the broader professionalization of life in all aspects.

DR. GÓMEZ-LOBO:  My source is actually Aristotle.

DR. MAY:  Yeah.  Well, the pathology, however, is a very large and growing, modern one.  You know, professionals hang out a shingle, and in doing that it specifies a little further and you invite certain strangers in to deal with, but at the same time, of course, off the streets comes an awful lot of things that are unbidden and not asked for.

And now you end up.  You've got a moral alternative there as a professional.  You can preserve the purity of your specialization and say, "But I don't deal with that," and therefore refrain from medicalizing everything or lawyers legalizing everything and so forth across the board in the professionals.

But on the other hand, at the same time, you happen to be neighbor to the problem because they've come in and you're nearest to that problem, a little bit like 19th Century doctors who became aware of the problem of sanitation even though they were not sanitary engineers.

Of course, in that case you saw the social remedy, and that led to important improvements in health care that were not available directly through the efforts  of the professional, but you are neighbor to the problem, and it may be a rather privileged moment for that individual.

She can't talk to her husband.  The relation is frozen in all sorts of ways.  They've moved at least once every five years.  Other forms of help and larger family and so forth are quite distant, and so forth.  And he or she has come to you with a problem.

Now, have you medicalized everything by not simply turning attentive ear?  It's a moment that may pass, and you have further responsibilities.  It seems to me that you may not be fully paid for if you stick simply to treating disorders, but in your ascending scale interrupting behaviors, guiding dispositions, and reframing life stories, you're moving farther away from the medical, but humanly you have certain responsibilities.

And how can we sort this out in such a way that one does not escape ones responsibilities as human being in order to preserve the purity of professional identity?

High school teachers or junior high teachers maybe even more than senior high are in a position of privileged neighbor when things aren't working out well with mother and father and so forth, and that's not what they teach, but they have a privileged position close to that problem.

Now, we have — and this is where Leon's economic issue, concern here.  It's easier to get compensation for this kind of time expended in life if one can define it as medical, and so we end up medicalizing an awful lot through the economic pressure here, but we don't want excessively to shrink responsibility simply in order to avoid medicalizing problems.

DR. McHUGH: And I think, Bill, if you look at the history of some of the great advances in psychiatry over the last several decades, it has been just exactly this being neighbor to a certain problem and then helping the society, the culture, the school and the like to enhance what it's doing for the betterment not just of this particular patient, but for people in general.

I mean, much of the advances, for example, in child psychiatry have been in relationship to speaking to the schools, offering a wide spectrum of opportunities for children to succeed in.  Once it was recognized that it helped children to become adults if they had had some kind of success earlier in life that came out of first looking at the individual patients, but ultimately it spoke to the public at large as to how a school should have a variety of things, from athletics out to scholarly work, to give more people a chance to succeed.

And I think that the place, it is a very privileged place to be close or neighbor to it.  I think that's a wonderful metaphor you draw there because it does speak to many of our situations to which we become responsive by calling attention to the patient and to the society that this is the place where they could work together.

DR. KRAUTHAMMER:  Could I make just one interjection on this?

CHAIRMAN KASS:  Yes.

DR. KRAUTHAMMER:  Bill, you brought up an interesting example of the person who comes into you and you feel a responsibility to respond humanly, even though it may not be a medical problem.

The complication here is that she came into you because you hung a shingle and you are a doctor.  She didn't go to the bartender or the man on the street.

And I felt this acutely.  I quit psychiatry exactly 25 years ago this month, an anniversary that I celebrate every year.  One of the reasons is that I always felt that uneasiness, a sense to respond humanly, but I was doing it because of her illusion that as a psychiatrist or as a doctor I had a special insight or wisdom or secret, as paul phrased it.

And I found that by actually using that misconception on her part, I could actually do good, essentially produce a placebo effect, but it was under a false premise.  I knew that there wasn't a secret, and it was in a sense a Wizard of Oz operation.

So you've got an obligation as a human to respond, but given the context, you're doing it under the rubric of having special medical powers, and that creates a real complication and a contradiction in some sense.

DR. MAY:  Yes, although the way Paul has described his work as a psychiatrist, he takes advantage of that in order to clarify instead of remain behind the vail.

DR. KRAUTHAMMER:  Well, he gives it up in the first half hour.

DR. MAY: Yes.

DR. KRAUTHAMMER:  I found out if you didn't you could actually get a real placebo effect, and that would actually help the patient, particularly in changing behaviors like smoking or excessive compulsive behavior.

I mean, hypnosis essentially, which is one of the things I practice, is essentially a way of using that aura as a way to achieve the results, and it actually does work remarkably.

CHAIRMAN KASS:  Janet Rowley.

DR. ROWLEY:  Well, first I have to express my surprise when I was reading this interchange of letters to note the comments about a lecture that I gave at Hopkins, and I certainly want to thank Paul for his very generous comments. 

I'd like to take a different track, and Paul McHHugh also mentioned the analogy of psychiatry being in the 19th Century as compared to many aspects of medicine.  One could certainly see now that we've moved to yet another century that it's in the 20th Century and not in the 21st.

And I think that psychiatry, as well as many areas of medicine are  both a moving target and clearly even better defined diseases are very heterogeneous.

I guess the concern I have about this discussion is to what extent are we mixing medicalization with increasing scientific understanding of the biological basis for behavior, and certainly in many aspects of understanding brain function and interneuronal connections and the importance of that, we're only on the threshold, and this increasing understanding of a very complex system is certainly going to  change both our understanding of behavior, but also a possibility of modifying behavior.

Now, certainly one modification of behavior can just be learning to take advantage of other aspects of the nervous system so you control unwanted behavior, but again, in a heterogeneous situation where there are tails of behavior, it may well be that some additional form of treatment might be helpful.

But I think that it is very important that we keep understanding that we're pretty ignorant about behavior.  We just had a lecture on the immune system and the complexity of the interaction of cells, B cells, T cells, antigen presenting cells, and antigen.  The nervous system has been likened to the immune system in that there are these multiple cellular interactions, which we are very, very ignorant of.

And just as cells communicate by releasing substances which tell other cells to do other things, this is certainly true in the nervous system as well, and we're early on in, say, understanding homosexuality.  Some of this is almost certainly going to be due to the lack of receptors on critical cells or the lack of ligands so that the kind of behavior that we accept as normal does not occur in these individuals because of these biological differences.

And we will some time in the next several decades be able to sort this out.  So as I say, I have concerns about worrying about some of these things.

Amongst the things that are listed as being medicalized are childbirth.  I think that it's pretty clear as you look at the statistics for maternal deaths and fetal deaths in the black population that their lack of health care emphasizes that childbirth is not just something that you can go off in the corn field and everything goes well.

And I think we also have to recognize that very soon obesity is going to become a very serious medical problem which will have many complex aspects of it, genetics as well as the total change in life style, our lack of exercise, our exposure to foods that are not good for us.  All of these things are going to be important.

But we have to then look at a very complicated response to this major health problem, and one response may well be some aspect of involving medicine or drugs at the same time as we also try to help people understand how they can change other things so that we don't have this problem, which leads to very serious, fatal medical consequences.

So this is a long winded expression of concern that we look at this in a broader context and are sort of cautious as to coming back to Michael Sandel, is this a problem or why is it a problem or what problem might we as a council be able to provide advice and guidance on?

CHAIRMAN KASS:  Okay.  We are late in the hour.  I have just — Frank, did you want a very quick thing?  Bill is in queue.

PROF. FUKUYAMA:  I mean, Janet, it seems to me that that doesn't really — it fails to recognize how politicized a lot of this is, and homosexuality is a perfect example of that.

As I understand it, homosexuality used to be classified as a psychiatric disorder, came out of the DSM at about the same time  that ADHD went in.  All right?  We know about both of those conditions.  Actually fairly similar.  They had biological correlates.  Over time there's been growing understanding of the biological bases of both of those disorders, but you know, the only way that you can actually understand the actual outcome, I think, is in terms of the politics and the sociology of the way the society, you know, constructs one as a disease and the other as not.

So I think that is is true that we are .- I mean it would be nice if there were this correlation between our understanding of the biological causes and the way we classify these things, but there's a huge element of social construction, I think, in the way we understand these psychiatric disorders.

CHAIRMAN KASS:  Bill —

DR. ROWLEY:  Well, all I'm saying is I think it's very important that we first understand that it's heterogeneous, and that we be very cautious in how we as a council, separate from society and politics, how we think about the broader issues.

CHAIRMAN KASS:  Bill.

DR. HURLBUT:  It's interesting Janet because as I ponder the emergence of scientific knowledge as you say, I feel what you mentioned, the possibility of interventions at various levels and the possibility that things that we attribute to some kind of construction of personal identity as being, in fact, driven by underlying chemistry.

But what impresses me even more is that our notion of cause is changing.  We've talked here about how medicalization is really a shift in the notion of causation, but what I would add to it is also a shift in our sense of what is appropriate by way of cure, if you will, for a given condition.

When I ponder what science is teaching me as I see the underlying processes by which the person emerges, if anything cause is becoming more complex and instead of labeling something biological versus whatever you call it, moral or personal character, it's beginning to seem more and more, as it should obviously, that the emergence of the person within the phylogenetic process was, in fact, a biological phenomenon with significance.  In other words, if you look at all of phylogeny, you see the steady assent from physicochemical determinism up to an increasing sense of genuine freedom, distancing from determinism.

So that the person actually makes a difference, has a meaning, and allows a specificity of response that you can't get with a chemical, and I think Paul's early letter actually had a lot of good things about this with psychiatric treatment, is that it's often directed at symptoms.  Symptoms are very broad, and the drugs lack the specificity of actually remediating an individual person.

And Charles' comment about the placebo effect and so forth is an interesting one because at least the placebo effect engages the reality of the person.

The problem, it seems to me, is that a simple, materialistic cause deletes the complexity of the cause and also the sense of solving something with a chemical erodes the engagement of the full human person and the manning of the human process.  So that it actually operates too low in the chain of causation.  Therefore, it's not specific enough.  It doesn't operate at the real level of what is causing things, which is both chemical and at the same time the convergence of chemistry with ideas, attitudes, memories, beliefs, and in other words, chemistry and the underlying chemistry and the overarching cognition that's actually part of human existence, and the proper approach to a real human problem, not a problem that has a genuine underlying medical or physical cause that probably is properly treated by medicine, but the problem is that medicalization is delivering into the medical hand and the medical gaze and the sense of where the cure should come from, those things which are actually humanizing in their way of being dealt with properly.

In other words, what I'm saying is that in a sense those fullest extensions of human nature, what you might call a mental spiritual psyche are actually extensions of more fundamental biological agencies so that what really makes a person a full person and a more effective person is not just physical, but what you might call the realm of philosophy and faith, a true integrated personal identity operating within a cosmology, which is at once deeply humanizing.  It both upholds the person and the process of the person alike.

I mean, in the final end what's going to happen with this medicalization is we're going to medicalize morality itself so that we think that there isn't really any free agency.  There is victimhood.

And this is what is the most corrosive quality of evolutionary psychology.  It essentially deletes the higher order meaning of human consciousness.  It actually converts ultimately everything to a simplistic medical explanation, deletes human fullness, and in the process converts everything into what you were calling earlier a libidinal problem just driven by unconscious drives and desires over which we have no agency.

In the final end then all of criminal behavior, all of behavior will be simply medical problems deleting the person and the meaning of life itself.

CHAIRMAN KASS:  Thank you.

We are at 12:30.  We have guests coming at two o'clock.  The hour is late.  I'll spare you a summary.

Please be prompt for our guests.

(Whereupon, at 12:29 p.m., the meeting was recessed for lunch, to reconvene at 2:00 p.m., the same day.)

CHAIRMAN KASS:  This afternoon we turn our attention to biotechnology and public policy, the regulation of the uses of biotechnology, the domain of activities touching the beginnings of human life.

Although we will be at this topic for the next four sessions, I would like at least to set the stage with some general remarks so that council members will be reminded of what we're about and that our guests might understand also perhaps more clearly than they would have beforehand what's going on here.

The council at its very first meeting signaled an interest in exploring how, if at all, the existing regulatory mechanisms in the United States addressed the ethical, moral and social issues that arise from advances in biomedical science and technology.

Some members of the council suggested that perhaps new regulatory institutions might need to be devised.  Others were skeptical, especially in the absence of knowledge of how well the current arrangements worked; in fact, first of all, what they were and then how well they worked, and also which principles should guide any such new activities.

In the council's 2002 report, "Human Cloning and Human Dignity," a suggestion emerged for pursuing this interest regarding regulation in the context of a specific domain larger than cloning itself.  Members observed that for the activities at the intersection of assisted reproduction, pre-implantation, genetic diagnosis, and human embryo research, and I quote the report:

"We lack comprehensive knowledge about what is being done, with what success, at what risk, under what ethical guidelines, respecting which moral boundaries, subject to what oversight and regulation, and with what sanctions for misconduct or abuse.  If we are to have wise public policy regarding these scientifically and medically promising but morally challenging activities, we need careful study and sustained public moral discourse on this general subject and not only on the narrowly defined pieces of the field, i.e., cloning."

And not long after the release of the report, the council members agreed to undertake a thoroughgoing inquiry into the current regulation of those biotechnologies that touch the beginnings of human life simply to inform ourselves of what the current situation is on the ground.

And the staff has been preparing materials on this, and tomorrow council members will be discussing the discussion document that comes out of, is in response to the council's charge.

In the process of doing this work, we thought it absolutely imperative that various stakeholders and their representatives in this field, which ethical principles and which human goods were important to them and deserved to be either promoted or protected in this activity sine, after all, one cannot devise regulatory activities, and one certainly can't evaluate them if one doesn't know what it is one is seeking either to advance or to safeguard.

And we thought that our work would be incomplete and improper if we didn't actually hear from the various people who had an interest in this, whether scientists and physicians or patients and their advocates, or public policy people or bioethicists and the like.

And we requested submissions, and we received quite a number, and from that group of submissions, we have invited a group of people to join us here today, and on behalf of the entire council I want to thank all of you here for your written submissions and for your willingness to come and join us today.

The two major questions on which, as you know, we want your help on are:   what are the human goods and values that should antimate monitoring the regulatory activities in this area or things that should be promoted or protected?

And then, secondarily, how well do you think current practices are succeeding in promoting and protecting these goods and values?

In short, what do and should we care about in this domain and how are we doing and, implicitly, what might we do to do it better?

The two sessions this afternoon, although they have no absolute division and people are free to say whatever it is that they're prepared to talk about, we have more or less tried to organize them so that the first panel will be to discuss more of the reproductive side of this activity, that is to say the assisted activities that help people produce children augmented by — and I want to emphasize this — augmented by the growing powers of genetic screening and selection.

That's really in a way what's new, the major new thing in the area of assisted reproduction.

And in the second session we will attend more to the research side, including also the commercial aspects of this activity.

A couple of words of explanation because I know that when people talk about regulation everybody gets nervous.  We should make quite clear what we are not doing.  We are not here with any preconceived plan that anything beyond the status quo is necessary or desirable, and we do not constitute ourselves a body to design new regulatory activities.  That's not our mandate.

At the moment, we are interested in getting information and some diagnosis with some evaluation of the status quo.  What you see is what you've got.  There are no hidden agendas.

People say that in Washington.  In this case it's true.

Second, the council staff has prepared a discussion document which we have withheld from you, from the presenters, partly because we didn't want you to react to what it was that we had found, but we waned to hear your presentations fresh as you see it.

The document will be available tomorrow here, posted on our Web site, I think Monday at the latest, perhaps even tomorrow afternoon.  It is not a council report.  It is a discussion document prepared by staff for the council members, and we certainly hope to have your reaction to this document in addition to the benefits of your presentations today.

Session 3: Biotechnology and Public Policy:
Assisted Reproduction and Reproductive Genetics

CHAIRMAN KASS:  The procedure this afternoon, although many of you have submitted things which are longer than what could be read in five minutes, we will stick to the five-minute allotment of presentation.  We will then have the presentations, all five in order.  Council members have seen and read your submitted statements.  So you can presume them as part of our understanding, and then we will have discussion.

And the order is slightly different.  We listed you in alphabetical order, but we'd like to go in the following order, and let me introduce people so that you all know who's here, and then we'll just proceed.

First, welcome Pamela Madsen, who is the Executive Director of the American Infertility Association, to my left.

Mary Mahowald, who is Professor Emeritus of the Department of Obstetrics and Gynecology, McLean Center for Clinical Medical Ethics and the Committee on Genetics at the University of Chicago.

Dr. Robert Brzyski, President of the Society for Assisted Reproductive Technology.

Kathy Hudson, who is the Director of the Genetics and Public Policy Center at Johns Hopkins University.

And David Smith, the Professor of Religious Studies and Director of the Pointer Center at Indiana University.

Welcome to you all.  Thank you in advance, and we look forward to hearing from you, and we'll start with Ms. Madsen, please.

MS. MADSEN:  I was third, but that's okay.

Well, good afternoon, Dr. Kass, and —

CHAIRMAN KASS:  Excuse me.  Might I ask you to move the microphone a little closer or else have someone to amplify this a bit more?

Thank you.

MS. MADSEN:  There we go.

CHAIRMAN KASS:  Yeah.

MS. MADSEN:  All right.  Good afternoon, ladies and gentlemen, Dr. Kass.  I'm honored to speak on behalf of the estimated six million Americans whose lives are compromised and sometimes devastated by infertility.

As the Executive Director of the American Infertility Association, one of the nation's leading patient advocacy organizations and a personal veteran of the infertility wars, I can assure you that our vast community is deeply concerned about the issues raised by this council.

What is at stake here is nothing less than the quality of our lives and for those of generations to come.  This is why any policy discussion of bioethics and regulation of assisted reproductive medicine must have at its core the welfare of the people most affected:  the patients, our children, and the children that we all hope to have.

As a group, we are educated, reasonable, and well informed, and we are persistent, determined to overcome the cruel twists of fate that leave us unable to reproduce without medical intervention.

We would prefer to have what is usually a private matter between consenting adults remain a private decision.  It's our believe that no governmental or religious body should control these uniquely individual decisions.

In my case, it was a leap of faith that gave my husband and me two boys, both IVF babies conceived through assisted reproductive technology when it was in its early years.  Our 14 year old was made the new old-fashioned way, with Mommy's egg, Daddy's sperm, no micromanipulation, and a fresh embryo transfer.

Our ten-year-old grew from a cryopreserved embryo, held over from one of our previous cycles at a time when freezing and thawing were considered newer technologies.  It was an informed choice, and we knew the success rates at that time were not very encouraging.

Our tenacity paid off with a healthy baby boy who hit is first home run last week in Little League.

We have our family precisely because my husband and I were able to make that most private choice unencumbered by any government, social, and research policy.  The science was sprinting.  This country had taken the lead in finding new ways to outwit, if not vanquish, the disease of infertility.

The technology was available.  It cost, but it was there for us to use, and for that we are eternally grateful.

The freedom to avail ourselves of progressive techniques is what we need.  For those afflicted with infertility, assisted reproduction transcends ideology or electorial politics.  It is about the opportunity to realize the possibility of family.

Yet to our dismay we have been drawn into battles far from our own immediate struggle, and it is the belief of the American Infertility Association that productive medicine is being dragged most unwillingly into abortion politics.

Why?  Because our treatment results in the creation of an embryo. 

However, we all must remember that these embryos are a part of our medical treatment to combat our infertility.  We take issue with the presumption that others can lay claim to what is rightfully ours.  We are incensed that we become the lightning rod of often vicious political debate around what some refer to as, I quote, "excess embryos."

Medical investigators want them for stem cell, DNA, research, disease cure research.  Anti-abortionists want our embryos to be donated to others who want to experience pregnancy.

And those are all perfectly reasonable options, but they are options that belong to us, the individuals who created those embryos.  Every decision about their disposition is emotionally fraught, even the choice to do nothing.  To keep them suspended in liquid nitrogen is hard.  Trust me.  I have four.  They're sitting.  It's hard.

Those of us who have gone through the unimaginable, life-altering experience of assisted reproduction have and should have the right to determine the fate of those three or five cells because their fate is bound with ours.

Unfortunately, we must depend on the intellectual and scientific creativity of researchers and clinical practitioners to develop the technologies that we need.  We expect our elected and appointed officials to help insure a hospitable environment for research and clinical practice of integrity.

We expect our government to take an enlightened approach to the science and encourage it, not impede it.

And we expect those who are weighing in on the most intimate part of our lives to please respect the intimate nature of the infertility experience.

Further, we demand unimpeachable ethical behavior from all because there's nothing on our agenda but children, healthy, normal children, regular boys and girls who make it into this world because we can pursue and should have equal access to a constantly evolving and expanding array of therapies.

To date, more than one million IVF children have been born, and they, for all intents and purposes, are indistinguishable from everyone else, and that is what we want.

You will find few others as keenly aware of the ethical ambiguities of assisted reproductive technology than the infertile.  We struggle with the large and the small philosophical, religious, and moral implications of treatment even before we walk in the door.

We analyze and carefully weigh the risks we knowingly assume before undergoing sometimes still experimental procedures.

How we resolve these dilemmas is as personal and singular as DNA.  We, the infertile, object to the manner in which our disease and the outcome of our treatments are increasingly depersonalized, treated as commodities, as things apart (from) who we are.

Even the language to us is really troublesome.  We hear about patentable human goods when what is really under discussion are patentable technologies.

We hear about embryo adoption as if it was an acceptable legal term, when what really is under discussion is embryo donation.  We worry about the government impinging on individual liberties, our religious and cultural beliefs, by determining for us what hundreds of years of philosophical and scientific debates have not when life begins.

And once again, the infertile have no wish to be roped into that particular debate.

Certainly the infertile community — I'm wrapping up — the infertile community welcomes the help of a compassionate government.  We would deeply appreciate a government commitment to health coverage for infertility treatment for all that need it.

We believe federal funding for research is essential to safely expedite the process and defray the financial burden that now falls squarely on mostly uninsured patients.

And we need solid, long-term studies of the welfare of infertile couples, the impact of the disease on parenting after ART that track the health and development of our children, that yield dependable data from large samples, and still protect privacy.  That is how the government can protect the general good.

We advocate the rigorous oversight of the development and application of assisted reproductive technologies.  Indeed, we have paid richly for the regulation already in place.

However, it has yet to be determined that heaping on more regulations would improve the ethical landscape.  Rather, we believe that government participation in a joint committee of physicians, psychologists, theologians, lawyers, as well as other professionals, and patients, we can strengthen existing mechanisms.

Let us have standardized informed consent and institutional review boards for all institutions involved with experimental infertility protocols.  Let's strive for transparency and openness, and hold people accountable.

We are not naive.

CHAIRMAN KASS:  Ms. Madsen.

MS. MADSEN:  Infertility patients —

CHAIRMAN KASS:  I'm going to have to stop you.

MS. MADSEN:  Just my last two sentences.

We know that there are no guarantees.  We adamantly oppose additional regulation without a concomitant throw of federal funds to underwrite research and support access to care.

We don't want you to slam the doors on all of those who are happy, wanting to have children, and I apologize for speaking too slowly.

Thank you.

CHAIRMAN KASS:  Thank you very much.

Professor Mahowald, please.

PROF. MAHOWALD:  First of all, thank you for inviting me.  I really have looked forward to meeting some people that I've known a while and admire a great deal and meeting a few others whose work I've admired but not have had the pleasure of meeting.

In the E-mail inviting me to this, Dean Clancy articulated a little differently than you did, Dr. Kass, but I think the same questions that you began this session with.  He said:  what values and principles currently do and which ideally should guide the regulation of assisted reproduction in the United States?

Now, this is, in fact, two questions, one mainly applicable to the self-regulation that prevails — that's a descriptive question, I think — and the other applicable to government regulation which would presumably have the force of law.

Now, I was asked to bring to the discussion, and I'm quoting again from Dean Clancy, the perspective of someone who's concerned about the ethical duties owed to women and children to be in the context of assisted reproduction.

So with these concerns in mind, my answers to the questions posed can be put very succinctly.  The principle that guides current practice is the right to have a biologically related child, and the principle that should ideally guide regulation is the principle of justice.

Now, in the longer piece that was distributed to you, I talked about these themes a lot more, although I would not say adequately in less than 3,000 words, but today I just want to highlight some of what I wrote there, and also on the outline that I think you have, I've identified some areas that deserve more regulation than currently exists, and I hope we can discuss some of these later.

In her presentation to the council, Sandra Carson identified three values as central to professional self-regulation:  safety, efficacy, and privacy.  Now, these are necessarily addressed through the basic bioethical principles of respect for autonomy, non-maleficence, beneficence, and the right to have a biologically related child is attributed to potential parents on grounds of the first of those, respect for their autonomy.

Justice, the fourth basic principle of bioethics, serves a mediating or balancing function when other principles or values cannot simultaneously be upheld.

Now, regarding my first answer, the right to have a biologically related child, this is a relative and negative right.  It's relative or contingent rather than absolute because its exercise depends not only on the cooperation of others, but also on factors that may prevent its expression even then.

It's a negative right rather than positive because it only obliges others not to interfere with its expression.  It does not oblige them to positively assist or facilitate its exercise.

The right to have a biologically related child is usually asserted with a crucial caveat that the child be healthy, and in her presentation to the council, Dr. Carson made it clear that the potential child's health is a goal of infertility treatment.

But the right to biological progeny doesn't necessarily entail the right to healthy progeny.  Some patients give priority to health by undergoing preimplantation or prenatal diagnosis to avoid having children who are unhealthy or disabled.

For the potential child it's seldom, if ever, better not to be than to be unhealthy, if these are the only alternative.

Regarding my second answer, even a minimalist approach to government regulation should be based on some conception of justice.  The conception that I would propose draws on the work of Nobel Laureate Amartya Sen.  This view eschews a policy of political correctness that ignores differences, insisting instead on attention to differences that provide advantages to some while disadvantaging others.

It starts from the premise that people are of equal value despite our differences, and it calls for efforts to reduce inequities that are often associated with the differences among us.

Differences that need to be examined to develop just regulation of assisted reproduction include those based on gender, class, age, marital status, sexuality, ability, ethnicity, and moral beliefs.  I won't bother trying to give you examples of all of these, but regarding gender, for example, women obviously incur risky, invasive, and uncomfortable or painful procedures that men don't experience even when the treatment is for male infertility.

Accordingly, women's decisions should generally have priority over those of their male partners if these are at odds, and it should not be assumed without question that the priorities of both members of a couple are always the same.

Regarding class, economically disadvantaged women and couples often don't have access to medical treatment for infertility or they only have access to suboptimal treatment.  The recent cases of octuplet and septuplet births are probable examples of suboptimal treatment.

If the right to have a biologically related child is fundamental, then justice demands that infertility treatment not be withheld from

individuals solely on grounds of their ability to pay for it.

Regarding age, the right to have a biologically related child is more compelling for those who are in their reproductive years, than for naturally and healthy post-menopausal women.  Moreover, if as a society we regard all children as of equal value, a recommendation that supports the right to have a biologically related child should be articulated in the context of a broader and more basic right of children to be parented.

On grounds of justice, the right to have a child already born, regardless of whether the child is biologically related, is more compelling than the right to have a biologically related child who has not yet been conceived.

In a pluralistic society such as ours, justice demands attention to moral differences, and with regard to infertility treatment, many of these stem, as you said, from different positions on the moral status of the embryo.

But U.S. law is clear that a woman has a right to abortion which entails destruction of embryos at least until fetal viability.  If moral differences ought to be respected, clinicians may be, I think, required to offer alternatives consistent with their patient's moral beliefs, and researchers should be encouraged to develop more of these alternatives.

In sum, and to repeat my answer to the question I was asked, the right to have a biologically related child is the main guide to current treatment of infertility, and the principle of justice is the ideal guide for regulation.

Both principles should be supported, I think, in the council's recommendations.  In cases of conflict though, justice should have priority.

Thank you.

CHAIRMAN KASS:  Thank you very much.

Dr. Brzyski.

DR. BRZYSKI:  Dr. Kass, members and guests, I appreciate the opportunity to speak on behalf of the Society for Assisted Reproductive Technology regarding the regulation of ART.

By way of introduction, let me provide some background about the society, SART, as we refer to it.

The idea for SART began in 1985 with a group of professionals who convened an effort to foster development of the field and communication within the field.

One of their first efforts and priorities was to publish an annual report of IVF technology to foster that communication development.

In 1988, the society was founded formally, and that first annual report was published as it has been every year since then by the society.

Today there are approximately 370 member programs of SART that are responsible for the vast majority of the 100,000 cycles of ART and 35,000 babies that are born annually in the United States.

SART's mission is to promote and advance the standards for the practice of assisted reproductive technology for the benefit of our patients, our members, and society at large.  I would state that the explicit benefit we seek for our patients is healthy children.

To meet this mission, SART's activities comprise several varied efforts.  First, the registry oversees the collection of annual clinic-specific data for publication by the Centers for Disease Control, and in fact, the registry was responsible for the development of the current data collection software program that is the basis of that system.

SART provides the validation process which reviews the data quality and accuracy submitted by the programs.  Not just SART members, but any IVF program is required to submit data annually, and that validation occurs by state visits of peers to the programs with chart reviews and reviews of the medical records and laboratory data.

Quality assurance efforts by SART provides a process for assessment and promotion of member performance through consultative services provided by SART members.  The Practice Committee continually develops and reviews guidelines and all aspects of ART, and all members are expected to abide by those guidelines, which include ethical guidelines as developed in conjunction with the American Society for Reproductive Medicine.

I have reviewed the current regulatory landscape as I see it in my invited written comments to the council in April.  This slide shows a summary.  Here I will just emphasize again that today as we meet that there are a variety of regulatory processes operating at the federal, state, and professional level.

In the short time I have, I'd like to point out some characteristics of professional regulations as I see them and provide some observations on the principles that I believe should inform regulation.

First, I would argue that the peer dialogue that is the basis of professional regulation promotes engagement and investment in the issues at hand by all of the parties involved.  Attitude and environment for professionalism fosters commitment to professional objectives.

Second, in contrast to legislative mechanisms of regulation, professional regulation and professional regulatory mechanisms support timely engagement of new issues.  This is important in fields such as assisted reproduction when progress is so rapid.

A final comment I would make is that associating professional performance with economic consequences creates, I believe, an opportunity to influence behavior.  For example, tying participation in a large insurance program by an IVF practice to board certification or professional society membership provides leverage to those boards and those societies to regulate and influence professional behavior.

That being said, I'll just make a few comments regarding principles of regulation which I touched upon, again, in more detail in my written comments in April.

First, I think beneficence considerations obligate an analysis of the cost and benefits of any regulatory schema because in the current environment, patients are the primary bearers of the cost of care.  These costs entail terrible burdens to patients and prevent many from ever receiving the necessary care.

Justice considerations require that regulation not discriminate against individuals based on their inability to reproduce without assistance.  Given the vital importance of reproduction and human life, justice and regulatory objectives are both served by promoting expanded insurance coverage for ART.

Likewise justice and beneficence would be served and a significant regulatory infrastructure would be brought to bear if federal support for ART research were promoted.

Finally, the principle of autonomy requires that reproduction be recognized as fundamentally private, and that this most intimate relationship between couples should not be unduly scrutinized or compromised by regulatory interventions.

As to the future, SART will continue to foster and promote collaborations with various professional organizations, government, and bureaucratic organizations, such as collaboration with the Centers for Disease Control for data collection, collaboration with the Food and Drug Administration regarding  guidelines to inform their oversight efforts, a collaboration with the Joint Commission for Hospital Review and their efforts to oversee laboratory regulation in the IVF field, and collaboration with our patient advocacy groups with whom we have had a rich and successful history.

The final comment I would make is I want to thank the council for bringing this social dialogue to the forefront.  I think that's probably the most important effort that you could pursue, and it's the fundamental basis to make ethical judgments that we understand the social environment, that voices are heard, and that information is collected so that informed decisions can be made.

I thank you again, and I look forward to further progress in the field.

CHAIRMAN KASS:  Thank you very much.

Dr. Hudson.

DR. HUDSON:  Dr. Kass, members of the council, thank you very much for the invitation to speak before you today.

I'm Kathy Hudson, the Director of the Genetics and Public Policy Center at Johns Hopkins University.

The center is a little bit over a year old, and we were created to build tools and resources to help policy makers and the public address issues emerging from advances in human genetics.

Our first project is on reproductive genetics, funded by the Pew Charitable Trusts.  As this committee knows and has discussed, the fusion of advances in genetic science and advances in human reproductive medicine have brought forth new technologies that give parents unprecedented new powers to identify, select, and perhaps in the future to modify the genetic characteristics of their children.

The specific aims of our attention to reproductive genetics are listed here.  We want to understand what the public is thinking about reproductive genetics.  We want to engage them in a conversation about reproductive genetics.

We would like to create objective, comprehensive, and hopefully comprehensible information resources, and ultimately to develop a set  of policy options that can be considered by the public and its representatives.

We will not be creating individual recommendations, but rather, an array of options with robust underlying analysis that can be used by others in making decisions.

Dr. Kass, in the center's written comments, we responded to the council's request for information about the current regulatory and legal landscape.  This morning I would like to make two points.

The first is that I think it's quite clear that safeguarding and improving human health is the key motivation and key principle that guides genetics not only in the research laboratory, but in the clinical context, and similarly reproductive medicine research and its practice.  And yet I believe there are weaknesses in the current system.

Second, I'd like to point out that public participation must be a core principle that guides policy development, process, and choices.

So of the core values or principles that should guide reproductive genetics policy, safeguarding human health is perhaps the easiest to identify, to understand, and ostensibly to address, and yet there are weaknesses in the current system of policy, and I use the term "policy" quite broadly to include research policy, that have significant implications for human health.

As Pam addressed, as did Robert, there are now over a million babies that have been born worldwide through assisted reproductive technologies.  And yet in the United States, we do not have an effective system to monitor the health and developmental outcomes of these children.

There have been a number of studies that have produced sometimes confusing, sometimes contradictory, and often incomplete information about the health status and developmental outcomes of these children.

To make sense of this information, the center this week convened a panel co-sponsored by the American Academy of Pediatrics and the American Society for Reproductive Medicine to evaluate the current medical knowledge and to make recommendations for future research to resolve uncertainties and fill gaps in our knowledge.

The second example of a weakness in the current reproductive genetics policy is the absence of a well paved and clearly marked road that genetic tests must traverse in moving from the research laboratory into widespread clinical use.  While the accuracy, reliability, and interpretability is important for all genetic tests, it is particularly critical in the reproductive genetic testing context.

There are now over 900 genetic tests that are available clinically or that are in development, and it's possible to do genetic testing at virtually every point in the human reproductive cycle.  We can test parents.  We can select gametes based on the presence of sex chromosomes.  We can test embryos, fetuses, and newborns.

In the reproductive context, it is often the genetics test alone that is the sole clinical information available for making important decisions.  Attempting a pregnancy or not, implanting an embryo or not, continuing a pregnancy or not, these are profoundly important decisions, and thus we need to have the very highest degree of confidence that the genetic test results and their interpretation are accurate.

So I believe there are weaknesses in the current system of oversight and policy that result in an inadequate understanding of the health risks of these technologies and an inadequate assurance of the health and safety of their use.

Briefly, on the second point, I would like to propose that a fundamental core principle that should govern the process by which policy decisions about reproductive genetics are made in the United States, and that principle is the public's participation.  The public should have a voice in public policies about reproductive genetics.

The goods and values that are advanced and embodied by policies governing reproductive genetics should be the goods and values that are held most dear by the citizens in this democracy, and yet we have only the faintest glimpse of what our citizens hope for and fear in this new realm.

We don't know largely because we haven't asked.  As you have heard from other speakers during the course of your deliberations, other nations when trying to develop a regulatory framework for these issues have turned to its citizens.  Both Canada and the United Kingdom consulted with tens of thousands of citizens in their consideration of human genetics policies.

The Genetics and Public Policy Center is engaged in a modest effort to understand and listen to the voices of the public.  We took an initial pulse through a survey last fall.  We recently completed 21 focus groups with Americans in five cities around the country, and we're now conducting over 200 interviews with individuals who have special experience, expertise, or perspective.

The themes and hypotheses emerging from this work will be validated and tested in a very large survey of citizens this fall, and in addition, this winter we will be engaging groups of citizens to learn about genetics, to learn about reproductive medicine, to learn about governance, and then provide to us their ideas and input about how we should move forward.

The center will use this input along with our extensive policy analysis to construct an array of options that can be considered as society grapples with the development and use of these technologies.

In closing, I'd like to quote Thomas Jefferson, who certainly had some interesting perceptions of genetics and the nature of families, and he said, "I know no safe depository of the ultimate powers of society but the people themselves, and if we think them not enlightened enough to exercise their control with wholesome discretion, the remedy is not to take it from them, but to inform their discretion by education."

Thank you for your attention.

CHAIRMAN KASS:  Thank you very much.

Professor Smith.

DR. SMITH:  It's an honor to be asked to be here, and I'll promise nothing but brevity, and I'll be rather conclusory.

I'm going to talk very briefly about two things.  One is parenting and the importance of children, and the other is embryonic life, which I think are issues the council has obviously addressed, but seem to me to be central.

I'm going to say four things about parenting and the importance of children.  The first is I think it's correct to say that having biological children is a good fortune, a gift, or a blessing rather than a right.

Secondly, I think adoption is an option that should always be presented to and be considered by parents seeking fertility services.

Thirdly, techniques, such as prenatal genetic diagnosis that select among gametes or embryos, may, I think, appropriately be used so long as they're proven safe and respectful of embryonic life.

Fourthly, my intuition is to support regulation by interdisciplinary boards with a professional as well as a lay component, whether they be local or regional.  More general regulations seems to me to be very likely to get things wrong.

With reference to embryonic life, I take the view theologically that it's a kind of vestigial image of God.  It's not to be created to be sacrificed, but unlike those of us sitting around the table, it's usable for research when there's no prospect of implantation or development.  They are, as others have said, potential people, but not possible people.

And I'll stop there and make up for some other time.

CHAIRMAN KASS:  Thank you very much.

Let me start.  I think there are lots of people around the table with questions of their own.  Let me put a couple of questions forward.

This one, I guess start with Dr. Brzyski, if I might.

I'm interested in how the professional standards, especially the professional ethical guidelines established by the society and by SART are forced.  I mean it in the broadest sense.  As I understand it, these guidelines are mostly hortatory, but it's not obligatory that people who are members in good standing, in fact, obey them.

An instance known to both of us, at least one member of the society that advertises publicly that they, in fact, engage in PGD for nonmedically related sex choice.  And yet this is an activity discouraged in the society's own guidelines.

I don't want to argue through that particular case, but if one wanted to trust to professional self-regulation and that there were certain kinds of values or concerns that the profession itself had, how does the profession see to it that its own recommendations are effective or does it and what can it do and what might it do better?

DR. BRZYSKI:  Well, I think that I touched upon a thought, an idea briefly in my oral presentation that I think might need to be explored more, and that's the issue of professionalism and the attitude of professionalism that promotes an environment where individuals are sort of exhorted to participate and to achieve the expectations of their professional colleagues, and that's a rather vague way of accomplishing something, but I think it's something that can't be ignored; that the dismissal of an attitude of being part of a profession as opposed to having a job or having a business; I think that those values and attitudes that go along with the membership in a profession need to be emphasized and form more of a basic attitude and principle with which to deal with each other.

CHAIRMAN KASS:  Well, let me pursue this a little bit.  I mean the American College of Surgeons, the American College of Physicians have certain kinds of norms and guidelines that people who accept membership agree to uphold, and at least in some cases, although it doesn't happen that often, people who sort of flaunt those recommendations, given several opportunities to reform their practice, but since fellowship is a privilege and not a right, the colleges are certainly free to say, "Look.  I'm sorry.  We recommend, for example, that ICSI is a new, relatively unstudied procedure for use in male infertility, but we find it odd that there are some clinics now using it at, say, 85 or 90 percent of cases not related, and that we think that's unreasonable.  Either show cause for doing it, change your practice, or we might have to reconsider your membership in the society."

And the other professional societies, while being collegial, nevertheless exercise more than "please do this," and I wonder whether — I mean, you're a young society relative to those others, and the guidelines are being developed as the field grows, but certainly the coming of preimplantation genetic diagnosis and the uses of those things beyond just reasons of the health and prevention of serious diseases, and sex selection is just the forerunner of this.

It does seem to me that there are things in which the whole society has a stake.  If it is to leave the regulation of this in the hands of the professionals, it wants at least to have some sense that the professionals will see to it that those kinds of norms are, in fact, observed.

If that sounded too much like a lawyer's brief, I apologize, but I'm trying to sort of push the question about what are the limits of professional self-regulation here, not in those cases where, you know, it's certainly obvious that those things should be followed, but in cases where some fellows think, look, the parents want to have a girl child now.  Why not? 

Or they say, "Look.  We want to increase our batting average here.  So we'll use ICSI rather than something else or we're going to start doing this kind of practice though it's relatively untested," and the couples don't mind and they've been properly informed of the risk.

Those are the general areas for sort of professional self-regulation and, generally speaking, enforcement or adherence.

DR. BRZYSKI:  Well, I would say that I would agree that this society is young, and part of the process that we go through as a society is to plot a course of development that will cement our recognition as setting the standards in ART as we have put as our mission.

And I think there's a growing collaboration that's developing over time among several aspects of the ART field.  When it becomes important economically, as I mentioned, for members to be members of the society, then that's one way to leverage behavior, and there are cases now where as I mentioned, insurance programs require that if you're a patient and you're going to seek assisted reproductive technology services, that those be provided by a member of SART. 

That's I would say a minority of individuals that are covered by those sorts of benefits, but if that became more widespread, then that would provide some impetus for individuals to maintain participation.

I would say that the society believes at this point that to try and maintain a communication with members and maintain a membership that could be potentially influenced in the future would be more important than taking a strong stance and depleting the membership based on those stances which have no potential impact on behavior.

DR. FOSTER:  Can I just ask a question in follow-up to this?

CHAIRMAN KASS:  Dan Foster.

DR. FOSTER:  Has ever anybody, since this is a young society, has ever anybody who is a member of the society where peers believe that there has been a practice that's not in accord with the standards, been in any sense counseled or dismissed?

As an aside, as I know you know, the residency programs in this country are controlled by the ACGME, and in internal medicine where I work, for example, there were strong standards about what you had to do to train residents, and so forth, and for years the programs that were recognized as being absolutely disastrous were never closed because of the fears, some of the fears that you just expressed, either lawsuits or that there would be a fallout.

So I think there is some concern on my part that regulation by societies — I mean, what happened is that the professors of medicine, the chairs of medicine, in essence, forced the RRCs to begin to close programs that did not actually meet the standards that were required of everybody.  I mean, we had the situation for a great academic program was put on probation, and at the same time a program in, let's say, Philadelphia or Dallas or somewhere that everybody knew was absolutely no good was not disciplined at all because of fear.

And so the question is twofold.  One, has anybody ever been called, in essence, to account for their practice in the two or three years that you've existed?

And secondly, do you have confidence that without some sort of discipline that might require somebody to lose their accreditation, the absence of that would be  effective?

These are just two questions that I wanted to — I got the sense that you thought that the fact that the membership itself was enough to be sure that everybody followed the programs that you have outlined here.

DR. BRZYSKI:  Well, one example that I can point to is that there are advertising guidelines that the membership adhere to, and when there are variations from those practice guidelines that are brought to the attention of the society, then there is an educational effort that's carried out with those memberships, and there are cases where — and the typical response of the member is to modify their advertising behavior just in response to those educational efforts.

Another case involved sort of the combination of advertising and practice, was utilization of experimental procedures in a clinical setting without documentation or support or evidence that the patients were being cared for in a clinical trial in a research setting with appropriate controls.

So a practice has instituted what professionals in the organization recognized as experimental, as accepted clinical practice, and offered that as a service to their patients, and that membership, after a long discussion back and forth, efforts led to the termination of that membership or that program.

CHAIRMAN KASS:  Michael Sandel.

PROF. SANDEL:  I had two questions, and I'd be interested to hear anybody respond to them who would like to, but I would like to address them initially to Professor Mahowald because the question arises from a distinction that you drew between two rights, the right to have a biologically related child and the right of an already existing child to have a parent.

And you said that the first was implicit in the current regulatory practice, but you suggested that the second was morally more important, if I understood you correctly.

And in your paper you said thinking about government regulation that policies that encourage and facilitate adoption are more morally incumbent on regulators than policies that facilitate infertility treatments, which reflects the priority you would give to the right of already existing children to have parents over the right to have a biologically.

If some limited funding were available in this area, you would say, would you, that given the choice between funding infertility treatment and funding adoption programs, we should do the second before the first.

Did I understand you correctly?

PROF. MAHOWALD:  Substantially, that is what I said.  Basically the right to be parented, the right to be nurtured, the right to be given what one needs to grow, I think, takes precedence over the right of parents to have a not yet existent child.

PROF. SANDEL:  Is there anyone on the panel who disagrees with that?

MS. MADSEN:  I'll chime in in a slightly different way.  I don't know necessarily that infertile people are the only people to adopt children.  Fertile people can adopt children, and putting us together as, well, if you can't have a biological child we'll help you adopt one is our solution.

Children need to be adopted, and people want to have biological children.

PROF. SANDEL:  Well, that addresses a different —

MS. MADSEN:  And they're separate.  And they're separate.

PROF. SANDEL:  That addresses my second question, which I don't think answers the first.  My second question was going to be that.  Is there any reason to think that the obligation to fulfill the right of children, already existing children, to have a parent should fall more heavily on those who are infertile than on those who are not?

You've said no.  The answer to that is no.  Is there anyone who —

PROF. MAHOWALD:  No.

PROF. SANDEL:  You would agree.

PROF. MAHOWALD:  Yes.

PROF. SANDEL:  But those are two separate issues, aren't they?

Though everyone here might agree that the answer to that question is no, that there's no special obligation to fulfill the right of children to have parents that falls upon those who are infertile.  It doesn't equally fall upon those who are capable of conceiving naturally.  So that's one issue.

But to answer that question in the negative still isn't to disagree with the first claim, namely, that the right to have a biologically related child is morally less important than the right of a child to have a parent.

That's why I was trying to separate those two questions and see whether people —

MS. MADSEN:  I think it's very, very difficult when you put lots of different groups with tremendous needs and pain and ask them to compete against each other.  Children deserve homes.  Children need to be adopted, deserve wonderful adoptive families.

People who have a disease deserve treatment, and I hate to be in a society where we can constantly make disease groups and people with special needs.  Real needs that are all legitimate, compete against each other and make us decide who should be cared for.

CHAIRMAN KASS:  I have Gil, Rebecca, Robby George.

Gil Meilaender.

PROF. MEILAENDER:  Yeah, this follows in a way on Michael's question, and I think I'm going to address it, Mary, to you, but I'd be happy to hear from others because I think at some level there is disagreement among the panel on issues.

What I want to think about is what you mean in terms of the right to have a biologically related child or perhaps the right to have a healthy biologically related child, what that language means exactly.

And I realize that in a certain sense at that point in the materials that you submitted to us and in your talk you were speaking descriptively, and so you're not necessarily arguing your own view, but nevertheless, you may be able to kind of think it through with us.

And it goes in some sense to the question about private/public, and how much of this is a private matter and how much is a public matter, in which there was some difference at least at the linguistic level among the panelists.

One of the things is what it means to have a biologically related child.  There are lots of ways to produce them, and the question is whether they all amount to doing the same thing, to having a biologically related child, and to take the example at one extreme, and I believe as I recall you do mention it, to use cloning, to produce a clone of myself might be said to be a means of having a biologically related child.

Now, are you saying that descriptively at the level of our practice right now, whatever you may happen to think normatively, descriptively that I do have a right to have a biologically related child by that means?

PROF. MAHOWALD:  I think people who have argued in support of reproductive cloning use exactly that argument.

PROF. MEILAENDER:  I guess let me follow it up, if I may, and invite others.

Does the fact that some sizable number of people have moral reservations about cloning to produce children suggest that the language of a right to have biologically related children is too broad and needs greater narrowing and precision?

PROF. MAHOWALD:  Yes.

CHAIRMAN KASS:  Please.

DR. BRZYSKI:  I would just comment that I'm not aware of any professional organization or patient advocacy group that's in favor of reproductive cloning to produce children, and I would contend that there are practically no scientists that would equate a clone with a child.

So I would make that distinction.  So the argument that cloning is a way to have children, I think fundamentally is a misconception that practically all professionals that work in reproduction would argue.

CHAIRMAN KASS:  I think if I understand the force of Gil's question, and it certainly is one of the things that springs from this discussion, granted that reproduction is a private matter in the first instance and an intimate matter in the first instance, and we generally believe that government has no business interfering, and some people even think government has an obligation to help where there are obstacles to realizing these private goals.

The question is whether the presumption of privacy and the rights to be exercised in that private realm are unqualified and embrace also having a child by whatever means, having a healthy child, which is very different from the right to have a child, and having a child with certain desirable characteristics.

Look.  If it weren't for the coming of the new genomic knowledge, I doubt that we would be having this conversation really.  I mean there are questions to be raised about the adequacy really, the concerns for the well-being of the child-to-be who is produced here, who is also a patient of this procedure, but invisible to the eye and merely hoped for when you get started, though that being is the patient of the operation and that person's well-being and safety was an uppermost consideration  not always regarded in advance.

But I don't think we would be having this conversation were it not for the fact that new kinds of choices now begin to enter into the right to have a child or the privacy here where the society might have an interest.

I mean, look.  You've got other nations where they practice sex selection not by PGD, but by sonography and abortion, and the sex ratio at birth approaches 120 males to 100 females.

Those are aggregated private choice with enormous social consequences, and the society can't be indifferent to whether that goes on and how it's practiced.

So here is an instance where one wonders whether or not the language of rights, the language of privacy, given what's coming before us, is going to be adequate to deal with the implications of what's here.

And that's partly why, while I share your starting point, I wonder whether from the social point of view all of the things that are of interest to us and that we all care about are adequately simply handled in terms of the language of rights.

And I think Gil's question is meant to probe the limits of that concern.

I'm sorry for jumping the queue, but I think it that's where we're —

PROF. MEILAENDER:  Thank you for the assistance.

CHAIRMAN KASS:  Yeah.

(Laughter.)

CHAIRMAN KASS:  I have Rebecca and then Robby, then Bill May.  I'm sorry.

PROF. DRESSER:  One of the major concerns in this area is when the prospective parents who, of course, are very much interested in trying to have children might have preferences that conflict with the well-being, particularly physical well-being, but also other kinds of well-being of our future.

So Leon just mentioned that this future child can be considered a patient.  So I was interested in whether you all agree with that.  Do you think that the to-be child or hoped for child is considered a patient, and if so, what safeguards should be in place professionally and perhaps in an oversight capacity from the government to handle situations when there is a conflict of interest between the prospective parents and the child to be?

And I guess the easiest thing to talk about would be a physical threat, and so let's look at ICSI.  That's a procedure which some people still have some questions about in terms of whether it's producing healthy kids, and it's not being studied in a very rigorous way.

And this would certainly be a case where many prospective parents might say, "Well, if it raises my chance of having a child, I want it, and don't make me go into a clinical trial or don't make me wait for the clinical trials and the data.  I want it now."

And, you know, that's perfectly understandable, but should there be any kind of oversight there?  What should the role of the physician be in that situation?

CHAIRMAN KASS:  Is that addressed to someone in particular?

PROF. DRESSER:  No.  I just wondered if anyone in the group had views on this.

DR. BRZYSKI:  Well, my microphone is on.  So I guess I talk.

First let me make a comment about ICSI.  there have been some recent articles about the safety of ICSI, but I think I would emphasize that there are also studies that suggest or don't suggest, that show that the health of the vast majority of ICSI children, who may be several years old now, is equivalent to that of other children.

And here I would emphasize again scientifically the issue that the easy way to look at outcomes is to compare ICSI babies or ART babies, IVF babies to the general population, and that may not be the best group to compare because there may be underlying problems that infertile individuals have that may be associated with their infertility that manifest themselves in ill health or disease in their offspring.

So although SART and ASRM are concerned about the safety of ICSI and believe very strongly that it needs to be examined carefully, the evidence that we have seen indicates that the vast majority of those children are healthy.

As far as the issue of conflicts between parents and the potential child, I think I'm going to pass on the discussion of the potential child.  Maybe Dr. Smith could.

DR. SMITH:  Well, I'm not going to talk about that, but I do just want to make two remarks.  First, I think it is obvious we have to distinguish rights from desires.  I mean, we can't assume that everything people desire they desire it with their whole heart.  For very good reason is, therefore, a right.

And at the end of the day, I come down on the side that says that having one's own biological child is not a right.

On the other hand, I have to say that I'm very uncomfortable with that because parenting was for me and has been for two of my three children a life transforming experience, and in my case, I'm lucky that it has been biological parenting.

So that it's a difficult one, and the possibility of adoption — actually I think Mary had some of this just exactly right — the possibility of adoption is a very relevant fact.

CHAIRMAN KASS:  Please.

DR. BRZYSKI:  I'm sorry.  I wanted to get to the initial issue that you raised about the conflicts between the parents and the potential child, and I guess I would go back to the concern I have about discrimination.

For instance, we know that there's a certain risk of transmission of HIV to offspring when HIV infected parents conceive, and I guess I'm concerned about having a different level or a different category of regulation or intervention for a couple that is able to conceive naturally, spontaneously in that regard versus a couple seeking medical care for other conditions where they happen to be HIV positive, and there's a judgment that has to be made there about is participation in health care delivery contributing or compromising the health of the child versus not meeting the needs of the patients there, the actual patients that are in front of you versus the potential patient that you might create.

And I think that's an issue that's been raised in discussions with the ASRM Ethics Committee, that it's difficult to isolate, segregate infertile couples and to somehow modify, you know, what to do to them versus what we allow us to do to individuals who aren't patients.

CHAIRMAN KASS:  Please, Mary.

PROF. MAHOWALD:  I guess Gil was right that that descriptive claim wouldn't be the one that I myself would make prescriptive, and as a matter of fact, I agree with David and would avoid the language of rights in my own arguments along this.

A word that I feel comfortable with for any parent by any means is that having a child is a privilege, and it ought to be viewed as such by anyone who becomes or hopes to become a parent.

But your question, Rebecca, really does nonetheless go to this notion of a right, and if there is any right to have a child, there surely is a right to have an unhealthy one.

PROF. DRESSER:  I guess I would wonder if there's a difference though.  Certainly if someone is a carrier of a genetic disease, the idea that we would somehow as a society say you're not allowed to reproduce is offensive to just about everyone.

But once the medical profession is involved and sometimes insurance and social resources and so forth, I think there are questions of responsibility and what is appropriate for the profession and the society to help.

I mean this is assisted reproduction.  So I guess I'm trying to get at your ideas about and back to this question of when prospective parents may prefer something that is perhaps not in the best interests of a future child.

MS. MADSEN:  This whole notion of children being a gift, life is a gift; we use this language an awful lot.  Good health is a gift, but when we do not have good health, we don't say, "Gee, I didn't get the gift.  I'm going to sit here and be really sick because I didn't get the gift.  I'm not going to see a doctor because, you know, God didn't give me the gift of good health."

So I didn't get the gift of fertility, but I was able to have the gift of a doctor who was able to help me have this wonderful basic human life activity, that I was able now to engage in and give birth to a child who at 14 understands that he's an IVF child, and who thanked me for the gift of being here and being a part of the family and couldn't wait to have his picture taken with Professor Edwards who had the first IVF child.  He was an embryologist.

He said, "I want to stand next to this man and have my picture taken because without him I wouldn't be here."

So there's lots of gifts, and I think that we should just be really clear about that.

And my children who are older now, ten and 14, they didn't get to vote that they were conceived.  It's true, but neither did I.  They're really happy to be here.

CHAIRMAN KASS:  I have Robby George, Bill May, Frank, and then we'll probably stop.

PROF. GEORGE:  Thank you, Leon.

I was going to follow up a little bit on the very interesting line of questioning that Gil opened and Leon then very helpfully advanced, and I wanted to take it a little bit further and raise a different fundamental question, I think, that flows from it.

I take it that at least in the case of Ms. Madsen and Dr. Brzyski, the position is that ART is an area that's appropriate for government funding to support research and to advance the science in the area in order to make this technology more widely available and better.

Am I right about that?

MS. MADSEN:  Yes.

PROF. GEORGE:  Now, the point was made by a couple of members of the panel that we live in a morally pluralistic society, and in this particular area we're touching very intimate and inherently private choices.

Is that also something you agree with?

These are areas in which people hold very different moral views and the moral views of different people ought to be respected.

Everybody seems to agree with that.

But then, if we're talking about an area that is fundamentally private and intimate, it's not like a public function, provision of a police force or national defense, where people might have moral objections to it, but we've always held as a society that people's moral objections to it notwithstanding, we're going to carry out this public function and even tax people to pay for it.

But if you take the position that everyone's moral views ought to be respected, that people have different moral views about ART, you want your views to be respected; you're saying their views should be respected, and this is an inherently private area, not like the military or provision of police forces, what justification can you offer for compelling using the course of the power of the state to tax people who don't share your view on ART to contribute, to implicate themselves in fundamentally private behavior?

MS. MADSEN:  This is health care, and we're not talking about anything other than health care here, and you do not have to seek treatment.  No one is telling a couple that they have to seek treatment.  That's a private decision with the couple, and that's the same in any other disease group.

Patients make private decisions, whether it's breast cancer or prostate cancer or infertility.  In this country we provide health care for these kinds of treatments, and whether or not you participate in that is your right.

I'm not going to ever tell a couple what they should do.  I will tell a couple what options are available for them.

PROF. GEORGE:  But the reason I think that response doesn't get you off the hook of the question is that to treat the creation of embryos to solve infertility problems as health care is already to make a controversial moral judgment.

Certainly, the infertility is a health care issue, but whether we're dealing with medicine strictly speaking in the creation of embryos, and certainly you yourself concede that the question of the morality of creating embryos by this method or dealing with fertility by this method is more fundamentally controversial than whether to treat breast cancer, whether to treat kidney failure.

MS. MADSEN:  I actually didn't say it was more fundamentally controversial.  I don't believe that it —

PROF. GEORGE:  So you believe that it's not controversial, that ART is not morally controversial?

PROF. SANDEL:  The issue, Robby, isn't whether it's controversial.  The issue is whether you can provide a compelling reason publicly by ART is so morally objectionable that it shouldn't be included in health care.

PROF. GEORGE:  Oh, sure.

PROF. SANDEL:  So the burden is on you.  It's not on her to say whether it's controversial or not.

PROF. GEORGE:  Oh, no, no, not at all, Michael.  I'm afraid the burden is on you or on her because we know as a matter of fact on the ground that it's morally controversial, that people have different moral views.

The premise for the argument for privacy here is that where we have different competing moral views, those moral views ought to be respected and nobody ought to be imposed upon.

PROF. SANDEL:  But if the controversy isn't based on an objection that's well founded, we shouldn't take any notice of it.  So you —

PROF. GEORGE:  So people who believe other people's moral views are not well founded can simply disrespect those views.  So the principle that we ought to respect diverse moral views only depends on an assumption that the other person's moral views are morally defensible; is that right?  Is that your view?

CHAIRMAN KASS:  Gentlemen.

PROF. SANDEL:  No.  You can be a conscientious objector to the tax if you can show you've got a good reason to subtract it.

CHAIRMAN KASS:  Without settling the dispute between these gentlemen, and I'll even resist an opportunity to advance the ball on the discussion, let me call on Bill May.

DR. MAY:  I would like to address a question to you, David Smith, on the whole question of regulation and discretion and building up case by case something that you say resembles the common law tradition.

On the subject of embryos, you say, "Under these circumstances I think we will be best served by a flexible and case-by-case regulatory system with teeth."

Apparently a flexible system also can have teeth.  That's interesting because that's not the way that that term is usually used, but it is interesting that you do put them together.

DR. SMITH:  Well, I grade papers.

DR. MAY:  Yeah.

(Laughter.)

DR. MAY:  "We should be regulating all uses of embryos whether in the public or private sector, but our regulatory process should be modeled on common law, on incremental and something like case-by-case decision making within a very few, broad parameters."

Now, I guess I wonder who is the decision maker, the courts or professionals and potential patients.  Is the law simply permissive, turning over such decisions in the setting of which some kind of quasi-common law tradition would develop within a profession maybe or are the parameters really regulative?

You haven't seen a document that we will be discussing later, but there's a sentence I noticed.  "Most governmental authorities simply lack the expertise to provide meaningful oversight of professional activity, and medicine is a profession where crucial judgments must be made on a case-by-case basis by a practitioner familiar with the details and circumstances involved.  The law tends to give physicians ample latitude to make such judgments."

So when you're talking about parameters and so forth, are you talking about parameters with some kind of content and then within which professionals operate and make the decisions or within the setting of which one further elaborates case by case the common law tradition in which case the courts are making decisions?

DR. SMITH:  (a)  I think these are very good questions. 

(b)  I think my instinct is to say that just — that's the first thing.  Secondly, my instinct is, in fact, to trust professional discretion, but I was not encouraged by the report that we heard a few minutes ago about the Fertility Society's community's history of self-regulation.

I do strongly sense — I really think that circumstances alter cases, and I want people on the ground making those decisions as much as possible, but if, in fact, there's a history of loss of teeth, of de facto no regulation and entirely permissive practice, then something else has to be set up.

I don't know if the IRB system in which you've got a combination of professionals and nonprofessionals serves as a useful model.  I do know one example that isn't good for my point.  When the U.K. altered its abortion law in the '60s, they opted for a regulatory system that was essentially local or, in the case of less populated areas, regional boards that would decide on a somewhat case-by-case basis if the stakes in individual cases were high enough to justify abortion, and I thought that made great sense.

De facto, however, it failed or it has failed because what it evolved to is total permission or evolved, in effect, to no regulation.

I still haven't given up on the idea, and I think this is an area where sweeping prohibitions or just blanket permission strike me as wrong.

I don't know.  That's not a very good answer.

CHAIRMAN KASS:  Frank Fukuyama.

PROF. FUKUYAMA:  Well, it turns out this question actually follows  on the last one, but it's actually directed to Kathy Hudson.

I agree with you, Kathy, completely that, you know, one of the basic principles ought to be participation by, you know, a fairly broad community, and I wonder whether you have given any thought to, and I'm very glad that you're doing these polls and focus groups.

Have you given any thought to how you institutionalize participation as you go down the road in the future?

You know, in a constitutional democracy, the basic guarantee of participation is elections, and you know, you elect people to Congress, and you can lobby them, and so forth.   When you get into biomedical regulation because it is so technical, democracies then tend to delegate regulatory authority through an epistemic community that has the knowledge and specialization, you know, to deal with that set of issues, which then tends to insulate, you know, that group from broader public participation.

Congress can always intervene, but you  know, it is not encouraged and so forth.

Now, do you think that the current situation where as we go down the road to these kinds of more controversial technologies like PGD and, you know, some day germline and other things, the current system where that delegation to the professional community with occasional focus groups and polling and the existing, you know, comment and, you know, posting regulations and opening them up for public comment; is that going to be adequate or do we need something else to get on an ongoing basis the views of a broader public other than, you know, the people that are professionally engaged in the practice of biomedicine?

DR. HUDSON:  I'm not sure I'm going to be able to satisfactorily answer the question because I don't know how this is all going to turn out.  I think there is an appropriate role for the public's voice or some representative sample of the public to provide their reflected opinion, not just their knee-jerk reactions.

That can provide sort of the framework, the bounds within which the professionals can then say in order to achieve that vision of the way we want the world to be, in order to uphold those goods and reflect those values, you know, we know what our course is, and now we'll do the tinkering to construct the regulatory framework that can best achieve that.  Looking in our policy toolbox, what tools can we apply to do that, to accomplish that?

I think that there can then be a disconnect because you are speaking different languages at some point.  Whether or not that process of public participation can be institutionalized I'm not sure exactly how to do that.

Engaging the public beyond just asking them five questions in a telephone survey is a very difficult and very expensive undertaking.  So in some ways it's a privilege for us to be able to have the opportunity to do this.

CHAIRMAN KASS:  The last question to Mary Ann Glendon, and then I'll have a comment and we'll break.

PROF. GLENDON:  I'd really like to know something about the kind of conversation that you have with a woman who's considering IVF.  I assume that your organization has guidelines for clinics about what subjects should be brought up, and I'm wondering in particular about two things. 

One is whether in any more than a cursory way the subject of adoption is brought up, the exploration of alternatives.

And, secondly, whether in addition to discussing the known risks of the procedure for the woman, there is any discussion of the potential long term health consequences.  It's a relatively new procedure, and you know, we found out some unpleasant things about diethylstilbestrol used to prevent miscarriages back in the 1950s.

Is there a conversation about those long-term risks incorporated into this preliminary counseling?

DR. BRZYSKI:  Well, I would say that the principles of informed consent, regardless of the therapeutic intervention that's proposed, incorporates a discussion always of alternatives and risks.

Specifically in the case of assisted reproduction, whether the discussion of adoption is more than cursory or not I think would be hard to say.  Most patients who come to the decision to do IVF, it's a process that they go through.  So it's not something — like a typical patient I see will come.  They're infertile.  They don't know why they can't have children.  They go through a diagnostic process.  We try some therapeutic interventions perhaps, and over the course of time, maybe even at the first consultation we'll say, "Well, I'll take fertility drugs, but I'd never do IVF, you know."

And then three years later as they've learned more about their condition, about their options for treatments, the expiration of the possibility of adoption, which practically all patients discuss with me over the course of that time, there's a consensus among the physician and the patient to pursue the IVF therapy.

So it's not like you just sit down and say, "Okay.  Now we're going to talk about this consent form," because practically it's a process that stretches over a long period of time.

But during that time the issue of long-term risk has certainly been brought to our attention or concerns about that has been brought to our attention, and again, practically the example of whether fertility drugs cause ovarian cancer is sort of open the door to that line of discussion with patients, you know.

Whether or not that's true or not, it provides an example to patients that they can understand regarding other possible risks to their children and to themselves.

So I would say that professionals are used to discussing and are comfortable discussing with patients.

CHAIRMAN KASS:  Thank you very much.

Let me make a request.  First, thank all five of you very much for being here, for clear presentations, for very thoughtful and forthcoming responses.

I would like to take the liberty of being able to write to you, have the council staff write to you to follow up on some kinds of questions that have emerged here.

In particular, I would flag the question that Rebecca Dresser asked.  To what extent is the child to be, in fact, regarded as a patient in this process?

And also more thought on the meaning of the fusion of assisted reproduction with the coming genomic knowledge.  We barely touched on that, and whether or not — this is for you, especially, Kathy — whether there are lessons that we might have learned as a result of genetic testing in the adult context that ought to prepare us for the kinds of questions to worry about here, as this is now coming here.

On that subject, by the way, let me call council members' attention to a paper by a person who couldn't be here to present today, Tonya Simoncelli, who has a paper that you have seen a presentation on PGD, regarded in her view as sort of the gate opening or the wedge technology toward a new kind of eugenic future and those kinds of concerns haven't yet really been discussed here, but the council members should notice that.

We'll take a break.  Let's make it ten minutes this time.  Our guests are waiting, and we don't want to keep them too long.  Ten minutes we'll reconvene.

Thank you all.

(Whereupon, the proceedings went off the record at 3:39 p.m. and resumed at 3:56 p.m.)

Session 4: Biotechnology and Public Policy: Embryo and Related Research

CHAIRMAN KASS:  I think we should get started.

This is the second of our panels with public presenters trying to help the Council understand the current state of regulation of biotechnologies touching the beginnings of human life.

Since I had long introduction of the first panel, which I won't repeat, I'll simply say that the Council is at the moment simply trying to understand the status quo and, in particular, to understand what human goods and what values now govern whatever regulatory activities we have; also, some suggestion as to what human goods and values ought to govern here, and how well we are doing in promoting and protecting those.

The last panel was selected with the view that they would largely talk about the actual reproductive uses of these technologies.  This panel was selected expecting that most of you might be more comfortable addressing the research questions and also the commercial questions.

But you are free to say whatever you want on whichever aspect of this topic strikes you as important.

We thank you for your submissions, in advance.  You should know that the Council has prepared its own staff document, instructed by the Council to take a look at the status quo.

We didn't distribute it to you in advance because we wanted you not to react to what the staff had done, but to have your own input, and we have your original submissions that were under consideration when the draft document was done.

Our document will be available tomorrow here and also on our Web site by the latest, I think, on Monday, and we would certainly welcome your comments on what the staff has done.

Let me welcome then in order of presentation Michael Manganiello, who is the President of the Coalition for the Advancement of Medical Research;

Richard Doerflinger, who is the Deputy director of the Secretariat for pro-life Activities at the United States Catholic Bishops Conference;

Maxine Singer, who is the Chairman of the Committee on Science, Engineering, and Public Policy at the National Academies of Sciences;

Michael Werner, who is the Vice President for Bioethics at the Biotechnology Industry Organization;

Andrew Kimbrell, who is the Executive Director of the International Center for Technology Assessment;

And William Kristol, who is the Chairman of the Bioethics Project.

We are going to ask you to try to hold as best you can to five minutes.  We will take you seriatim, hold our questions and discussion to the end.

We thank you for your presence.  We look forward to your comments.

Please.  I think you have to press -  maybe it would be best if you could get it a little closer to you.

MR. MANGANIELLO:  How's that?

CHAIRMAN KASS:  Is that all right?  Can you hear from the back?

Please.  Thank you.

MR. MANGANIELLO:  Good afternoon, Chairman Kass and members of the Bioethics Council.

The Coalition for the Advancement of Medical Research, CAMR, values the opportunity to offer remarks on the regulation of technologies and practices relating to embryonic stem cell research.  Although CAMR is honored to testify today, the coalition feels the voices and strong beliefs of the patients in this country suffering from disease and disability should have been considered in the formulation of this commission and in the conclusions you came to last year.

The coalition is comprised of more than 75 patient organizations, universities, scientific societies and foundations advocating for the advancement of breakthrough research and technologies in regenerative medicine in order to cure disease and alleviate suffering.

It is disappointing that the voices of so many organizations dedicated to medical and scientific research were not considered in establishing a policy that affects over 100 million Americans suffering from presently incurable diseases and disabilities.

CAMR strongly supports the freedom to conduct ethical research and explore biomedical science in the hope of finding potential treatments and cures for society.

Furthermore, we strongly support federal regulation of research to insure that it is safely and responsibly executed.  By stalling the advancement of regenerative medicine, we are sending a message to researchers and young academics, in particular, that scientific inquiry is suspect.

For example, it should be noted that over two- thirds of the U.S. population supports somatic cell nuclear transfer research to produce stem cells.

However, your commission's recommendations for a moratorium will delay and deny hope to millions of Americans.

The field of biomedical research, biomedical science adheres to regulations set by state and federal regulatory systems.  As you know, Congress has failed to regulate cloning, but scientific discovery continues in this field without a ban on reproductive cloning and no regulations on SCNT for research.

CAMR concurs with the report issued by the National Academies of Science in June of 2002.  The National Academy of Science, the nation's most august scientific group, concluded that while the science of reproductive cloning must not be pursued, SCNT is likely to be the best technology to cure deadly and crippling diseases.

SCNT can also be used to understand the genesis of disease and provide an opportunity to advance the understanding and biological and cellular mechanisms.

All Americans will suffer from the restrictive environment in our scientific community which has indefinitely delayed the development of stem cell therapies.  The President's policy limits federal funded research to a homogeneous group of human embryonic stem cell lines.  Since some diseases are gender, race, and ethnicity specific, it is vital to have a genetically diverse group of lines to study.

A greater number of stem cell lines available for a study would provide statistically significant results.  Our scientists are being driven into a sequential form of research rather than research done on parallel tracks.

In addition, as was stressed recently by Dr. Ron McKay and Dr. John Kessler in recent Senate testimony, "The history of the cells or the way they are derived may change their behavior."

The President's policy means, as Dr. Kessler said, "We will perhaps be developing cells the one way that is not the optimal way, so we need to expand our ways of trying to develop the cells."

Additionally, the President's policy not only severely restricts the work of stem cell researchers, but encourages the exportation of a very promising field in the biotech industry.  Scientists in many countries of Europe and Asia do not face the constraints in place in the United States.  These nations are making embryonic stem cell research the cornerstone of their biotechnology industry.

America is losing its preeminence in medical research.  Rather than sitting on the sidelines, we should be supporting America's ingenuity and experience by promoting and regulating the expertise of our scientists.

CAMR has strong reservations about the President's decision that was announced August 9th, 2001, regarding funding human embryonic stem cell lines.  This broad public policy was grounded in political expediency.

Dr. Zerhouni, the Director of NIH, has publicly admitted that there are only 11 stem cell lines available at this time, not 64, and they are simply not enough.

The American Society of Reproductive Medicine recently established that there are over 14,000 embryos in the U.S. that would be donated for stem cell research by the couples that created them.  If that research is not permitted, those 14,000 frozen embryos are set to be discarded as waste.

It makes no sense to forfeit the knowledge that our scientists would gain from the stem cell lines that could be derived from these embryos.

The field of stem cell biology should move ahead on all fronts.  It would be devastating to proceed in only limited fields of research and discover the science is flawed.

Our scientists should receive federal funding to conduct research using stem cells from any source:  adult, embryonic, and those created by SCNT.

Working independently, with limited funding, scientists in the private sector and the laboratories of our universities have already achieved breakthroughs that clearly demonstrate the promise of stem cells, but without a reversal of the administration's policy, their efforts may go unrealized.

Congress and the administration should support SCNT, ban reproductive cloning, and allow broader federal funding of stem cell research to provide hope for better treatments - I repeat hope for better treatments - and cures for our fellow citizens; maintain America's dominance in the biotech industry; and pro-actively regulate new medical treatments.

The 75-plus members of the coalition, the National Academies of Science, the 40 Nobel laureates who sent a letter to President Bush, Senator Orrin Hatch, former First Lady Nancy Reagan, the State of California, England, Israel, Sweden, Singapore, and China, among countless groups, states and countries have given serious thought and attention to this matter, and they have spoken.

Promising medical research must proceed.  These are our neighbors, our friends, our allies, just as moral and as ethical as anyone sitting in this room.  Who are we to ignore them?

Thank you.

CHAIRMAN KASS:  Mr. Doerflinger.

MR. DOERFLINGER:  Thank you, Mr. Chairman, and the Bishops' Conference is grateful for this opportunity.

I have a longer statement and appendix that I've distributed to the council.

I was asked to comment on the principles and values that are at stake on these issues, and that is the aspect of the issue that we feel most comfortable talking about.

There has been a substantial, though certainly not a unanimous, consensus on certain key values and principles that are relevant here.  Tragically, even when those key values and principles have sometimes been stated by advisory boards to the government dealing with this issue, they have then been neglected when the time came to use them as a basis for public policy.

The first norm I'd like to talk about is simply the importance of ethics itself— that medical research can and should always be guided by fundamental ethical norms.  I say "guided by" rather than "balanced against,"because one of the ways in which the principles of declarations like the Nuremberg code, the Declaration of Helsinki and other instruments have been somewhat eroded in recent years is with the claim, sometimes written into proposed legislation, that ethical and scientific considerations must be balanced against each other in promoting research.

But if they have to be balanced, that means that even when you know something is unethical, you can go ahead and do it anyway as long as the medical benefit is, or is thought to be, great enough.

And that is what the Nuremberg code and so many other instruments in our history stand against.  CAMR, for example, says it supports ethical research, but that is exactly what we're here for.  They say we have to give greater weight to the demands of patients — I am one of those who thinks that the demands being made by the patient groups are not at all, on embryo research, coordinate with the actual needs of patients.

But to say that that has to be weighed in the equation is to turn this into a cost-benefit calculus.  If ethics matters, then it has to matter when it keeps you from doing something that you very much wanted to do.  If the only things ethics keeps you from doing are things that were useless anyway, it doesn't have much weight.  It doesn't have any weight.

And that's what has happened in some of the government advisory panels that dealt with this issue.  The Human Embryo Research Panel actually endorsed the ethical theory of its ethics co-chair, Ronald Green, who set up what he called a Copernican revolution in our thinking about the ethics of research.

Essentially the Copernican revolution is to turn the Nuremberg code on its head, and instead of saying that ethical norms form an ultimate barrier to potentially useful research that ignores the interest of the human subject, that medical benefit simply can cause one to redefine that subject as not being due any respect.

That brings me to the second norm, which is respect for developing human life, even at the embryonic stage.  It is commonly thought that this argument is about when life begins.  The astonishing thing is that all the government advisory panels that have dealt with this issue —the Ethics Advisory Board in 1979; the Human Embryo Research Panel in 1994; NBAC, the predecessor to this commission in 1999; and the National Academy of Sciences — all describe the early embryo as a developing human, in the case of the NAS, or as a developing human life that deserves respect.

Respect is a very important term.  It means a kind of inviolability.  It means someone who should be respected as an end in him- or herself not only as a means to something else. And that means that when we have avenues of research presenting themselves, each of possible benefit — at the very least NBAC did recognize this —  it means that we should pursue and exhaust the avenues that do not contravene that respect before we consider doing something that would violate that respect, even as a last resort.

That burden has not been met in the case of embryo research.  For instance one could make a very good case that it is far less promising for the full range of diseases represented in CAMR than many avenues that present no moral problem.

The third norm that I think is important here, and it relates to the reproductive technologies, is the dignity of procreation of marriage and family.  There are aspects to some of the reproductive technologies, cloning being the most obvious, in which we very much endanger dehumanizing or denaturing our very notion of the relationship between parents and children.

That's most obvious in cloning when the entire procedure is reduced to a manufacturing process to preset specifications.  But some of those problems arise in the other reproductive technologies as well.

Setting aside the fact that parents who resort to IVF can be very loving parents, the procedure by its nature is the kind of procedure that tends to invite abuses like seeing this embryo as an object for experimentation, particularly among those who actually practice it in the laboratory.

Finally, in terms of specific recommendations, we propose a series of those at the end of our prepared text.  We support, of course, a complete ban on cloning for research or reproduction.  We support a ban on federal funding of human embryo research, and we would invite the council to look at laws in Louisiana and South Dakota that try to embody the principle of respect for embryonic life in the research context.

We also are very interested in what this council may have to say about the regulation of reproductive technologies, such as IVF.  But we would also caution against any regulatory approach that assumes that one has to fund or actively support that industry in its basic form in order to prevent abuses, particularly since in our analysis it is the very nature of the IVF procedure that has led to and invited those abuses.

I have much more to say, including contradictions of much of what Mr. Manganiello said, but maybe we will get into those in the discussion.

Thank you.

CHAIRMAN KASS:  Thank you.

Dr. Singer.

DR. SINGER:  Chairman Kass, thank you for the opportunity to come.

I'm going to try and answer the questions that were posed from the point of view of at least one member of the scientific community, and I'd like to say that although I am the Chair of COSEPP, my remarks today do not represent the views of COSEPP or the academy's.

So the education of scientists actually builds on two historically validated values:  first, to increase knowledge and understanding, in particular, about the natural world; and, second, to apply that knowledge for the benefit of human beings.

Physician scientists have additional values, including the commitment to do no harm, and it is these values together with intense curiosity that drive most scientists to ask and try to answer technically and intellectually challenging questions.

In all fields of science the application of knowledge means, first of all, sharing it with non-scientists, but application of new knowledge also has more material effects, and people have for millennia used scientific insights from various fields for new materials, for new tools, for new agriculture.

Starting perhaps from Jenner and his cowpox vaccinations in the early 19th Century, biology began to impact people's lives more directly through medicine. 

At the same time, some research itself and most of the material benefits of research can be associated with new kinds of problems.  Some research is dangerous for the researchers and the general public, and examples would include work with pathogenic organisms.  Scientists welcome and even initiate regulation and restriction of such research.

In a pluralistic nation like ours, scientists are also respectful of restrictions based not on possible hazards, but on other kinds of societal concerns that are sufficiently widely held to justify cautionary practices.

Current examples would include the rules and laws governing clinical research with patients and human subjects, the humane treatment of animals, and even the planting of genetically engineered crops.

But it is essential to keep in mind that regulation, restrictions, and controls are not the same as an outright ban on research.  Contemplation of such bans is only appropriate under particularly compelling situations.

Well, what I've just described is the context in which many, if not most, biological scientists see the Council's current agenda.  Thus, as far as we know, most scientists, but in fact not all, agree with this Council's conclusion that human reproductive cloning should now be outlawed, and as you all know, several reports from the National Academies agreed with that.

This conclusion is based on compelling scientific evidence from research on other mammals that reproductive cloning is both dangerous and likely to fail.

The situation for other avenues of research with human embryos is quite different.  First of all, no hazards to researchers or the general public have been identified.

Second, as evidenced by testimony to NBAC, to Congress, and to this Council, there is no common view among the public about how to balance concerns expressed by some segments of the general public against the possible knowledge and applications that can follow from the research.

And in this I clearly agree with Mr. Doerflinger about the need to balance concerns.

So the conclusion is that a moratorium on such research is not justified.

But restrictions and cautionary practices are another matter, and thus, according to the policy enunciated by President George Bush on August 9, 2001, federally supported U.S. scientists can use for research certain lines of embryonic stem cells that were established prior to that date from spare embryos made for reproductive purposes, provided that there is informed consent by the donors and no financial inducement.

The NIH has taken a variety of steps to assure the availability of such cells and their use under appropriate conditions, and this has allowed important research to proceed.

Nevertheless, these few cell lines - at last count 11 were available - cannot for a variety of reasons permit the full program of important research that scientists envision.

Additional cell lines from diverse populations and developed under different protocols will be essential.  Moreover, to realize the full potential of the research, it will be important to work with embryonic stem cell lines derived from the transplantation of a somatic cell nucleus into an enucleated egg.

Here, too, there is evidence that societal concerns about the research do not reflect a broad consensus.  The Congress is stalemated over the issue of allowing this research with the unfortunate consequence of providing no moratorium on reproductive cloning.

It would be appropriate now to outlaw the implantation of a blastocyst made by somatic cell nuclear transplantation, into a uterus because that's a bright line.  While research with such cells can be done by a single scientist in a laboratory, implantation requires several people, and this is unlikely to be done surreptitiously if the penalties are severe because the more people involved, the more unlikely it is that they would conspire successfully to break the law.

So rather than a slippery slope, it seems to me this is more like the edge of a steep cliff.

The views in our country about the nature of a fertilized egg cell and a blastocyst are so opposing as to appear to be unreconcilable at the present time.  And we have dealt with the situation in the messy ways that a democracy does deal with such a situation.

So we find that reproductive cloning remains legal.  Research on developing eggs, blastocysta, and embryos also remains legal even if they're made by SCNT so long as it is not carried out with federal funds, in which case it is perfectly legal and possible.

Most of the nation's scientists depend on federal funding, and thus are similarly barred from developing new cell lines by nuclear transfer, and from carrying out research with fertilized eggs in a dish or blastocyst.

At the same time, research with such materials can, as I said, proceed with private resources and is not subject to any governmental oversight or regulation.

Various states have passed, and others are considering legislation, and those laws are really all over the map.  Some of them encourage the research.  Some of them prohibit it, and so we have a patchwork.

That patchwork may have advantages for a few people, but it can encourage undesirable procedures and exploitation for personal gain at the same time that it prohibits our best scientists from undertaking this important research.

Thank you.

CHAIRMAN KASS:  Thank you.

Mr. Werner, please.

MR. WERNER:  Good afternoon, Mr. Chairman, members of this distinguished Council.  My name is Michael Werner.  I'm Vice President for Bioethics for the Biotechnology Industry Organization, BIO.

Thank you for the opportunity to speak today about the values underlying appropriate regulation of biotechnology and biomedical research.

BIO members conduct genetic, cellular, and protein research and develop health care, agricultural, industrial, and environmental biotechnology products that are used by billions of people worldwide to identify an unmet medical need, improve the quality of the food supply, and broaden scientific understanding.

The biotechnology industry is a remarkable success story.  There are currently 157 FDA-approved products on the market that have helped more than 325 million people worldwide.  These people suffer from illnesses such as Hepatitis B and C, arthritis, cystic fibrosis, multiple sclerosis, many forms of cancer, and on and on.

Our industry has achieved these accomplishments in part because the state and federal regulatory system that governs the development and use of our products works very well.  Our nation's regulatory system assures patients and their physicians that they can rely on the safety and efficacy of our products.

Biotechnology companies have always worked with and within this regulatory system to ethically bring safe and effective products to market, and we're proud that our scientists have been able to sustain aggressive lines of inquiry while complying with a robust and diverse regulatory system, including oversight from agencies such as the U.S. Food and Drug Administration, the National Institutes of Health, and others.

We believe that knowledge and understanding progresses not only through scientific research, but also through dialogue and discussion.  Throughout its history BIO has been actively involved in bioethics education and discussion inside the industry at all levels and branches of government and with the public.

Many years ago, BIO formed a bioethics committee chaired by a member of our board of directors to discuss bioethics issues, and our board has adopted a statement of ethical principles that details ethical uses of biotechnology, and we're proud that the previous chair of our committee served on the National Bioethics Advisory Commission, the group that preceded you.

The existing regulatory and ethical framework within which biotechnology companies operate has successfully protected patients while allowing critical research to advance.  Appropriately, current regulations embody values, such as autonomy, such as whether to participate in a clinical trial, beneficence, and social justice.

These values should remain the basis of any regulatory system, and in addition, personal autonomy and privacy as well as academic freedom should be a crucial part of the discourse for further understanding the use of what you refer to as new technologies and practices in assisted reproduction, embryo research and human genetics.

The American legal system is grounded in the fundamental right of individuals to define their own existence through personal and shared decision - making.  BIO members share the belief inherent in American civil rights laws that our lives are not preordained by our genetics, but are often the result of choices that individuals make, choices that parents make for their children, and the opportunities available in our communities and our physical environment.

Choices such as whom to marry, whether to have children, how to raise those children, whether to accept or refuse medical care have all been protected by the Constitution, and the individual has the right to make these decisions whether or not biotechnology products or an understanding of genetics is involved.

Individuals' freedom of self-determination extends to parental rights.  American law and societal norms have historically respected the family's rights to autonomy and have long recognized patients' rights and responsibilities to make decisions that affect their children's future.

These rights and duties should be read to include responsible use of genetic information, as well as other medical, social, and personal information about a child. 

BIO strongly supports education about biotechnology and genetics and the freedom to explore their potential uses for the benefit of humankind.  State and federal regulatory systems must support and promote freedom of responsible inquiry which is at the heart of First Amendment protected academic freedom.

These values animate our members' research and their development of products that licensed practitioners use to provide services that may be elected for themselves and their children.  Such products and services allow millions of people to pursue their own destinies as they choose to live productive and healthy lives.

So, in conclusion, appropriate regulation of biotechnology is solidly rooted in values such as autonomy, privacy, beneficence, social justice, and intellectual freedom.  BIO supports responsible and ethical testing of new technologies and believes that decisions regarding whether and how to use medical products and technologies always must be made with profound respect for the rights of patients.

We cannot condone regulations that unjustifiably curtail intellectual freedom of researchers to think and dream in the pursuit of greater understanding which could lead to a better life for all of us.  Patients and their families are counting on our companies to develop products to meet unmet medical and health care needs.

Thank you very much.

CHAIRMAN KASS:  Thank you.

Mr. Kimbrell.

MR. KIMBRELL:  Thank you, Mr. Chairman.  I thank the Council for inviting me here.  This is a fascinating and important subject that so many of us around this table have grown gray dealing with over all of these many years.

We have submitted a paper on pre-implantation genetic diagnosis, and I will be here during the public comment period tomorrow and maybe we can talk about some of the issues there that we thought were important for the Council to think about, Mr. Chairman.

CHAIRMAN KASS:  Thank you.

MR. KIMBRELL:  In the brief time that I've been given, I want to try and make three points, which is probably hubris in itself.

The first one really comes from that long history that so many of us have on this issue and I've had as an attorney on this issue for almost 20 years.  We often approach these issues, it seems to me, with kind of a technological amnesia as if we were looking at these issues for the very first time, and of course we're not.

I remember at least two instances of where we were looking at a miracle cure du jour, which unfortunately means that we had to trample some of our most important ethical norms, and this is really the third one that I've been looking at.  I'd like to bring you back through that history.

By the way I'd probably just like to start by saying that Dr. Michael West of ACT went before the Senate almost two years ago and said within six months that he would not only have isolated stem cells from cloned human embryos, but that they would have been differentiated sufficiently so that he could cure several major diseases.

He told Senator Harkin, who was chairing that committee hearing, that even a six-month moratorium would cost millions of lives, at which Senator Harkin said, "Thank God we have some real numbers to look at in this debate."

So the subject of this little session is hyperbole versus healing.  I remember very well doing a lot of litigation in the fetal tissue controversy of the middle '80s.  I remember The New York Timeseditorial that warned, "To interfere with these fetal tissue experiments is to interfere with the progress that could save countless lives."

You may have already heard some of that from this panel.  I'm sure you've heard it from a number of other panels.

We brought up several important issues that needed to be looked at.  Should these fetal organs, should the fetuses themselves be for sale?  Should there be some limit on their use?  Could you use them for cosmetics, or in one case in England, for earrings, freeze-dried embryos, or should you only use them for serious diseases?  Should you use them for all?

What about changing the method and manner of abortion in order to get fetal tissue that was more valuable or could be more valuable?

What about informed consent?  What does informed consent mean when something isn't dying of itself?  It's a chosen death.  What does the concept of informed consent mean?

The Reagan administration, based on many of these concerns, correctly, I believe, declared a moratorium.  One of the first acts of the Clinton administration was to lift this moratorium, without asking a single one of these questions, under the rubric we need to save countless lives.

Well, let's look back now 15 years, 200 million federal dollars spent on fetal tissue research.  I don't know how much private.  I don't have those figures, but well over 200 million.  How many lives have been saved?  Zero.

And with 15 percent of these patients that I don't think ever should have gotten this fetal tissue, what happened?  Well, let's quote the guy, Dr. Paul Green, who is at Columbia University College of Physicians and Surgeons who actually was the lead researcher in the federally funded study, and he described his patients - because what happens, when they put the fetal tissue in their brains, they cannot control the amount of chemicals they put out.  And so he described these patients writhing, twisting, jerking their heads, flinging their arms about, spasms so severe they could no longer eat, needing feeding tubes.  This is 15 percent of the patients.

For others, spasms made their speech completely unintelligible.  Despite these effects, Dr. Green says there's no way to remove the transplanted fetal cells to stop them from creating these impacts on the patients.  "It's tragic, catastrophic," Dr. Green explained.  "It's a real nightmare, and we can't selectively turn it off."

As for the near future, Green said, "No more fetal transplants.  We are absolutely and adamantly convinced there should be research only."

Countless lives?  We don't have regulations right now.  We have basically open sale of fetal tissue.  We gave the HHS some very vague guidelines which they've never enforced by their own admission.

All of those important ethical questions trampled over, no regulations because, oh, goodness, we don't want to get in the way of something that might save countless lives.

So who are the victims?  The very patient groups that have been talked about.  They are the ones who are the victims of this, and of course, again, our ethical norms.

Let's look at another one, gene therapy.  I filed the first lawsuit against the Recombinant DNA Advisory Committee.  Dr. Singer may remember some of this history.  We successfully sued them because they didn't have an open process for deciding who would get gene therapy and who wouldn't.  All right?

We talked about the incredibly important questions about once we start changing genetic make-up of human beings, shouldn't we wait?  Shouldn't we look at this?

No, we need to save countless lives.  French Anderson and others were called genetic wizards, miracle cures.  Fifteen years later, hundreds of millions of dollars later, how many people have been cured in the United States with gene therapy?  Zero.

First we heard about one death.  Then we heard of another death of a patient.  Now they're looking at over 1,000 serious adverse events, and from one of the purported cures in France, we get a report that this retroviral vector they used, which many of us knew and I wrote about in my book in the early 1990s, has caused a rare and unknown form of leukemia in two of the young patients.

So now we have another miracle cure du jour, which is a very naive sort of American view of how to cure disease anyway.  Disease is obviously very complex.  It has environmental, genetic ideas, and once again we're asked to trample over these.

So we have been here before, and I think to approach this issue in a kind of, again, technological amnesia, does not reflect both the suffering of those who have been misused in this process for venture capital and other reasons and the failure of Congress, and the failure of our regulatory agencies to take these ethical issues seriously and to be railroaded by these false hyperbolic claims.

And I hope this Council and I hope, as well, members of Congress will no longer be subject to that kind of blackmail, particularly with this history.

The second point I'd like to make is that we shouldn't substitute regulation for ethics.  All right?  Richard Weaver said we should never substitute arguments of consequence for arguments of definition.  If we believe something definitionally shouldn't happen, it shouldn't happen.

In both of those cases we gave HHS guidelines saying, "Hey, you look at the ethics of fetal tissue and you go out there and make sure that whatever ethics you decide on, HHS" - well, we haven't done anything. 

We had the Recombinant DNA Advisory Committee looking at all of these gene therapy experiments.  Of those 1,000 serious adverse instances I talked about, researchers only reported 37 of the 1,000.  It took independent investigators to come in to find the rest of them.

So let's not substitute regulation for ethics and make sure if we have something to say ethically we say it.  It's said by our policy makers and not give it over to the agencies because it just doesn't happen there, and as an administrative law attorney, I can tell you if you're looking at enforcement these days, it's a very, very difficult issue.

The third thing I would like to say very, very quickly is I would like  to recommend that this Council take a look at a very important legal precedence that is developing that might create a kind of a consensus that Dr. Singer was talking about, that Doerflinger was talking about, and that's the Tennessee Supreme Court case, Davis v. Davis.  They came up with this idea of a special entity, the idea that an embryo is neither property nor a full adult person, but is perhaps a special entity because of its in potentia, human life in potentia.  It has a trajectory that could make it a full human being.

As such it is due respect.  As such it is due protection.  In this way we cannot remain deadlocked in this ideological divide between it has the legal status of a person, it's murder, or it's no more important than a toenail, or it can be used as a medical device and be patented.

And I'm hoping that perhaps by looking at a consensus around either a special entity and that combining with other ethics - I'm not suggesting that it be a fundamental that we can all agree with, but as a policy given our current legal precedent, as a policy context that that special - that we look at the embryo as legally a special object that needs certain respect, and in that sense I hope we would do at least three things.

Say if it is a human life in potential, no sale, no patenting, and it should never be created solely for its own economic exploitation or destruction.

Thank you.

CHAIRMAN KASS:  Thank you very much.

Bill Kristol.

MR. KRISTOL:  Thank you, Dr. Kass. 

Maybe I should say a word about how I came to be particularly interested in these sets of issues.  I had studied and taught political science and political philosophy for a few years and then served in government for a few years and then have edited a magazine for a few years.

And in all of these, as someone who, therefore, believes in a vigorous debate in a whole bunch of areas of public life, I was struck in 1999 and 2000 how little serious public debate there was beyond specialists and beyond experts in this whole range, about this whole range of questions in the field of bioethics, the so-called "Brave New World" issues of where we were going with the biogenetic revolution.

I remember writing an editorial on the eve of election day 2000 saying that I was really shocked.  I think historians reflect that these  pretty fundamental issues about shaping our nation's future and even the future of the human race had not even been considered during the election campaign or at all or barely in our public life.  Dolly was cloned and there was a flurry of interest, and it quickly subsided.

There were occasional similar flurries of interest.  They quickly subsided.  I actually was heartened in 2001 when we started the Bioethics Project to try to foster this debate and with a certain point of view of skepticism about or at least a point of view that there needed to be some countervailing force to the huge dominance of the avatars of progress, untrammeled scientific and genetic progress in this area.

We started the Bioethics Project.  We were heartened actually by the debate in early 2001 about embryonic stem cell funding.  It was a serious debate actually and raised important issues. 

The President made his decision on August 9 and then September 11 happened.  It's hard to know whether the short-circuiting of the debate might not have occurred, I suppose, if everyone hadn't moved on to an awfully important threat and how to deal with it after September 11, but I think it is fair to say that since then I don't think we've had a particularly enlightened or enlightening - really with the exception of the efforts of this Council - public political debate about these issues.

I find that depressing.  I find it something of a scandal really since these are awfully important decisions that are being made about our future with no debate comparable to the debate I think that  takes place in all kinds of other areas:  foreign policy, economic policy, you name it really, but in this one area there's not much debate.

People are intimidated, of course, because of the scientific expertise that's required or that's claimed to be required.  Those who were dominant in this field that were driving policy, as is always the case with dominant interest groups, have no particular reason to welcome debate.  If you're in the driver's seat, there's no reason to encourage a big public debate, and I think that has been actually the behavior of the scientists, of the business types who have been getting their way with rather little regulation, as has been pointed out, in a fairly untrammeled way.

There's a tendency to sort of caricature the opponents and beat back the efforts of modest legislation and regulation and then move on.  The values, so to speak, that are embodied by scientific progress, by health, by business, if you put those three together -  science, health and business, and they basically do come together in this area -  against any serious curbs, ban, or even regulation, those are awfully hard to fight, especially when there's no, as I remember from my days in political science, when there's no equally organized interest group with real interests on the other side.

There are certain people with strong views on the other side, some of whom are somewhat well organized, but that's not really enough, ultimately, to stand up to the assault by the entire scientific establishment, much of the medical establishment, those who claim to speak on behalf of patients and on behalf of health, and those who claim to speak on behalf of scientific progress and large chunks of the business community, which is powerful in a commercial republic like ours.

And so I think the state of debate, if I can address just that little part of what you asked us to address, what do we think of the state of debate on these issues is, with the exception of the work of this Council, something of a scandal; and an awful lot of disingenuousness is gotten away with.  There's an awful lot of talk about respecting nascent human life; and respecting the embryo, though it doesn't deserve full protection, it deserves respect.

It never turns out that any embryo should actually ever be protected from any procedure as a result of this vague respect, but this is simply a way of throwing a bone to those who are discomfited, and then moving right along with whatever.  People who run IVF clinics or scientists who want to do embryonic research, who want to do -  we slide down a path from assisted reproduction, to selective reproduction, to enhanced reproduction, and again, at each stage these steps are incremental.  They're small, and sometimes the scientific and medical establishment will acknowledge that at some point there probably should be a ban on something, but it should always be the something that is over the horizon, and indeed we've seen this, of course, very clearly with stem cells and cloning where many advocates of government funding for embryonic stem cell research strongly made the point that, "Well, there are these spare embryos; it's ridiculous not to use them to advance human health."

But, of course, that's a very different thing from creating embryos de novo and then destroying them and then, as soon as that became scientifically desirable, of course, the limitation that had been expressed quite powerfully, actually just months or very few years before, was forgotten and anyone who stood in the way of so-called research on cloning or experimental cloning was then standing in the way of scientific progress.

So I have no recommendation, except this:  that I think the debate is important, and I think the debate, to be serious, must be not just public but political, and I think the political debate, to be serious, must at some point call on participants in it to be honest about what they would permit and what they would not permit.

And it is not in my view sufficient to sort of pocket everything that has happened up till now, put all of that out of bounds, one is not allowed to question anything about the status quo.  And I would just ask this of all the very powerful, well - financed groups that represent patients' groups, physicians, scientists:  Is there anything about the status quo that discomfits them?  Is there anything they would like to change or bend?  Is the status quo of IVF clinics - 400,000 spare embryos, no ban on creating embryos for the sake of destroying them - is that just fine?  Is there anything that should be limited that currently is permitted?

So, first of all, I think to be serious one has to talk about limitations and restrictions at some point, and I'm curious whether people think there's anything that now exists that shouldn't exist and anything that is now permitted that shouldn't be permitted.

And, secondly, as I say, looking forward, I think it shouldn't be acceptable to sort of claim to be for debate, for thoughtfulness, for respect for everyone's opinion, but then it just turns out that in every single possible concrete choice that has to be made, well, in this particular case, the ostensible claims of health and science and progress trump whatever ban or limitation or moratorium those who are more skeptical are suggesting.

CHAIRMAN KASS:  Thank you all, and let me start to see if I can pull together some threads and actually where Bill Kristol left off is one of the two kind of general questions I would like to put to the panel.

I would hope that this not turn into a specific argument on the status of the embryo.  We could be here all day.  We know that our group is divided on that.  The panel before us is divided.

I would like to try to generalize from that to certain larger questions.

It seems to me that we have heard from three of our panelists a strong defense of the values of the growth of knowledge and understanding, translating that for the benefit of humankind, especially the benefits of health and the cure of disease, and the sort of betterment of human prospects through science based technological application.

Those speakers acknowledge the importance of doing this ethically.  In some cases the ethical norms that were operative were given some specification as in, for example, avoid doing harm, the question of danger and safety, one that's congenial to everybody and we need not argue about it.

But beyond that question, respect for the human subject of research so that we adhere to certain kinds of guidelines and research.  Maxine Singer mentioned even some concern for animal welfare, although the respect question there is again one of these difficult questions that gets debated.

And in Michael Werner's presentation, a listing of autonomy, beneficence, social justice, intellectual freedom, that was sort of one family of concerns.

Richard Doerflinger suggests, first of all, the importance of ethics not as something to be balanced, but as something to guide or to regulate, and then goes on to emphasize respect -  questions of respect and questions of dignity which are not exactly the same as the questions of rights, privacy and autonomy, and that's at least one of the areas where we've got some kind of disagreement, and then some kind of concern really for truthfulness and not taking advantage, in fact, of the people in whose name we speak. And the importance also, as Bill Kristol suggests, that up at least until this point we have had a more or less laissez-faire attitude with respect to these innovations, but given that the stakes appear, at least to some people, to be much higher, and that these technologies serve not merely human health, but goals beyond health, and that the means to attain that technology is also threatening to trample values that some people hold dear, the importance at least of lifting up to public debate and actual public scrutiny and political argument the questions of where we are going, how fast, and under what kind of guidelines.

I think that summarizes reasonably well, if I say so myself, the things that I heard to bring it down.

Now, it seems to me that two kinds of challenges might be raised to the different parts of the panel.  I would be interested to know from, let's call it the science/research/technology/patient side of the panel, what kinds of goods or values you yourself might see justifying limitations on the freedom to conduct research, even beneficial research in this area or that might get in the way of business as usual in commerce?

In other words, assuming that the government left you alone, but you were simply trying to think through how you might deal with the concerns of the other people in this discussion, who, by the way, I would think we would say are defending things that if you don't hold dear, you ought to hold dear.

The question is:  What are the kinds of moral boundaries apart from questions of safety or letting the patients have what they want?

And I could give you some lurid cases to try things out, but I'll leave the question general at first.

Whereas it seems to me Richard Doerflinger or Bill Kristol or Andrew Kimbrell, the question might be put in a different way.  We now have a very awkward situation where this whole area of reprogenetics has not really been subjected to federal scrutiny or regulation except indirectly through safety and efficacy criteria of the FDA or IRBs that govern research proposals involving human subjects.

We don't have it, in part, because at least some of the values that are of importance to people suggest that to suggest that this practice be regulated is to countenance it in the first place, and that we refuse to do.

So it does seem to me that for the first group of people who are regulation-shy, the question is:  in the absence of regulation - I guess let me make it two questions.

What kinds of moral boundaries would you impose upon yourself or your scientific colleagues or your industrial colleagues, and are you prepared to enter into a discussion with people outside your community to seriously discuss what those boundaries might be and actually live by them as a result of the political process?

Because if I might correct Mr. Werner, this isn't just wishing and dreaming, thinking and dreaming or inquiring.  There are deeds here.  There are deeds involving human materials and human subjects, which means that you're in the realm of action and not just thought.

And for the other side, what's the cost of doing nothing in this area and leaving this area completely unregulated, the sole benefit of which is you do not expend public funds and do not give public sanction to an area of research that you regard as deeply morally questionable?

It seems to me both sides here - I would like to lean on both sides in this discussion as the Council tries to think about our regulatory difficulty and see what you might have to offer.

If you wouldn't mind, if I could address the first question to the scientists, the BIO people, and then the other question to the other three of you.

Maxine Singer, please.

DR. SINGER:  I'd like to make two points, Leon.

First of all, I don't think it's appropriate to describe the current situation as being without any limits.  It is impossible to carry out research with embryos or with fertilized eggs in dishes or with blastocysts with federal funding, and that means that most of the research that could be done cannot be done because most scientists in the United States are dependent on federal funds.  So that's a reality.

CHAIRMAN KASS:  But that research can go on in the private sector.

DR. SINGER:  Exactly.

CHAIRMAN KASS:  And it does.

DR. SINGER:  It can go on in the private sector, and it goes on now without any restrictions or controls as I think I've pointed out, and I believe, and I think that there's good evidence for this, that most people who thought about this in the scientific community understand that there ought to be controls on this kind of work.

But at the present time we have no controls, and most of the scientists in the country can't do their research, and therefore, they're not interested in discussing how they might do it or regulations or controls because they can't do it anyway.  So that's -

CHAIRMAN KASS:  But let me put it the other way, Maxine.  I mean, it seems to me the argument seems to be, give us the money and then we'll figure out what regulations -

DR. SINGER:  No.

CHAIRMAN KASS:  Whereas -

DR. SINGER:  Not at all.

CHAIRMAN KASS:  But I'm simply asking you, quite apart from whether the money is there, so that I understand when we start to fund this research that there might be certain kinds of boundaries that the scientific community wants to respect here even if they're not forced to.

DR. SINGER:  First of all, I think it's incorrect to assume that there aren't considerations about the kinds of controls that you might put on this work.  There are.

There are people thinking about it.  There are people thinking about it at the NIH.  People have thought about it before.  We, in fact, have guidelines that were prepared, but are not operative.

I don't think it's true that no one is thinking about it or willing to think about it.  I think they are.  But they will think more urgently if they imagined that they could possibly carry out the research, and I think that's quite normal.

And with respect to the second point that you raised, I tried to say that I thought that putting aside questions of safety and so forth, scientists are willing to reflect societal values in restrictions and control on research, so long as the societal values are very widely held and there's wide agreement about that.

And I think one of the problems in the current situation is that we don't have that kind of wide agreement.  And I gave the Congress, just as an example, one piece of evidence for the fact that we're stymied over what appeared to be irreconcilable views.

CHAIRMAN KASS:  Well, thank you.

Michael Werner, please.

MR. WERNER:  Well, I think a couple of things. 

First of all, I do think that, by the way, protecting human subjects in research in many ways is about dignity, and I think — so I wouldn't make quite the dichotomy you made.

I do think that's an important thing, and it is about the dignity of patients and about people involved in research.

And then as to the other part of your question, our companies have essentially in various contexts called for ethical review of our work.  The one I'm thinking about actually has to do with protecting human subjects, which is - It came about in the debate about HIPAA and privacy regulation, where our industry essentially took the position that even research that was not covered by Institutional Review Board review, which is, of course, at least in part an ethical review of a protocol, should, in fact, be overseen.

So I think that's one issue, one time.  Also, there's a moratorium on germline gene therapy, genetic modification of the germline in the scientific community now which is something we certainly support.

We certainly support other legislation and regulations that have to do with use and disclosure, for example, of genetic information and, of course, a ban on reproductive cloning.

So I think there are situations where we've either accepted oversight or accepted limits on how far research should go or how it should be conducted to ensure that it's done ethically.

CHAIRMAN KASS:  Would you like to comment?

MR. MANGANIELLO:  You know, I'm neither an economist, to talk about goods and services, nor am I a scientist, nor am I a regulatory lawyer.  I'm just an advocate for patients.

But I was raised with a certain set of values by my parents, who were raised with a set of values by their parents, and I think our scientists in many ways -  if you're asking in lieu of anything in terms of self-regulation, I think that we aren't a nation of mad scientists.  I think we're a nation of people like Maxine Singer.

I attended the ISSCR meetings that are happening here in the city right now.  Probably 500 of the most brilliant stem cell researchers in the world are gathered here in the city right now, and in lieu of a regulation, they had an ethics panel with great thinkers and religious leaders, and the order given to the scientists was: We need to start regulating ourselves.

So I have all confidence that in lieu of regulation, which we look for and are hoping is going to happen through the federal government, that our good scientists will hopefully regulate themselves.

Thank you.

CHAIRMAN KASS:  Let me follow up just one on this side.

There are a couple of areas in the area of sort of reprogenetics that - let me just be hypothetical.  Questions about prolonging the gestation of human embryos ex vivo or chimeras involving human and nonhuman embryonic material, are these kinds of questions that you think deserve public decision?  Should scientists simply be free to go ahead and do these things on their own?

I mean, I'm trying to pick certain kinds of things which are out there which are being explored.  The public doesn't even know yet that they ought to have an opinion about these matters, and we're going to wake up one day if the profession doesn't somehow say to itself, "Look.  You  know, these things are coming.  Maybe we should watch our step here," and as in the case of germline modification where I think the objections are at the moment primarily those of safety at least to begin with.   There is, it seems to me, for the time being agreement.

But could you take it one step further if I offered those sorts of things?  Are there people talking about that as opposed to certain kinds of large things like respect of human autonomy?  But to dig in really in this area and say, "Here are things that are coming along the way.  We're not going to do it until we bring this question to the larger public and find out what the public wants done here."

Dr. Singer.

DR. SINGER:  I'll make a comment about that.  As I think you and I have talked about this before, I don't think that anyone knows that you can clone, do reproductive cloning, on a human.

CHAIRMAN KASS:  Right.

DR. SINGER:  The latest information has to do with a description of at least one of the explanations why attempts to clone non-human primates has not worked, and it's a complicated biological explanation.

So we don't, in fact, know.  We know that our nearest neighbors so far have not been amenable to the techniques that gave rise to Dolly and other cloned animals.  So we don't know whether that would work.

So for scientists involved in that kind of research to be worrying about the modification of such cloned blastocysts or whatever you want to call them, when they don't even know that the whole thing will work, it's just not likely, and I don't think it's because they would shy away from it.  They haven't shied away from a lot of other things.

But my colleagues are very much here and now, and we worry about what's here now, and that's very far- fetched.  It's a bit like science fiction at the present time.  So nobody is likely to be worrying about it a lot, but they will worry about the other kinds of things that we talked about.

MR. WERNER:  Yeah, if I could echo that.  It's similar to what I was going to say, and I think there's also a little bit of a chronology question, which is, you know, are you suggesting, sort of, things don't happen until there's a public vetting and some kind of societal, maybe, consensus or are we saying that sort of as things progress and as research moves forward and if these things become more real, then there should be some public discussion about them.

I think, speaking for our scientists, I think they would agree with what Dr. Singer said.  And also having said that, I think, you know, public discussion, public awareness about ethical issues as research goes forward, I think is important and I think our industry does, too, and so we certainly wouldn't hesitate to participate in discussions about the ethics of certain research.

But I think for some of the things that you mentioned and things like that that are so far out there, for a lot of our members it does have a little bit of a, you know, science fiction quality which is, you  know, it's way out there.  Is that happening in - Where is that happening?  How many people are doing it?  Is that something that's real?

CHAIRMAN KASS:  Okay.  Let me turn to the other - Janet, sorry.

DR. ROWLEY:  Let me just intervene here because I'm concerned about both some of the questions and also some of the comments.  I think it's extraordinarily important to emphasize, firstly, in the report of the National Academy of Science published in September 2001, and I quote, the academy said, "The panel stresses that a broad ethical debate must be encouraged so that the public can be prepared to make decisions about these issues."

So to say that scientists have been trying to cut off debate is, I think, not a fair statement of the situation.

And I again emphasize that it was the scientists who recognize the potential problems with recombinant DNA technology and who themselves declared a moratorium in 1973 and developed what became the Recombinant DNA Advisory Committee, the RAC.

I think both the academy and all of the scientific reports that have taken place have all said that this must take place in the context of appropriate, careful review for the science as well as the safety and the ethical issues of any kind of research that went forward.

So, again, to say that scientists are running away from and trying to avoid regulation is not a correct statement of the facts.

CHAIRMAN KASS:  Could I turn the other question around to see if I could get the response before we leave the scientist side of it?

Could I get a response on the other side?  And then Michael will follow up.  Richard Doerflinger, Bill Kristol, Andrew Kimbrell, a question to you.

Right now we have nothing, relatively speaking.  We have certain restraint having to do with the absence of funding, but otherwise things proceed as people wish, and I'm not suggesting that there are mad scientists or rogues, but there are things that are proceeding that affect all of us, and they proceed in private places, and that's partly because people don't want to countenance this activity sufficiently to see it brought under regulation.

Is that a problem?

MR. DOERFLINGER:  Well, I think you might be understating what's happening in policy circles, because certainly regulation of privately funded research has generally been a matter for the states.  The federal government has in the past gotten into it mainly by way of federal funding.

And in the states a number of things are happening —  some new laws against research in which embryos are destroyed; some new bans on cloning.  The bans that have been passing in the past year or so are chiefly complete bans on cloning in Iowa, Arkansas, North Dakota, and so on.

I think the area for even federal regulation is fairly broad, and I think of the restrictions that could be placed by the federal Patent and Trademark Office on patenting human organisms.  Can we agree?

I believe I've seen a letter from BIO to a member of Congress saying that BIO is against patenting human embryos.  A point of agreement.

There are opportunities for the FDA and other federal agencies to use the interstate commerce clause to look at th interstate trafficking engaged in by the fertility industry. The ways in which success rates are hyped to couples, the ways in which first women are superovulated, then multiple embryos produced, many frozen without informed consent from the parents, many parents left wondering after the fact, "why didn't I think about this beforehand, about the fact that I now have five or ten or fifteen frozen embryos?"

There are regulations in Louisiana based on respect for the life of the embryo that limit some of these practices. 

There are laws in Europe that limit, for example, embryo freezing.  There is a move towards freezing unfertilized eggs instead of the already conceived embryo, which somewhat reduces the ethical problem there. They are limiting the number of embryos that could be produced at one time or placed in the womb at one time.  There are limits on using embryos for experimentation or on creating only for experimentation.

These are all things I think can be done at the state level, but also things that the federal government may have a hand in, and I think that the federal government has a role in looking into those things even without funding any of this.  I think the new documentation on increased birth defects from IVF is a cause for federal agencies to look at IVF, and see whether it is being oversold unnecessarily to couples who may benefit from far less radical procedures that don't pose these risks of increased birth defects.

But I think the range of possible regulation is available.  I think that any road into that regulation that starts by saying the first thing we have to do is contradict  the longstanding congressional judgment from 1996 against federally funding research that destroys embryos, is going to be a nonstarter.  I don't think that's the way to show your moral high ground to start regulating the industry.

CHAIRMAN KASS:  Either of the two of you want to comment on this?

MR. KIMBRELL:  It's a very important question, and a difficult one.  I do have to just spend 30 seconds saying some of the examples you were giving as far as patented embryos or human fetal organs in animals, these are happening.  They're not science fiction.  They're science facts.

So you were actually not bringing up a hypothetical, as you probably know, but actual facts, and scientists are working with those, and to my knowledge haven't questioned the ethics of those in any published journal I've seen.

It's very instructive if you go back to 1987.  A firm called Hana Biologics out of Alameda, California decided to try and get FDA approval for fetal organs as medical devices.  Which allowed them not only, of course, to patent these devices, but to sell them.

That was a fascinating moment actually in sort of reductionism, and particularly giving a legal definition of fetal organism as medical devices.  So we filed a petition with Dr. Otis Bowen, who was running HHS for the Reagan administration, and believe it or not, the HHS even in that administration said, "We actually think that they really should be regulated as medical devices, and that that's appropriate."

We were concerned with that and threatened them with litigation, and they kind of retreated on that.  And then we went to Senator Gordon Humphrey, and we had exactly the kind of conundrum you're talking about, Mr. Chairman, which is that Senator Humphrey, in light of his pro-life constituents, said, "Wait a minute.  If we say," which is what we were asking him to do, "if we add fetal tissue to the Organ Transplant Act saying you can't sell it, then a lot of our constituents are going to say that doesn't make it right because we don't think it should be used at all because we're pro-life.  We don't think that should be something we should use, aborted fetuses for transplantation."

We went to Senator Kennedy's office, and he said, "Are you kidding me?  If we elevate fetal tissue to the level of other human tissue protected from sale under the Organ Transplant Act, couldn't that be the beginning of the diminishment of Roe v. Wade?"

And I said, "Now, wait a minute.  If both of you guys succeed, we're going to have an open sale of fetuses in the United States where economically disenfranchised women are going to be selling fetuses to the highest bidder," and it wasn't a hypothetical because that was during the middle of the surrogate motherhood issue, and we were representing some of these surrogate mothers where they were doing that with babies.  They are actually...So this wasn't, again, theoretical.

Finally, actually I'll give Vincent Ventimiglia as a wonderful activist on the Hill and who was working with Senator Gordon Humphrey then.  He got all of the sides to agree that you have to give up on this position if you're going to have adequate regulation.  If we're not going to have the sale, everyone is going to have to give a little.

And everyone did give a little, and that was passed in 1988.  So there's an example of where it can work.

And in this regard, again, the Davis v. Davis case, and again, I'm speaking now not as an ethicist.  I mean, was it Thomas Aquinas who said that abortion isn't murder; it's frustration of God's will?

These are very difficult questions, which an administrative law lawyer has very little grasp on.  I find them fascinating, but a little knowledge is a very dangerous thing.

But the one thing I do know a little bit about is public policy, and I know that in this current context, for example, in cloning we are at a deadlock exactly for that reason, and I could dispute what Dr. Singer was saying about, you know, the regulatory aspect of that.  We can save that for another time.

But I do think that the Davis v. Davis case should be of interest.  I'm not saying this is something I personally agree with, but I think it might be important as a context here.

The Davis v. Davis case was an argument about the disposition in a divorce case of embryos.  Right?  They had frozen embryos.  During a divorce does Mom get them or does Dad get them?  This is the fight, right?

And they went to the lower court.  It was a pro-life judge, and he said these embryos have the legal status of people.  We can't treat them as property in a divorce settlement.

The husband appealed because that wouldn't have worked for his side, and then the appellate court said the opinion is completely invalid.  It violates Roe v. Wade, and these embryos are merely property.  They're not different than hair, semen, blood, any other biological product.

Well, the wife appealed and it went to the Supreme Court of Tennessee, and they came up with sort of a Solomonic thing, which again I suggest would be of interest to this Council, which is they said, and I'm quoting now, "Pre-embryos are not, strictly speaking, either persons or property, but occupy an interim category that entitles them to special respect."

And this has been called a special entity.  By the way, the State Supreme Court of Massachusetts and others now have followed this.

And the idea of the special entity that they talked about is that this is, again, a human life in potential, an adult human life in potential with a trajectory that, therefore, differs from hair, differs from blood, because this could become a human life.  That is something absolutely different from any other biological product.  It should be distinguished from those products and given respect.

Now, that's the context for discussion, Mr. Chairman.  It's not the answer to what you then do with that context.  I suggested in my remarks that I think some of the things you need to do is if this is human life in potential, this special entity certainly shouldn't be sold.  It shouldn't be patented, and I think it certainly deserves respect and should never be created solely for its own economic exploitation and destruction like some other product.

I think those would be minimal things that  this special entity status would grant it.

But perhaps that special entity status is a way of bringing some of the ethical norms into this, not in a way that many of us would morally agree with on one side or the other, but to provide a context to break some of the ideological deadlock that I think you correctly talked about and that certainly is currently blocking our legislation on cloning from passing.

CHAIRMAN KASS:  William.

MR. KRISTOL:  The ideological deadlock in cloning hasn't got much to do with funding or regulation really.  I just think there are legitimate arguments about bans, moratoria, regulatory structures.  There are legitimate arguments about funding mechanisms as a matter of public policy, whether the federal government or state governments, I suppose, should or shouldn't fund various medical research.  Those are debated every day, week, month and year in Congress.  They're not necessarily hinged together.

We regulate.  We legislate against, and have huge regulatory structures to govern industries that do not get federal funding or don't directly get federal funding, and conversely, we fund things that we then regulate extremely lightly, you know, just to make sure that the money is used for whatever it's supposed to be used for, but with very little substantive regulation.  You know, college student loans would be an example of that.

So I don't think there's much to be gained frankly from sort of a complicated, alleged tradeoff of funding and regulation, though I mean if someone wants to make a precise argument about what we're talking about, I guess I'd be interested in it, but it's not the issue on cloning.

And if you look, it seems to me maybe it would help just a second to separate two things.  There are two, it seems to me, sets of issues that have come up in our discussion here in this panel.  There is the current situation and whether legislation should reform, restrict, change the current practices that go on.  We have right now, as I understand it, selective reduction of embryos in IVF clinics that is entirely legal and unregulated.  Is that a good thing or not?

This is not a "Brave New World" issue.  It is not a scientific progress issue.  It is a current practice and one's judgment on it, I suppose will depend on one's judgment about how much respect one wants to give nascent life or the embryos.

So you can't avoid an embryo debate on a lot of these issues because what is being debated is how much weight to give the embryo.  It's that simple.

So that debate should be had.  One could then raise constitutional issues if one tried, for example, to ban this, but that could be argued out like any other piece of legislation before the court.

So there's sort of the current situation, which I think does largely depend on how much status one has to give the embryo.  The fact that the society disagrees on that doesn't mean it shouldn't be debated.  We disagree on all kinds of things, and that's why we debate them.

We didn't agree on civil rights in 1957 or '60 or '64, and we didn't agree on the war, and we debate all of these things.

The second set of issues is different, which I think germline modification, as Dr. Singer suggested, is perhaps a good embodiment of that, but there it seems to me actually from the point of view of democratic theory or democratic practice, frankly, aren't acceptable that any group no matter how well meaning, well educated, and public spirited, through self - I'm not saying that Dr. Singer was suggesting this, but if this were to be the model for the future - through self-regulation or voluntary regulation would resolve an issue of this magnitude, I'm not even sure what I think about - I'm not so sure I think all germline modification should be banned.

But in any case, if we don't as a society not only get to decide on this, but have to decide on this, then what are we?  Then we're leaving to professional groups the most fundamental decisions about the future of the human race?

I can't choose to delegate certain things as we often do to professional groups under some general legislative guidance.

So there are the kind of current issues, which I think are legitimate issues for debate.  Are we morally behaving as well as we should?

And I think there I'm not happy with the status quo, but others can defend it and we can argue that out.  Many of those do depend on the status of the embryo.

And then there's the sort of future genetic revolution sorts of issues, but there I think you absolutely need to have public policy, and I don't think anything there hinges on funding.  That's just a question of what we're going to permit and what we're going to encourage, and what we're not.

CHAIRMAN KASS:  Thank you.

Michael Sandel and then Gil.

PROF. SANDEL:  I'd like to pursue and push and sharpen Leon's question, and to do so, first of all, I think Bill is right.  We should put the issue of funding to one side for the moment.  I understand, and I'd like to direct the question to Mr. Doerflinger.

I understand you don't want to regulate practices you object to at the price of federal funding.  So let's put that issue aside.

What I'd like to explore and I think was the spirit of Leon's question was not the tradeoff between regulation and funding, but an ethical dilemma about regulating a morally objectionable practice.

There's no federal regulation on ART in this country or on embryo research or on reproductive cloning, federal regulation restriction, and one of the reasons for that is not just because the libertarians and the free marketeers and the scientists and the patient advocates are so effective.

One of the reasons is that those who object in principle to those practices hesitate to support regulation out of a concern that to favor regulations of those practices would be implicitly to condone them, to confer legitimacy on them.

So it's not funding, but it's that feature of the hesitancy that I want to explore.

So the question is:  Is it ever justified, do you think, to regulate a practice that you consider to be morally objectionable, or does that carry the moral taint of complicity, that you become complicit in the practice?

So, for example, would you favor a federal regulation banning the use of PGD for non-therapeutic sex selection, or would you not favor that out of concern that you consider PGD morally objectionable to begin with, and to ban that particular application of it, though it would prevent some wrong, would implicitly condone underlying wrong?

Now, I can imagine one possible reply might be, no, we wouldn't want to ban that because we consider it so wrong any more than we would want to participate in regulating slavery, regulating the worst abuses of slavery, because that very regulation would implicitly accept and make us complicit in the underlying practice, the evil of slavery itself.

Yes, we might be able to eliminate some suffering, but at the cost of endorsing implicitly the practice.

So is it more like slavery or is it more like another case?  Consider prostitution.  Where one might consider prostitution morally objectionable, but in a case of an epidemic of sexually transmitted disease, the question might arise:  would you favor regulating prostitution for its health effects to alleviate the epidemic even though that might implicate you morally in condoning a practice by recognizing it publicly?

We're not talking about federal funding of prostitution.   We're just talking about the price you pay of a certain implicit -

So the question is:  are these -

CHAIRMAN KASS:  Go ahead.

PROF. SANDEL:  So with those two, with the slavery case, is it more like slavery or is it more like prostitution?  And here's the case I'd like you to address:

German federal law limits the number of embryos that can be created in IVF.  Would you favor federal regulation to restrict the number of embryos that can be created in any given cycle in IVF?  Would that be more like slavery or more like prostitution?

MR. DOERFLINGER:  I might surprise some members of the council by saying even if it is like slavery, one could morally seek to regulate it if that's the best we could do.  That's what Abraham Lincoln did, and his whole campaign theme was "I want to keep slavery from spreading to the territories.  Leave it where it is.  Don't expand it."

And of course, the abolitionists were very distrustful of him because of his middle position.

Let me answer your question in two ways.  One is that I think there's a discussion of this very point on page 15 of our prepared statement, which goes into this and provides some sources.

I like the word "hesitation" that you used, for this reason.  It's not immoral, if it is the best that one can do, to regulate against the most egregious abuses of an industry, even if the industry itself is morally objectionable.

A single example for the Catholic Church would be that we have supported clinic regulations at abortion clinics, to at least limit the damage done by that industry.  Sometimes those laws only limit the damage that might be done to women and not to the unborn, but it is still worthwhile to prevent damage to the woman, and I don't think that those regulations and informed consent requirements, waiting period, parental consent requirements, and so on, condone the underlying practice.

There are some pro-life groups who disagree with us on that, but Catholic teaching is pretty firm in saying that if it is the best that can be achieved, you may limit the worst and most reachable abuses and then build for a more just society in the future.

The reason why there is hesitation is not that it's immoral to support such laws, but because one has to support them in a certain context.  Otherwise one creates scandal by leading people to think, even if it's a misimpression, that that is one's ultimate goal or that is one's ideal. That is one reason why, having raised some particular points and particular deficiencies in current law at the end of our document, the Bishops, Conference says, "We'll be very interested to see what you produce that we can react to," to see what range of regulation and law the Bishop,s Conference can support, now that it has been offered and is the best that there is a consensus can be done.

Does that make —

PROF. SANDEL:  Yes.  Just a quick follow-up. 

Would you extend that line of reasoning to support a law that banned reproductive cloning by outlawing implantation of the product of SCNT?

MR. DOERFLINGER:  That is very different, because we actually don't think that implantation in a womb is or should be a crime.  It's actually what embryos have been doing for many centuries, which is why any of us are here.

It is a completely misdirected law in our view.  What it does is, it allows the cloning procedure — which I know I'm not supposed to call "cloning,"  I'm supposed to call it SCNT whenever people want to do it, but it's cloning.  It's the cloning procedure. You know, those whom the gods of science would destroy they first call by an acronym, but SCNT is cloning.

So you do the cloning procedure, without meaningful limit, and then you regulate the consequences, in a sense, of that wrong procedure by doing a second wrong, which is to make it illegal for that embryo to survive.

So in our view that's two wrongs claiming to make a right.  It's worse than no law at all, and that's why the impasse.

If that were simply a partial law that regulates against the worst evils, we could in principle support it. But we don't think the birth of a baby is an evil.  We think the cloning is the evil.

CHAIRMAN KASS:  Gil Meilaender.

Just so that people know where we are, we started a little late.  You took some extra time for food, and people want to get in here.  Ten minutes and we'll break.  We'll run five minutes over here.

Gil Meilaender and then Robby.

PROF. MEILAENDER:  Well, there are so many things by now actually that one might want to talk about, but I want to say a word about something that Dr. Singer first brought up, the National Academy's report on cloning, and then Janet quoted from it, because I don't think enough was said about it by you, Dr. Singer, to sort of get to all of the issues.

Let me say what I think the "more" is, and you may wish to react.  As you point out, the Academy report supported a prohibition of what it called reproductive cloning, and it said that on safety grounds, given the results in animal studies, that prohibition was warranted, but that even if at some point those studies became more promising, there should be a wide public debate on the moral and ethical questions before proceeding with what it called reproductive cloning.

In the case of what it called nuclear transfer to produce stem cells, but which we can just call research cloning here, it was prepared to support going ahead because there weren't safety questions of the same sort.  We understand that.  If you're not going to implant the embryo certain kinds of safety questions can't arise.

But it did not say -  and this is the thing that you left out — it did not say that a wide public debate on the moral and ethical questions should take place first.

And it seems to me it's important to ask why not.  If in the case of what's called in the report reproductive cloning, even were it safe, a wide ethical debate in the public should take place before proceeding.  Why in the case of what we'll call research cloning, even if it doesn't raise certain sorts of safety questions, should that same public debate not take place before we simply assume that we may proceed with it?

It seems to me that that's the question that needs answering and that you didn't get to, and I'd be glad to hear you comment on it.

DR. SINGER:  So I can't resist just saying that I'm going to talk about nuclear transfer.  I think that abrogation of the word "cloning" in general has been a big problem.  It used to have a completely different meaning for those of us in biology, and so I don't talk about "research cloning," but I understand you when you do, for sure.

So I think that one reason why that wasn't said in connection with nuclear transfer is that there was not a sense in that panel that that raised any ethical or moral issues that would be debated.

PROF. MEILAENDER:  Don't you need to broaden your horizons at that point?  I mean, if the burden of your testimony to us has been that scientists are interested in these questions, that they don't want to short circuit such debate, that they're interested in having it take place, I mean, how could one suppose that this was not a live moral question?

DR. SINGER:  Well, it's very clear that the question about reproductive cloning raises issues that are moral and ethical issues.  But I would need to turn it around and ask you to define for me what you think the moral and ethical issues are for nuclear transfer when we have no idea in transferring a human somatic cell nucleus into an enucleated egg whether there's even the potential for this to become an organism.

PROF. MEILAENDER:  If I even embarked on that, the Chairman would want me to stop, but I don't think it's crucial for me to try to sort out those things right now, but simply to say that I simply report that I have a hard time taking seriously the report that scientists want to engage in widespread discussion of the ethical issues if you're telling me that you don't even find here a moral question.

I just have to report that to you.

DR. SINGER:  Well, unfortunately I think that tells us something about just how difficult these disagreements are and why they are so difficult to resolve.

Dr. Rowley rehearsed for you various steps that the scientific community has taken over many years, and there are many more examples where scientists have certainly been willing and have, indeed, taken the initiative to face issues where there were clearly issues among which even scientists disagree because they are people like everyone else.

But I think in this particular instance, certainly speaking for me personally, I don't understand what the issue is.

CHAIRMAN KASS:  Dr. Singer, I just point out that the Council report with one exception, however people came down finally on whether to favor cloning for biomedical research or not, all members but one thought that there was a moral issue and that the other side had something to defend, and I commend Chapter 6 of our report to you and your colleagues, a chapter which was approved by everybody.

DR. SINGER:  So, again, I'm speaking just for myself.

CHAIRMAN KASS:  Of course.

DR. SINGER:  I have read the report.  I did not understand those arguments.

CHAIRMAN KASS:  Come to dinner.  We'll work it out.

DR. SINGER:  Every time I have dinner with you, I get in more trouble.

CHAIRMAN KASS:  We won't tell anybody.

Let's me see. Robby.

DR. GÓMEZ-LOBO:  One sentence.

CHAIRMAN KASS:  Yeah, please.

DR. GÓMEZ-LOBO:  Let me try in one sentence to explain the moral problem.

Dolly was created by, generated by somatic cell nuclear transfer, and she was a sheep.  A human being generated by somatic cell nuclear transfer would be human.

DR. SINGER:  Well, I don't disagree with that if you make a whole organism, but we don't know that you can make an organism, and moreover, I've made it very clear that both personally and in terms of the COSEPP report, we believe that trying to do that should be banned.  No question.

DR. GÓMEZ-LOBO:  No, I was referring to the embryo. You get a human embryo through somatic cell nuclear transfer with a human ovum and the whole set of 46 chromosomes.

DR. SINGER:  And that's where we part.

DR. GÓMEZ-LOBO:  I'm sorry?

DR. SINGER:  And that's where we part.

DR. GÓMEZ-LOBO:  Well, that's what generates the moral problem.  I mean, even before our ways part, that's where the problem lies.

CHAIRMAN KASS:  We at least see where the discussion has to go.

Robby George has the last question and then we will break, please, and let's try to keep it modest.

PROF. GEORGE:  Okay.  I'm going to try to set a -

CHAIRMAN KASS:  Just no 30-minute cross-examinations.

PROF. GEORGE:  Okay.  Before turning to it, just to make sure I understand, and I won't argue with you, Dr. Singer.

PROF. SANDEL:  You did understand.

PROF. GEORGE:  Just to make sure.

Are you arguing that it's unclear whether we have an organism at the blastocyst stage when that blastocyst came into existence by nuclear transfer, although we would be clear that we have an organism at the blastocyst stage if that organism came into existence by gamete union?

Is it the nuclear transfer that generates the doubt about whether we actually have an organism or is the position indifferent as to whether the means is nuclear transfer or gamete union?

DR. SINGER:  So for any normal gamete union we don't know if we have an organism?

PROF. GEORGE:  That's what I'm wondering.

DR. SINGER:  There's a certain probability that we have an organism, and we don't actually have as good numbers as we would like about what percentage of fertilized eggs, eggs fertilized in vivo in a normal way, what percentage of those actually make it.

We know that it's probably not more than 50 percent.  Okay.  So that's -

PROF. GEORGE:  Yeah, but my only question, just for clarification is -

DR. SINGER:  Well, you called a blastocyst an organism, which I would never do.

PROF. GEORGE:  Whether it's gamete union or nuclear transfer.

DR. SINGER:  Right.

PROF. GEORGE:  That's all I wanted to know.  So either way it's not -

DR. SINGER:  So either way -

PROF. GEORGE:  It doesn't have to do with it being nuclear transfer.  It's just however it came into existence, you're not going to call that an organism.

DR. SINGER:  Either way, either way you don't know for any given blastocyst what the probability is that it will become or has the potential to become a full organism.

PROF. GEORGE:  Okay.

DR. SINGER:  And what we do know is that those that are made with other mammals other than humans, the probability of becoming a complete organism when it's done by nuclear transfer is very low, and for many mammals we have very hard data.

PROF. GEORGE:  Okay.  I think I understand the position.  Thank you.

A question for the two Michaels.  It's something that Bill Kristol raised, and I'm grateful for the opportunity to raise it with you, and I really would appreciate your candid reply to it.

Again, I won't argue with you.  I just want to know sort of where you stand on this.

Mr. Kristol raised the issue about a kind of moving of the goal posts that went on.  Bill Hurlbut has raised it in the Council before.  In the run up to the President's stem cell decision of August 2001, there were a number of people both in the political field and among scientists - now everyone is just speaking for himself, I'm not accusing anybody for speaking for any organization - who advocated, who defended the change in the law to permit funding of embryonic stem cell research and who at the same time said that, of course, they would not be in favor of creating embryos by whatever method for research involving their destruction, but they wanted to use embryos that would otherwise be wasted, as they would characterize it.

Well, then it was months later when some of these same people changed their position in favor of creating embryos for research.

Is it, therefore, fair - isn't it fair - for those of us who are critical of the position that you've adopted here to at least ask and get an answer to the question:  What is the limit of what is being asked for?

Is it not fair to ask:  Are you saying that you're in favor of embryo research and funding on embryo research ought to be permitted to the blastocyst stage, to the 14-day limit, implantation?

Is it possible for you to take a firm position on exactly where you would limit funding for embryo research?  What degree of development of nascent human life would constitute the point at which you would say, you would agree, well, no more research then, no implantation, for example, for purposes of research?

MR. WERNER:  I have an answer.  First of all, there was a debate in Congress, as you probably know, in 1998, I guess, also about whatever we want to call it, therapeutic cloning, cloning for research, whatever, and during that debate my organization took the position we've taken subsequently, which is that, you know, we thought the research should go forward.

So I guess in terms of the first part of your question I feel like we were clear, you know, pre-isolation of the human embryonic stem cell and the debate within the Bush administration and all of that that, you know, therapeutic cloning was something that we thought should be allowed to continue.

So I feel like we've been on record about that for a while.  So I don't think we were one of the organizations that you referred to which said what we were saying, this was okay and then, oops, we've moved the goal posts now a little bit; now X.

You know, we've been clear all along that we thought this research would go forward.

And then in terms of the limits, I mean, you know, I think the 14 days is the one that we feel comfortable with.

PROF. GEORGE:  Is that the position of BIO?

MR. WERNER:  Well, I'll put it this way.  We were supportive of the legislation that contains that provision.  So I can't tell you that we've sat around and said, "Gee, should we allow federal funding for 14 days or 20 days?"  You know, I haven't had that kind of conversation.

But I do know that when we have talked about it, we have talked with our researchers in our companies, and we have talked about the various proposals, and especially we have a lot of our folks who are operating in the U.K., and we are comfortable with the 14 days, and as that as a limit.

PROF. GEORGE:  So if there were promising lines of research that would require implantation, you would not be in favor of pursuing those lines of research?

MR. WERNER:  Yes, that's correct.

Having said that, I will be fair and say I think that - No, I think that it's fair to say that, you know, science advances, ethical thinking advances.  We constantly are reexamining our views and our principles.  I think it's okay for us to say we've said it throughout history with new technology.  It's okay to say, you know, this is something that's troubling, but now, you  know, umpteen years later we for some reason feel like, you know, we can reexplore whether that's an appropriate limit.

I will tell you that I have no view that, sure, we're  going to move the goal post.  I would say our view is 14 days because the primitive streak seems like an appropriate boundary, and that's where we are.

PROF. GEORGE:  So for you that's a principal limit.

CHAIRMAN KASS:  For the time being.

MR. WERNER:  Yeah.

PROF. GEORGE:  Well, that's the question.

MR. WERNER:  Now.  That's correct.  No, look.  And you know, for what it's worth, I understand that that's frustrating, and that's why I sort of hesitated to say it, but I do think that that's where we are, and I don't know that it's appropriate to say that limits on scientific research should stay static over the course of decades as things change.

PROF. GEORGE:  But isn't the status of the embryo something one has got to have a principal position on at some point?  The status of developing human life, there's got to be some point at which you say as a matter of principle we're not going to experiment on human beings at this developmental stage.

PARTICIPANT:  I thought you promised not to interrogate.

PROF. GEORGE:  Oh, sorry.

CHAIRMAN KASS:  Yes.  Do you want to comment?

Look, thank you for a really wonderful panel, spirited and frank and lively.

Council members, we start tomorrow 8:30.  Please review the discussion document and you have at your place the information regarding tonight's dinner.

The meeting is adjourned.

(Whereupon, at 5:41 p.m., the meeting was adjourned, to reconvene at 8:30 a.m., Friday, June 12, 2003.)