...What is the biggest hurdle holding back xenotransplantation at this
Right now, the hurdles are immunologic ones -- rejection. And it's not just
one hurdle; there's a series of hurdles, each of which is very difficult on its
own to work with. There's hyperacute rejection, which happens in a matter of
minutes. There are many different ways that the transplant community is
attacking that problem, and there certainly is hope that we can overcome that
hurdle. You then run into the next hurdle, which is acute rejection. There's
a whole series of these different types of immunologic-based hurdles, and
they're just not easy to deal with. It may be that we never can really get
beyond all those hurdles.
What about the risk of a virus crossing into the population? How big a
concern is that?
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.
So I would caution not to get overly excited about being able to thwart or try
and stop one particular virus, when there are several viruses out there. We've
got clear examples of the swine flu in 1918 that actually killed at least 20
million people, upwards to 40 million people. Now, that's not a good example,
because it is a respiratory tract infection, which means you cough it onto
someone else and they get infected. And those aren't the kinds of viruses that
you worry about in the transplant setting.
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, immunosupressing the
heck out of them. So you're creating the most ideal situation for a virus to
The other piece of information is where the risk really is. And the risk
really isn't to the individual; it's to the population in general. So an
individual can sign a consent form and say, "Hey, I'm going to die. I'll
accept the risk. I don't care if I get a virus and it causes AIDS or something
else horrible or I get cancer. I'll take the risk, because without it, I'm
dead." The problem is that that person accepts the risk, but if that person
survives and transmits that virus to someone else, and it gets into the
population, that person has essentially signed a consent form for the whole
We're really worried about those viruses jumping from the patient to other
contacts and starting a new infectious disease in the population. So that's
where it comes down.
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.
And what do we know about the possibility that, once infection is spreading,
whether a disease is seen as a result of that?
These are really important questions to ask. No one has the answers to the
questions. What we do have is history. We have a lot of experience in terms
of other viruses and what they've done. Here's an example. We know that the
AIDS virus, HIV, started in Africa, in non-human primates. The interesting
thing there, which has a lot of parallels, is that the virus doesn't cause any
disease in the natural host. Nothing happens. There was no way to know that
the virus even exists in that species until it actually jumped into humans.
So these monkeys were carrying these viruses for thousands of years. No one
was even aware of these viruses' existence until people started dying of AIDS.
And then they found a virus and traced it back to monkeys in Africa. That's a
big lesson. You don't have to see disease in the animal species to know that
the virus exists. Pigs could carry viruses that don't cause any disease in
that species. When it jumps to humans, it could be decades before you see
First of all, if it's a new pig virus that you have no idea exists, and it then
tracks into the humans, there's no way to find it. If its latency period --
the period of incubation between when you're infected and when you get sick --
is ten years, the virus has a chance to replicate and infect other individuals
for many years before one first begins to see a disease.
We have examples of that with another virus called STLV, or HTLV. It's another
retrovirus, and it has an incubation period of decades. This virus was
initially found in the late 1970s. This virus causes cancers in humans. It
causes lymphomas and leukemias, but only after 20, 30, 40 years of being
infected by the virus, and only in about four percent of those that are
infected. So this virus spreads through the population; it's hard to detect,
because most people don't have any signs of disease. So if you are to unleash
a virus from pigs to humans, and you weren't aware of the fact that this virus
even exists -- if it's still an undiscovered virus -- it could be 20 years
before you see the effect of that transmission.
What is the particular virus they're talking about and that you're concerned
about in others?
The virus that most people are discussing is a pig endogenous retrovirus
(PERV). That is a genetically inherited virus that's found in every cell, in
every tissue, in every organ, in every pig. It's a virus that has the
potential of being transmitted to humans, because it's been shown that it can
infect human cells in tissue culture, at least in a test tube. But we don't
know at this point whether that virus would actually replicate in a human
patient, or, worst-case scenario, be transmitted from that patient to any
contacts. So that's the big unknown.
But there are others?
There are other viruses.
Why are people concentrating on this inherited virus?
Because it seems so difficult. Because it is inherited, and it is in every
cell, and it is something that you kind of look at, scratch your head and say,
"How do we get rid of this virus?" And so a lot of the work is to demonstrate
that, in fact, it isn't infectious in humans, or that we can breed pigs so that
they don't have the infectious types. And those are really the two areas where
the concentration is.
There's some difficulty with both of those. One is, first of all, can you
really, in fact, breed a pig so it doesn't have this particular virus? That's
somewhat questionable. The other thing is, can you actually demonstrate that
the virus wouldn't be infectious in humans? There have been retrospective
studies. They've gone back and looked at people who've already received cells,
tissues, whatever, from pigs. And these are retrospectives, as they got
freezers full of stuff. And they go pull the freezer out, and they go, "Yes,
this stuff looks okay. Let's test it."
They weren't able to find evidence of actual active replication of this pig
endogenous retrovirus in those patients. And that's good news. But one needs
to be cautious, because those studies inherently have problems. You don't have
access to the follow-up tissues. . . . And so it's not a good study.
Prospective studies give you more information, because you can control and
design them to give you the answers you want.
. . . Can you tell me generally what happened at that moment in history of
learning about this PERV virus?
Well, the Weiss paper essentially sent reverberations through the transplant
community, because here is a respected virologist saying that, "Pigs aren't as
safe as we thought they were, and there is a virus lurking in pigs that I've
just shown can infect human cells and tissue culture. And we need to look at
this, because this could be potentially dangerous. From what we know about
this kind of virus, it could cause cancer. If it gets unleashed, it could be
very difficult to get rid of, because it's the same family of viruses with
which we find AIDS and leukemia."
How did the FDA and regulators react? What happened to the trials, and what
Certainly the FDA was very concerned. And basically the clinical trials that
were occurring were indeed put on hold until there was enough discussion. The
advisory committee of the FDA met, and looked at the data, and took a few steps
backwards. They thought about what needed to be done to look at this virus to
make sure that, in fact, we weren't seeding the population with a new virus.
And then went ahead with clinical trials, at least to cell transplants, that
are still going on. Some people say that cell transplants are less dangerous,
or there's less risk potentially than organ transplants. Why is that? Do you
agree with that?
There are a lot of complexities. Most people believe that xenotransplantation
only relates to whole organs. And so we have time, because no one is going to
be sticking a pig heart into a human in the next year or two years, maybe even
five years. We have plenty of time to figure out whether there's any viruses
carried by pigs that could cause problems in humans.
Xenotransplantation is more than that. It's cells. It's extra-corporal
procedures such as ex-vivo profusion through pig livers. It's hollow fiber
filter devices seeded with pig cells that you run human blood through for
different treatments. And so it's very complex.
The whole organs obviously create 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.
And given the risk, how do we quantify them or decide whether as a society
we want to take them?
That's a tough one, because you can't quantify it. I remember being at an FDA
committee meeting where one of the transplant people was furious at me and
stood up and said, "You need to be able to quantify this. Give me a number."
And I just looked at him, I said, "I can't give you a number. That's not
numerical." That's the hard part.
So on what basis will it be decided whether to go forward or not? Who's
going to make this call in the name of the public, and on what basis?
I would think the FDA would make the call. And they'll make it in conjunction
with this national committee that's informed on xenotransplantation. And
they've already made the decision in some respects, because they're already
allowing certain clinical trials to happen, such as treatment for Parkinson's
patients, then ex-vivo profusion with the ... liver. Those things have
already happened. For infectious disease risks, nothing is on hold because of
disease. It's all on hold because of the science behind the transplant.
In other words, they haven't been able to get a pig liver or heart to function
in an animal model system such as a baboon long enough to convince the FDA and
the transplant community that they're ready to go in humans. So they're not
waiting to find out whether this virus is bad or good; they don't have the
science together yet to make it work.
. . . What's the problem?
At the moment, the problem with long-term survival in an animal model system,
such as pigs to baboon, is keeping the baboon alive. The problem with that is
immunology rejection; you get rejection of the heart. In order to overcome
rejection, most of the therapies have been directed at high doses of
immunosuppressive agents. And that indirectly has a negative impact on the
recipients. Using high levels of immunosuppressives can cause deterioration in
animal species. And so rejection seems to be the hurdle. It has been the
hurdle for the last hundred years, two hundred years. And it continues to be
. . . Even if we can solve hyperacute rejection . . . then what do you
When you're dealing with forms of rejection, the first one to overcome is
hyperacute rejection. . . . What happens is humans, and even monkeys, have
naturally occurring antibodies to pig molecules. They're called sugar
molecules, and are on the surface of every pig cell. Those antibodies bind and
kill the cells within a period of minutes. If you stick a pig organ into a
human or a monkey, that organ dies in a period of minutes.
So to attack that problem, researchers have come up with several model ways to
do it. One is to make genetically modified pigs. Another way is to try and
suck up all of the antibodies out of the human patients so that they don't foul
up the organ.
And those have some promise. But it's still very difficult. Even if you could
overcome that, you've got acute vascular rejection, you've got more chronic
long-term cellular rejection. So the different arms of immune system come into
play and attack the organ. It's not very difficult scientifically to see that,
if you have very distant species, like pigs, when you're trying to put that
over into a human, that they're so different that the immune system is going to
be very difficult to overcome.
Let's just talk about Dan Salomon's study for a second. In San Diego, pig
virus was put into immunosuppressed mice. What was the significance of
The significance to me was the finding that they could actually demonstrate
that the virus was transmitted from the pig cells to mouse tissue. So,
apparently, the virus was infectious for the mouse via cross-species
transmission. That means the potential is there if you put that organ or
those pig cells into a human, they could also transmit the virus. So it's just
a first demonstration that this particular virus, again, this pig endogenous
retrovirus, is potentially infectious in other species. . . .
What does it lead you to believe might happen? What would the next step be
in terms of trying to figure out or reconfirm that? Where would you like to go
Well, probably the best way to go would be to use . . . a species that's
closely related to humans, and that would be a primate, such as a baboon or
some other monkey species. And if you put . . . this particular retrovirus
into a baboon, or into a rhesus monkey, you could determine whether, in fact,
that virus was infectious for a primate. . . .
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