Centers For Disease Control
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
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
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
FDA Subcommittee on Xenotransplantation
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?
Virologist, Scripps Research Institute
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.
Immunologist, Massachusetts General Hospital
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.
Centers For Disease Control
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.
Executive Director, Animal Protection Institute
. . . 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.
Department Of Virology And Immunology, Southwest Foundation For
[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.
University Of Pittsburgh Medical Center
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
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
Professor Of Medical Ethics, Tufts University
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
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
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
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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