interviewFRONTLINE presents Organ Farm

david h. sachs, m.d.

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Sachs is professor of surgery at Harvard Medical School and director of Transplantation Biology Research Center at Massachusetts General Hospital. He is the founding editor of the journal Xenotransplantation and currently sits on its editorial board. Over the past twenty-five years, Sachs has bred a line of miniature swine for use in xenotransplantation. In this interview, he discusses his discovery that one particular line of these miniature swine does not transmit the PERV virus. (Interviewed Spring-Winter 2000.)

. . . In ten years' time, how many people could xenotransplant help worldwide?

Estimates vary. It depends on many factors. If you look at the number of people who are waiting for transplants and will not get one, you'll come up with a fairly large number -- in the many thousands. Those will be patients who are waiting for a transplant, but will die while waiting. But there are many who don't even get on those lists, because the lists are very selective. . . .

What would be a transplant heaven for people like yourself, the scientists and the surgeons? What would you like to be delivering to patients in the future?

I would think that, if xenotransplantation were to really be successful, it would be equivalent to giving a transplant from a member of the same species today, which has, of course, achieved great success. The need for xenotransplants is really paradoxical. It occurred because the field of transplantation has itself been so successful. Thirty years ago, no one would have predicted how successful transplantation as a field was going to become. And we've actually, by that success, led to our own limitation in terms of number of organs available. So today, one of the major limitations to the field of transplantation is the lack of available donor organs.

What is the prize is at the end of this? . . .

It's very important to realize that none of us are interested in just extending death. What we really want to do is prolong useful life. So not everybody who's dying will qualify for a xenotransplant. It will only be those patients who have met the criteria that they have a useful life to return to if the failure of one organ can be overcome.

How would organs on demand revolutionize transplantation procedures?

One of the problems in transplantation today is that frequently, it has to be done in a great hurry, under very suboptimal conditions, because you're dealing with an organ that's available from a cadaver donor. A cadaver donor is a patient who's brain-dead because of a tragic accident. And certainly, not everyone who dies can be a donor. It's only those unfortunate persons who are killed in such a way, in a car accident, or motorcycle accident, that their brain is dead, but their organs are still functioning normally. Now, in those conditions, you have to do everything very, very quickly. And certainly, you don't have time to do the kind of testing and preparation of the recipient that would be optimal.

I have not seen any problems yet along the way which seem to me to be insurmountableÉ.The problems we're facing are problems of the immune system. In the case of a xenotransplant, you would have time in your favor. It would all be elective. You'd be able to select the time and exactly the right preparative state of the recipient, be sure that the recipient doesn't have a cold, and other things that you just can't avoid when you're dealing with something where you have only a few hours.

The immunosuppressive drugs that transplant patients currently have to live out their life on, are they, to some extent, a double-edged sword for the patient?

Immunosuppression has been the real answer to this field. That's really how we have made all the progress that has been made over the past few decades. But everyone who uses immunosuppressive drugs, both the patients and the doctors, realize that there are problems associated with immunosuppression. The whole concept of immunosuppression means suppressing a system that is present to avoid infections. You have an immune system to avoid infections and pathogens. By suppressing the immune system in order to not reject the transplant, you are also suppressing the ability to fight those infections, and, in some cases, to fight tumors.

So, when using immunosuppression, you are always on the fence. If you don't give enough immunosuppression, you risk losing your transplant to rejection. If you give too much immunosuppression, you risk a complication, such as infection or cancer. There's no question that, if we could get away from immunosuppression and still be able to accept a transplant, we would be in a much better state.

So is it part of the ideal world for transplant and xeno that you have a universal donor organ?

The idea of not having to use immunosuppression is called tolerance. Tolerance means acceptance of a tissue or an organ as though it were self, instead of non-self. Now, this is of great importance and benefit, even for transplants within a species, from one human being to another. We've been working hard on that now for many years. And we now have been successful in inducing this kind of tolerance for transplants within the species. We did it first in mice, and we've then subsequently done it in pigs, and most recently in non-human primates. And we have animals who are totally mismatched, just as mismatched as you and I, who have now accepted organs -- in particular, kidneys -- for over five years, and have not had any immunosuppression since Day 28. So this idea of inducing tolerance, making the immune system look at the transplant as though it were self, is something that can now be done.

And we are working very hard on it in the case of transplants within a species, because we think it will have benefit for patients to be off of immunosuppressive drugs. But even more important will be the use of this technology for xenotransplantation, because . . . the amount of immunosuppression that's needed is so great, that I'm afraid many patients, or perhaps all patients, would succumb to the complications. Therefore, I think the idea of inducing tolerance is even more appealing, and will be of even greater importance, when we talk about xenotransplantation. And I think it will be possible.

Based on your animal experiments, what would happen to a patient if you were trying to induce tolerance in a pig to human transplant?

At this point in our research, we have now gotten to a point where we believe we can induce tolerance at the T-cell level. But there are two types of immunity that are important for transplantation. There's the T-cell, and then there's also the antibody-producing cell. And at this stage, we have not yet been able to induce this tolerance for antibody mediated rejection. . . .

Practically speaking, if in the future a human was to accept a pig organ, and you wanted to induce tolerance to that organ in the human recipient, what would you have to do?

The way we induce tolerance right now, in terms of organs between individuals of the same species, is by the use of bone marrow transplantation to induce the tolerance. And we know that if a bone marrow transplant is accepted, the recipient becomes tolerant to any other tissue or organ from the same donor.

That's been shown many times in experimental animals, but it's also been shown in human beings. There are patients who have had a bone marrow transplant, in general for leukemia or some other hematologic malignancy, and who have then been cured by a bone marrow transplant, usually from a sibling. Some of these patients have subsequently developed renal failure, and have required a kidney transplant. If they have remained on good enough terms with the same sibling, that sibling was willing to give them the kidney. In those cases, you don't need any immunosuppression. Those patients will accept the kidney from that same donor who gave the bone marrow, without further immunosuppressive drugs. So we know that this can work. Essentially, a bone marrow transplant changes the immune system of the recipient, and it makes the recipient look at the donor as though it were self. . . .

For a full bone marrow transplant, as I just described, you really want to get of the recipient's entire immune system, and then replace it with donor bone marrow. For leukemia, for example, you want to get rid of every last leukemic cell. But we now know that you don't have to get rid of the whole host's immune response in order to get tolerance from a bone marrow transplant. If you can get just a small percentage of the bone marrow of the donor to survive in the recipient, you will get the full tolerance. So the advantage of that is that you don't have to use ablation to get rid of the recipient's own marrow completely.

You want them to coexist.

And that's what we call mixed chimerism. It's a mixture; it's both recipient and donor bone marrow cells that survive, and that mixture leads to tolerance.

So in the future, if this worked, the patient who was planning to receive the pig organ would have their bone marrow partially destroyed?

The idea would be that, prior to the transplant of the organ, or at the same time, to also provide a source of donor cells from the bone marrow, or perhaps from the peripheral blood, perhaps from the thymus. We're not sure yet what will be the optimal source of those donor cells to induce this kind of tolerance, but we're working very hard on that in the laboratory. The idea would be that prior to, or at the same time as the organ transplant, a source of donor cells would also be given, which would induce this kind of tolerance at the T-cell level. And we actually have evidence that we're able to do that right now.

What sort of survival rate have you had with animal experiments to test this tolerance out?

For closely related species, such as baboon to synamologous monkey, we now have animals that have accepted organs after this kind of mixed chimerism procedure for over two years. So for a xenograft between closely related species, we already have this working. But when you go to more distant species, such as pig into primate, then in addition to the T-cell immunity, which is what the mixed chimerism overcomes, you also have these natural antibodies that are a major problem. And at this point, we've been able to avoid the antibodies by absorbing them, or by using tricks to prevent their activity, such as stopping the complement from reacting with these antibodies.

But we have not yet been able to prevent these antibodies from coming back. We have not yet been able to induce tolerance at the B-cell level. The B-cells are what make antibody. And so for the xenograft from a distant species, such as pig to primate, to be fully accepted, we have to overcome both the T-cell and the B-cell forms of immunity.

You've developed a particular type of pig, which you believe will work better in the transplants of the future. How did you to discover or find the animal?

Over the past 25 years, we have bred a line of miniature swine, as what we believe to be the most appropriate donor for xenotransplantation. These miniature swine get to about 200 to 300 pounds when they're fully grown. . . . Domestic swine, ordinary pigs that you'll see in the market, get to over 1,000 pounds when they're fully grown. They're huge; they're not just cute little animals. They're actually very, very big animals, and many people don't realize that. They're too big to be donors of an organ to most human beings. And they're too big after they're maybe a year old.

The miniature swine are just the right size to be donors for a human being, and the donor organ could be matched in size to any human being, from a newborn baby to a very large adult. So one of the reasons for choosing the miniature swine was exactly that -- that it could be an ideal donor for xenotransplantation. There are also many other advantages to miniature swine for use as experimental animals, because they can be housed in a reasonable animal facility, whereas domestic swine really can't.

Do you want to make those animals transgenic? Do you want to introduce human genes into them to make the organs more compatible with us?

The use of transgenic animals has major advantages to the field of transplantation, because you can either change or eliminate or add genes that will make the donor more compatible with the recipient. But you will never change enough genes to make them identical, so you will always have to, in addition, either suppress the immune response, or tolerize the immune response.

We clearly want to make the job easier, and we intend to continually modify the donor pig, to make it more and more ideal. So my expectation would be that, with time, more genes will be added, and other genes removed from the genome of the ideal donor pig to make it more and more compatible, with a human recipient. But it will never be identical.

As the miniature swine you work with stand at the moment, have any of them been genetically modified?

The genetic modification in our miniature swine has been done naturally, not by transgenesis. It's been done by selective inbreeding. These animals have been inbred by brother-sister matings, in a very controlled fashion, typing for the antigens that are important to transplantation. And I've done that now over a 25-year period. So these are really the only large animals that you can do this kind of reproducible transplantation experimentation in, because they all have identical genes.

And at the moment, what has that inbreeding produced? Has it suppressed what our bodies' defense system recognizes as animal within those pigs?

No. The idea of having an inbred donor, and the reason that would be important for transplantation to a human being, for example, is that all of the animals are identical. Therefore, if you work out a procedure to induce tolerance to one donor, that tolerance would also be available for an organ from another donor. You could use cells from one animal, and then use a heart or a kidney from another. If that organ were to fail, the recipient would still be tolerant to a new organ from that same inbred donor animal.

So you're trying to create by a natural selection process that you've managed -- pigs that are so close to each other that they're almost as good as clones?

They are essentially clones. They are essentially identical twins. And we've known this has been possible for mice for many, many years. There are numerous strains of inbred mice, and we call them syngeneic. It really means they're like identical twins. And the problem has been that inbred animals, up until now, have only been available for very small animals, like mice and rats. But now we have this line of miniature swine, which are similarly inbred. And the most recent animals now have a coefficient of inbreeding, which is what we call the similarity of over 90 percent. With these animals, if you exchange skin grafts among them, they don't reject. So from the point of view of transplantation, these animals are identical.



In the course of doing that, have there been any other benefits that have come to light? I'm thinking of cross-species infections. Is that an issue in the last couple of years?

Quite by chance, one of the lines of miniature swine that we chose to inbreed apparently has also a much diminished, if not absent, transmissibility of the PERV virus. And this was a surprise to me, but, in fact, a very nice surprise. . . .

Three PERV viruses have been identified as transmissible to humans. Do your pigs possess them?

I believe that all pigs have copies of these viruses, but that they don't all transmit these viruses. That is how I understand it. . . .

There are those who feel that we do not have the right to use animals in this way for our own benefit, to prolong our own lives. What do you say to that?

. . . The only really closely related species that would be a potential donor for transplants to a human being would be chimpanzees or apes, both of which are endangered species. And I don't think any of us, or anyone in his or her right mind would consider using such animals as donors for transplantation. . . . But when we're talking about using pigs as a donor . . . our societies have determined that it's all right to use pigs as a source of food. And it's hard for me to understand how it would be unreasonable to use a heart from a pig, for example, to save someone's life, if it's all right to use the pigs to produce bacon and pork sausages.

Are there also animal welfare issues that spin out of this, if in the future we will intervene in the lives of these animals, and make them live in very unusual ways in order to benefit us?

I believe firmly in humane treatment of animals. I think there's a big difference between humane treatment of animals and "animal rights." I think we have determined that it is reasonable to use animals to sustain human life, and I think that that does not change in any way the need to always treat animals humanely. We would not want any of our animals to suffer, and I think that everyone working in this field feels the same way.

But the public will have to accept, will they not, that animals will have to live in unusual conditions, so that they can be absolutely clean and pathogen-free, in order to donate their organs for us?

Donor animals, donor pigs for transplants, will definitely have to be maintained in very clean environments, in order to avoid the possibility of carrying an infection. But the conditions can still be quite humane and quite reasonable. Much more reasonable, I'm sure, than many situations in which animals are raised as a source of food.

And likewise, the public will have to accept that we will intervene in the lives of these animals at very crucial stages, won't we, in the fertilization, the ovulation, the birth of these animals. We will have to manage and farm them specifically for their organs, won't we? It's not farming in the traditional sense, is it?

It's not farming in the traditional sense. But I don't see anything about it that would be inhumane, or which would cause the animal to suffer. I would not condone such a practice.

What do you say to those people who feel that we are tinkering with a fundamental keystone in the arch of our whole immune system -- the barrier between us and the animals -- and that we are risking too much?

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.

When do you think that xenotransplantation might become a treatment available to patients?

My own feeling is that we should not consider xenotransplantation into human beings until we have a reasonable expectation that it will be successful. And by that, I mean when the experiments we're doing of a pig into non-human primates have been as successful as transplants between individuals of the same species, and have shown no signs of rejection over periods of hundreds of days. And we're not at that stage yet.

But what I can say is that I have not seen any problems yet along the way which seem to me to be insurmountable. . . . The problems we're facing are problems of the immune system, the inability to prevent these antibodies from returning. I'm confident we will overcome that problem. Right now we have already overcome the problem of the T-cell immunity.

I really think that if we overcome the problem of the antibodies, we'll be very close to success. When that will happen, I cannot yet predict, but I do feel it will happen. And I think at that point, we'll start to have the kind of results in our pig to non-human primate studies that would lead me to say we're ready to go to the patient.

Do you think you have to have the courage to fail in all this? In the history of transplantation and its experimentation, people died at the beginning.

You always have to have that courage to the possibility of failure to make progress, and the patients have to have that courage as well. I've always felt that I should work on the most important problem that I really think will be solvable. And to me, that's what xenotransplantation is.

How much do we actually know about how a pig organ would perform if it was transplanted into a human?

The organs of other species are every bit as good as the organs of humans in maintaining the functions of life, with exception, perhaps, of the brain. But certainly, we've already seen that a pig kidney can support the life of a non-human primate for a matter of months. . . . We know the same is true for a heart from a pig. So, physiologically, we believe that these will work. The reason these organs have failed has been the immune system, not a failure physiologically.

Do we know that if I had a pig organ in my chest and I ran for the bus, would it respond to my adrenaline and beat faster?

Yes, we believe that that would be no different from a heart transplant from one human being to another. The requirements for demand on the heart appear to be satisfied just by the heart itself, because when you do a heart transplant from one human being to another, you don't hook up anything else but the vessels. You don't hook up the nerves, and yet, that heart functions normally. There's no reason to expect that that would not be true for a pig heart, and, indeed, in those experiments so far where that has been done, the heart has functioned normally.

So, we think that, that from a physiological point of view, many of the organs of the pig will be just as good as those or another human being. For example, the pancreas, which carries the islet cells that produce insulin and is needed to cure diabetes -- we know that the pig islet cells are fully compatible with producing an insulin that sustains human beings with diabetes, because it's been used for years. So we would expect that another tissue, like islet cells, would give normal function in the human being.

The liver is perhaps a problem, because the liver makes so many proteins, that some of them are bound not to work properly in a human being. But if you think into the future, you could also conceive of changing those protein structures in a pig by the use of transgenics, so even that I don't think is impossible.

A pig is unlikely to live more than 15 years. How could I be sure, if I had one of its organs, that it wouldn't expire before me?

The lifetime of an individual is not necessarily indicative of the lifetime of its individual parts. We know that many human beings die at the age of 80 with perfectly normal, functioning livers, pancreas, kidneys, lungs, even hearts. So it's not clear that, because the lifespan of a pig is generally thought to be about 15 years, that each of its organs would fail in 15 years. However, from what I've told you about our procedure of using inbred animals and tolerance, we think that if we have evidence that an organ were aging prematurely, so to speak, we could replace it with an organ from another identical animal, and maintain the patient by another xenotransplant.

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