FRONTLINE presents Organ Farm

the ethical and social questions

Selections from FRONTLINE's full interviews with xeno researchers and a medical ethicist on the issues involved in financing xenotransplants, conflicts of interest in its development, unknown risks to the population, and the need for more open public discussion on xenotransplantation.

four patients
animal welfare
the business
the regulators

alan h. berger
He is Executive Director of the Animal Protection Institute and is a member of the Secretary's Advisory Committee on Xenotransplantation.

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The big financial picture. Does xenotransplantation make sense?

Well, it depends on how you want to spend your money as to whether xenotransplantation makes any sense at all. ...I think it's really important, when we're dealing with health care dollars, to be able to set priorities in terms of what we're trying to do and where that money can be best used. And xenotransplantation is so expensive and it will benefit a certain group of people, that it may not be worth the dollars spent.

Those same dollars may be better spent or may save more lives or improve the quality of more people's lives spent in different arenas and certainly spent better in the arena of preventing illness rather than trying to cure diseases.

. . . What about the cost to the consumer? Do you have a sense of what it will cost to get a pig heart?

I think the cost to the consumer could be astronomical. Let me give you some estimates in terms of cost. The Institute of Medicine in 1996 tried to estimate what the actual cost of xenotransplantation would be in terms of health care. And they estimated the cost to $20 billion a year. Last year I went through and tried to use my own figures--just based on published figures that are out there, to try and estimate what I thought the actual cost would be. And I came up close to $35 billion a year.

The question would be: how is that paid for? How is it that we're going to support a $20 billion a year industry, a $35 billion a year industry? It has to be supported by Medicaid. It has to be supported by Medicare and it has to be supported by private health insurance. And the cost of that is very interesting because the cost comes in a number of ways. The major one being that premiums go up. Because you now have very expensive new surgical techniques and the only way it's going to be paid for is if premiums go up. And the other way it can be paid for is that you get rid of certain other coverages to be able to support xenotransplantation. So the cost to all of us could be frightening.

Do you have a figure on how much per procedure or how much per organ or is that just something we don't know yet?

I don't really know yet in terms of the price per organ. I have heard prices going from as little as maybe $10,000 dollars to as much as possibly $50,000 dollars. The actual transplant surgery itself, putting all of the costs together, depends on whether it's heart or kidneys or liver or so forth. And I've seen estimates for the transplantation surgery itself, all of the costs going anywhere from maybe $125,000 dollars to maybe as high as $400,000 or $450,000 dollars.

Daniel R Solomon, M.D.
He 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 Xenotransplantation.

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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, before we can define the dimensions of the new technology, before we even can define the risks of the new technology---to delve into the ethnics is in some ways critical, but premature.

So 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.

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?

It is now becoming very clear 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.

Now, 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, that's a high--you know, that's 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.

So 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.

Fritz Bach, M.D.
Bach is professor of surgery at Harvard Medical School and Beth Israel Deaconess Medical Center and director of the Immunobiology Research Center. He is on the editorial board of the journal Xenotransplantation.

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What are some of the key ethical issues posed by xeno?

If we put the public at potential risk we have to inform the public and take segments of the public who are well-informed to discuss with us and help us to find the conditions under which we could proceed.

In addition to the infectious risk, there are other issues that are very troubling that need to be addressed. Informed consent: A key part of informed consent is that the patient can withdraw at any point afterwards. We need these patients to be monitored for life or for a very long time.

A third point: There are people who are very offended by the idea of putting human genes into a pig or putting pig organs into a human. [And] people are deeply offended, are deeply troubled by this, I think it needs to be addressed.

We're not yet at human clinical trials on organ transplants. So why, before we can even technically find out if it's going to work, should we address the ethical issues? Why address them before?

I have to give two parts to that answer. The first relates to xenotransplantation; we would like to have this discussion -- and in fact we should have started it three years ago -- we would like to have this discussion so that if we get to the point we don't have to hold back one day in terms of applying it. We can potentially save lives, and if we wait with the discussion until we're sort of there, somebody is going to want to put in a kidney or a heart, and has every right to if we have the methodology, and we won't have had the discussion. It's a perfect opportunity.

The second part is it's a more generic problem. It's not xenotransplantation alone; there are many technologies out there, many bio-technologies which the public is going to have to look at and evaluate. And the sooner we get started to understand the public's concerns -- their fears, in fact, and how they would handle this in society, the better off we are. . .

Why have the discussion now? Why is it important?

There's a terrible conflict between the need to save lives -- without wanting to be dramatic -- and the need not to put somebody at risk without informing them and getting their response. Fortunately, in some technologies, we're not ready to use them yet, but we know they're going to be available. And those technologies, we need to have the discussion now so that we have the response from the public and are aware of what the public wants if we're going to proceed with those technologies. We need to use this space that we have now. It's a wonderful window of opportunity.

Why call for a moratorium on xenotransplant?

A moratorium is a temporary hold. It's not a banning forever. We felt, and I still feel strongly, that we need to go to the public before we put them at risk. Just wrong to put them at risk and after having put them at risk -- because we're already doing transplants which have this potential risk -- say, "Let's discuss it now." The purpose of the moratorium was to have a hold, a period of time while we could have that discussion, define the parameters under which we could then do a xenotransplantation, hopefully, and then go ahead without having to wait if the technology were already developed. . .

Do people have an agenda and are--

Oh, yes, the people have agendas, no question, the people who want to promote xenotransplantation. I'd love to promote xenotransplantation, and forgetting the ethical issues I'm one of the strongest supporters. There are others, some of whom are doing it perhaps because it will add to their fame or it will add to their financial wealth or whatever. There are people who are dead-set against it and who I think have not bothered to look at the facts very much, they just have taken one issue.

I think the way to proceed is to get all of these facts together and present them in a balance way. The extremes will be included, but people will realize that big arguments for, big arguments against a given issue that is ethical, let us say, but then have a discussion of that where somebody helps, as a facilitator for the discussion but not a facilitator trying to push it one way or the other, just trying to get those people to consider all the fact. They'll realize that even if they could never benefit from xenotransplantation that altruistically their decision may decide whether the three year old girl who needs a transplant will die or live. They have to know all of that and then help make the decision.

And has their been a real public discussion about xenotransplantation -- where are we?

We're not very far as I see it in the United States. In the United States, the FDA, Food and Drug Administration, has had open hearings, which means that a person would have to know the hearing is taking place, pay their way to Bethesda, Maryland, and then try to get time to speak.

I went down there and I think I'm a rather prominent individual in xenotransplantation and was told I couldn't speak from the podium, I should speak from the floor, keep it very brief. Very difficult; it's not a way to get public participation. There's been a lot in the news, but it hasn't been in a way to catch the public's attention. The vast majority of people, if you go to them, they still say, "What are you talking about?"

But in other countries yes, for instance, in Canada there's now a public consultation program that is being run, where exactly what I've been talking about will be done. That has happened in Holland. They have a xenotransplantation website, they've had meetings, they've publicized it, the highest level officials have been there. It's going on in England, there's a big trial. So in other countries, public engagement, public consultation is going on, and in fact many of those countries have taken the stand that we proposed in the paper: Until we have the public discussion, let's have a moratorium and then see how we might proceed. . .

. . . There's a need for another effort which will deal with the ethical issues-- I use the term ethical very broadly-- the potential risks, be they physical, economic, be they value risks, to society, family, or self. Something else needs to be there, another organization, another committee, another structure, but it has to be a structure acting on behalf of the people and that has the faith of the people. . .

From the point of view of other issues, there are people who are very disturbed at the idea of moving genes around, which is being considered enormously for the future of medicine. And in the case of xenotransplantation of course, it was putting a human gene into a pig that allowed us to get over the first, vicious phase of rejection that we ordinarily see in the xenotransplant.

The kinds of issues are a pig, if it's like a human -- we now know how many genes there are in a human because the genome has been sequenced -- if it's one gene out of thirty-five thousand, does that make the pig part human? What if it's five genes? What if we have to use fifteen genes, which nobody has considered? When do we start humanizing a pig, something very disturbing to many people.

These are very difficult issues, and I could tell you that some of the religions feel very strongly about this and that people in society feel very strongly about it. Again, I think it needs discussion, but it's clearly an issue that needs to be addressed.

We need to remember that our responsibility as physicians and as citizens is, for altruistic and for reasons of self-interest and for reasons of interest in our family and our community, greater than just saving the life of a patient who needs a transplant. That's very commanding, but we also have to think of the general effects of anything we do these days, be it changing the weather, be it a new way of making children more intelligent by giving them genes at the time of conception; any of these things.

We need to think of what are the potential ramifications. And again, from an ethical point of view, if I put you at risk, I can't make that decision without coming to you and saying, "I'm doing this," you know, explain it to you. You don't need to know how you make a transgenic pig. It's irrelevant to you. "This is what the experts say, this is where they disagree." I'm giving you a balanced view, now let's talk about it, and you talk about with friends and your community and your associates, and let's together work toward helping everybody maximally and to the extent we can, having the risk be as low as possible, at least acceptable to those who have been put at risk.

David K.C. Cooper, M.D., PhD
He 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 Xenotransplantation and the co-author of Xeno: The Promise of Transplanting Animal Organs into Humans.

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How and when should the public debate this?

If there's a risk of infection to the patient, but then there's a risk of infection from the patient to the public, a lot of people have suggested then the public should be in on making this decision. It's extremely difficult, though, to know how is we get them in on other decisions that are equally important to them.

When we go into a war, we don't ask the public usually. So, I'm not sure it's possible to actually ask the public. But, I think it is important to inform the public of the possibilities, and then it's up to the public to try to make themselves heard. And, I think, this sort of program is one such way. Or writing a book about it is another sort of way to keep the public informed about what are the benefits and the risks.

But, I think, we're going to actually have to depend on committees appointed by like the Public Health Service for the FDA or somebody or other to represent the public. And those committees, which will include not only physicians and scientists but laypeople, I think their responsibility will be to determine if this is safe enough to move ahead no. . .

And what about the transplant physician, who says debate this--but every minute you debate this, we're losing somebody who could benefit from it.

I think 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. And 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.

And, trying to sort out these remaining problems, I think will take a few years. Then 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.

Norman Daniels, PhD
Norman Daniels, PhD is a professor of medical ethics at Tufts Medical School as well as the Goldthwaite Professor in the Tufts Philosophy University Department.

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What do you see as the key ethical issues being raised by xenotransplantation?

We have to distinguish issues that are common to, to xenotransplantation and many other areas of advance and ones that are really distinctive for xenotransplantation.

Let's start with issues that are distinctive for xenotransplantation. The one that we've heard the most about internationally is the potential risk to third parties. This is of course on the public's mind. We now know that HIV was transmitted to people, through a variation on an agent that came from animals, but we're hearing all about Europe mad cow disease and its effect on people and industry

What we now see as distinctive is the following: Most medical research and most medical treatment involves a tradeoff of risks and benefits. That there are risks and benefits to the same person, the patient, and the whole focus of medical ethics has been on drawing attention to that and providing informed consent to that tradeoff.

Xenotransplantation has a different component. The benefits and risks are again to a patient. But there are now a set of risks to third parties who are not any part of the agreement between the doctor and the patient when an organ is transplanted. And it's the third party risk that is distinctive about xenotransplantation. . .

The fear is that some virus that might be carried inside pig tissues will turn out to be very dangerous to people when their immune systems are compromised, as they often are in transplant settings. These viruses can transform themselves when they cross species barriers. An agent that's not dangerous to a pig may turn out to be very dangerous to people. A new agent may evolve through combination between the material that's in the human and what was in the pig, and it's the combination that may be distinctive and dangerous.

So if there is this risk, how do we quantify it?

The risk to third parties is something that we at this point can't quantify. And that of course means some people want to dismiss it; other people say it's miniscule. But how small it really is, is not something we can put a number on. And given that the stakes might be very large -- for example, viruses that cross animal boundaries that are not dangerous to their hosts are often deadly to other animals when they do cross the boundaries.

We can't quantify the probabilities here, or the overall magnitude of the payoff and the risk. But, there is an enormous uncertainty, and what we have to deal with is the fact of uncertainty. . . There has to be an adequate mechanism in place through which third parties can consent to the kinds of risks that this procedure might impose.

If there's a potential public health risk, who should be weighing and making the decisions about whether to take it or not?

Let's suppose for a moment that there's a public health risk. We don't know how to quantify it. This is a decision that the public has to undertake. And my view is that this has to be through a fairly elaborate process that involves a broad range of stakeholders in the decision. Not only the experts who obviously have to be involved and the clinicians who are anxious to save their patients, but representatives of a broader group of the public that have to participate in this. And the mechanism has got to be a broad one that engages in education of the public over time.

Otherwise, we risk a harm that we haven't talked about yet, the harm that if it turns out these are dangerous procedures, people who have undergone them may become stigmatized, may be viewed as Typhoid Mary, and will be the object of enormous concern by the public. The people who did the procedures will build public fears of new technologies.

And it seems very important to have a process in place that undertakes a careful evaluation of the risk and gives the public some broader way to consent to that risk, rather than simply leave it in the hands of a narrow group of experts.

. . . Why broach these issues now? As you say, they haven't even technically gotten to the point where they can show it works?

This is exactly the point at which we have to raise these questions, before we know it works. We can't know it works without running clinical trials on people, without putting organs into people. We can do a lot of animal research that will help pave the way for making those procedures on humans more safe and the risks better understood. But we can't get away without trying this on people.

And so what's needed is a public process that's well in place so ahead of time, so that what we're not facing is a particular patient on television saying, "I will die tomorrow unless you let me have this organ tomorrow," and you haven't thought about what the risks are to the third parties. We have to think about it now before we have something that works.

Isn't it fairly new that we're talking about the possibility of a major virus being introduced into the greater population and being introduced by men? It's a new kind of question for us, isn't it?

Well, it's a commonplace now in public health discussions to comment on the early death of what we had taken to be the end of the era of infectious disease.

We now see that on a global scale, we are not free of infectious diseases. There are new kinds of resistance emerging in various very prominent diseases. And so a new agent like HIV virus, that has created one of the worst epidemics we have ever seen in the world, is very much on people's minds.

The fear that we could accidentally create something of comparable stature is, you know, a fear that has to be dealt with. It may be that it's an exaggerated fear. But how do we know it's exaggerated until there's been a reasonable public discussion? Simply listening to an expert say, "This can't happen," is to repeat what we've seen throughout the century: experts are wrong about often things that they claim to know the most about.

Is there a question too about whatever responsibilities we have to future generations about the decisions we take now? Do you see it that way or not?

Yes, there certainly are questions about obligations to future generations. But I don't think we have to think very far into the future. Certainly the concerns that we ought to have to future generations are big ones on a global scale, such as protection of the environment, global warming, and the release of new disease agents that we inadvertently accelerate.

. . . But we don't have to have a grandiose thought about distant generations. Our children and grandchildren are around us and they will have to put up with the decisions we make.

Why call for a moratorium then?

The call for a moratorium was primarily a call to put a certain kind of public process in place and not to risk letting the cow out of the barn without adequate caution. . . The risk here is letting the pig out of the pen, just as we let the cow out of the barn.

And my concern is that we could set back a useful and valuable technology if we don't manage public perception of the risk properly. And that management of the public perception requires an ethical requirement -- that we give the public and opportunity to consent to that risk. This is the fundamental ethical issue that is distinctive.

. . . And there are other important ethical issues, in addition to the issue about consent. For example, one important issue is how could we describe the benefits to people and describe what counts as a success?

Suppose that pig hearts or pig livers only live for a short period of time in people -- two or three years, four years. Now, that's significant to somebody who's dying. But if the technology only offered that prospect of success -- because, for example, pig organs are programmed to live in an animal that doesn't have a human life span, then perhaps we will find that we've now invited on board a technology that requires people to go through spark plug changes every six months. Well, it might be three or four years.

Not only are the costs phenomenal, but the quality of life sacrifices are huge. And we will then be caught in a situation where we have not evaluated what counts as success.

The scientists who are most expert in this are no longer going for just career fame, but there's a fortune now in a big way possibly?

It's certainly true that many scientists who are engaged in this piece of research around xenotransplantation could make fortunes through their investments or founding relationships to companies that stand to benefit from this technology. But this is not a distinctive feature of xenotransplantation. This is now the emerging feature surrounding all of biotechnology. And it's not less of an ethical problem because it's not distinctive. It's, in fact, a fundamental problem facing the whole of technology in this world.

We're not used to dealing with the kinds of conflict of interest that will be perceived to be present in this situation. What do we say when a researcher who is now also a company owner and who stands to make tens, hundreds of millions of dollars from a new technology, says, "Join my protocol; be a research subject. I'm just interested in the generation of knowledge and in saving lives"? We can't that that fully at face value, even with disclosure. We have to have a new understanding of how to address this problem.

What would the worst case risk scenario be with xenotransplantation?

The worst case risk scenario would be that we produce a new disease agent that is of grave danger to humans. You know, it's also possible we can produce a new disease agent of grave danger to pigs, and that should not be lost sight of. We could turn out to turn the harmless retroviruses that now exist in pigs into very dangerous viruses once human elements are included in them.

And what are the things that people need to keep in mind?

You know, there's a very interesting contradiction that we see. After all, we're in an error of direct-to-consumer advertising of drugs. And we see these drugs being pushed on television and in newspapers and other media all the time. So clearly, institutions like large pharmaceutical companies and bioengineering companies know that public interest in an issue is a valuable commodity if they can shape it the right way.

At the same time, there's an enormous fear that the public will not understand the benefits that are being offered and will react in irrational and ways that exaggerate risks.

So on the one hand, we have companies that are trying to make people enthusiastic about things that might benefit them whether or not they are really that important, and on the other hand, shy away from having a clear discussion of what the risks are because they fear the public will be irrational in the way it grasps risks. There's a kind of contradiction in that. You want to trust the public to buy your products, but you don't want to trust the public to make decisions about what's risky to them.

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