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hugh auchincloss, jr. m.d. home
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Auchincloss is associate professor of surgery at Harvard Medical School and associate visiting surgeon at Massachusetts General Hospital, as well as chair of the FDA's Subcommittee on Xeno-transplantation. He serves on the editorial board of the journals Xeno-transplantation and Transplantation Reviews. He believes that although there is not enough data to justify whole organ xenotransplants, we should proceed with limited, carefully monitored cellular xenotransplant clinical trials. (Interviewed Spring-Winter 2000)

Would you like to see xenotransplantation work?

Absolutely. In fact, I have devoted most of my career to contributing to that effort. You're probably aware already that, in transplantation, one of several major limiting features of the field is that we don't have enough organs to go around, and that people are dying waiting for heart transplants, liver transplants. People are waiting for four or five years in this country to get kidney transplants. And while they don't necessarily die during that time, it's a tremendously lower quality of life, and that's only the beginning of the problem.

If we truly had enough organs to go around, we'd have the opportunities to treat new diseases, and to treat different kinds of people who currently aren't even candidates for transplants. And even on top of that, we'd have the possibility that you could add gene modifications and gene therapy to xenotransplantation. That all means that this field could potentially change the whole character of transplantation.

So if it worked, it wouldn't be a treatment for the few? Would people like you see it as a mass transplantation operation?

I truly believe that, and I think it's an important point to make. In the debate on the xenotransplantation, we keep talking about how there's a risk to the many, but only a very small number of people get the benefit. The fact of the matter is that's not the case. Not only are there a large number of patients who could benefit from xenotransplantation right now; but you're talking about changing the field in such a fundamental way that it truly would be a different kind of medicine for the future for all people.

. . . Let me give you one tiny example. One of the fascinating features of xenotransplantation is that you have an organ that's used to functioning in one species and one environment -- say, a pig liver -- and at the point when we put it into a human, you will find that there are things that the pig liver does, that the human liver does, or the pig liver doesn't and the human liver does do. And we can learn actually about the physiology of our organs by doing these transplants. It's an extraordinary learning experience from everything that we do -- not just the immunology -- but in all aspects.

Is there any downside to this? Is there a risk in this?

The answer is clearly yes. All transplantation, of course, has enormous risks associated with it, both from the drugs that we use to keep transplants in place, and because the operations are large operations. But here we are going beyond a significant risk to the individual patient. Here we are talking about unknown risks of transmitting infections from animal species into the human population in a way that hasn't happened before.

I don't believe that the survival that has been achieved for solid organ xenotransplants into non-human primate recipients has been sufficient to justify clinical trials. All  essentially have been rejected by, say, three months. That's not long enough toSo this is a public health risk?

That's the distinction to be made. There wouldn't be any of the public debate going on right now if we were simply talking about how to make this a safe procedure for the individual recipient. The fact of the matter is that, from an infection point of view, we can undoubtedly make animal organs safer than human organs, because we have so much more time to screen them and really find out that they are safe. The issue is a public health risk -- a very, very tiny risk of introducing a brand-new, disease-causing agent into the human population. That's where the debate is. . . .

In the difficult decision-making overall, do you have to take public opinion with you? Do you have to educate the public about these risks?

It's an extremely complicated question to know exactly how to incorporate the public's view on an issue that is clearly of importance to the public. It is so complicated that, frankly, the experts don't really understand entirely what the risks are. How do you turn to Mr. Man-in-the-Street and say, "How do you feel about this?" when no one knows what the risks really are?

I think that the right way to handle this is to continue to involve the public to the extent that the public finds this interesting. The public is best served by turning to its official agencies -- in the United States, the FDA -- which can gather the expertise on behalf of the public to address these issues, with the public's welfare in mind. I don't know of any other reasonable way to go about this. This is not something you can take a vote on; you wouldn't get an intelligent answer. . . .

. . . Do you see any marked difference between the cellular transplants -- carrying with them, as they do, the retrovirus in every single cell -- and maybe later in the future, a whole organ transplant? Is there much of an order of difference?

From the point of view of the infectious risk, I really don't think there is any significant difference. We have been struggling with the FDA to try and determine if there certain kinds of transplants that would have such a low level of risk associated with them that they should perhaps go first. Some of those include the artificial liver, where the pig cells are on one side of a membrane separated from the body, and they don't live for a long period of time. The fact of the matter is, that even in those circumstances where there is a conceivable transmission of the retrovirus to the human cells, if I have not identified a particular type of transplant that is so risk-free that we can just say go ahead and do that one, then we'll concentrate on others.

Haven't we then, in a sense, already begun xenotransplants?

Oh, I think it's so important that people understand that. Xenotransplantation is not a future event; it's a current event. And it has been a current event; first of all, in a number of trials, as you're aware of, dating back even to the 1960s; but more practically, right now. Over the course of the past several years, cell transplants from pigs to humans have been occurring. They've been occurring under the supervision of the FDA, and are carefully, carefully monitored. They're not in large numbers, but they are happening. Xenotransplantation is happening right now.

. . . Is it possible that a virus can be activated or made more virulent by the transplant process?

I think the answer is probably yes, the transplant process could activate this virus. A more significant feature is that the techniques that we are imagining using to make xenotransplantation successful -- which include genetic modifications of the pig and various treatments of the recipient -- those modifications and treatments clearly reduce the ability to prevent the entry of this virus into the human cell. So there are features of how we do a transplant that make the transfer of this virus to the human cells more likely than it would be otherwise, and I think that's a very important point.

Obviously, human beings and pigs and many other species have lived in the same environment together for a very long period of time. And this transfer of the endogenous retrovirus from a pig to a human hasn't happened. So what's different about xenotransplantation?

What's different is the feature that the cells are, we hope, going to live long-term in the human body. Second, the natural processes or defense mechanisms that prevent the transfer of this virus will have been removed.

Living with pigs is very different from living with living pig cells inside you, isn't it?

Yes, but you can imagine that, over the course of eons, there's contact, say, in a slaughterhouse, or a patient on chemotherapy for leukemia could work on a farm and come in contact with pig blood in some fashion or another. I think one has to imagine that human-pig contact over all of the ages has been of a sort that would enable transfer to occur, except that we have defense mechanisms in place to prevent it.

One quality that viruses have is the ability to change; they can mutate. They can also lay dormant for long periods of time. Do these qualities of the virus give you any comfort, as it were?

I don't think they give me comfort. Could the current pig endogenous retrovirus, the sequence that defines that virus, change to turn it into a more virulent or different kind of virus? The answer is yes, it could. And we talk about recombination events, where the pig virus joins up with genetic material that's already in the human cells and makes something completely brand-new. These events can occur, we believe, and we don't know what the outcome of them would be. One has to keep in mind that these events probably do occur in nature, regardless of whether a surgeon is talking about xenotransplantation. So there's a fuzzy line here -- what are we really doing that's different?

The body's rejection system . . . is also our main mechanism of defense against animal viruses. Do you get the sense, or do you feel the responsibility, that we are actually tinkering with a very major barrier between us and the beasts?

I think that's a little too dramatic a way of putting it. . . . The fact of the matter is that all transplantation is a delicate balance between diminishing the body's defense system in order to allow human organs to be transplanted, and allowing people to survive despite the fact that they are taking those immunosuppressive drugs. It's something of a miracle that drugs like these have been developed to make transplantation possible. I think there will be new drugs, new modifications of the immune system, and new modifications of donor animals that make it increasingly likely that xenotransplantation can be successful. But I don't see it as a fundamental shift in what is happening in medicine in all areas.

. . . There's lifelong immunosuppression of the transplant patient, together with the insertion of human genes into the organ from the pig that's coming to the human recipient. Do you think that could actually assist animal viruses to evolve in new ways to infect us?

Yes, I think that's true. Some of the genetic modifications of pigs that have already been performed make it easier for the pig virus to transfer into the human cell. That is true.

. . . The blood-to-blood contact between humans and live pig cells were extremely rare events. Are we, in a sense, increasing the number and regularity of those events?

I think that there is no question. If you are successful in getting pig cells to survive in a human, we are increasing the exposure of humans to the pig and the retrovirus. And there is no way you can escape the feature that we are doing something that's important to monitor and determine the outcome.

I believe the FDA has taken on its responsibilities in a superb manner -- involving the public, conducting the debate, involving experts, gathering the information, and proceeding ahead with trials in a responsible, cautious mannerWe moved away from primates to pigs as a potential source of organs in these xenotransplants in the belief that, because the pigs are not close genetic neighbors of us, the chances of any of these crossovers would be lessened. Do we know that?

We absolutely do not know that. I have listened to the real expert scientists debate this at length, and it's clear to me that we don't know the answer to that. Are we really safer using a pig instead of a non-human primate as the donor? To be honest with you, my view from listening to the experts talk is that we have no particular evidence to justify that.

It's reasonable not to use the non-human primates at this point, primarily because of the breeding circumstances. If we really want to produce the cleanest possible animals, then several generations of breeding in captivity are the way to do that, and you can do that realistically with pigs. It's very difficult to do that in substantial numbers for non-human primates. . . .

Are we at the stage now where, quite soon, we actually need some kind of human clinical trial to resolve a lot of these problems?

Not only are we there -- but it's happening. I do not believe that there is good, sufficient evidence to justify solid organ xenotransplantation. So I don't believe we're ready to put pig hearts into people. I don't believe we're ready to pig kidneys into people. I just have not seen the evidence that we have overcome the immunological hurdles.

But some cell transplant trials are in progress now, and I think that's good. I'm talking about neural cell transplants, and potentially, islet transplants to treat diabetes, and liver cell transplants to treat various forms of liver failure. I think there is sufficient evidence to justify that. And it provides us the opportunity to do that in small scale, to monitor those patients with incredible diligence, and to learn. There is no way we are going to learn about the real dangers of this endogenous retrovirus without doing the clinical trials.

How closely do you feel we have to monitor these patients?

You have to monitor them very carefully, and I think you have to monitor them essentially for life, as long as this xenotransplant is in place. We need to be collecting blood samples before the transplant, around the time of the transplant, and at periodic intervals thereafter. We need to be watching carefully to determine whether unusual events happen to these patients, and if so, can we determine an explanation for them? And all of those things are happening in the FDA monitor trials that are occurring right now.

What's the motivation behind some of their life restrictions? We have spoken to a number of patients who are recording their sexual partners. What's the thinking behind that? . . .

The concern is that if this unknown virus were to develop . . . it might be transmitted or probably would be transmissible . . . by blood contact or by sexual contact. And therefore the lifestyle restrictions that have been established for patients who are receiving xenotransplants at this point really mirror those that you would expect somebody who was HIV-positive. So there is no blood donation; there's safe sex and recording of partners. That's so the FDA in the future could potentially go find those people and determine whether transmission had occurred. So, yes, it's blood transmission and sexual contact that we're concerned about.

And was the immediate family of that patient who has received the transplant also tested?

Some of them were tested. We have been referring in the FDA conversations to intimate contacts.

Kissing partners.

Yes, not necessarily grandma and Easter; the people who are really day-to-day in very intimate contact are the people that we're most concerned with.

If there was a virus, could we deal with it?

I think the answer is, of course we don't know, because we don't know what this virus looks like. The expectation is that it wouldn't cause a disease, but the ultimate concern is that you create AIDS II by doing xenotransplantation. And nobody is quite capable of saying that that's impossible.

The beginning of this biotech revolution is rather like the beginning of the industrial revolution. We don't know everything. We can't offer guarantees of safety to the public, can we?

I think the true statement would be that we don't even know what the questions are at this point. The way we look at this is undoubtedly going to change so dramatically over the course of the next hundred years that we don't even know what the issues are that we're going to be addressing.

In a sense, do you, as one of the regulators, feel the pressure or the responsibility of not lifting the lid on Pandora's Box?

I do, but I think it would be an equally wrong thing to prevent potential benefit to as many people as can benefit. I see no way of going at this except to proceed very cautiously, very responsibly, and to do the monitoring. I don't think you flip open the box and let everything out. I think you peek and you peek a little bit more and you peek a little bit more. I don't see that you can stand still, and I don't see that you should just assume that it will be okay.

Some of the animal experiments and the sort of survivability of animals and baboons who have had pig organs transplanted into them are used as the model for us, in a sense. Are you happy with the sort of survival rates for various organs that have been achieved so far?

I don't believe that the survival that has been achieved for solid organ xenotransplants into the non-human primate recipients has been sufficient to justify clinical trials. I believe that for two reasons. All of them essentially have been rejected by, say, three months, and that's not long enough to warrant clinical trials. We don't think that xenotransplantation brings a benefit to people if it gives them three months of survival.

There is the group that then will argue against that and say, "But gee, it's so hard to do these experiments in animals. It's much easier in people. We have better drugs, so we could do much better. And this is better than the survival that we had before we started doing human to human transplantation." And that is true, but in my view, there are two major differences. One is that here we have an alternative. We don't have enough of them, but for the individual patient, there is the alternative of having a transplant from a human being. And that is by far a more successful transplant at this point.

But there's another difference. And that is that the failure of the survival of these pig organs in the baboons or monkeys is clearly due to some immunologic causes for which we don't yet have an answer. We have made some progress in overcoming the immunologic hurdles to xenotransplantation, but we have not solved them all. . . . I can imagine solutions coming along, and then it may be time to go ahead and do trials. I don't think we have sufficient data at this point to justify human trials of solid organ xenotransplantation.

Again, it's completely different when you start talking about cells. The reason for that is that the major immunologic attack that is particularly strong in the case of a xenotransplant is against the lining of the blood vessels that come with the solid organs. That's where that attack is occurring, in the so-called endothelium. Cell transplants don't bring blood vessels, they don't have an endothelium, and they don't have that site. That isn't to say that there isn't an important immunologic event going on when you transplant animal cells into people. It's that we've taken away two big problems. And there, I think, we have sufficient evidence to justify some cell trials at this time. . . .

There have been a couple of safety studies done, and one very recently, on human recipients of living pig tissue in different scenarios. Overall, what is the value of those kind of safety studies?

Oh, I think the value is enormous, because what we need in this field is data. We need information. It's very easy for people to sit around a table and construct potential risks and to imagine that X might happen or that Y might happen, and talk about this in a hypothetical kind of way. We need information. Well, here there are 200 human beings over the course of the past 20 or 30 years who in one way or another have had pig tissue transplanted into their body or in contact with their body. That's obviously vital, to go back and to look at them, that incredible resource and find out what happened. . . . There are many different groups who really looked carefully at those individuals and determined that they could find no evidence of transmission of a pig endogenous retrovirus. Now there is information for us to work with.

How much information do you need before you say, "Enough. We're sure there is no risk?" Well, the answer is, a lot more, and a lot more for a number of reasons. Essentially, all of those patients received their transplants without the kinds of genetic modifications, without the kinds of drugs that we now have available that will make it easier for a transfer of the virus to occur. So they are not a perfect example of what might happen in the future. And 200 patients just aren't enough, and ten years may not be enough. This is going to be a long-term monitoring of patients. We need to do more into the future. And as the genetic modifications of the pigs become available, we need to find out what happens in those cases. . . .

Xeno proponents say that it is for the benefit of dying patients. But aren't there commercial pressures driving this forward? Are you aware of those pressures?

Fortunately, in my own personal situation, no, I don't feel them. I am aware that there are a number of companies that would benefit enormously, were xenotransplantation to be successful. I think that, by and large, the medical community has behaved responsibly in not going ahead prematurely with trials for which this isn't sufficient supporting data. But you're right that there are companies that want to get going and, you know, I'm glad.

It's like a motorway, isn't it? There's a slow lane of ethicists; there's a fast lane of biotransplant companies; there are clinicians and regulators in the middle. Do you think we will reconcile the varying speeds of this?

Well, I do think we will reconcile, at least in this country. As you know, xenotransplantation is regulated by the FDA. You cannot do xenotransplantation in this country without formal approval from the FDA. And I believe the FDA has taken on its responsibilities in a superb manner -- involving the public, conducting the debate, involving the experts, gathering the information, and proceeding ahead with trials in a responsible, cautious manner. So I think the regulation is happening. And I think it's happening in exactly the way that you would want it to happen, namely, by the responsible agencies of your government setting out to protect both your welfare and your future welfare in the best possible manner.

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