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, Dr. phil.
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 University School of Medicine

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