Why are we concentrating on pigs now?
. . . The reason we've moved to the pig, rather than the non-human primate such
as the chimpanzee and so on, is that first of all, they're very much easier to
breed in large numbers, and to house and develop. The non-human primates have
difficulties with breeding programs, etc. So one is a logistic reason.
The second reason is the ethical concerns about using primates in large numbers
for donation or organs, whereas we're much more ready to use the pig, because
we already do use the pig for food and so on. And the third reason is that as
the non-human primates have largely been caught in the wild, we have much less
information about what bacteria and viruses they carry than we do about pigs.
And so the risk of the infection is considered very much greater if we use a
non-human primate than if we use a pig. . . .
Are there questions about the ethics of the animal trials of pig organs
I think all of us involved with non-human primate work are concerned that we're
using these animals for experimental purposes. I think, however, that we do
everything strictly very ethically. We give painkillers as we would to human
patients, and I think we, at the back of our mind, have to keep in mind that
the potential benefit to humans is going to be immense if we can solve this
problem. I think that's the only way you can justify using these sorts of
animals for this sort of work.
Is there a groundswell of animal rights activism in the US as it seems there
is in the UK?
In the US, there has been patchy animal activism, largely, it seems, in the
Midwest. But I don't think that it's got to the state that it's got to in the
UK at the present time.
Why is that?
I'm not quite sure why. I am from Britain originally; the British always have
had a love for animals, but I think it's more than just that. I think it's a
group who have decided that they've got to make some sort of stand in the
world, and they've chosen animal rights as the way to make the stand.
If you consider all of the things that we benefit from in the world,
particularly in healthcare, they have all in one way or another been tested in
animals. And as long as one is not inflicting pain on the animal, I think it's
perhaps not very different from killing the animal to eat it.
Are there questions about manipulating the genes of animals?
I think in some areas there is concern, but for those of us in the field,
there's not a great deal of concern. The manipulation of the pig will in no
way make it anything still but a pig. It will have a minute amount, perhaps,
of a human protein lining the surface of its blood vessel to give it some
protection against the human immune response. The plan is to try to knock out
in the pig a particular gene that makes a sugar or an enzyme that makes a sugar
that lines the surface of the pig's blood vessels, against which our immune
response is directed.
Now, that is not a big thing to do, particularly to a pig. For example, we
used to have this sugar ourselves, and millions of years ago, somehow or other
it got knocked out. And there are numerous other examples of this. This pig
will have no human tissue in it, but it will have one of its normal genes
knocked out. So what we're doing is not very dramatic; we're not changing the
profile, in any way, of the pig. . . .
What are the regulators looking for now in terms of success with the animal
trials? . . . What's it going to take to get to a human clinical trial with
I was recently on a committee that looked into this for the International
Society of Heart and Lung Transplantation. Our committee came up with a
suggestion. We felt that if you could get ten baboons surviving for at least
three months with some of them surviving for six months, being completely
life-supported by a pig heart, in this case, or pig organ, then that may
justify consideration to go into a clinical trial in humans.
Three months may not sound very long when we're really hoping that these hearts
are going to keep people alive for years. But the difficulties of looking
after baboons under the conditions that baboons live -- in cages, they're not
very hygienic and so on -- the difficulty of looking after those compared with
humans is very considerable. And we believe that if we could get to three and
six months with a significant number of baboons with the same regimen that
we're going to try in humans, we would do a lot better in humans. . . .
How close are we to the human trial?
We're not that close yet. We still have several problems to overcome. Most
groups in this field can get pig organs surviving in the baboons or monkeys for
at least a month. . . . A group in the United Kingdom got out to two or three
months in occasional baboons, but the average is somewhere around a month or
And that has required a fairly significant amount of immunosuppressive therapy.
So I think we still have a few steps to take before we'd be ready for a
clinical trial. And in fact, this committee that I was on decided that the
time was not right for it at the moment. That's why we would be very
encouraged to have a pig that didn't have this sugar on, because we think we
may get significantly better results in that case.
What's your guess? How far away is it? Weeks, months, years?
At the most optimistic estimate, getting a pig like this is probably going to
take several more months, and then, of course, you've got to breed a herd of
them. So I think we're still two or three or four years, perhaps, before we're
ready for humans. That's my own conservative estimate. But you never know.
Somebody may come up with another breakthrough at any time and we may be lucky,
we may be able to speed that up. But I think it's going to take a few
Where's the controversy in this? Is there a public debate? Is there a need
I think there are two areas of controversy. The first is the use of animals
for this purpose. I don't think that's a big issue, because we use animals for
all sorts of purposes, and I think to anesthetize a pig and take his organs out
is rather more humane than slaughtering [it] in the slaughterhouse.
But the second, perhaps greater area of controversy is if we're going to
transfer a pig infection with the organ to the patient. Even that wouldn't be
too bad, because the patient may benefit from the organ for ten years before he
or she dies of the infection. But the concern is whether the patient will then
infect people around him.
We're working very hard on that problem too. My own feeling is from the
microbiologists. They tell me that the risk is pretty small, and I think
within the next two or three years, we probably will have been able to overcome
that risk entirely. So I don't think that's a major risk. I do say entirely;
we may have been able to rule out any infection that we know about. There are
always going to be infections that perhaps we don't know about, and one can't
plan for that.
But I think if you don't move ahead because of unknowns with something that
could be immensely beneficial, we probably would never move ahead in any sort
of medical advance. So I think that if we've eradicated all known risks, that
would be a risk worth taking.
What is the ultimate concern? What is the deepest fear?
The deepest fear is that we would have something like an AIDS epidemic on our
hands; that the human population would have no resistance to some pig virus
that we transfer, and it would spread from contact to contact. And soon we'd
have another AIDS epidemic on our hands.
Are there issues also about the unnaturalness of all this? . . .
A segment of the population does have concerns about the unnaturalness of it.
But I think it is probably no more unnatural than taking organs out of dead
people and putting them into humans. This was considered revolutionary 30, 40,
50 years ago, and now the vast majority of people accept it and realize the
benefits that can accrue from it.
And I think we just have to get our thoughts along the benefits that could
accrue from animal organs. We've used these animals for many years. As you
probably know, every diabetic who took insulin until a few years ago was taking
pig insulin. . . So we've been using the natural resources of these animals for
many years. I personally have put a large number of pig heart valves into
human patients, because they're very similar and they do well. So we've been
doing this little by little, and is it very different from putting in a valve
to putting in the whole heart? That's the only step we're taking. . . .
What about this public debate about the virus and deciding at what point the
public, for lack of a better word, gives its consent for this to go forward?
How and when should the public debate this?
When we go into a war, we don't usually ask the public. I'm not sure it's
possible to actually ask the public. But it is important to inform the public
of the possibilities, and then it's up to the public to try to make themselves
heard. . . . I think we're going to actually have to depend on committees
appointed by the Public Health Service or the FDA or somebody to represent the
public. And those committees -- which will include not only physicians and
scientists, but also laypeople -- will be responsible to determine if this is
safe enough to move ahead.
There seems to be a general mistrust of science in certain areas. Genetic
food is a great concern now. Mad cow disease is a concern. Is there a concern
that the public won't embrace this?
I agree there have been some episodes in recent years that have made the public
perhaps a little more skeptical about what the scientists and the physicians
tell them. . . . But if we could show that this is immensely beneficial to a
significant percentage of the population -- to those patients who are dying of
these various conditions -- then I think the public will be more ready to
accept a small risk. It's a matter of the risk-benefit ratio.
Once we can show them that this really has some potential to impact their loved
ones who may be unwell from one of these conditions, then I think the public
will be more ready to say, "Let's do it."
And then there's the transplant physician, who says "Debate this. But every
minute you debate this, we're losing somebody who could benefit from
At this stage, they have no reason to say that, because we're not ready to do
it. We've got to solve the problem of the infection a little bit more. We've
got certainly to solve the problem of rejection. Therefore, I think it's very
good that the public can have the opportunity to debate this at this stage, and
people can be heard, and the committees should be set up to consider public
opinion. Sorting out these remaining problems will take a few years, so we
have an opportunity to debate this. And we're not delaying the benefits to the
patients, because we're not ready to benefit the patients. . . .
Let's go to that issue of informed consent. What are we asking of people?
What are we demanding of people who are getting involved in clinical
In any clinical trial, of course, you ask the person for informed consent. In
many cases, it's very difficult for the patient to fully understand what he or
she is going to go into, because the science is getting so technical and so
But in this sort of situation, they usually realize that they're dying, that
their days are numbered. Therefore, they're usually prepared to accept some
sort of experimental therapy if it's got a reasonable chance of keeping them
alive with a reasonable quality of life. Now, it doesn't always work out like
that. But people are willing to take that risk.
The big difference with xenotransplantation is that if there is still perceived
risk to the patient's family, of infection, for example, then we may have to
ask the family for informed consent as well. And then it gets very difficult,
because how close in the family do you include? Do you include friends and so
on? It would really get almost unmanageable.
We really have to be pretty certain about this risk of infection to the public
and get that solved. And then we're really more or less on the same sort of
ground as we were on with any other experimental surgery. The patient has got
to have a pretty good understanding, and it should be explained as carefully as
possible before they make a decision.
But until that point, isn't the issue of consent, in fact, very different
where we're asking people for potentially lifelong reporting of sexual
contacts? That's very different.
At the moment, if we are asking the patient to sign a consent form, but we're
worried that there may be a transfer of an infection to a patient and to the
patient's friends and family, then we're in a very difficult situation. Never
before have we asked patients for this lifelong monitoring. And certainly
we've never asked the patient's family for lifelong monitoring.
We have to resolve the problem of this infection, and be pretty sure that if
there were infection, it would be confined to the patient and not to anybody
else. . . .
How does informed consent work? And what would happen if somebody said, "No,
One fundamental of asking for informed consent for any clinical trial is that
the patient has the right to withdraw from the trial at any time if he or she
wishes to. And that is so engrained in clinical trials that this would be a
very different trial if you would not allow the patient to withdraw.
But, obviously, if you're worried that the patient might develop an infection,
and that infection might be spread to the population, you obviously don't want
the patient to withdraw, because then you can't manage them, and check their
blood, etc., etc. . . .
Describe the monitoring that goes on now. What's the procedure?
One basic aspect of the guidelines is that you must keep blood and tissues from
the patients from time to time, and store them, and test them. The storage is
important, because maybe next year somebody will come up with a new virus that
we should be looking for. So you then look at the stored material. There's
very careful monitoring of the few patients that have actually been exposed to
pig tissues in these trials up to date. . . .
What happened when Robin Weiss discovered this PERV virus? How did the FDA
Within the last ten years, knowing that people were already beginning clinical
trials of cell transplants, and knowing that people were planning, or would
like to plan organ transplants from pigs, one or two groups, particularly of
microbiologists, looked into these pig cells to see what infection they could
transfer. A group in London came up with this pig virus that's in every cell.
And they found that if you culture that cell with a human cell in the
laboratory, the virus will jump into the human cells. That suggested that if
you put a pig organ into a human, eventually the human would have the same
Now, there's really virtually no data that it causes the pig any trouble. And
we have a very similar virus in our cells that doesn't seem to cause us any
trouble, as far as we're aware. But there was the risk that if you put a pig
virus into the human, maybe it would cause some trouble.
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.
There was a group in San Diego that got the virus to transfer in mice.
What's the significance of that?
The trial in mice that you refer had specially bred mice. They basically have
no immune system. They have no protection against infection. They're rather
like these bubble babies who are born with no cells that can protect them, and
they have to stay in a bubble away from the environment. So it's an extreme
trial. . . . And not surprisingly, they showed that if you put pig cells in,
the virus gets out of the pig cells and infects the mouse. We would have all
expected that to take place. I don't think there's anything really dramatic
about that at all. It would have been expected, because these mice were so
If you have to immunosuppress a patient with a transplant heavily, it begins to
be like those mice. And so the significance of the trial was that if you
heavily immunosuppress a patient, there is a risk that the virus will spread
throughout your body. But, again, we have no evidence yet that the virus is
going to do any harm. So there are several areas that we still need to
clarify. Will the virus get into the body? Will it cause the patient harm?
Will it get into anybody else? And if it gets into somebody else who is not
immunosuppressed, will it cause them any harm? We have a lot of questions
still to answer. . . .
What is the financial potential here? What's the market we're talking
The financial potential is considerable. And probably this is why some
pharmaceutical companies and biotech companies are particularly interested. It
has been estimated that probably we could do about four times as many
transplants as we do now if we had an unlimited number of donors. . . .
Let's say you're going to do four times to five times as many transplants.
That's a big potential, not only in sale of the pigs, but if you have to use
drugs, that's a considerable amount of money. We spent in the United States
something like about $5 billion a year on the care of patients with
transplants. This would go up to, say, $20 billion.
The second thing is that if we could use pig organs, we could also use pig
cells. For example, every diabetic patient, instead of having injections of
pig insulin or other insulin, would be able to get some pig cells put into
them, and they would then make their own insulin. And there's probably a
couple of million patients at least in the United States, and probably a couple
of million in Europe, if not more, who would benefit from pig islet cell
transplants. So then, of course, you're talking of a considerable financial
If you talk about that financial motivation of a company like Novartis, that
I think I've read has put in a billion dollars, or is willing to put a billion
dollars into this research, why are they doing that? And what is the
One shouldn't differentiate this from the development of any drug. Any very
valuable drug is going to be beneficial to millions of people. And developing
this field of medicine, developing these pigs, is going to be no different from
developing a dialysis machine or a pig heart valve, or a mechanical heart, or
whatever we want.
They're obviously looking to the commercial side of it, because if they're
going to put a lot of money into development, there's got to be some prospect
of getting that money back. But I don't think it's any different, really, from
development of a drug or any sort of healthcare device.
It's very different from the human organ transplant model we're talking
about. So what are you really what you're talking about -- companies trying to
develop pigs that will then be a product that they can sell, just as if they
were a mechanical device or something like that? Which model are we looking at
I believe that we will go completely away from this present system of putting a
patient on the waiting list, and the organ being allocated to the next patient
on the list and so on. I believe it will become very much the same as use of
any drug or any other devices that are easily available. The patient will come
to see you as a doctor. And if you think the patient needs a heart transplant,
you will then phone up the pig place and you'll get in a heart tomorrow and
you'll do the transplant.
This will have immense savings in some respects. Dialysis is much more
expensive than a kidney transplant. So people will not be on dialysis for ten
years waiting for a kidney. They will come in, and they'll have the kidney
transplant while they're still in reasonably good shape, and there won't be all
this delay. I've had patients waiting in the intensive care unit for two or
three months at $2,000 to $5,000 per day. They will have the transplant the
day they come in, or the next day. There will be immense savings that we will
have to take into the equation.
And is there the possibility of fundamentally transforming the way some of
this medicine is done? . . . Will you have those animal organs nearby a
My own feeling is that there will be several centers around North America and
Europe where these pigs will be bred. Probably the organs will be taken out on
the spot, and shipped, the same way we ship human organs in ice, etc. But it
will be planned. They will be there at 8 o'clock in the morning when you're
just opening the patient, and you're going to put the kidney in or whatever it
is. . . .
There's one other aspect of the financial side of things that we should
consider. We think of human organ donation as being free of cost, because the
organ is donated for nothing from the patient's family's generosity. It isn't
free at all. There's the expense of setting up to look after the donor after
the patient is diagnosed brain-dead; the expense of taking the donor to the
operating room; the expense of the teams coming in from different hospitals to
take out the organs. That all costs quite a lot of money. And, in fact, if
you add up the expenditure that is passed onto the patient, it ranges from
something like $7,000 or $8,000 for a kidney, to perhaps $20,000 for a lung or
a liver sometimes. The patient's insurance bears the cost of those expenses.
And it may be that the cost of the pig will be in the same sort of range as the
cost of going to get a human organ. So it may not be much more expensive. . .
What is the motivation of a company like Novartis to do this work? I'm
wondering how it connects to their work in immunosuppression drugs and feeling
like, "Boy, if this thing is going and we're not a part of it, it could go past
us." What is their motivation to be in this business?
One of Novartis' main drugs has been the most important of the
immunosuppressive drugs that we've used in human heart transplants and human
kidney transplants in the last 20 years. And it made a major impact on the
survival and quality of life of patients. So it was a tremendous contribution.
And if they could increase the number of transplants being carried out, then
obviously the sales of the drugs would quadruple or whatever it would be. They
felt that the only way to do this was to develop xenotransplantation. And
that's why they decided to fund a lot of the research. It seems a sensible
I think they perhaps slightly misread the rate of progress. And I was a little
surprised that they were pushing ahead so rapidly, when it seemed pretty clear
to me that we hadn't got all the answers. I think they tried to develop it
perhaps rather quicker than the science would really allow. Having put that
tremendous effort into it -- which was a tremendous stimulus to the field -- I
think they probably became more disheartened than they would have done if they
hadn't expected things to develop quite so quickly. That is my own reading of
the situation. . .
And if you had to frame what the company sees the market potential to be in
investment terms, what would that be?
The worldwide expenditure on xenotransplantation will run into perhaps $20,
$30, $40 billion. What percentage of that Novartis or any other company will
get will depend on how successful they are in their research. It's even
possible that the pharmaceutical companies may be cut out of the field, because
here in Boston, we're working on ways to try to make the recipient, the human,
what we call "tolerant" to the pig organ. That means that you modify the
human's response during the first few days when they have the transplant.
Thereafter, when their immune response recovers, it no longer tries to reject
the pig organ, but it treats it as if it's its own, so it becomes tolerant to
If that can take place . . . it means you never need any more drugs after the
first month or two. And you no longer try to reject this organ. So if you
don't need any drugs, the drug companies are in big trouble. They may support
work that actually will be to their own detriment in the long run, as far as
drugs go. But probably then, if you have to use their pigs, they perhaps will
recoup their losses on the pigs.
How will that work exactly? Will the pigs be patented? Who will own the
pigs? And will the pig organs be sold?
Several different groups have different pigs, and I'm sure they're all patented
in one way or the other, like the way of protecting the pig organ from the
human antibody or whatever it may be. The company who owns the patent or was
licensing the patent or something will then obviously sell those pigs to
hospitals, physicians, surgeons and so on. And they will recoup their money
from selling the pigs, just as if they designed a mechanical heart or a
dialysis machine. They would sell that to the hospital and they would be paid
And if a drug company like Novartis is investing in that kind of effort or
several of those efforts, how does that work? . . .
Presumably, Infigen will own it, because they will have the patent to it. And
they will have shown that it could be done. But, probably, then maybe a big
drug company will come in and license the patent from them to have control over
breeding the pigs and distributing and so on. It's the same as with any other
biotechnology advance. Somebody discovers it, patents it, licenses the patent
to somebody else, who may in turn license it to a bigger company who can
distribute or manufacture whatever they're doing on a bigger scale. . . .
When we talk about those people who are championing xenotransplantation, at
least in the context of the film we're presenting, we see desperate patients,
we see ambitious doctors and scientists, and we see pharmaceutical companies
willing to fund this. Can you talk about that dynamic?
You've mentioned three points. The patient is desperate. And a desperate
patient doesn't always make the right decisions, so we have to guard against
that. What will happen in that respect, though, is that if we can develop this
as a form of therapy, a few years down the line the patients won't be so
desperate, because we'll be choosing patients who are less advanced in their
disease. This has happened in so many of these transplants, certainly in heart
surgery. The first patients they used to do were desperately sick. Now you do
it electively, before the patient gets desperately sick. So that will evolve
And it would probably be unethical to take patients initially who were not
desperate, because why take somebody who's managing and put them through an
experimental procedure like this? They've got too much to lose, whereas the
desperate patient hasn't got too much to lose. That is one aspect that will
gradually evolve with time.
You mentioned ambitious surgeons and ambitious scientists, and that is quite
true. Many of us are ambitious in one way or the other. That is probably what
drives a lot of these scientists and surgeons to do this sort of work --
because they want to make a mark in the world. They want to achieve something.
They want to do something that will have an impact, and there's nothing wrong
in that. But we do have to have committees set up by, say, the Public Health
Service, and in Britain, by the government and so on, who make sure that that
is not the only reason why we're going into a clinical trial. They've got to
temper the enthusiasm of some of the scientists and so on. . . .
Similarly, with the pharmaceutical companies, we tend to look at them and
criticize them for wanting to make money out of all this. But if we didn't
have pharmaceutical companies who are willing to risk all this money, most of
us would probably be dead by now, because we would have had some disease that
we wouldn't have been able to treat.
We have to put the whole thing in perspective. I don't think we should look at
the pharmaceutical companies as the big bad wolf. We must look at them as
companies that are prepared to take considerable financial risks to try to help
develop this further. My understanding is that, for every thousand drugs they
develop, only one gets onto the market. And the cost of developing the others
to one degree or the other is so immense that they have to recoup their costs
with that one that reaches the market. It's going to be the same with the
Once upon a time, a doctor pushing forward a new technique or procedure
would have gained fame and made his mark and be in the history books and be
remembered. Now, some of the key scientists, who are really the experts at some
level in this new field, also stand to make a lot of money if it goes forward.
Is there a concern about that?
I don't necessarily think there is. In the past, as you mentioned, there may
be a surgeon who develops a new operation. He made a lot of money because
people came to him, and they wanted to have the operation. And so he had a
very busy practice. Many scientists in the past have made money from their
discoveries. I don't think there's anything wrong in discovering something
that may benefit lots of other people. I think what we must ensure, though, is
that we are not experimenting with patients purely because an ambitious person
wants to make money or whatever it is. We have to have some regulatory
oversight of the whole thing, deciding if we're ready to go into a clinical
trial, and deciding if we should stop the clinical trial if necessary. . . .
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