interviewFRONTLINE presents Organ Farm

david k.c. cooper, m.d., phd

four patients
animal welfare
the business
the regulators

Cooper is an associate professor of surgery at Harvard Medical School, and an immunologist at the Transplantation Biology Research Center at Massachusetts General Hospital. He is the editor of the journal Xeno-transplantation and the co-author of Xeno: The Promise of Transplanting Animal Organs into Humans (Oxford UP, 2000). He believes we need to see organ survival in baboons for three to six months before we will be ready for human clinical trials. (Interviewed Winter 2001)

Why are we concentrating on pigs now?

. . . The reason we've moved to the pig, rather than the non-human primate such as the chimpanzee and so on, is that first of all, they're very much easier to breed in large numbers, and to house and develop. The non-human primates have difficulties with breeding programs, etc. So one is a logistic reason.

The second reason is the ethical concerns about using primates in large numbers for donation or organs, whereas we're much more ready to use the pig, because we already do use the pig for food and so on. And the third reason is that as the non-human primates have largely been caught in the wild, we have much less information about what bacteria and viruses they carry than we do about pigs. And so the risk of the infection is considered very much greater if we use a non-human primate than if we use a pig. . . .

Are there questions about the ethics of the animal trials of pig organs to primates?

I think all of us involved with non-human primate work are concerned that we're using these animals for experimental purposes. I think, however, that we do everything strictly very ethically. We give painkillers as we would to human patients, and I think we, at the back of our mind, have to keep in mind that the potential benefit to humans is going to be immense if we can solve this problem. I think that's the only way you can justify using these sorts of animals for this sort of work.

Is there a groundswell of animal rights activism in the US as it seems there is in the UK?

In the US, there has been patchy animal activism, largely, it seems, in the Midwest. But I don't think that it's got to the state that it's got to in the UK at the present time.

Why is that?

I'm not quite sure why. I am from Britain originally; the British always have had a love for animals, but I think it's more than just that. I think it's a group who have decided that they've got to make some sort of stand in the world, and they've chosen animal rights as the way to make the stand.

If you consider all of the things that we benefit from in the world, particularly in healthcare, they have all in one way or another been tested in animals. And as long as one is not inflicting pain on the animal, I think it's perhaps not very different from killing the animal to eat it.

It's even possible that pharmaceutical companies may be cut out of the field. Because here in Boston we're working on ways to try to make the human recipient what we call "tolerant" to the pig organ. Are there questions about manipulating the genes of animals?

I think in some areas there is concern, but for those of us in the field, there's not a great deal of concern. The manipulation of the pig will in no way make it anything still but a pig. It will have a minute amount, perhaps, of a human protein lining the surface of its blood vessel to give it some protection against the human immune response. The plan is to try to knock out in the pig a particular gene that makes a sugar or an enzyme that makes a sugar that lines the surface of the pig's blood vessels, against which our immune response is directed.

Now, that is not a big thing to do, particularly to a pig. For example, we used to have this sugar ourselves, and millions of years ago, somehow or other it got knocked out. And there are numerous other examples of this. This pig will have no human tissue in it, but it will have one of its normal genes knocked out. So what we're doing is not very dramatic; we're not changing the profile, in any way, of the pig. . . .

What are the regulators looking for now in terms of success with the animal trials? . . . What's it going to take to get to a human clinical trial with organs?

I was recently on a committee that looked into this for the International Society of Heart and Lung Transplantation. Our committee came up with a suggestion. We felt that if you could get ten baboons surviving for at least three months with some of them surviving for six months, being completely life-supported by a pig heart, in this case, or pig organ, then that may justify consideration to go into a clinical trial in humans.

Three months may not sound very long when we're really hoping that these hearts are going to keep people alive for years. But the difficulties of looking after baboons under the conditions that baboons live -- in cages, they're not very hygienic and so on -- the difficulty of looking after those compared with humans is very considerable. And we believe that if we could get to three and six months with a significant number of baboons with the same regimen that we're going to try in humans, we would do a lot better in humans. . . .

How close are we to the human trial?

We're not that close yet. We still have several problems to overcome. Most groups in this field can get pig organs surviving in the baboons or monkeys for at least a month. . . . A group in the United Kingdom got out to two or three months in occasional baboons, but the average is somewhere around a month or just over.

And that has required a fairly significant amount of immunosuppressive therapy. So I think we still have a few steps to take before we'd be ready for a clinical trial. And in fact, this committee that I was on decided that the time was not right for it at the moment. That's why we would be very encouraged to have a pig that didn't have this sugar on, because we think we may get significantly better results in that case.

What's your guess? How far away is it? Weeks, months, years?

At the most optimistic estimate, getting a pig like this is probably going to take several more months, and then, of course, you've got to breed a herd of them. So I think we're still two or three or four years, perhaps, before we're ready for humans. That's my own conservative estimate. But you never know. Somebody may come up with another breakthrough at any time and we may be lucky, we may be able to speed that up. But I think it's going to take a few years.

Where's the controversy in this? Is there a public debate? Is there a need for one?

I think there are two areas of controversy. The first is the use of animals for this purpose. I don't think that's a big issue, because we use animals for all sorts of purposes, and I think to anesthetize a pig and take his organs out is rather more humane than slaughtering [it] in the slaughterhouse.

But the second, perhaps greater area of controversy is if we're going to transfer a pig infection with the organ to the patient. Even that wouldn't be too bad, because the patient may benefit from the organ for ten years before he or she dies of the infection. But the concern is whether the patient will then infect people around him.

We're working very hard on that problem too. My own feeling is from the microbiologists. They tell me that the risk is pretty small, and I think within the next two or three years, we probably will have been able to overcome that risk entirely. So I don't think that's a major risk. I do say entirely; we may have been able to rule out any infection that we know about. There are always going to be infections that perhaps we don't know about, and one can't plan for that.

But I think if you don't move ahead because of unknowns with something that could be immensely beneficial, we probably would never move ahead in any sort of medical advance. So I think that if we've eradicated all known risks, that would be a risk worth taking.

What is the ultimate concern? What is the deepest fear?

The deepest fear is that we would have something like an AIDS epidemic on our hands; that the human population would have no resistance to some pig virus that we transfer, and it would spread from contact to contact. And soon we'd have another AIDS epidemic on our hands.

Are there issues also about the unnaturalness of all this? . . .

A segment of the population does have concerns about the unnaturalness of it. But I think it is probably no more unnatural than taking organs out of dead people and putting them into humans. This was considered revolutionary 30, 40, 50 years ago, and now the vast majority of people accept it and realize the benefits that can accrue from it.

And I think we just have to get our thoughts along the benefits that could accrue from animal organs. We've used these animals for many years. As you probably know, every diabetic who took insulin until a few years ago was taking pig insulin. . . So we've been using the natural resources of these animals for many years. I personally have put a large number of pig heart valves into human patients, because they're very similar and they do well. So we've been doing this little by little, and is it very different from putting in a valve to putting in the whole heart? That's the only step we're taking. . . .

What about this public debate about the virus and deciding at what point the public, for lack of a better word, gives its consent for this to go forward? How and when should the public debate this?

When we go into a war, we don't usually ask the public. I'm not sure it's possible to actually ask the public. But it is important to inform the public of the possibilities, and then it's up to the public to try to make themselves heard. . . . I think we're going to actually have to depend on committees appointed by the Public Health Service or the FDA or somebody to represent the public. And those committees -- which will include not only physicians and scientists, but also laypeople -- will be responsible to determine if this is safe enough to move ahead.

There seems to be a general mistrust of science in certain areas. Genetic food is a great concern now. Mad cow disease is a concern. Is there a concern that the public won't embrace this?

I agree there have been some episodes in recent years that have made the public perhaps a little more skeptical about what the scientists and the physicians tell them. . . . But if we could show that this is immensely beneficial to a significant percentage of the population -- to those patients who are dying of these various conditions -- then I think the public will be more ready to accept a small risk. It's a matter of the risk-benefit ratio.

Once we can show them that this really has some potential to impact their loved ones who may be unwell from one of these conditions, then I think the public will be more ready to say, "Let's do it."

And then there's the transplant physician, who says "Debate this. But every minute you debate this, we're losing somebody who could benefit from it."

At this stage, they have no reason to say that, because we're not ready to do it. We've got to solve the problem of the infection a little bit more. We've got certainly to solve the problem of rejection. Therefore, I think it's very good that the public can have the opportunity to debate this at this stage, and people can be heard, and the committees should be set up to consider public opinion. Sorting out these remaining problems will take a few years, so we have an opportunity to debate this. And we're not delaying the benefits to the patients, because we're not ready to benefit the patients. . . .

Let's go to that issue of informed consent. What are we asking of people? What are we demanding of people who are getting involved in clinical trials?

In any clinical trial, of course, you ask the person for informed consent. In many cases, it's very difficult for the patient to fully understand what he or she is going to go into, because the science is getting so technical and so on.

But in this sort of situation, they usually realize that they're dying, that their days are numbered. Therefore, they're usually prepared to accept some sort of experimental therapy if it's got a reasonable chance of keeping them alive with a reasonable quality of life. Now, it doesn't always work out like that. But people are willing to take that risk.

The big difference with xenotransplantation is that if there is still perceived risk to the patient's family, of infection, for example, then we may have to ask the family for informed consent as well. And then it gets very difficult, because how close in the family do you include? Do you include friends and so on? It would really get almost unmanageable.

We really have to be pretty certain about this risk of infection to the public and get that solved. And then we're really more or less on the same sort of ground as we were on with any other experimental surgery. The patient has got to have a pretty good understanding, and it should be explained as carefully as possible before they make a decision.

But until that point, isn't the issue of consent, in fact, very different where we're asking people for potentially lifelong reporting of sexual contacts? That's very different.

At the moment, if we are asking the patient to sign a consent form, but we're worried that there may be a transfer of an infection to a patient and to the patient's friends and family, then we're in a very difficult situation. Never before have we asked patients for this lifelong monitoring. And certainly we've never asked the patient's family for lifelong monitoring.

We have to resolve the problem of this infection, and be pretty sure that if there were infection, it would be confined to the patient and not to anybody else. . . .

How does informed consent work? And what would happen if somebody said, "No, thank you?"

One fundamental of asking for informed consent for any clinical trial is that the patient has the right to withdraw from the trial at any time if he or she wishes to. And that is so engrained in clinical trials that this would be a very different trial if you would not allow the patient to withdraw.

But, obviously, if you're worried that the patient might develop an infection, and that infection might be spread to the population, you obviously don't want the patient to withdraw, because then you can't manage them, and check their blood, etc., etc. . . .

Describe the monitoring that goes on now. What's the procedure?

One basic aspect of the guidelines is that you must keep blood and tissues from the patients from time to time, and store them, and test them. The storage is important, because maybe next year somebody will come up with a new virus that we should be looking for. So you then look at the stored material. There's very careful monitoring of the few patients that have actually been exposed to pig tissues in these trials up to date. . . .

What happened when Robin Weiss discovered this PERV virus? How did the FDA react? ...

Within the last ten years, knowing that people were already beginning clinical trials of cell transplants, and knowing that people were planning, or would like to plan organ transplants from pigs, one or two groups, particularly of microbiologists, looked into these pig cells to see what infection they could transfer. A group in London came up with this pig virus that's in every cell. And they found that if you culture that cell with a human cell in the laboratory, the virus will jump into the human cells. That suggested that if you put a pig organ into a human, eventually the human would have the same virus.

Now, there's really virtually no data that it causes the pig any trouble. And we have a very similar virus in our cells that doesn't seem to cause us any trouble, as far as we're aware. But there was the risk that if you put a pig virus into the human, maybe it would cause some trouble.

The microbiologists and virologists tell me -- and I'm not a virologist -- that this is a very "wimpy" virus. It's really not a very aggressive virus. But even so, it still may cause some trouble, particularly if it's there for 10 or 20 years. Their main concern is that it might cause an AIDS-like condition or possibly cancer. Now, if it causes cancer in the patient 20 years later, it may still have been worth the patient having the transplant. But if it causes an AIDS-like condition that is transferred to everybody else, obviously that's a big matter we have to consider.

So that raises the possibility that this bad scenario might come about. I think it stopped people from rushing in to do clinical trials, and made us think and do more research into this area. And a lot of research is going on at the moment to try to clarify this.

There was a group in San Diego that got the virus to transfer in mice. What's the significance of that?

The trial in mice that you refer had specially bred mice. They basically have no immune system. They have no protection against infection. They're rather like these bubble babies who are born with no cells that can protect them, and they have to stay in a bubble away from the environment. So it's an extreme trial. . . . And not surprisingly, they showed that if you put pig cells in, the virus gets out of the pig cells and infects the mouse. We would have all expected that to take place. I don't think there's anything really dramatic about that at all. It would have been expected, because these mice were so abnormal.

If you have to immunosuppress a patient with a transplant heavily, it begins to be like those mice. And so the significance of the trial was that if you heavily immunosuppress a patient, there is a risk that the virus will spread throughout your body. But, again, we have no evidence yet that the virus is going to do any harm. So there are several areas that we still need to clarify. Will the virus get into the body? Will it cause the patient harm? Will it get into anybody else? And if it gets into somebody else who is not immunosuppressed, will it cause them any harm? We have a lot of questions still to answer. . . .

What is the financial potential here? What's the market we're talking about?

The financial potential is considerable. And probably this is why some pharmaceutical companies and biotech companies are particularly interested. It has been estimated that probably we could do about four times as many transplants as we do now if we had an unlimited number of donors. . . .

Let's say you're going to do four times to five times as many transplants. That's a big potential, not only in sale of the pigs, but if you have to use drugs, that's a considerable amount of money. We spent in the United States something like about $5 billion a year on the care of patients with transplants. This would go up to, say, $20 billion.

The second thing is that if we could use pig organs, we could also use pig cells. For example, every diabetic patient, instead of having injections of pig insulin or other insulin, would be able to get some pig cells put into them, and they would then make their own insulin. And there's probably a couple of million patients at least in the United States, and probably a couple of million in Europe, if not more, who would benefit from pig islet cell transplants. So then, of course, you're talking of a considerable financial impact.

If you talk about that financial motivation of a company like Novartis, that I think I've read has put in a billion dollars, or is willing to put a billion dollars into this research, why are they doing that? And what is the expectation?

One shouldn't differentiate this from the development of any drug. Any very valuable drug is going to be beneficial to millions of people. And developing this field of medicine, developing these pigs, is going to be no different from developing a dialysis machine or a pig heart valve, or a mechanical heart, or whatever we want.

They're obviously looking to the commercial side of it, because if they're going to put a lot of money into development, there's got to be some prospect of getting that money back. But I don't think it's any different, really, from development of a drug or any sort of healthcare device.

It's very different from the human organ transplant model we're talking about. So what are you really what you're talking about -- companies trying to develop pigs that will then be a product that they can sell, just as if they were a mechanical device or something like that? Which model are we looking at here?

I believe that we will go completely away from this present system of putting a patient on the waiting list, and the organ being allocated to the next patient on the list and so on. I believe it will become very much the same as use of any drug or any other devices that are easily available. The patient will come to see you as a doctor. And if you think the patient needs a heart transplant, you will then phone up the pig place and you'll get in a heart tomorrow and you'll do the transplant.

This will have immense savings in some respects. Dialysis is much more expensive than a kidney transplant. So people will not be on dialysis for ten years waiting for a kidney. They will come in, and they'll have the kidney transplant while they're still in reasonably good shape, and there won't be all this delay. I've had patients waiting in the intensive care unit for two or three months at $2,000 to $5,000 per day. They will have the transplant the day they come in, or the next day. There will be immense savings that we will have to take into the equation.

And is there the possibility of fundamentally transforming the way some of this medicine is done? . . . Will you have those animal organs nearby a surgery unit?

My own feeling is that there will be several centers around North America and Europe where these pigs will be bred. Probably the organs will be taken out on the spot, and shipped, the same way we ship human organs in ice, etc. But it will be planned. They will be there at 8 o'clock in the morning when you're just opening the patient, and you're going to put the kidney in or whatever it is. . . .

There's one other aspect of the financial side of things that we should consider. We think of human organ donation as being free of cost, because the organ is donated for nothing from the patient's family's generosity. It isn't free at all. There's the expense of setting up to look after the donor after the patient is diagnosed brain-dead; the expense of taking the donor to the operating room; the expense of the teams coming in from different hospitals to take out the organs. That all costs quite a lot of money. And, in fact, if you add up the expenditure that is passed onto the patient, it ranges from something like $7,000 or $8,000 for a kidney, to perhaps $20,000 for a lung or a liver sometimes. The patient's insurance bears the cost of those expenses. And it may be that the cost of the pig will be in the same sort of range as the cost of going to get a human organ. So it may not be much more expensive. . . .

What is the motivation of a company like Novartis to do this work? I'm wondering how it connects to their work in immunosuppression drugs and feeling like, "Boy, if this thing is going and we're not a part of it, it could go past us." What is their motivation to be in this business?

One of Novartis' main drugs has been the most important of the immunosuppressive drugs that we've used in human heart transplants and human kidney transplants in the last 20 years. And it made a major impact on the survival and quality of life of patients. So it was a tremendous contribution. And if they could increase the number of transplants being carried out, then obviously the sales of the drugs would quadruple or whatever it would be. They felt that the only way to do this was to develop xenotransplantation. And that's why they decided to fund a lot of the research. It seems a sensible business move.

I think they perhaps slightly misread the rate of progress. And I was a little surprised that they were pushing ahead so rapidly, when it seemed pretty clear to me that we hadn't got all the answers. I think they tried to develop it perhaps rather quicker than the science would really allow. Having put that tremendous effort into it -- which was a tremendous stimulus to the field -- I think they probably became more disheartened than they would have done if they hadn't expected things to develop quite so quickly. That is my own reading of the situation. . .

And if you had to frame what the company sees the market potential to be in investment terms, what would that be?

The worldwide expenditure on xenotransplantation will run into perhaps $20, $30, $40 billion. What percentage of that Novartis or any other company will get will depend on how successful they are in their research. It's even possible that the pharmaceutical companies may be cut out of the field, because here in Boston, we're working on ways to try to make the recipient, the human, what we call "tolerant" to the pig organ. That means that you modify the human's response during the first few days when they have the transplant. Thereafter, when their immune response recovers, it no longer tries to reject the pig organ, but it treats it as if it's its own, so it becomes tolerant to it.

If that can take place . . . it means you never need any more drugs after the first month or two. And you no longer try to reject this organ. So if you don't need any drugs, the drug companies are in big trouble. They may support work that actually will be to their own detriment in the long run, as far as drugs go. But probably then, if you have to use their pigs, they perhaps will recoup their losses on the pigs.

How will that work exactly? Will the pigs be patented? Who will own the pigs? And will the pig organs be sold?

Several different groups have different pigs, and I'm sure they're all patented in one way or the other, like the way of protecting the pig organ from the human antibody or whatever it may be. The company who owns the patent or was licensing the patent or something will then obviously sell those pigs to hospitals, physicians, surgeons and so on. And they will recoup their money from selling the pigs, just as if they designed a mechanical heart or a dialysis machine. They would sell that to the hospital and they would be paid for it.

And if a drug company like Novartis is investing in that kind of effort or several of those efforts, how does that work? . . .

Presumably, Infigen will own it, because they will have the patent to it. And they will have shown that it could be done. But, probably, then maybe a big drug company will come in and license the patent from them to have control over breeding the pigs and distributing and so on. It's the same as with any other biotechnology advance. Somebody discovers it, patents it, licenses the patent to somebody else, who may in turn license it to a bigger company who can distribute or manufacture whatever they're doing on a bigger scale. . . .

When we talk about those people who are championing xenotransplantation, at least in the context of the film we're presenting, we see desperate patients, we see ambitious doctors and scientists, and we see pharmaceutical companies willing to fund this. Can you talk about that dynamic?

You've mentioned three points. The patient is desperate. And a desperate patient doesn't always make the right decisions, so we have to guard against that. What will happen in that respect, though, is that if we can develop this as a form of therapy, a few years down the line the patients won't be so desperate, because we'll be choosing patients who are less advanced in their disease. This has happened in so many of these transplants, certainly in heart surgery. The first patients they used to do were desperately sick. Now you do it electively, before the patient gets desperately sick. So that will evolve with time.

And it would probably be unethical to take patients initially who were not desperate, because why take somebody who's managing and put them through an experimental procedure like this? They've got too much to lose, whereas the desperate patient hasn't got too much to lose. That is one aspect that will gradually evolve with time.

You mentioned ambitious surgeons and ambitious scientists, and that is quite true. Many of us are ambitious in one way or the other. That is probably what drives a lot of these scientists and surgeons to do this sort of work -- because they want to make a mark in the world. They want to achieve something. They want to do something that will have an impact, and there's nothing wrong in that. But we do have to have committees set up by, say, the Public Health Service, and in Britain, by the government and so on, who make sure that that is not the only reason why we're going into a clinical trial. They've got to temper the enthusiasm of some of the scientists and so on. . . .

Similarly, with the pharmaceutical companies, we tend to look at them and criticize them for wanting to make money out of all this. But if we didn't have pharmaceutical companies who are willing to risk all this money, most of us would probably be dead by now, because we would have had some disease that we wouldn't have been able to treat.

We have to put the whole thing in perspective. I don't think we should look at the pharmaceutical companies as the big bad wolf. We must look at them as companies that are prepared to take considerable financial risks to try to help develop this further. My understanding is that, for every thousand drugs they develop, only one gets onto the market. And the cost of developing the others to one degree or the other is so immense that they have to recoup their costs with that one that reaches the market. It's going to be the same with the pigs.

Once upon a time, a doctor pushing forward a new technique or procedure would have gained fame and made his mark and be in the history books and be remembered. Now, some of the key scientists, who are really the experts at some level in this new field, also stand to make a lot of money if it goes forward. Is there a concern about that?

I don't necessarily think there is. In the past, as you mentioned, there may be a surgeon who develops a new operation. He made a lot of money because people came to him, and they wanted to have the operation. And so he had a very busy practice. Many scientists in the past have made money from their discoveries. I don't think there's anything wrong in discovering something that may benefit lots of other people. I think what we must ensure, though, is that we are not experimenting with patients purely because an ambitious person wants to make money or whatever it is. We have to have some regulatory oversight of the whole thing, deciding if we're ready to go into a clinical trial, and deciding if we should stop the clinical trial if necessary. . . .

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