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how big is the risk?

Excerpts from FRONTLINE's interviews with xenotransplantation and animal retrovirus researchers, here discussing the potential threat of a cross-species virus being transmitted in xenotransplantation.


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WALID HENEINE
Centers For Disease Control

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Does giving the pig organ human genes increase the risk of pig viruses evolving to infect us?

It's an open question. No one really knows whether these viruses would, for example, resist the defense mechanisms more than we have for porcine viruses that do not have these human antigens, so [they] could escape some of our defense mechanisms.

As you may know, we have antibodies and we have our specific defenses that now we know can protect us against some of these porcine retroviruses. If, for example, you start manipulating the pigs and introducing some of these human antigens on them, it's an open question whether you would compromise those natural defenses that you have for intact porcine viruses. And, of course if you further humanize the porcine tissue or organ, then you would allow it to persist longer in the patient. That would give it more time for a possible infection and so forth to take hold.

JONATHAN ALLAN
Department Of Virology And Immunology, Southwest Foundation For Biomedical Research

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The question really is "viruses," not "virus." When you think about the kinds of viruses that could be present in one species that could jump into humans, you have to think about a whole class of viruses or a whole family of viruses, not just one virus.

One issue that has been overlooked in looking at infectious diseases is that we tend to get microscopic. We tend to think about this one virus, this one retrovirus found in pigs, and think that if we can find a way to prevent that transmission or we find out that the virus isn't a problem in humans, then we have a safe organ. . . . But there may be many other viruses that are present -- that we don't have a handle on -- that could also be transmitted to humans, and that could potentially be even a larger problem. . .

The viruses you worry about in the transplant setting are blood-borne diseases or sexually transmitted types of diseases. People argue that we've been in contact with pigs for hundreds of thousands of years; we slaughter them every day; we live next to them every day; so, they argue, if pigs had anything that could be nasty for us, we would have already gotten it. And the answer to that is, "Yes, the ones that we could easily get from them. But in a transplant setting, you may be dealing with viruses that don't normally have access to humans, ones that are blood-borne, ones that are sexually transmitted." In the transplant setting, you provide the most ideal environment by introducing a virus with the organ, overcoming all natural barriers, immunosuppressing the heck out of them. So you're creating the most ideal situation for a virus to arise.

HUGH AUCHINCLOSS
FDA Subcommittee on Xenotransplantation

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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?

DANIEL SALOMON, MD
Virologist, Scripps Research Institute

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What we know about the family of viruses that are closely related to the virus in the pig that we're concerned about is that they all produce lymphomas and leukemias. These are cancers of the blood system. And if we saw activation of this pig virus in human transplants, we predict that we would also see the same sort of spectrum of blood cancers -- leukemia, lymphoma. There is going to be a lag time between the moment of infection and the production of this possible cancer. And during that lag time, we are going to have to rely on very sensitive molecular diagnostic tests to detect the replication of the virus before we see the evidence of the leukemia or the lymphoma or any sort of cancer from these patients. . .

What do we know so far about these pig viruses? How active and aggressive do they seem to be?

What we know about these pig viruses today is that, first of all, they do infect human cells. Secondly, under certain circumstances, they can actively infect human cells. In other words, they can infect a human cell initially, replicate themselves, and spread to other human cells. So that's part of why there's a real concern.

However, in other types of primary human cells, the virus may get in or not get in at all. But in either case, it replicates very poorly, doesn't spread, and doesn't produce active infection. In the animal work that we have done and published, pig virus was identified in the animals. It infected animal cells in the transplanted animals, but it never produced an active or productive infection. It appears to have gone dormant very early in the process.

So at the present time, the evidence would suggest that, number one, there's a real risk of infection [of] cells; number two, there is a possibility of productive, active infection. However, that risk would appear to be relatively low, based on what we know today.

David Cooper
Immunologist, Massachusetts General Hospital

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

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

Dr. Walid Heneine
Centers For Disease Control

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From a PERV and virologic point of view, I think we did not know a lot about these viruses when clinical trials started. So there was a lack of information about the characteristics of these viruses, or availability of diagnostic assays able to monitor patients for infection with these viruses. So clearly, we started with very little information. And there was a lot of pressure on our lab and other labs as well, to provide rapidly important information about what these viruses mean: how do they behave; how they infect the human cells or not; how to develop appropriate and adequate assays to allow monitoring of patients who have been exposed to pig tissues. And while all this was happening there were some clinical trials occurring at the same time. So, in a way, yes, there has been some work with a little bit racing with time, trying to find some information about what these viruses mean in terms of cross-species infections and so forth.

Alan Berger
Executive Director, Animal Protection Institute

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. . . The possibility of letting loose an infectious disease into the general population is real, and we have no way to try and stop it from happening. If a disease gets out into the population, we'll have some enormous problems with it. . . . HIV is a really good example that has been out in the marketplace for a long time. Prevention is common knowledge. But in the San Francisco Bay area, you have an increase in the number of victims of HIV, despite all of these surveillance techniques that are out there. So just think of a new disease that we may not even know about being unleashed into the general population, and what kind of methodology that we have available to us to try and control it. And it's frightening. It's absolutely frightening.

Jonathan Allan
Department Of Virology And Immunology, Southwest Foundation For Biomedical Research

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[Transplanting] whole organs obviously create[s] the greatest risk immediately, because it's an ecosystem waiting to happen. You've got many different cells, perhaps billions and billions of cells, and the whole mixture . . . may have different viruses. And so you throw a whole cocktail of potential viruses out there. Single cells . . . are more purified, and are less likely to have a lot of different viruses. So, it seems, at least at the outset, that these would be less of a risk.

The risk really comes with survival. If you take a patient, and they get a whole organ and they die, the risk to the population isn't very grave. If you do small therapies with someone, if you shoot a few cells into 10,000 people and they all survive, and they all go and do their thing, and there's a sexually transmitted virus involved, you could see that virus going into the population. So it's numbers, too. You may have less risk because of the cell types, but you have higher numbers of people that get the procedure, which means increasing chances of transmission. . .

... Some people have called that risk of virus being transported to the population a very, very, very tiny risk.

Crystal ball . . . that's a tough one. It's likely that the risk is small. Now you have to define what's small. "Small" is that there's a very small risk that a virus could be transmitted from the patient to contacts and get disseminated into the population. If, in fact, that small risk were to occur, one could still be dealing with of tens of thousands of people becoming infected with that virus, maybe thousands dying every year of cancers, or some neurologic disease -- something that we hadn't seen before. So out of a small risk in terms of the actual events happening, if it does happen, the potential negative or the harm that could be done could be great.

Thomas Starzl
University Of Pittsburgh Medical Center

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I think the PERV is a red herring, myself. Personally, I think that the scare about creating a new black plague or something like that is so remote that it's not a factor. The central problem is that we don't know how to get the discordant allograft, or even a concordant allograft, accepted by the human immune system. And if that objective were met, everything else would just dissolve.

The debates about PERV are interesting. Of course it needs to be studied. But the PERV is part of the pig genome, and you know, the pig and the human genome have picked up little bits and pieces of DNA from microorganisms in the course of evolution, so I don't think that . . .

Is it not risky to leave the PERV element inside the pig cells?

I don't think so.

If it were to activate, if it became a hot virus by whatever means, it would then possibly be cloaked in a cell with human genes?

I can't answer that question, because I'm really not qualified. . . . But you're asking me what my opinion is, and my opinion, as somebody who has seen tremendous cross section of experience in transplantation, is that control of the infectious disease problem with xenotransplantation would be vastly easier and more effective than has ever been accomplished with allotransplantation.

Now, maybe a million people have undergone allotransplantation. If there were going to be some kind of transmographication of weird viruses . . . that would have already occurred. If you had these clean pigs, I think that the possibility of infectious complications of that kind, or the emergence a of hot PERV virus, is very remote.

We do know that in human-to-human transplants, we can amplify the effect of viruses, especially when the recipient has never seen that virus before. Is it not arguable that there will be viruses? Some of the retroviruses and endogenous retroviruses that can't be removed in the pig that the recipients of these xenoorgans will never have seen before? Do you accept that we could amplify the effect of the virus?

You're asking me if we could create infections that haven't been seen before. I'm sure you'll find people who will support that theoretical possibility. I think it's a small one, and with the xenografts, under the conditions that have been stipulated now by government agencies, that risk is very, very remote. And that risk is not in the same league as the risk that you might face just with allotransplantation.

Norman Daniels
Professor Of Medical Ethics, Tufts University

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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.

. . . 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. . .

David Sachs
Director, Transplantation Biology Research Center, Massachusetts General Hospital

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I think there is always risk associated with any new innovation. And the real balance has to be between the benefit and the risk. Now unfortunately at the moment, because transplantation has not yet been successful, we can't really measure the benefit. We can assess some of the risks. I think we have to be very mindful of that; I think we have to be very careful about it. I think we have to be very wary of doing anything that could cause a problem either to the recipient, or to the community. Fortunately, there are many people who are worried about that, and who are being very careful about the safeguards they are putting on research, as well as potential human experimentation in this regard. The FDA, for example, has some very stringent guidelines, which I support fully.

But I don't think the idea of having no risk is one which will lead to progress. I think we have to be willing to accept some level of risk and minimize that risk. And I have to return always to the fact that patients are dying every day waiting for organs. And the benefit, if we can make this work appropriately, will be enormous to relieving human suffering.

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