FRONTLINE presents Organ Farm
photo of daniel r salomon
daniel r salomon, m.d. home
four patients
animal welfare
the business
the regulators

Salomon is an associate professor in the Department of Molecular and Experimental Medicine at the Scripps research Institute in La Jolla, California, and chair of the FDA's Biological Response Modifiers Advisory Committee. He also serves on the Secretary's Advisory Committee on Xeno-transplantation. While he believes maintaining public safety is paramount to moving forward with xeno-transplantation, he also argues "If you regulate the technology out of existence before the technology has shown any evidence of its promise, then you've robbed future generations of a tremendous boon." (Interviewed Winter 2001.)

What is the promise of this technology?

Xenotransplantation, the ability to transplant tissues, cells, and organs from animals, is a tremendous scientific advance. Basically, it allows us to have an almost unlimited supply of organs for transplantation. But even more importantly, it gives you an almost unlimited supply of cells. . .

The stakes are huge. Right now, there are about 60,000 patients waiting for a kidney transplant. They're on the waiting list for up to four or five years before they can even see a transplant these days. There are patients dying every day from a need for an organ like a heart or a lung or a liver.

So those patients could be saved almost immediately. But even more importantly, rather than having to be so sick that they're in an intensive care unit on death's door, these people could be transplanted very early in their disease, and the effects on these people and on their families, the amount of suffering reduced, is just incredible to think about.

On the other hand, with cellular transplantation, there are a million and a half diabetic children in the United States alone. You're never going to touch that need with human organ donation. Only something like cell transplantation, only something like xenotransplantation is going to address this incredible health need.

So the promise of xenotransplantation extends over a remarkably broad group of people and diseases. It can go anywhere from end-stage kidney disease, liver disease, and heart disease to multiple sclerosis, stroke, and diabetes. The impact of the successful therapy based on xenotransplantation will be tremendous.

If it works, how big a breakthrough could it be?

I think that xenotransplantation as a success would provide a therapy that would give us unlimited tissues and organs for transplantation. Therefore, we could apply it very early in the stage of disease, long before the kind of suffering and risk of death that is routinely a part of organ transplantation today.

In terms of cell transplantation, the impact is there that we could even do it at all, because at the current time, the amount of tissues available for this sort of thing, say for cell transplantation for diabetes mellitus, is not even close to being able to fulfill the need. Xenotransplantation then creates a whole opportunity to treat a group of patients that, right now, we couldn't even treat.

. . . I think what's remarkable is to think of this as a continuum. There's xenotransplantation. But the incredible successes of the human genome project now allow us to see life and disease as part of a molecular phenomenon, as part of genes functioning and dysfunctioning in the body. And to the extent that these are connected, that we're going to have to deliver gene therapy, we're going to have to deliver on this incredible promise of the human genome project -- xenotransplantation, cell transplantation, gene transplantation, which, in a way, are all linked. When you put them together, and consider them as a continuum, our ability to reach out and treat a remarkable range of diseases becomes real.

it's critical that we don't regulate a promising technology out of existenceÉ because nothing that's ever occurred in medicine had no risk. What does xeno mean for us in terms of a breakthrough in technology? Does it have the potential to change, in fundamental ways, how we do medicine?

First of all, xenotransplantation has aspects of it that are an outgrowth of conventional human-human organ transplantation. What's fascinating, however, is that a simple application of what we're doing in human-human organ transplantation is not working for xenotransplantation. In other words, there's a series of fundamental barriers that are added by xenotransplantation. And that's the challenge right now to solve.

Now, in the process of solving them, we're gaining very important insights that I believe will also be applicable back to human-human organ transplantation. There are a lot of things that we're learning about how the immune response deals with blood vessels, for example, and why injury occurs to blood vessels, that I think will be extremely important in an understanding of chronic rejection. Right now, that is one of the biggest challenges in human-human organ transplantation. So certainly advances in xenotransplantation, just like in many areas of medicine, will drive other advances -- some advances that one can't even anticipate at this point.

There are some other remarkable features that are unique to xenotransplantation. It is going to be the first area in which genetic engineering of animals, of animal tissues in order to get a desired effect after the transplant, is actually going to be tested in principle. Success there then becomes a model for genetic engineering of any sort of cell or tissue transplant. And in the end, that could be human stem cells being engineered, for example, and that gets back to this whole excitement over the human genome project that's now very public. Delivery on the promise of the human genome project will require genetic engineering. And genetic engineering is now being tested for the very first time in xenotransplantation. So it's all linked in an exciting development.

How fundamental a change are we looking at? In terms of breakthrough, how could it change medicine and how we practice it?

Successful xenotransplantation would essentially create a set of options for practicing physicians that would extend over such a remarkably broad range of diseases that it would fundamentally change the practice of medicine now, and in the foreseeable future.

Presently, when faced with the deterioration of organ systems, we really are obligated to spend years, literally, with all kinds of medications. And as things get more serious, we use increasingly toxic medication regimens, trying to keep the patient's system functioning, to keep the patient alive, to keep the patient as healthy as possible.

But the reality is that the tradeoffs are tremendous for those patients, and they're negative. The patients are never as healthy as they could be. A lot of them just can't work. They certainly can't enjoy their lives or their families and do the kinds of things that they want to do. So they pay a tremendous price for our inability to intervene in their diseases at the most fundamental level, and that is to basically replace diseased tissues and systems.

Xenotransplantation is part of the future of medicine in which, very early in this inexorable process of deterioration of tissues and organs, one could step in definitively and successfully and cure it. No toxic regimens. One could cure it.

What's the big challenge? What's the big hurdle to get over in xenotransplantation?

One of the problems in xenotransplantation has been a tendency to oversimplify. To think about xenotransplantation as having a single barrier -- you get over the single barrier, and then you've got a successful transplant program. And earlier, that led a lot of people about five, six, seven years ago to predict that, because their view was that there was only one big barrier, hyperacute rejection -- the fulminant immune response and destruction of the graft. If you got over that, these people argued, it would be just like human-human allotransplantation. And we'd suddenly see 80%-90% one-year graft survival and 75%-80% two- and five-year graft survival.

Great. But that's not what happened. And then a number of people had to go back and explain to the public why xenotransplantation wasn't working. And in the end, it didn't really serve the purpose that it was intended to do, to get people excited and to move the field forward.

So is there a single barrier to xenotransplantation? No, I don't really believe so. I believe there's a whole series of barriers. In the end, these are animal organs going into humans. And one cannot ignore the importance of evolution. I mean, we've spent a lot of years as human beings evolving our systems away from the level we were at when we were back at the level of pigs. We're going to have to realize that the biology of pigs is fundamentally different than the biology of humans. And all of that's a barrier to successful xenotransplantation.

So in summary, what is the little voice of caution that you would add?

I think that the reality here is that in organ transplantation, we're really not there yet. The data suggests that we're talking about a month to maybe a month and a half, maybe one guy out of ten is claiming two months' survival of any sort of organ in a legitimate model for xenotransplantation. That's not going to work. Patients are not going to undergo any of these sort of tremendous risks, surgery, pain, suffering, and recovery for an organ that's going to function for a month or two. It's common sense. It isn't ready for primetime. This is still a work in development. This is research.

Now, in cell transplantation, it's different. In cell transplantation, we're actually ready. There is some success in cell transplantation. A lot more needs to be seen in order to really see the future and the promise of it. But at least it's ready to be tested in limited numbers of patients.

How far off are we from seeing the first clinical full organ xenotransplant...?

The honest answer is that I really don't know. If one takes the view I have, that there are multiple barriers and you only see the next barrier when you overcome the one before it, then it's really hard to guess. I would suspect that they'll be able to move forward perhaps sometime in the next five to ten years.

So what does the public need to know about this?

Xenotransplantation as a new technology is breaking some scientific ground. It's also breaking ethical ground. And at all those levels, public discussion and public understanding is critical. From a new scientific ground, we're talking about genetic engineering of animals. We're well aware of the public's fears and concerns over genetic engineering of anything living, including plants. And we have to respect that concern, address it, discuss it with the public, and include them in the process of moving this field forward.

Xenotransplantation will involve large-scale herds of animals. We accept this sort of thing in most of the developed world for food -- cattle, pigs, chickens, etc. But there are some significant ethical issues for raising animals for food, and equally significant issues of raising genetically engineered animals for healthcare. And again, the public should be a part of that discussion, and it's important.

There are also risks that are inherent in xenotransplantation, risks that we are just now beginning to define, risks of viruses, and possibly other animal infectious agents that could be moved from animals to humans in the process of transplantation. The public is very aware of this. They're aware of flu epidemics that threaten public health. They're aware of mad cow disease that comes possibly from eating certain kinds of infected beef.

Once again, the public deserves a discussion of the risks of transplanting animal organs into human patients, particularly at the moment, animal organs into human patients who are receiving lots of drugs to suppress their immune response.

What about the idea of consent -- not just from the patient or participant involved -- but the potential that some of these viruses could become a public health factor?

I think one of the fundamental things in xenotransplantation, because of the possibility that one might move an infectious agent from an animal organ transplanted into a human, is that consent now has to be looked at in a new way. If a consent is obtained from an individual and the risk is to the individual, then consent is theoretically possible. The individual can consent, even risk their life, if there is a perceived benefit that it may save their life.

The game is totally different if it's possible that, in the process of saving this patient's life, I transmit an infection into that patient that now would be transmitted to his wife, his children, or any of our children. The idea that there is a public health risk inherent in xenotransplantation changes the consent process dramatically. One can consent for yourself; you cannot consent for the public. In that sense, public discussion, public review, public debate, is the public's part of the consent process for xenotransplantation.

How do you get public or societal consent for something like this?

Well, the actual truth is that you're never going to get public consent for this. And in fact, the idea that you're going to get public consent is something that's been manipulated by some people. What scientists and physicians are obligated to do in xenotransplantation or in gene therapy or any new cutting-edge technology is, frankly, to outline for the public the spectrum of risks, the spectrum of benefits, to help the public comprehend what we call a risk-benefit ratio. And in the context of an intelligent discussion of risk and benefit, allow the public to see what the ethical world is around those problems, contribute, discuss, ask questions, understand. That, to me, is the purpose of public discussion.

How does one answer those doctors who bring us their desperate and often dying patients as an example of their enthusiasm to see xenotransplantation? They say things that show that they're incredibly confident that the costs of this outweigh any concerns that the public may have on any level. How does one answer that?

I greatly respect the passion and the dedication of these physicians to their patients. Frankly, that's what patients should expect from their physicians, and no less. . . .

However, there are other points of view. There are others in this spectrum of debate who make a very critical point that there are risks here -- risks to the public -- risks of bringing an infection into the public which could be as serious as the AIDS epidemic. This is just as serious, and they're just as passionate.

The appropriate response to both these extremes and what the public expects from science is that we define the extremes and then go to the laboratory; do the basic research; do the clinical research; answer the questions; and then come back to the public.

At a certain point, all the handwaving and dramatics from either end of the spectrum have done their job, and it's over. It's time to get facts, to come back to the public, to give the public the facts based on science. That's what the public supports research for.

Can one quantify the risks in xenotransplantation?

We can quantify the risks of xenotransplantation, provided we have enough scientific information based on rigorous models for xenotransplantation infection risk, and eventually very carefully acquired experience in clinical medicine. But yes, eventually we can quantify the risk.

Can we quantify the risk right now?

No. Presently what we can say with surety is that there is a risk of infectious disease in xenotransplantation. There is a risk of transmitting infectious agents from animal organs to human patients during a transplant. We can also say that there is a risk that those infectious agents will move from the patient to the public. It's real that there is a risk to both the patient and to the public. So in that context, there is a risk.

What we can't say is the dimension of the risk. There are people who will tell you it's very, very small, and others who will tell you it's very, very large. The truth, in my opinion as a scientist in this field, is that we just can't quantify the risk right now.

What should the public do then right now? If we can't quantify the risk . . .

In the last four or five years, the public, in partnership with governmental regulatory agencies like the FDA, the NIH, and the CDC, and scientists and physicians in xenotransplantation have done a very good job of defining the issues. They've showed the spectrums, from the impassioned physician who needs to save the patients who are dying to the others that are concerned about a catastrophic health consequence -- public health epidemics -- from this.

So we've defined the issues. And now what should the public do? Nothing. The public should wait while we do the science that we owe the public to fill in the gaps; to provide knowledge and results upon which to come back to the public; and to reenter the debate, but with more knowledge.

What's pushing xeno forward?

. . . For the physicians with sick and dying patients, the pressure's obvious. They want their patients to be healthy. They want new ways to treat. For drug companies and biotechnology companies, the stakes are equally huge, because this is a market that's tens of millions of people, and they realize it. And it's okay, because right now, that money that these companies are willing to invest is driving the field forward toward the success that everyone is so excited about. There's nothing wrong, in my opinion, with drug companies and biopharmacology companies having a reasonable expectation that they will profit if their investment in xenotransplantation is successful.

It is becoming very clear to the public, regulatory agencies, physicians and scientists--that we have to account for conflicts of interest before responsibly going forward to clinical trials and new technologies So should we barrel ahead and order up clinical trials?

No. From a regulatory point of view, there has to be a balance. There has to be a group empowered to review the data as it comes out, and objectively decide when it's time to go forward with specific xenotransplantation procedures. You're breaking brand new ground. There's going to have to be an inspired balance, if you will, between allowing a field to move forward into absolutely brand-new territory and yet, at every point along the way, ensuring that safety is utmost in the minds of the scientists and physicians doing these studies.

I think that that kind of balance is perfectly possible. We've moved forward with gene therapy under those guises; we've moved forward with new drugs, new vaccine trials.

So, from a regulatory point of view, there is already a very well defined regulatory context established by the Food and Drug Administration in partnership with the National Institutes of Health and the Centers for Disease Control in Atlanta. And it's all being overseen by the secretary of health and human services at the presidential cabinet level. So I think that we're in a pretty good situation right now, having a strong regulatory oversight to help guide xenotransplantation safely through the first clinical trials.

Right now, trials are going forward in xenotransplantation with cells--not organ transplantation. But we're moving forward right now with cell transplantation, specifically with pig cells. We're also exposing some patients to pig cells by circulation outside the body. In these instances, some people argue that with cell transplantation, because the dose is smaller, the dose of potential virus exposure is smaller, that there would be less risk. That might seem to be true, if you just think about the size of an organ versus a few cells.

But the reality is that if a cell is transplanted and survives long-term and day after day is putting out infectious virus, the risk is every bit as real as a bigger organ surviving for the same period of time putting out a little more virus everyday. Once you reach a threshold of infectious exposure, you get infected. It doesn't matter if it's larger or smaller, if it gets over the top of the threshold.

Can you talk about assessing risk and benefit?

The basic principle in regulation of a new technology is assessing risk and benefit. And we talk about the risk-benefit ratio. To assess benefit for a new therapy, we have to look at the disease the therapy is intended to benefit.

So let's take replacement of a failing kidney; let's take replacement of a failing heart. What we expect is that someone who wants to move forward with a clinical trial of human patients with xenotransplantation for a failing kidney or heart demonstrates to the regulatory agency, and to other peers in the field, that the heart or kidney that's being replaced will function for a pretty reasonable period of time without destruction by the immune system. That's what we would call benefit.

Now, of course, exactly how much benefit becomes somewhat of a judgment. We have to remember that, in many ways, we're talking about benefit being demonstrated in animal models of kidney failure and heart failure, and that we're trying to figure out then from there what benefit would be for human patients getting the same. And that's not a perfect process.

But within reason, there have been very high-level discussions in the regulatory agencies and the subcommittees of the FDA on exactly defining what the level of success would be. And we're nowhere near that today. But we have a good idea where we want to be before we allow the first clinical trials.

What is the current criteria for evaluating benefit and getting approval for going ahead with clinical trials to transplant pig organs into humans?

In the sense of defining what level of benefit a federal regulatory level would allow us to go forward in clinical trials, there have been very detailed discussions had at the FDA in the Subcommittee for Xenotransplantation. The results of those discussions are that, for kidney and heart transplantation, there should be approximately six months of life-sustaining function of xenotransplanted organs without any evidence of a terrible destruction of those organs at that time.

At the present time . . . the facts are that for kidney transplantation, we're talking about 45 days -- not even two months' survival -- of a kidney in a life-sustaining model of kidney failure in an animal. And for heart transplantation, it's approximately two months as well. So we're really quite a bit short of achieving even the minimal benefit that we would consider reasonable to justify clinical trials now.

What are the barriers?

What everybody understands today is that the first barrier to successful xenotransplantation is hyperacute rejection, the fulminant destruction of an organ by the immune system. We made progress. We've gone from survival of organs for literally minutes to survival of organs for a month to two months. This is a tremendous scientific success.

But patients undergoing a kidney transplant or a heart transplant are going to expect their organs to last for years, not weeks. And so there really is a tremendous gap yet to fill before we can go forward to clinical trials. It's reasonable to hold back going to clinical trials until the science progresses further.

As much as some want to move forward fast, what, in sum, are your views?

Having participated in the discussions at the federal level, in the FDA's Xenotransplantation Subcommittee meetings, having seen the data presented by the different groups who are working on transplantation of organs into different animal models, I agree with the current view that it is too early. There's not enough benefit demonstrated in these animal models to justify going forward in the clinical trials today. I think that we've made tremendous progress. I believe that there is nothing standing in our way that can't be solved by further scientific research. But we're not there yet.

Why have clinical trials anyway? What can you learn from human clinical trials that you can't learn from animal trials?

I think a very important point to make to the public is that, while animal models are extremely valuable in moving new technologies in medicine forward, an animal is not a human. Of course that's obvious to everybody. So at some point, we need to reassure the public that if medicine is going to move forward responsibly to new therapies for disease, there has to be a point in which you go from an animal trial to a human clinical trial.

And you have to accept the fact that, no matter how much energy and time you spend perfecting your animal model, it's an animal model. And in the end, we're treating patients; we need to know what happens in human patients. It's important that we realize that there may be surprises in human patients, and we'd better be prepared for that, too.

What are the issues involving the patient's informed consent?

. . . At a regulatory level, because of the possibility of moving an infectious agent from the animal organ to the human, and because of the possibility that it might move from the patient to the family, we have broached some really new ground. We're talking in terms of asking not only the patient, but also the patient's family, to basically consenting to a long-term follow-up.

We're talking about years during which we would take blood samples, we would monitor their clinical course, we would look for any unusual sorts of diseases or complaints that might give us the first clue of a possible infectious agent that we didn't predict. We would actually get blood samples from the nearest relatives, the wife or husband and the children of these patients. We would not allow them to give blood or semen or other tissues for donation, as many public-spirited individuals are wont to do.

And it's very interesting, because there are really very few legal precedents for what we're expecting a patient to do. Inherent in a consent, right in bold black at the bottom of the consent, it has to say that, at any time, you can withdraw from the trial. If we do a xenotransplant and six months later the patient can withdraw from the trial, and we have no call to legally enforce sampling of that patient for any infectious blood -- in fact, that patient never has to report to us again; he can disappear, she can disappear -- it raises some very interesting questions.

On one hand, we've gone to all these extents to reassure the public that we have all these safeguards. We're going to do the testing and we're going to follow the patient long-term and we're going to keep track of them and we're really going to stay on top of it. And yet the truth is that, because of the legalities of the consent process in the United States today, it really will require a tremendous amount of voluntary participation by the patients and the patient's family for this to work.

And what are we asking them, concerning long-term follow-up?

At the moment, the kinds of things being proposed for clinical trials of xenotransplantation for long-term follow-up include at least yearly sampling of blood, possibly saliva, possibly semen from patients, and also from intimate contacts -- spouses and children. We are specifying that if the patient develops any sort of disease during this period of time, that that information be disclosed to the regulatory agencies -- not to the public, of course -- so that symptoms of new diseases might be linked possibly back to the xenotransplant.

We would very much like to be able to get permission for an autopsy if the patient should pass away during the period of follow-up, and permission to do experimental research on the tissues and the organs from that autopsy in order to look for possible pig viruses. We'd want to look for anything that could potentially have caused the death of that patient from the xenotransplant. These are things that are way beyond the current definition of the universe for a consent form today.

Can we ethically go there?

I think that here is an excellent example of where public discussion becomes very critical to moving forward a new field. If the public can participate; if the public can understand the tremendous importance of moving this technology forward; if the public can understand the special nature of these changes to the consent process as currently seen; if the public can support this sort of movement forward as part of the guarantee of safety in an area like this; then that's a very powerful message to the law-making organizations, such as Congress in the United States, which would be responsible for changes in the consent form.

Is it fair? Is it what we should do?

I believe that if we want to safely move a new technology like xenotransplantation forward, we need to do whatever is necessary to ensure the public's safety. In this case, it is to maintain long-term follow-up on all the patients and intimate contacts of these patients.

So people have to understand that we're talking long-term here, and we don't know how long it will take to manifest.

Right. To properly guarantee the safety of xenotransplantation for future generations, what we're actually asking patients to do upfront is to agree to follow-up for life. We're also asking for access to their tissues after death for the kind of research studies that are going to be required to determine if their death had anything at all to do with the xenotransplant. Even if the death wasn't directly caused by the xenotransplant, if in this patient that died there is any evidence for spreading infection or a tumor or any sort of complication of xenotransplantation, then we owe that to the public and to all future generations in the implementation of a new technology like this. The contract with the patient is a remarkable one. It's one that literally is unprecedented in medicine.

And there's definitely now the beginnings of a movement in Congress to acknowledge the fact that part of the trade-off for guaranteeing safety in new medical technologies is some dealing with the special issues of consent and patient interactions that are involved.

What about the possibility of rogue experimental efforts in other countries?

No matter how much effort we all spend regulating xenotransplantation, arguing about the best way to protect the individual and protect future generations, the stark reality of this world is that, for all our efforts, there are going to be many areas of the world in which xenotransplantation could move forward without any of this kind of regulatory oversight.

Now at this point, you might say, "Oh, yes, anything could happen." No. The reality is that it is happening. We are aware of several what we call "rogue" xenotransplantation programs in Europe and in Central and South America. Some are being advertised on the worldwide web that are literally ready, for a fee, to transplant a whole variety of animal organs to human patients for diseases that range from aging to depression.

I actually had a phone call from a woman who, after some publicity on one of the papers that we wrote on xenotransplantation and infection, called me and asked me whether I thought it was okay for her to go to a special clinic and undergo animal parts transplantation in order for rejuvenation, to protect her beauty. And of course I explained to her that it wasn't okay, that it was a very serious step and she should think about it very carefully, and I would advise not going. But the fact is, this is happening now.

If human trials go forward and infection happens, how long could it take for us to understanding if infection occurred?

If an infectious particle gets transmitted from a pig organ to a patient after a point of transplantation, we could see things as early as days. But it could also take several years. The idea of some of these new molecular testing technologies we've developed is that, even though it might take years for us to see clinical disease, evidence for viral replication would be evident very early.

So we really don't think that it would take longer than three, four, or five years max to get a pretty good idea of whether or not there was some really overwhelming risk of infection in a human patient which was not anticipated in the animal studies . . . that were done up to that.

. . . A key point, however, is that there's also the element of unknown. In the last few years, there have been several new infectious diseases that came from animals and were transmitted to humans, and we had no idea they existed before they started. Certainly within the last several decades, we've seen the AIDS epidemic come from monkeys in Africa to humans and then spread throughout the world. As recently as a few years ago, a virus in Malaysia spread from domestic pigs to people, killing literally hundreds of Malaysians before the epidemic was stopped. We've also seen several recent outbreaks of Ebola virus, which is probably also coming from a different group of monkeys in Africa.

So the point here is that it's always possible, when dealing with the unknown, that an infectious event that was transmitted from the pig to the human during a xenotransplant is not going to be covered by all our best efforts to have these beautifully sophisticated molecular diagnostics. You can only make a diagnostic for an agent that you know about.

What's the specific scenario involved here?

Well, the infectious risk presented by transplanting an animal organ into a human has several different features. One is that we don't know enough about how animal cells and animal tissues will behave in a foreign environment. In other words, going from an animal environment to a human environment potentially under attack by the immune system is obviously a very abnormal situation to model.

In our own studies, we demonstrated, for example, that transplantation of pig cells into another animal -- in our case, an immune-deficient mouse -- resulted in the accelerated production of virus by those pig cells. And we demonstrated that it was due to stress on the cells, as part of the transplantation process.

So one feature that's unique to xenotransplantation is what sort of impact the transplantation itself is going to have. Secondly, xenotransplantation, at least as we currently are planning it, is going to involve immunosuppressives, powerful drugs that prevent rejection of the new organ. Well, those are very important for success, but they also suppress the patient's ability to fight the infection.

The third major issue is that we're going to be genetically engineering animals in order to enhance our potential for success in xenotransplantation. The process of this engineering can also, and will also, have an impact on the behavior of these cells in the new patient, as well as possibly on the infectious nature of the virus.

Somebody says, "Forget about it. I want to opt out." What do you do?

You mean after they've got the transplant? The reality today is that if a patient signs a consent for a xenotransplantation trial, and decides at any time after the xenotransplant to opt out, to say, "Forget about it," that is within that patient's legal right, and there is at the moment nothing that we could do.

Is it a problem?

Of course it's a problem. We just have spent so much time at the level of federal regulatory agencies, reassuring ourselves and then selling to the public the fact that we've done everything possible to protect present and future generations from the risks inherent in this procedure. If patients decide, after all of that, after all our best efforts, to simply opt out after the transplant, of course it's a problem.

Now, there's another interesting part of the problem. There are no laws, right now, to prevent a US patient from going to another country and receiving a xenotransplant, and then getting an airplane the next day and flying back to the United States. And if that patient gets sick, there is no law that would allow me to force testing on that patient for a possible xenogenic infection. And there's no law that would prevent that patient from coming to any hospital in the United States and demanding and receiving therapy. So there are many layers to how individual patients could frustrate our very best attempts to ensure the safety of this new technology.

What is the right moment to confront the ethical issues involved in this? Is it before we do clinical trials?

The problem with taking a new technology and examining in detail the ethical issues before the new technology can really be implemented in human patients is that it is, in some ways, critical, but it is premature. It's premature to delve into the ethics before we can define the dimensions of the new technology, before we even can define the risks of the new technology.

The ethical debate has to have some of the same principles as the scientific debate: These are the facts as we know them; this is what we can say about the ethical universe that we confront with this set of facts. We know that these facts are changing, and we will be there to reexamine new facts and be flexible about the ethical decisions that we make as these new facts unfold.

That's the nature of a new technology. One has to be very cautious that we balance the critical importance of maintaining safety -- public safety and patient safety -- against the tremendous promise of a new technology. If you regulate the technology out of existence before the technology has shown any evidence of its promise, then you've robbed future generations of a tremendous boon.

What about the conflict of interest issues?

One of the major challenges in the development of a new technology is to sort through the potential for conflicts of interest. It is now becoming very clear to all of us--to the public, to the regulatory agencies, and to physicians and scientists -- that we have to account for conflicts of interest before responsibly going forward to clinical trials and new technologies. Principal investigators cannot own the patent on a particular new technology. Principal investigators can't have significant holdings of stock in a company that will benefit dramatically. Principal investigators shouldn't be highly paid consultants of companies. There has to be some objective group overseeing these studies at the level of patient-to-physician contact.

The dynamic here is that you certainly don't want to go forward in clinical trials, in brand-new cutting-edge technologies, without physicians and scientists who are absolutely involved in the genesis of these scientific discoveries. So it's very important that we don't create a situation in which no one can be involved in the trial that owns a patent, that has a stock right, who is a consultant for the company. That's not at all what I'm saying. They have to be involved in the trial, because they're the experts in the trial. You can't pick an internist out of the general medical clinic and say, "Hey, you've got no interest in this trial, you're great, you're going to run this trial in gene therapy," or, "You're going to run this trial in xenotransplantation." That's ridiculous.

What I'm saying is that we have to acknowledge the potential conflict, create safeguards within the design of the trials, and then monitor them well. And I think we can do all of those things, and do them well.

Currently, aren't some of the key players -- the principal investigators -- also stockholders of companies that stand to gain tremendously? And isn't there a question of perception that one needs to be careful about?

At the present time, the reality is that, in a number of proposed clinical trials, the principal investigators have been the developers of the technology, the patent holders, the owners of the company that's developing the technology, or consultants to that company. And therefore they have tremendous amounts of vested interest, financial and otherwise, in the success of these trials.

However, you have to therefore have physicians involved in the trial who have nothing to do with the profits, have nothing to do with the patent, and nothing to do with the company. And they have to have a dynamic and productive interaction with these scientists and physicians that do other vested interests. Achieving that balance, and doing it safely and monitoring it well, is what the big challenge is right now, for going forward responsibly in these clinical trials. The way we'll do it is through institutional review boards, and through regulations at the level of the Food and Drug Administration ... process. And that's all in play right now.

We recognize the limitations of that. We recognize the fact that that is not part of our agreement with the public. And specific changes in regulations are now being discussed at the level of local institutional review boards, which are responsible for approving and monitoring any of these studies, and also, at the federal level, at the level of the FDA ... process.

What are some of the issues about the virus?

In simple terms, a virus is a small packet of genetic material that's essentially packed tightly in a particle, and that particle can be transmitted to a human cell. When it gets into the human cell, it actually incorporates itself in the human cell's own DNA. If the infection by this viral particle is successful in getting into what we call germline cells, then all the children that result from that individual will contain the viral DNA forever.

What's a retrovirus?

Everyone is aware of the fact that there are many different kids of viruses. We know about the flu viruses, we know about the cold viruses. Retroviruses are one group of viruses that are distinguished by the fact that they essentially have to make their own DNA after they get into the human cell. So they inject themselves into the human cell, and then they have special enzymes that they bring along with them, that reverse transcribe --retro-- the RNA into DNA. That DNA is then inserted into the human cell's genes, into the human cell's chromosomes.

Is part of the idea here that, unlike some viruses, there are certain viruses that end up replicating themselves through generations and become part of the basic DNA make-up of an animal?

Right. I think that one of the special concerns over viral infection in xenotransplantation is . . . over retroviruses. . . . If, in the process of inserting themselves into the host cell's chromosomes, they insert themselves into germline cells -- sperm and egg -- then all the progeny, all the children, of those individuals will carry this infection virus into the future. That's the special aspect of the infectious disease risk we're facing in xenotransplantation now.

Another unique feature about this group of retroviruses is that, when a retrovirus infects a cell and inserts itself in the cell's chromosomes, it actually blocks infection by any other retroviruses. What's happened in the process of incorporating retroviruses into germline cells, so that they're passed along, now, in the species in perpetuity, is that these offspring are actually resistant to the virus.

What we come to understand is that these germline-incorporated viral DNA particles are actually the reflections of ancient plagues that, after decimating perhaps hundreds and thousands of individuals within that species, finally became incorporated in the germline, leading to offspring that were resistant to the infection.

The irony of all of this is that the success of the species in incorporating these viral DNA into the chromosomes and creating subsequent resistance is that it doesn't create resistance if you now take those cells and transplant them into another species. So you protect the species -- in this case, let's say, we're protecting the pig -- but if you take the pig cells now and transplant them into a human patient, there's nothing protecting the human patient. So that virus now can come out and infect the new species.

How does a virus get passed out into the next generation?

Retroviruses incorporate themselves into the host cell's chromosomes. Imagine that sperm and egg cells, which are just another form of host cell, are each infected with the retrovirus, and each incorporate the retrovirus into the chromosomes. Then any fusion of egg and sperm to generate a child will carry the two copies of the infectious chromosome into the child. And that's every cell in the child. So when that child gives rise to children, that viral DNA will be incorporated faithfully in that child and into the children's children and on, in all generations, in perpetuity.

Viruses are very small infectious particles, and essentially, if we think about their job, it's to get themselves inside a cell that's permissive for them to survive. And then they actually reproduce themselves in great number, infect other cells, and therefore carry on.

Some retroviruses in this process actually are successful in getting themselves into germline cells -- the eggs and the sperm -- that basically carry on our genetic traits to the next generation. If they're successful in getting into this germline, this basically a free ride for this cell, because it then is carried on to all future generations in that species.

How would that work?

Let's start off with understanding that all pig cells carry multiple copies of infectious virus. That infectious virus is not dangerous to the pig, but there are no such rules for humans. We already demonstrated in the laboratory that that infectious virus infects human cells. And we know that when you move an infectious agent from its host environment -- in this case, the pig -- and put it in a completely new host environment -- in this case, a human patient after a transplant -- that there is no way to predict the pathological consequences. There's no way to predict what kind of disease could be produced when this pig virus is accidentally transmitted and becomes infectious in the human patient.

Indeed, there are many examples in which viruses that basically are carried by certain animals and cause no disease in the animals, when transmitted to humans, can be deadly. A really good example of this is the hantavirus. It's carried by an innocent little deer mouse. And the deer mouse is absolutely healthy. If a human gets infected with that very same virus, there's a 70 percent death rate in these human patients.

Take Ebola virus for another example. There's no evidence that any monkeys are sick with Ebola virus, but if Ebola gets into a human patient, there is 75 percent, 80 percent mortality, and it's a horrible disease.

If a pig virus got into a human, how would it manifest? What would you see? What kind of disease would be involved?

What we know about the family of viruses that are closely related to the virus in the pig that we're concerned about is that they all produce lymphomas and leukemias. These are cancers of the blood system. And if we saw activation of this pig virus in human transplants, we predict that we would also see the same sort of spectrum of blood cancers -- leukemia, lymphoma. There is going to be a lag time between the moment of infection and the production of this possible cancer. And during that lag time, we are going to have to rely on very sensitive molecular diagnostic tests to detect the replication of the virus before we see the evidence of the leukemia or the lymphoma or any sort of cancer from these patients.

Let's say that someone has received some sort of xenotransplantation. What would have to happen for there to be a disease at the end of the process?

A series of steps would have to occur to produce any kind of disease after transplantation of an infectious agent, like a virus, from an animal organ to a human. First of all, the virus has to get into the human cells. There has to be basically a receptor on the human cells that recognizes that virus and mediates that viral infection. Then there has to be mechanisms in the virus that allow it to be reproduced in large numbers and released by the infected cell. There is only any real risk with release of new particles of infectious virus, the new generation of cells, and the spread of the virus, in what we call an active or a productive infection.

So one could conceive of several different things occurring after xenotransplantation. We could imagine the possibility that there might be no infection of a human cell. In other words, the virus in question just does not have the ability to see, in fact, and enter a human cell. That would be great. It's possible that we may have viruses, like the retroviruses we've been concerned about in pig cells, that we do know can get into a human cell.

They can get into the human cell and cause infection. But then . . . if they don't replicate actively and spread to subsequent cells in the patient, you don't have active infection; you don't have productive infection. That wouldn't be likely to produce any kind of disease. The infection could then simply go dormant. And there are many viruses already in humans that we know get in, replicate once or twice and go dormant, and you then carry them for the rest of your life with no consequences at all for disease.

What do we know so far about these pig viruses? How active and aggressive do they seem to be?

What we know about these pig viruses today is that, first of all, they do infect human cells. Secondly, under certain circumstances, they can actively infect human cells. In other words, they can infect a human cell initially, replicate themselves, and spread to other human cells. So that's part of why there's a real concern.

However, in other types of primary human cells, the virus may get in or not get in at all. But in either case, it replicates very poorly, doesn't spread, and doesn't produce active infection. In the animal work that we have done and published, pig virus was identified in the animals. It infected animal cells in the transplanted animals, but it never produced an active or productive infection. It appears to have gone dormant very early in the process.

So at the present time, the evidence would suggest that, number one, there's a real risk of infection cells; number two, there is a possibility of productive, active infection. However, that risk would appear to be relatively low, based on what we know today.

You've infected mice with pig virus?

What we set out to do was to determine whether or not we could infect an animal after transplantation of pig islet cells. . . . A major question is whether the transplantation of pig cells or tissues would result in the production of infectious virus in a transplanted situation, and whether that virus would get transmitted to the transplant patient. We transplanted pig cells into mice that have a very profound immune defect. This was done as a worst-case scenario -- a patient who had no immune response against the pig cells. What we found was, first of all, that pig cells continued to produce infectious virus after the transplantation. In fact, actually, pig cells transiently increased their production of virus, due, we feel, to the stress of the transplant on these cells.

Secondly, production of the virus continued for as long as we followed these animals, so that we had animals out over three months. These pig cells were still producing virus. The lesson to us is that successful pig cell or tissue transplantation will expose this patient to a constant low-grade production of infectious virus.

The second thing we found is that, in that circumstance, some of these virus particles actually infected mouse cells -- we got infection. This was the first example of infection of living cells within an animal following a pig tissue transplant, and therefore is, if you will, a proof of principle for the disease-producing potential -- the infection production potential--in pig virus.

The good news is that none of our animals were sick. In fact, our evidence suggests that the virus, after a replication or two, basically went dormant; didn't spread to other cells within the mouse. Therefore, as a concept of what the dimensions of the risk are, we can say that, at least in the current time, in this model, we have infection, but we don't see active, productive spreading infection. And that's somewhat reassuring at this time.

What do the mice experiments lead you to believe?

Based on what we found in the mouse experiments, we predict that if we put virus, or pig cells, into non-human primates, that we will also see infection of cells, production of virus, long-term. And we would predict that we will not see productive active infection but rather, the same sort of process of dormancy that we saw in the mice. And we need to test that.

And therefore, what is the likelihood at the moment for this kind of infection in humans?

If our conclusions from the mouse model are correct and the disease indeed goes dormant, the risk of this particular pig virus for human transplants will be relatively low. Now, there's always a danger that a virus entering a whole new world--going from a pig to a human--will undergo a mutation or mutations that will totally change that virus's potential for spreading and potential for causing disease. And that's the big unknown. It's one thing to do 20 mice or 40 mice; it's not a lot of mice. It's another thing entirely to do 100,000 human patients a year.

What did your work show for the first time?

The importance of the work that we published recently was demonstrating for the first time that in an animal model of transplantation, the simple transplantation of pig cells, prepared and transplanted in a way that would be done in a clinical trial of transplantation of pig cells,

A principle for gene therapy--just to put this into context -- is that you would never allow exposure of a patient to what is called "replication competent" or infectious virus. Yet what I've just got done telling you is that transplantation of pig cells in our immune-deficient animal evidenced very clear, ongoing chronic production of infectious virus.

When you transplanted pig cells into immunosuppressed mice, how did that fit into the bigger picture?

When we were deciding how to create this animal model for transplantation, we chose a severely immunocompromised, or immunodeficient mouse. This is, in some sense, a worst-case scenario. There is no immunity in this mouse to kill a virus or reject an organ.

Yet what you have to understand is that a successful pig cell or pig organ transplant, by definition, means that you've come up with a strategy to prevent any sort of immune response against pig cells or tissue. So in that sense, the use of a severely immunodeficient animal that can't reject the pig cells is perfectly reasonable. . . . Well, that part's true, but you still could allow the animal, or the patient, to reject or kill the virus; a failure to reject the organ isn't the same as a failure to reject the virus. And that's a reasonable point. However, it turns out that many of the genetic engineering strategies currently being proposed would also significant inhibit the ability of the immune system to target and kill the virus.

What do you hope to do next?

Based on this work in the mouse model, it is our plan to continue the work forward into non-human primates, as a much closer model for what would happen when pig cells are transplanted into human patients. This is particularly relevant, in that the criteria established by the Food and Drug Administration's expert advisory committees for allowing the first clinical trials to go forward in human patients has been survival for six months or more in non-human primates.

So we're going to have access to non-human primates being transplanted as the basis for establishing the first clinical trials. And so the idea that we would, at the same time, also pursue these experiments of potential infection risk in these same animals is obviously a very attractive, very reasonable, very ethical way to move forward in protecting the public from the risk issue.

What happened to the trials . . . when this kind of virus was discovered? How did people react?

When evidence first appeared that the pig virus that we were concerned about could infect human cells, and that those human cells then would produce more virus and infect other human cells, the FDA immediately put a hold on xenotransplantation trials in the United States.

What then followed was a series of very high-level meetings, over a period of about a year, in which experts of all sorts from both sides of the Atlantic came together at the National Institutes of Health, at the Food and Drug Administration, and with the Centers for Disease Control in Atlanta. The meeting was to discuss specifically what we could do to ensure the safety of this new process in a clinical trial. The focus of those discussions was the development of accurate, sensitive, new molecular diagnostic techniques that could say if a patient was infected with virus.

When those trials of new diagnostics were completed and presented to these expert advisory committees about a year after all this happened, it was felt that so much significant progress had been made that it satisfied the criteria for allowing the hold to come off and for the trials to continue. In the meantime, things didn't just stop there. What's fascinating is that a number of biopharmacy companies, including major pharmaceutical support from Novartis, went forward and did a trial of every patient that they could get tissues and blood samples from, in the history of xenotransplantation, that had been exposed to pig cells. And they came up with 160 patients.

When this was analyzed in detail by company scientists, in close collaboration with government scientists at the US Centers for Disease Control and at the Food and Drug Administration, it turned out that there was no evidence, in any of these 160 patients for infectious transmission. Pig virus was not seen in any of those patients or in any of the cells.

There are flaws in any sort of what we call a "look-back" study, a retrospective study, so this doesn't solve it, and doesn't prove that this is safe. But it is very important evidence to reassure scientists and physicians and regulatory agencies and the public.

What are the statistics on the organ shortage now?

There are approximately 60,000 people waiting for a kidney transplant in the U.S. There are about 20,000 people each waiting for heart and heart and liver transplants at any given time. And you understand the number is smaller for the liver and heart transplants, because the sad truth is that those patients are dying before they get the organ transplant. The kidney transplant patients being listed at least can survive on dialysis.

Can you talk about that patient who's very desperately ill, and their willingness to take the risk of getting a pig virus? What's involved in that decision for them?

For an individual patient who's facing the possibility of a xenotransplant, we really have to think for a minute about what that patient is facing in terms of the chance of living and dying. For a patient with a failing kidney, a failing heart, a failing liver, they're really looking at either a profound loss of their ability to function and enjoy their life and even death, in the case of a heart and liver and lung transplants.

There are a lot of things that people are willing to accept as risks in the setting of being desperate enough to be basically at the door of death. For that patient to accept a xenotransplant, they're going to, right now, accept some risk of transmission of a new infection. We think that, based on the family of viruses that these pig viruses belong to, that that new infection would probably be some sort of blood cancer--leukemia, lymphoma, maybe a tumor. That patient will also accept the fact that there are unknown pig viruses and other pig pathogens that we can't predict. So there could be diseases that we cannot anticipate.

Another critical thing is that there'll be new immunosuppressive drugs and strategies. The traditional human-human organ transplant cocktails are not sufficient for xenotransplantation. So there really are going to be a whole series of challenges and risks for that patient to comprehend prior to agreeing to participate in the first xenotransplant trials. The bottom line, though, is if it's life and death, there's going to be a lot that patients will be willing to agree on, if they're assured of any reasonable benefit.

What about this question about the patient's risk versus the public's risk?

The history of medical and clinical research has dealt for many, many years with the risk to the individual. What's really somewhat unique in this new era of biotechnology is the risk to the public.

A patient and a patient's family can discuss in an informed way, and accept in an informed way, personal risks -- risk of an infection, the risk of a tumor, the risk of dying. A patient and a patient's family cannot accept risks for the public. They can't accept risks for you or for me, for your children, for my children. So this new element of the public risk of the new technology changes the whole nature of the consent as we know it today.

How do we get to that consent? The new features, the new challenges to the consent process are presently under quite a bit of debate, both at the federal level, in Congress; and at the regulatory level, at the FDA; and it should be brought forward to a similar level of debate in the public. What can you do?

Well, I don't know. I really have no idea how, at this point, one can intelligently make a decision on the consent form for a public health risk, when the truth is that we can't quantify the dimension of the risk.

Moreover, when we think about a consent form and these issues, we're really talking about all of new biotechnology; we're not talking about the pig virus risk. So even if tomorrow I would feel comfortable sitting here and quantifying for you the risk of a pig virus, these questions about the public's risk in a consent form that an individual signs go way beyond anything to do with a pig virus. It goes way beyond xenotransplantation. It extends to all new biotechnologies.

So I don't know if specialists in some of these new technologies, like myself, can really know where the public wants to go, where the federal government wants to go, in constructing a consent that works for everyone -- a consent that guarantees reasonable consent for a new biotechnology for a public that's worried about its impact.

With that said, admitting that this is a difficult area, it's critical that we don't regulate a promising technology out of existence. If we take a position like that, if we say, "There's a risk, therefore we can't do it, we can't allow it, we can't develop it," then the history of medicine ends right there, on that day. There's no future, because nothing that's ever occurred in medicine had no risk.

Think about the early vaccine trials. Can you imagine trying to explain to someone when Edward Jenner inoculated cowpox into individuals at the turn of the century, that they weren't going to get sick, and there was no risk that the virus would spread and mutate and all these things that we're talking about in the context of xenotransplantation and infection risk?

But yet, the miracle was that he did it, and created the first functional vaccine for smallpox, and the effect on public health was absolutely remarkable. The polio vaccine . . . just think about the millions of children, worldwide, who've been spared the devastation of polio. Was there a risk with the early polio vaccines? Not only was there a risk, there were complications.

So we need to make sure that the public understands that medicine moves forward through some risk. The public should be involved; the public should think about it; the public should participate; but they shouldn't overreact. They need to be reassured that there is a future here, that we're going to do this, that we can do it safely, and we can do it with a remarkable benefit to human beings in the future. It's worth some risk.

And what about this new dynamic of the companies' and doctors' involvement?

One of the things that is really unique about this new biotechnology is that you have physicians and scientists who've made discoveries in their own laboratories, who have realized some of the dramatic potential. Then they've gone out, patented those discoveries, created companies, sold companies to large pharmaceutical companies, all of whom see that with a tremendous clinical success would come tremendous potential for making money.

And now, you're sitting there with all of this investment, all of this potential conflict of interest, and these are the experts who are ready to move these things forward into the final clinical trials that define this whole system. And it's quite a remarkable irony. On one hand, these are the people who have to be involved in these clinical trials. You don't want clinical trials done by people who have no idea. You want clinical trials done by the people who really did it hands-on. Yet these very people are conflicted now by owning the technology in some way or shape. How do you deal with it? How do you deal with this responsibly? How do you assure the public that these experts, who are so important in this last step -- application to clinical trial -- don't do anything to ensure their private interest? It's not easy. It's a real issue.

At the federal regulatory level, there are now rules being made that these guys should be involved in the trials, but not be the primary overseeing supervising investigator. Involved hands-on in the trial, but other scientists, other physicians, who have no personal financial interest, are making the day-to-day decisions, are talking to the patients, looking at the data, communicating with the regulatory agencies, communicating with the institutional review boards. That's the way we're going to deal with this intersection between these scientists and physicians with special interests. And there is this absolute requirement that they be directly involved, in some way, in these clinical trials.

And how do we answer those physicians who are saying, "You can debate this in the public all you want. Just know that every few minutes you do, somebody's dying." How do you answer that passionate argument?

I don't think you counter a passionate argument by physicians who are concerned that unreasonable, unnecessary delays in bringing promising new technologies forward results in patient death, patient suffering, lives lost, families disrupted. There isn't any reason to argue with those physicians. They have to be heard. They have to be balanced by a reasonable approach to initiating these trials that reflects a serious understanding and concern for public safety, now and in the future. They have to be balanced by a reasonable scientific potential for benefit. To do it just because the disease is horrible isn't an argument to do something that has no potential for success. When I listen to these passionate arguments for patient care, my response is that that's a very appropriate thing to keep in mind every time I think about this area.

And every time I think about this area, I feel equally responsible to be concerned about the safety to the public, the safety to the patient, the safety to future generations.

. . . And it should be expected that there is a reasonable benefit potential for the patient before you go forward to a clinical trial. The idea of just doing a clinical trial because the patient's sick or dying is not enough, no matter how passionate and compassionate I feel for that patient. There has to be a reasonable benefit. The idea of saying, "Well, there's no reasonable benefit right now, but I'm going to learn something," isn't the best argument in the world, either.

Is there a bit of hype in xeno now?

A few years ago, I would have been more concerned that certain groups in this area of xenotransplantation were hyping the future of xenotransplantation a little too hard. . . . I think the wind is out of the sails, for the moment, on xenotransplantation. Everybody realizes its tremendous potential, and there's continual and very active, work underway to bring this to a real clinical therapy. But I think it's pretty well founded in reality today. I don't think it's being hyped. And I think there are very powerful forces opposing xenotransplantation clinical trials, both in Europe and the United States, and Canada, that are insisting on benefit; are insisting on reasonable awareness of public risk; are insisting on consent forms that are done privately; and public discussions.

Right now, I would honestly say it's fairly well balanced. The extremes are well represented by articulate physicians and scientists on one hand, who see the promise and are compassionate about their patients, and other groups that see the possible risks and have done a good job of articulating it publicly.

Why are pigs the best model?

Pigs are presently used in great numbers throughout the world for food and other products, such as leather. Therefore, there is excellent knowledge of how to raise pigs, how to keep them healthy, what kind of diseases they have. There are tremendous amounts of resource for pig breeding, pig engineering. We can now clone pig cells. So there are many, many good reasons why the pig has kind of emerged as the first major animal species. They breed several times a year, with multiple children in every litter, so it's relatively easy to quickly expand a pig herd.

With that said, though, there are potentials of doing some of this work in sheep, some of this work in goats. Some transplants could even be done with cattle, and there are cloning technologies available for each of these other species. So it's important in perspective to say that the pig has got a number of very compelling reasons to be the first commercial species to be exploited for xenotransplantation, but that there are also potentials for specific other species to be used as well in the future.

What is the model here? Is it new that in fact we're really talking about new mechanisms for something that's related to a new technology, rather than what we traditionally think of as human to human transplant? After all, they're trying to make a product, make it reliably and plenty of it. Can you just explain that?

One principle behind biotechnology is that you actually make a product, and take the product and make a profit. It's in that context that one can understand the interest in using the pig as the first species for xenotransplantation. Pig farming, if you will, has been going on for centuries, across the world. We're very good at caring for pigs. They reproduce well. They're relatively cheap to house. And we've become quite comfortable with the commercial use of pigs for a number of different things--food and other products. So it's really a very logical commercial venture to do in the pig.

And I think that's why the focus has been on the pig. The dramatic success with cloning pigs extends significantly the kinds of genetic engineering that we can now do on the pig. Before, we were able to knock new genes into the pig. But now we can also knock genes out of the pig. And so the pig now becomes even a better species for this sort of biotechnology commercial venture.

It's ironic . . . that our efforts to try to knock out a sugar in the pig . . . may make it easier for the viruses that they carry to reproduce.

Right. It's very important to consider that, with every new strategy to improve xenotransplantation, we have to reexamine its possible impact on the infectious disease risk there. One good example of this is that hyperacute rejection of a pig transplant is mediated through a special kind of sugar that's expressed on the cell surfaces of most pig cells. It makes sense, then, that if one wanted to avoid hyper-acute rejection, that a target for genetic engineering would be to remove that sugar and transplant pigs that don't have that sugar. There should be much less or no hyper-acute rejection. Great idea.

The problem with that, from an infectious disease point of view, is that when the pig virus comes out of the pig cells and looks around now to infect the cells around it, it carries with it these pig sugars. Now, the human immune response sees the pig sugars on the pig cell and kills it; it sees the pig sugars on the virus and kills it. If you remove the pig sugar from the pig cells--because that's a great idea for hyper-acute rejection--the consequences of it for the infection is you also remove it from the virus. Therefore, you basically hide the virus from the human immune system. Obviously, that's not a good idea, from the infectious disease point of view.

So that's the kind of dynamic that we're going to have to face. Advances intended to improve success of the xenotransplant procedure itself may have unintended negative consequence for the viral infection issue.

So, if you wanted to design . . . a way for the virus to spread, you could almost do nothing better than to create this knockout effect, right?

This is a very serious increase in the potential risk of spreading this infection, to the extent that removal of this set of pig sugars from pig cells, and therefore its removal from the surface of the viral particles, really masks the virus from the immune system.

What about the Baby Fae case?

One major very public event in the history of xenotransplantation was the Baby Fae case. In that situation, an infant was born with basically a life-ending defect in the formation of the heart. And to make an effort to save the life of this young baby, surgeons performed a dramatic transplant between a young baboon and this child.

It got worldwide publicity. Number one, it was obviously very dramatic; number two, it was an infant, and, if nothing else defines the real cutting-edge of new technology, it's our children. The results were that this baboon's heart functioned for several weeks, maintaining this infant alive, before failing. And that also captured the imagination of the world.

In the history of xenotransplantation, the Baby Fae case will be judged differently by different people. In my opinion, it was, at least, a very powerful proof of the concept that you could take an animal organ and save the life of an infant, an innocent child who was born without a functioning heart and who would die. So in the history of xenotransplantation, in my view, this was a very important event.

To others, it was an also an event that demonstrated that three weeks of function of a baboon heart in an infant is not the level of benefit that we would expect to justify, today, a clinical trial. And I also agree with that.

Eight years later, Tom Starzl takes the next step. What did he do?

Several years later, another major event in the history of xenotransplantation took place, when surgeons in Pittsburgh transplanted baboon livers into several patients under full immunosuppression. And those patients also lived for two, three months with function of the liver transplants. And yet all of then, again, eventually failed. Many of the patients succumbed to overwhelming infection, because the level of immunosuppression that was required to keep these livers from rejecting was so great.

Proof of concept? Well, again, it's a proof of concept that these patients survived, and that these non-human baboon livers did function in these patients for weeks, successfully, and kept these patients alive.

In the end, the surgeons at the University of Pittsburgh concluded that, despite the fact that this was a powerful proof of concept, that our inability to keep these patients alive with a functioning baboon liver for more than several weeks was still a barrier to going forward with any further clinical trials. And they themselves put their further plans on hold, until the technology would move forward to such a time that we'd have better benefit.

How much has been invested in this? The term we hear talked about is that a billion dollars has been invested in xenotransplantation.

To date, a reasonable estimate for the kinds of dollars that have been invested in xenotransplantation to date, is somewhere between $600 million and a billion dollars. Now, that's against a projected market that, worldwide, could be between $8 billion and $12 billion a year. So it's a pretty good investment, so far, for those sort of dramatic returns.

If successful xenotransplantation is achieved, the first group that benefits is all our patients, and that's fundamental to keep in mind here. The profits will be humongous, but they'll be based on its applications in a dramatic spectrum of different diseases, leading to all kinds of important advantages for patients.

Now, reality-wise, the dollars will be earned by a handful of very large international pharmaceutical companies; they will be earned by a number of small adventurous biotechnology companies that have contributed to different important stages in the achievement of this. And I think it's very important to also point out that it'll open up incredible opportunities for new biotechnology companies and new strategies to take advantage of.

It's so very important to remember that all of this new technology is a continuum. You go from xenotransplantation to cell transplantation to gene therapy. The opportunities for future companies, for future scientists to come up with new technologies and to take advantage of this tremendous new market, is very real.

And what's unique about this new biotechnology?

What is unique is it is such a complex mix of different fundamental new technologies. Biotechnology doesn't succeed on a single molecule, on a single gene, on a single process. It's not like the old days, when you had bacteria and you made an antibiotic like penicillin and it killed the bacteria and you had a blockbuster drug.

Biotechnology is actually something that, to be successful, mixes dozens of different technologies eventually. That means that the final success of a new biotechnology may involve dozens of companies in achieving the final, refined, successful strategy that works to cure human disease.

And as a result, the rules are new. There are scientists who actually did the basic work in their own laboratories, and then, along with their institutions, have gone on and taken the patents out. Then they've taken those patents and they've started their own new companies, which then have brought in investments from large pharmaceutical companies. So now you end up with these really complex collaborations between basic scientists, academic institutions, the universities, the private research institutions--who own the patents, and who have equity interests in the companies that have been formed. The scientists and the physicians have equity interests. They're consultants. They have these big pharmaceutical companies which are overlooking them and have put in hundreds of millions of dollars.

I don't think there's ever been a situation in which things have been this complicated. And now the complexity will increase all that much more, if you think about the fact that one of those companies is going to have to get together with half a dozen companies in order to get the final successful product,

What else is unique about xenotransplantation?

If we look at the history of organ transplantation, there's another feature that's very unique to xenotransplantation, and that, namely, is the profit motive. Human to human organ transplantation is done without any money being paid for the organ. By federal law a donor organ cannot be sold. Can't be done. You can pay a professional fee to harvest the organ, but you can't sell the organ in any way, shape or form--it's against the law.

Xenotransplantation is the total opposite. These companies will own these animals. They will own the organs. And they will sell the organs and make a profit. It's a completely different paradigm for organ transplantation and cell transplantation.

What about the costs per patient for these procedures?

There's been a lot of discussion about what would be even reasonable to charge for a pig kidney or a pig heart. And that would be based on the companies involved, that that charge would allow them a reasonable profit. At the same time, government agencies and healthcare plans . . . need to see it as being a reasonable charge to be able to do anything widespread . . . on a clinical level.

So, based on these sort of models, a reasonable charge for organs has been bantered around, somewhere around $40,000 to $50,000 for an animal organ. And these are speculated charges, because we're not going to know what they're going to cost until the day they have them to transplant.

Is it evil?

No. There's nothing evil in companies investing hundreds of millions of dollars of investment in bringing a new technology forward, not to speak of hundreds of thousands of hours of hard work by their employees, and then expecting to make a profit. Why is that different than a semiconductor or a new technology applied to cars, or any such example in new technology?

Will there be a pig farm on the other side of my hospital now?

That's a fun question. One of the many challenges that faces the whole field of xenotransplantation, if and when it becomes a successful tool, is exactly how to handle the movement and harvest of these animal organs and tissues from the herd to the patient. Some organs and tissues can be harvested at distant points and shipped. So companies now are thinking in terms of models in which they would have special facilities matching special herds, and then you would essentially get organs and tissues on order.

And the coordination then would be that I bring a patient into the hospital at a given date and time, with the idea that it would be coordinated with delivery of the organ or tissue that I need for this patient's transplant, in a timely fashion, clean, healthy, ready to go into my patient.

In other circumstances, these organs or cells are not going to be shipped; they won't be able to be shipped. In which case, it does raise the very interesting situation in which a biotechnology could never afford to have a herd and a production facility in every single city in the whole United States or in the world. And then what do you do?

So it raises some interesting challenges about whether hospitals and institutions would either have to pool resources, so each city would have a central resource for doing xenotransplantation. Or it's even possible that they'll accept the responsibility that every hospital will have to have some sort of xenotransplantation preparation facility. And how that's going to be supplied, and how that's going to be billed, is way beyond anything I can speculate on.

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