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.

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.


Department Of Virology And Immunology, Southwest Foundation For Biomedical Research

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.


FDA Subcommittee on Xenotransplantation

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?


Virologist, Scripps Research Institute

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.


Immunologist, Massachusetts General Hospital

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.


Centers For Disease Control

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.


University Of Pittsburgh Medical Center

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.


Professor Of Medical Ethics, Tufts University

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. . .


Director, Transplantation Biology Research Center, Massachusetts General Hospital

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.