FRONTLINE presents Organ Farm
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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. Bach and colleagues have called for a moratorium on clinical trials until the public fully understands the risks and benefits of xenotransplants. (Interviewed Winter 2001)

. . . What are a couple of the key ethical issues posed by xeno that we have to face?

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, such as informed consent. A key part of informed consent is that the patient can withdraw at any point afterwards. But we'd 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. If people are deeply offended and deeply troubled by this, I think it needs to be addressed.

Why should we address the ethical issues before we can even technically find out if it's going to work?

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, so 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 a more generic problem. It's not xenotransplantation alone; there are many technologies out there, many biotechnologies, 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, and how they would handle this in society, the better off we are.

What do you say to the transplant surgeon who is facing desperate patients and is talking about need and he says, "Discuss, discuss, public debate . . . just remember, the clock is ticking. Just remember, every seven minutes, somebody who could benefit is dying."

I'd say that we're in the fortunate position in xenotransplantation where we can't do the organ transplants yet, because we're not ready to. It's a perfect opportunity for that transplant surgeon to participate with us, to discuss with the public what their feelings are. We cannot proceed, putting the public at potential risk, without doing this. Ethically, we can't. And so this is a perfect time to do it, I say that to the surgeon.

We're functioning in a society.  And we need to inform the society of what we're doing, and I think we need, again, to bring balance into this by involving the public.And I don't want to wait until that surgeon comes to me and says, "I know how to do this and the organ will probably last a lifetime," because then the tension is enormous. . . . We need to use this space that we have now. It's a wonderful window of opportunity. . . .

There's an enormous pressure on any physician who has a patient in need; the Hippocratic Oath commands that we take care of that patient. But as physicians today, given the technologies that are developing, I would say as a physician, that we need to take care of our patients, as well as any potential patients that are affected by our actions.

The Hippocratic Oath today, I think, should at least imply or explicitly cover the responsibility that we carry to consider both the patient and others who might be affected. The dictum of medicine is, "Primum Non Nocere." ["First do no harm."] That's not only for the patient; that's for anyone else you affect by what you're doing. And it's a very difficult problem, but it has to be attended to. You can't just say, "I have a patient dying; I have to save the patient's life." . . .

Before we use xenotransplantation, can we guarantee public safety?

No. But we live in a world of risk. The big differential I make is . . . these decisions that we're making affect others, who frequently don't even know we're making the decision, who don't know how to spell xenotransplantation or maybe even don't know what xenotransplantation means. That's a very different kind of risk. We will never be able to say there's no risk. But I think that the public is there to help us. . . .

How do you get the public to say yes?

You don't get the public to say yes. You don't walk in there with an agenda ahead of time. You walk into the public and you give them an absolutely balanced -- insofar as that's possible -- recounting of all the facts, the wonderful benefits and the risks. And if people disagree about the risk, you tell the public about the disagreement. They have to have good, complete facts insofar as they can be gathered. And once they're informed, then you discuss it with them.

You don't try to get them to one side or the other. That would defeat the whole purpose. And there are highly developed methods to try to get the public to help, in a sense, hopefully to define conditions that would allow them to buy in. But you can't walk in with an agenda. You have to walk in and listen to the public.

What is the situation today? Do people have an agenda?

Oh, yes, 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.

What I'm saying is that I don't think this is the way to proceed. I think the way to proceed is to get all of these facts together and present them in a balanced way. The extremes will be included. . . . But people will realize that, even if they could never benefit from xenotransplantation, 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.

Has there been a real public discussion about xenotransplantation? Where are we now?

As I see it, we're not very far in the United States. In the United States, the 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. I think I'm a rather prominent individual in xenotransplantation, and I was told that I couldn't speak from the podium, that I should speak from the floor, and keep it very brief. That's very difficult; it's not a way to get public participation. There's been a lot of coverage in the news, but it hasn't been in a way to catch the public's attention. If you ask the vast majority of people, they still say, "What are you talking about?"

But in other countries, yes. For instance, in Canada, there's now a public consultation program. . . . In Holland, they have a xenotransplantation web site; they've had meetings; they've publicized it; the highest level officials have been there. In England, there's a big trial going on. In other words, in other countries, public engagement and public consultation is going on. In fact, many of those countries have taken the stand that we proposed in the paper, which is, that until we have the public discussion, let's have a moratorium, and then see how we might proceed.

What kind of discussion do we need to have?

We need much more effort to inform the public in the United States. The public needs to be aware of the potential risks in a balanced way, along with the potential good, which . . . is potentially enormous. But then we need a discussion with select informed groups, probably across the country, who will be able to cross-examine the experts, who will really try to grapple with this and define the issues that the public is concerned about. They'll help us define the conditions under which those issues would be acceptable. And that should go in with the opinions of the experts or the other stakeholders, and then a decision should be make. Doing it without that, no matter what the great potential of xenotransplantation -- which I applaud and participate in -- is unethical.

How are we asking something different of someone in a xenotransplantation situation than we have asked in the past? What's new about this issue of informed consent for a patient?

If we speak about informed consent with regard to the patient, it's exactly the same. There's one huge difference. . . . If that patient, having heard all the disadvantages and advantages, still wants a xenotransplantation, then we need that patient, and probably the close contacts of that patient, to sign on the dotted line and say, "I am willing to be monitored for life." I'm not sure there's a legal structure that permits that. I think that the dignity of the human being, the rights of a human being, allow that patient, as is true under informed consent, to withdraw from the trial.

Let's take it that one step further -- the close contacts of concern. It's possible that the disease could get past a close contact, and that patient would first show the symptoms even before the organ recipient showed symptoms. What if the person changes their close contacts? How are we going to handle that? I just want a discussion of this. I'm not sure there are solutions. But the facts have to be out there, and the people that are being put at potential risk have to have a serious say in this after being well informed. . . .

What are we asking of people? How realistic is it?

. . . If you see a patient whose choice is a xenotransplantation or death, I think that most patients would say, "I'm willing to be put under a lot of restrictions. I like my life." But for the sake of society, we have to have the right legal structure in place and the right ethical concepts that would allow one to say," You will have to be monitored for life," if that is the decision of the experts, and after the public input has come in. But I have heard no experts say that we shouldn't have monitoring, and at least for many, many years.

Is it reasonable? I think for the patient, to decide that would be quite simple for most. If I had to give blood every week for the rest of my life, and it was a choice of I live that way or I don't live, I don't think it's much of a choice. But it gets more complex when you go to their closest contacts and when you consider that people do change their contacts. We need a discussion of this and we need to go to the public, who is being put at risk, to help us in that discussion. . . .

What combination of forces is . . . championing the idea of xenotransplantation? On one hand, you have desperate patients. On another hand, you have ambitious docs being funded by drug companies. . . . It's a pretty potent mix, isn't it?

It's not only potent; it's a wonderful mix, and a very dangerous mix. . . . There are the patients in need -- a very powerful force. There are the physicians who really want to take care of those patients, who really want to help patients, as presumably we all should be doing.

But there are also scientists and physicians who see this as a tremendous boost to their careers, their reputations, and the potential of big prizes coming their way. And of course there is perhaps the major force in our world today -- the multinational corporations. Where the balance of power sits between them and the governments today is a very interesting topic of study. Is that wrong? No, they're there to make drugs, to develop procedures that will help humanity. Is it wrong for them to have the power to make the decision without further input? Yes.

And that is why you should have a balance, not to slow xenotransplantation, but to have a discussion of the ethical issues. And ethically, the people who have the most say should be the people who are being put at risk -- the public.

. . . So against this array of people who, for one reason or another, want to move it forward, there has to be a balance of discussion for ethical reasons. But I would think that many of the multinational companies, the biotech companies, are beginning to see that if they don't do this, they risk disaster. And we've seen that often enough, so that a lot of companies are setting up a way of involving the public. Some are setting up ethics committees inside the company, I think with the best of intent, sometimes. But I don't think many people believe that that's an independent ethics evaluation. The public is going to have to regain its confidence that their interests are being well served, and we need mechanisms for that.

What happens when you have drug companies at the heart of funding and promoting this kind of new technique and research?

If you look over the past 20 years, there's been an enormous change in the relationship of the drug companies, the pharmaceutical companies, and the laboratories that produce a lot of the original science that goes into therapy. At first it was, "Can we look in? We'll give you some money for your research. Can we sort of look at what you're doing?" . . . Today, in some cases, the pharmaceutical companies are the only ones who have the money to undertake procedures that are really expensive.

To make a transgenic pig is a huge commitment. To test that in non-human primates as the recipient is a huge expense. It becomes a problem when the pharmaceutical companies can control whether or not a given line of research will go forward when they're funding it because nobody else can afford to fund it. And they can use their PR apparatus to put out their view to the public in those cases where it's not balanced. In some cases, I think they make a major effort to have it balanced.

And what about the scientists? What about just the potential for, or even the perception of conflict of interest for the scientists? On one hand, they are the experts doing the work, the key players. Yet they stand to benefit, both in terms of career -- which has been the traditional case -- but now suddenly, potentially, by millions of dollars in the process. . .

There's also a problem of conflict of interest at the level of the scientist-physician. The scientist today frequently owns a part of a biotech company, may have founded a biotech company, and his or her work may contribute to that individual becoming a very rich individual. One should never diminish the importance to many scientists of fame and fortune, with the emphasis on fame. This kind of thing has enormous value, in that regard.

The medical establishment is perhaps the biggest offender in terms of having created its own little compound. That includes the government, the regulatory agencies, the pharmaceutical companies, the biotech companies, the physician-scientists, the surgeons, everybody, and saying, "We have studied so hard and so long that we don't have the time to explain to the public what is going on here." One of my best friends at dinner last week said to me, "I don't have the time to deal with this issue. I'm trying to solve the problem."

I don't want to be critical of my colleagues, because probably they could be critical of me in the same way, but I find that a bit arrogant. We're functioning in a society. And we need to inform the society of what we're doing, and I think we need, again, to bring balance into this by involving the public. I think they're going to force us to do it anyway; why don't we look like the good guys and say, "We're putting you at potential risk; come help us, come discuss with us"?

What's the size of the market we're talking about here? People have said that Novartis and others are spending a billion dollars. What are we talking about here?

Since you bring up Novartis, you should know that I'm a paid consultant to Novartis. . . . I can only quote you the figures that I've read. We're talking of a $6 billion to $10 billion a year market for xenotransplantation. It's a huge market. But I would look at it from the other side too; it's a huge need.

. . . In fact, the enthusiasm of so many, including myself, for xenotransplantation, is because there's such a huge need. We're talking of potentially hundreds of thousands of people being helped per year, and being given a good quality of life by xenotransplantation. But we would be foolish to ignore the fact that a huge market is involved in this. I'm not an economist, but what I read says we're talking of a $6 billion to $10 billion a year market. That's all right, if it's handled properly. It's good, if it's handled properly. It presumably is good for our economy and it certainly is good for the patients. But if it's not done well, and it's not done in an ethical manner with the public involved, then I would view it a little differently. . . .

The FDA has an ongoing committee . . . to grapple with the technical issues. But I also understand that we're talking about getting together a broader advisory committee to talk about the larger issues. Where are we, and where aren't we, in terms of government regulatory agencies?

In the United States, the Food and Drug Administration, as I understand it, has the ultimate authority to regulate xenotransplantation. They've been working for years, and I think in a very credible way, to deal with the technical issues of this infectious risk. They've had committees; they've had meetings of stakeholders. They've really gone through multiple revisions of their policy, based in part on feedback that they've gotten from the public -- although it's not clear to me what that public is -- certainly not the public I'm talking about that I'd like to consult here.

And in 1998 when I went there, my main point, and the paper that we passed out, was that, "We need to involve the public." We need a broader public that is going to deal with this with some of these issues. At that time -- and whether it was based on our paper or not is irrelevant -- they said, "We're in the process of establishing a committee to do this. We just spoke of the importance of doing this quickly, so that if we can start saving lives with xenotransplantation, we can do it without delay." But it is now more than three years later, and as far as I know, there's no established committee.

And when it gets established, I, at least, don't know whether the constitution of that committee is going to be the right one for most of us to deal with the ethical issues on behalf of the public in a way that the public is going to trust.

Why should we have a moratorium?

We should have a moratorium to allow the public discussion, to allow the public to be informed -- as many people as possible -- and to have segments of that public participate in what is known as public engagement, public deliberation, to help guide us in how to play. And as soon as they've helped us and we can define the conditions of how to proceed, then we should drop the moratorium, and, if we're ready to do it, move ahead with xenotransplantation.

What are the stakes for those companies funding this research?

It's very hard for me to tell you what the stakes are for a company like Novartis, in terms of funding this research. In part, they do it because they feel it's right for them to fund research that hopefully will lead to better medical care. They have a fiduciary responsibility to do it on behalf of their stockholders. In that case, I assume that asking if it's a good investment or not is part of their reasoning.

The part that I'm sure they considered deeply -- the part that was being considered even while I still was consulting for them -- was: What is the risk here? What is our exposure if there were to be a complication from xenotransplantation that we have promoted? What is the risk here to us if huge settlements start coming in? . . .

How does the FDA regulate in this field, where it can encourage the innovation that's needed, but protect public safety at the same time?

. . . The FDA and the CDC need to grapple with what they're grappling with: that is, the infectious risk and other potential risks that are technical in nature. 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, or 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. . . .

Is that realistic?

Oh, it's absolutely realistic. Private groups -- private in the sense that they're not involved with the government or with industry -- are trying to do this, are trying to look at the ethical issues. There's a committee that might well have done it -- I think they would have needed more experts -- and that's the President's National Bioethics Advisory Committee, NBEAC, as it's known. They dealt with cloning when Clinton asked them to. But they deal with the ethics, and I believe they are insulated from pressure. . . .

What's the big problem to moving forward with xenotransplantation?

Number one is to solve the rejection problem. We're talking about organs. The other problem . . . comes under the heading of ethical issues, such as, what if the pig virus were to infect the recipient of a pig organ and that recipient spreads it to close contacts and then into the population? How do we handle this? This is a potential risk: how do we handle it in terms of who makes a decision as to how we're going to handle that?

How big a risk it that a virus could escape into the public?

I believe nobody knows how big the risk is that a virus would escape [into the public] based on xenotransplantation of pig organs into humans. And I think people who reason through the fact that it's a very small risk because of this, this, and this, are basing it on their very small knowledge. But it's hypothesis; it's their reasoning, and it's not fact. The answer is that we don't know what the chance is.

But at the same time, I have to say to you that there are two kinds of risks. One is a risk that is quite likely to happen, but the result is somebody gets a cold for four days. The second is a risk which may be very unlikely to happen -- and I'm not saying that's the case here -- it's very unlikely to happen, but if it happens, the end result could be catastrophe at a global level. . . .

What will it take for us to move to human trials of organ transplants in xeno?

I would love to see happen what I think is needed to move on to human trials. Number one, we need to solve the remaining rejection problems. We need to think out ways to prevent the pig organ from being rejected after transplantation, in ways that use acceptable medical treatments.

Number two, we need involve a public that is well-informed in a balanced way in the discussion of the conditions under which they would find it acceptable to undergo the potential risk that they will be exposed to. . . .

Are there ethical issues that we're not thinking about in terms of manipulating the genes of the transgenic pig?

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.

. . . And we now know how many genes there are in a human, because the genome has been sequenced. If it's one gene out of 35,000, does that make the pig part human? What if it's five genes? What if we have to use 15 genes, which nobody has considered? Many people find it very disturbing when we start humanizing a pig.

These are very difficult issues. 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. . . .

Are there issues the other way that are disturbing to people relating to this question of the unnaturalness of pigs in humans?

In terms of having pig parts in a human, we've actually done that for many, many years. We've used pig valves. Now, that's non-living, if you like, but it's still a pig part. But if you start thinking about an eight-year-old kid running around the schoolyard and none of his friends know that the boy has a pig heart, you start dealing with some real social issues. And even at the ethical level, there are people who object. . . . I don't think it's a huge part of the reaction, but I'm always ready to be surprised.

In England, we've seen . . . very strong animal rights voices that we don't seem to see here. I've talked to animal rights people who say, "Pigs saving lives for people is a one-on-one trade-off; it's not something we're going to win." Is there a more comfortable environment in this country, both regulatory and in terms of acceptance that invites the research coming this way?

Certainly, the United States is an easier place with regard to animal rights to do this kind of experimentation than Britain is. . . . It's very clear that, as we proceed to try to set up a sense of under which conditions can we proceed, that we need to address this globally. The potential risks are global, especially in something like a viral infection if it were to be like AIDS. And in that sense, we need to have some sort of a global group that will address this. Is it ethical for one country to proceed for something where a potential outcome of that procedure puts another country at risk, where that country said, "No, we don't want to be doing this because of the risk?"

You try to get consensus; you try to get agreement, and you try to define those conditions. And there are countries where they've said, "No, we don't want to proceed at the moment. At the least, we have a moratorium in place." We need a global effort. We need to get people together on this. . . .

Why are companies leaving England and coming to the US for xeno research?

To do the kind of research that is needed if we're going to move xenotransplantation towards clinical application requires an environment where the regulatory agencies, as well as certain advocacy groups in the public, are accepting of this kind of an approach. Clearly, England is not. The regulations that England has put out for xenotransplantation are lengthy and quite fastidious. Also, the issues of animal rights in England are very big. The fact that we've had this Mad Cow Disease has not helped the issue.

I think America is a much more inviting environment. America is wonderfully willing to push back the frontiers. I love it. I think it's great. And I think the regulatory agencies and the government want to see new ideas used and have people benefit from them. I think that goes even to animal rights. There are groups here that are very conscientious, and even groups that I find a bit extreme in animal rights, but it's nothing like England. . . . I don't have to point out to you the difficulty in this, in terms of living in a global society.

Does that put an extra degree of pressure, or present a concern that agencies like the FDA should be aware of, to take into account? Companies are coming here because it's easier. It's friendlier here; the money is here; the will is here. So what kind of burden does that place on regulating the field?

There should be no change in the burden that an agency, such as the FDA, has because companies want to do this kind of research here. They should have a set of principles and criteria that they follow. . . . So many people look to America to set the regulations; to have done the research that is necessary and everything. So I do hope, and I suspect, that the FDA is fully cognizant of its responsibility, because its decisions affect much more than the United States.

. . . Do you see xenotransplantation being a realistic thing on our horizon?

I do. I think the approach of some of the pharmaceutical companies and biotech companies has been the wrong one, but that's my personal opinion. I think we need to do more genetic engineering of the pig. I've been saying that for years and years. And I think we have candidate genes -- in fact, there's one company now that clearly will take that approach -- and I'm still semi-optimistic that we will have this. If we could have it in an ethical framework, it will be an incredible move forward in medicine. . . .

Amidst the enthusiasm for xeno, what else do we need to remember?

We need to remember that our responsibility as physicians and as citizens is greater than just saving the life of a patient who needs a transplant -- for altruistic reasons, for reasons of self-interest, and for reasons of interest in our family and our community. 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 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," and 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. Then let's together work toward helping everybody maximally, and to the extent we can, have the risk be as low as possible, and be at least acceptable to those who have been put at risk." . . .

As a society is there a point at which we should say, "Benefit-risk, okay, let's do it?"

I think there will be technologies -- and I don't want to say xenotransplantation is one of them -- where we'll say, "This is just not acceptable." I think there are other technologies where we'll say, "Okay, we understand it. If you take these security measures -- if I can call them that -- then okay, let's go ahead. But let's not say okay for the next hundred years. Let's say that we're going to do this for one year, and see what happens and then revisit the issue." I think people are altruistic. And I think that they will realize the need for xenotransplantation, and they will find conditions that make them comfortable.

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