Xenotransplantation is very dramatic. Not only are we taking an organ from an animal, but we're saving a life. There are thousands of people on waiting lists who will die without organ transplants. There are many researchers who stand to benefit enormously from the breakthroughs that come here, not just in terms of their honest interest in saving lives, but from the career and prestige that comes from it, and now the huge amounts of money that will come from this new industry. So there are a lot of vested interests interested in showing that this technology has to move forward without obstacles. . . .

What about the mix of desperate patients, ambitious doctors who are willing and wanting to help them, scientists who are stakeholders in ways, and drug companies willing to fund them? What does that mix produce?

There's an explosive mix of people who are interested in promoting this technology as well as others. We always see a desperate group of patients who will die without some breakthrough. It could be cancer or it could be something else, and a new technology down the road promises solutions. Corporations are now heavily invested in promoting those technologies -- it could be big pharmaceutical companies, it could be bioengineering companies -- and researchers who find themselves invested heavily in the technologies that they are trying to promote.

This mix does not produce caution. . . . It produces a situation in which it's very easy to forego caution. It's very easy to say that anybody who wants to think twice about the rate at which we're proceeding and the process we go through in order to proceed is simply sacrificing lives. And we hear that message, that anybody who raises a question has lives on his hands.

That seems to me to be an unfair point, because one of the points being made about xenotransplantation is that there are risks to third parties that have to be evaluated. And those lives are also worth something.

What do you see as the key ethical issues being raised by 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. Of course, this is on the public's mind. Not only do we now know that HIV was transmitted to people through a variation of an agent that came from animals, but we're hearing all about Europe and mad cow disease and its effect on people and on industry. The idea that we can become infected from agents that come from animals is, to some extent, in the public mind.

What we now see as distinctive is that most medical research and most medical treatment involves a tradeoff of risks and benefits. 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 is 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. It's the third-party risk that is distinctive about xenotransplantation.

What's the big fearful concern about what might happen?

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 can't quantify at this point. That, of course, means that some people want to dismiss it. Other people say it's miniscule. But how small it really is isn't something we can put a number on. And the stakes might be very high. 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.

A circle of experts who are highly engaged and involved in the research are saying, basically, on some level, "Leave it to us. We know what we're doing. Trust us. It is a tiny, tiny risk we're talking about."

My inclination is to believe experts, as many people would, because they do know more about these things than we do. But that isn't really the issue. In a medical setting, we have emphasized the importance of informed consent. Patients don't know as much as their doctors, but they must give informed consent to whatever procedures they go through. We've had a revolution in our understanding of the power relationship between doctors and patients. And the main weapon that's been used is to try to emphasize the importance of informed consent.

But what is the consent here of the public to the will of the experts? 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. . . .

So is that mechanism in place? Who do we trust? Who will be making this decision?

There is a set of guidelines that the FDA has announced, and many of the features that you'd want to pay attention to are singled out in those guidelines. Emphasis is placed on the importance of informed consent. But there are a lot of loose ends to this problem that are not adequately addressed in guidelines. . . .

Let's take the standard research protocols. Suppose somebody undergoes a research experiment, and they know that they will be monitored over some short period of time, usually for the effects of the experimental regimen that was introduced. That person can later say, "I don't want to go through this anymore. I've given enough blood, and I don't want to be tested anymore." There's no risk to a third party in that person backing out of the experiment. The person will simply reduce their value to the experimenter in producing the information needed. That's the only risk.

But if somebody who's undergone a clinical trial, an experiment of an organ such as this is now being asked to be monitored for years, and to inform the researcher of all sexual partners or changes in sexual partners. We're beginning to see a new level of intrusiveness in monitoring that we don't find in any other setting. And we have no way to enforce agreements that people made at the moment at which they undertook to get the organ.

Is there a simple way around that in xeno? Will it be a matter of a year or two before we know that long-term monitoring is not going to come into play?

I'm not a scientist who can answer that question. But my perception is that we can't know that there's no risk except over a period of years. Most of the understanding of the research protocols calls for monitoring people over a period of years. The reason for that is that the process through which viruses could recombine within people might take a period of time. An agent that is transmitted by an organ to a patient may take a while before some particular recombination emerges from it that is dangerous, and we would have to find that. We have no way to test in advance for what it is.

. . . What about the patients who are desperate at that moment for a cell transplant or an organ transplant, and who say, "Yes, happily. I'm signing on. Do you want my brain afterward? I'll give you that, too." How do you relate that to what you just said, and to the situation that those patients find themselves in?

A patient who would die without an organ is going to be desperate to undergo some way of saving herself. . . . A patient like that poses what's often the hardest case for informed consent. Not that it's irrational to take risks when you have nothing to lose -- it isn't irrational. But we do want some reassurance that a patient is well informed about what the risks are.

And here we have to give people enormous uncertainty as an answer. We can't say that we know exactly what the risks are. . . . This is a research context. We have to say to somebody, "Look, there may be a risk to you of getting a disease that we've never encountered before. There may be a risk to your family of encountering this disease. Now, would you like to save your life? Of course, we can't tell you it's going to work. We only have results in animals."

So now this is a very complicated problem for a patient. It's not just the benefits and risks to the patient; it's the benefits and risks to the people that that patient loves.

Is it reasonable for us to make those demands on a patient; to say, "We want to monitor you for life, and by the way, in death, too, we need a few parts back from you"?

It seemed quite reasonable to ask people for this kind of commitment, under the conditions that we're operating. . . . We can't forget the promise in worrying about the risks. The promise is that we will save many, many lives. There is a public benefit that can result from this, and that is the driving force in most people's minds.

Yet, we have to be cautious, and we do have to ask patients for a commitment on this part. We have no way, however, and no institutional mechanisms and no legal framework for enforcing those agreements that people make in the moment of desperation. And that is of grave concern.

Let's go back to this other idea you mentioned before about third parties, which in some sense, we tend to describe in terms of public health. 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 that are anxious to save their patients, but representatives of a broader group of the public 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 been 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. 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.

And what do you say to that transplant surgeon who says, "Look, process it all you want. Debate it forever. Just remember, every seven minutes I've got somebody dying here who could benefit from this thing." What do you say?

A lot of that is, after all, just promise. They don't have procedures now that will save patients who are dying every seven minutes. They're hoping to develop those procedures. And I don't think we should get stampeded in ignoring what may be a public risk simply because there are people in need. We probably could save many more lives than the lives of these patients through other procedures we could follow in a public health domain, and nobody talks about the risks to those patients here and abroad. We get caught in a kind of avalanche of emotion to save this particular group of patients, when in fact there are probably many things we could do to save larger groups of patients if we attended to them.

So I don't think we should be so driven by the worry of these transplant surgeons who are looking at patients facing death every day. Yes, there are patients facing death every day, but there are many people facing death every day. We all face death some time or other. And the issue is, how do we evaluate the best ways to use a new technology, and are we being adequate in our consideration of the risks?

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, 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 ahead of time. What we don't want is to face 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 third parties. We have to think about it now, before we have something that works.

You said we could be stampeded. But I'm wondering, in this era of awareness of AIDS and mad cow disease, where is society's trust now with scientists when they bring us an exciting and promising new technology like xenotransplantation and say, "We're on the cusp. This could change things?"

I am not somebody who is skeptical about technology and the advances it can bring, because all of us who are of my age have seen a revolution in what medicine does, just within our adult lives. On the other hand, it's very important to understand that the health of the public, the health of a whole population, is not primarily the result of what medicine does for us. It's primarily the result of a lot of social structures in the society and broader public health measures. And yet we believe that it's the next magic bullet that is going to suddenly revolutionize our lives. That isn't the main thing that's contributed to our health and the longevity that we now see around us.

So we have to take with a grain of caution the concerns that are advanced when experts say we are going to change the way the public lives. . . .

On what basis should the public decide to take this risk or not?

The public has to have a process in place that lets them understand the risks to family members, to relatives, to sexual partners, and to the public at large. And the public has to have an opportunity to play a role in designing the institutional responses to those risks. When that's done, the public may be very happy to take certain risks. We take risks all the time. We go skiing, we take risks; we drive a car and we take risks. Life is full of risks. The issue here is not how to live in a risk-free environment. The issue is, how do you come to grips with the risks and have a sense that you are somewhat in control of the risks you're taking?

It's fundamentally important that the public feel that it's controlling the risks, and the risks are ones that it has considered. If the risks are risks that other people are imposing on the public, then we get an exaggerated response to the level of risk. Most of the cases in which the public has risen up with an uproar against risks that they perceive have been because of the lack of control of those risks. Genetically modified food is one example. Not that there aren't risks that have to be considered, but the public feels it had no control in the process.

Isn't it a fairly new kind of question, when we're talking about . . . the possibility of public health risks from a major virus being introduced by humans into the greater population?

It's common 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 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 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, where experts are often wrong about things that they claim to know the most about. ...

Why, then, call for a moratorium?

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. . . . 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 carries an ethical requirement that we give the public an opportunity to consent to that risk.

The call for a moratorium is a call to put into place the mechanisms that give the public an opportunity to consent. This is the fundamental ethical issue that is distinctive about xenotransplants.

What are the other ethical decisions here? What's the most controversial aspect of xenotransplantation? Is it the queasiness people feel about the unnaturalness of animal organs going into people? What's at stake here?

I don't think that's a huge problem. I don't think the problem of the fact that we're using animal parts in people is something that people really feel terribly about. We've been using valve parts for many, many years, and people who've had pig valves in their hearts don't think that they've become pigs as a result. I don't think people will be anything but grateful for the sacrifice that the animal made for them. I don't think those are the central issues.

The central issue here is the ability for people to give appropriate kinds of consent. And there are other important ethical issues, in addition to the issue about consent. For example, 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, or 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 using a technology that requires people to go through spark plug changes every six months for 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. So one of the important pieces of research that has to be done here, and conceptualizing of the problem, is to characterize what success is in this situation.

Is this organ transplanting the same as we're accustomed to thinking of, or is this going to a different kind of mode -- where companies are developing a product that they'll be able to shift onto man? How is it fundamentally different?

There's a fundamental difference between the kind of human giving that has been a central component of the ethical framework around organ transplantation -- a gift of life given by one dying person or their family members to another who might then live. This has framed the whole problem of organ transplantation, and it's very dramatic, and we think of it as a wonderful move that somebody can make. There was a child who was killed in Italy, and his organs saved seven people, and that family is now revered in Italy.

If we now shift to a new mode, we have benefits and perhaps a little bit of the loss of the sense of giving. The benefit is obvious. We are now not dependent on people being willing to give their organs. We have a commodity that we can buy. And that's, in fact, probably a benefit overall, because it will mean many more lives are saved. It's more important, perhaps, than the issue about the donation of the life.

Is it also different that the people who are championing this stand are now at the heads of biotech companies and stand to prosper from it?

It's very important to understand that there are features of the xenotransplantation environment that are shared with many other areas of medical research. There's a set of ethical issues here that are not distinctive to xenotransplantation, but are common to many areas of new research. We have large industries being started around new technologies, with billions of dollars ultimately at stake, and huge rewards to the people who found companies . . . that promote advance for people.

Is there a worry that the scientists who are most expert in this are not just going for career fame, but are also going for fortune now, and in a big way?

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. In fact, it's 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 or 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 . . . accept that fully at face value, even with disclosure. We have to have a new understanding of how to address this problem.

How do you balance that enthusiasm? Certainly in a program like this, you hear from both the patients who are expressing need and doctors who are very enthusiastic about each next step being taken. What is the voice tempering those?

There has to be public understanding of the benefits and risks of new technologies. And we have to undercut a bit the infatuation that the public has with new technologies -- an infatuation cultivated extensively by the media and by the vested interests that stand to benefit from these technologies. . . .

Part of the reason that these drug companies let in documentary filmmakers to look at the process is that they hope to influence public perception. What are the things to keep in mind?

We see a very interesting contradiction. After all, we're in an era 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 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, they 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.

What do you think is motivating a company like Novartis to get involved in this?

Most large companies are motivated by two things. Many people in those companies want to save lives and produce a benefit for a public. At the same time, they have a responsibility to their shareholders to generate a profit. And those two concerns have to interact within any corporation that is dealing with medical benefits for people. And sometimes, the corporate considerations clearly outweigh concerns about human welfare, which is why we have to take government actions and have orphan drug laws and other ways of trying to subsidize things that won't actually be profitable for particular companies.

Is this a patented product? How will the economics of this work?

It may well be possible to patent some of the components of these procedures. And there may well be proprietary gains for companies. Companies wouldn't be investing in this unless there was a way to exclude competitors from what they're doing research in.

So my guess is that, down the road is probably a multibillion dollar industry built around harvesting animal parts and selling them as commodities on a medical market, where there will be considerable demand for them. There's nothing wrong with that, in my view, provided that we deliver reasonable benefits to a broad public, that there's adequate access for all parties to the benefits that are delivered, and that we treat people in a just way in distributing the benefits. Part of that issue of justice is distributing the burdens fairly, and that means allowing for consent to risk where there is some. . . .

And do you think that the FDA and CDC are taking a very active and cautious approach on this, or not particularly so? Are they being overwhelmed and swamped by the research and drug community efforts?

My sense is that the FDA has approached this problem the way it has approached many other areas of technology development -- without adequate attention to the concerns about public risk assessment, which is the distinctive feature of xenotransplantation.

Public hearings are held and guidelines are released, and the public is invited to comment on them. But the kind of public education campaign and involvement of people at a high level in a commission intended to review this from a broad public perspective has not been done. A committee was promised several years ago that, to my knowledge, has not been set up -- a committee that would have addressed these public issues in a more appropriate way. . . .

How important, or not, as the case may be, are some of these other issues that will clearly be raised in viewers' minds, despite the pictures they see? Manipulating genes in animals, using animals in research -- how important are all those things versus what you see as the real central question?

It's interesting that animal rights activists who have a history of being quite militant in this country, with regard to, say, use of animals for furs or cosmetics, are not saying anything about xenotransplantation. And it's actually quite wise of them not to say something. They have nothing to gain by saying something here. They're dealing with a line of research that has great promise of saving human lives. And I don't think the animal activists will be in a good position if they have to come out and say these animal lives are worth more than human lives. There are many other cases where the main point of their message can be gotten across, where we mistreat animals for what may be thought of as frivolous human purposes. . . .

As far as manipulating genes and modifying animals, we have the pigs we have only because we've been doing that for centuries. We have the dogs we have only because we've been doing that for centuries. It seems to me that we modify animals all the time for good and bad purposes. We breed dogs that are vicious. . . .

Some of the research is coming here from England. Is there a sense that there's a much more friendly and accepting and easier regulatory atmosphere in the US for xeno?

In Europe and in England, there has been a lot of discussion on a more public level about the risks. Parts of Europe have an explicit moratorium on clinical research. The Netherlands is engaging in a process of public education and deliberation about this before they authorize going forward with other steps.

The regulatory climate in the United States has treated this line of research as standard research, without giving adequate attention to the third-party risks to the public. In that sense, there's been a different climate here than abroad.

What about the criticism that we're throwing money at to basically extend people's lives and having people who are living too long anyway?

This raises this question about whether investing in this area is worth it, compared to other things we could do with our resources. Are we worshipping the extension of life at the sacrifice of other goods? That is a very broad and deep question. I would not like to see the burden of it placed just on this particular technology. It's part of a much broader question. How do you improve population health in a society?

We have enormous amounts of evidence that the heavy investment in particular medical technology -- xenotransplant and other technologies -- doesn't have a major effect either on population health levels or the distribution of health within that population. And there are many other things we could probably do that would actually work to the benefit of the public health more than the investment in these dramatic procedures that save individual lives and extend them marginally.

So why the excitement over xeno?

I don't think it's excitement over xenotransplantation more than certain other promises that were being offered in the medical arena. The genome project has promised us revolutions up and down the line in the way we handle many other diseases, not just organ failures. We are in the grip of a public demand that is partly shaped by the drama that programs like this bring to issues like xenotransplantation. The public is constantly educated about the next revolution, at least as far as its promise goes. What it's not educated about are the tradeoffs and the opportunity costs of investing in this, rather than investing in something else.