In Greek mythology a chimera is a monstrous fusion of species, a fire-breathing she-goat with a lion's head and a serpent's tail. In the fast evolving world of genetics, chimera currently refers to a living creature in which tissue from two different animals have been fused in a symbiotic relationship.
In the most striking recent transgenetic experiments, mice, pigs, sheep and cattle are being injected with human genes to provide them with specific human characteristics. The object is to sidestep the violent rejection of animal tissue by human immune systems so that animal organs, the liver or heart of a pig for example, can be transplanted into a human patient. While Jeff Getty, the AIDS patient who is receiving a bone marrow transplant from a baboon, has recently caught public attention, Getty is likely to be only the first in a series of increasingly daring animal-to-human transplant experiments. Getty's baboon bone marrow transplant is relatively straight forward and does not involve complex genetic manipulation, but it is also not expected to succeed. Other, more advanced experiments however, could begin to change the face of modern medicine. That is one reason that the FDA stepped in to watch the Getty case more closely than previous experiments. Says Dr. Philip Noguchi, head of cellular and gene therapy at the FDA, "This is the beginning of the use of animal organs and tissues on a widespread scale. What you are going to see is the commercial development of these approaches. It is going to require much closer interaction between the federal government, health services and local communities to bring this off." Noguchi says that the FDA stepped in to monitor the Getty operation because the proprietary method of collecting baboon bone marrow for the transplant approaches a biological product. Dr. Suzanne Ildstad, who developed the procedure, contacted the FDA herself once she had received approval to proceed with the experiment in California. Another advantage to involving the FDA in the case is that the operation can be carried out under controlled observation. "It has never been done in a controlled manner before," says Noguchi, who adds that previously, "patients haven't lived long enough for us to have any meaningful knowledge about what happens."
Both Getty's case and the more innovative genetic engineering technologies are raising troubling ethical and public health questions. Jonathan Balcombe, who handles animal research topics at the Humane Society of the United States, notes: "One can envisage a disturbing scenario in which animals are going to be bred as spare parts to be used for humans. The approach is to turn the animal into a chimera--part animal, part human." To a certain extent that is already happening.
Twenty years ago, heart and liver transplants were risky propositions, and were relatively rare. Major advances in immunosupressant drugs which stopped the body from rejecting a newly grafted foreign organ changed that. Today, the chances of surviving a heart transplant are good. As a result the demand for transplant operations has soared. At least 45,000 people are currently on the waiting list for heart transplants in the US. Nearly a third can be expected to die before a suitable donor is found. 70% of patients who need bone marrow transplants to fight off leukemia cannot find suitably matched donors. If the need for transplanted kidneys and livers is included the total demand for transplants of all kinds exceeds 100,000. If a transplant from an animal to a human, technically dubbed a "xenotransplant" could be made the supply could be increased dramatically.
In the case of AIDS patient Jeff Getty, a transplant of bone marrow from a baboon has an even more tantalizing advantage. The baboon's immune system is impervious to HIV. If the baboon's bone marrow were to take hold in Getty, it might give his body a functioning immune system despite the virus. The danger, especially in Getty's case, is that the transplant risks passing a new virus from animal to human with possibly catastrophic results.
The most immediate problem that Getty and other potential xenotransplant patients face is that the human immune system rejects animal tissue even more ferociously than it does foreign tissue from other humans. Drugs that might suppress a rejection in a transplant from one human to another, have almost no effect when a transplant of animal tissue to a human is made. The result is a reaction that doctors call "hyper acute rejection."
That is exactly the problem that most threatens Getty. He is far from the first candidate for an animal to human transplant and the record up to now has not been promising. Since 1905 when a French doctor tried to graft a rabbit's kidney onto a child suffering from renal failure, there have been more than 30 attempts at xenotransplantation. At least eight have involved trying to place an animal heart in a human being. In 1964, an attempt was made to transplant kidneys from Chimpanzees into seven patients. Six of the kidneys functioned immediately, but despite high doses of immunosuppressant drugs, acute rejection developed. Five of the patients died from infections or imbalances due to the overuse of the drugs. The longest surviving kidney lasted six months. Intriguingly, in that case the kidney appeared to still be functioning when the patient died from an electrolytic imbalance.
In a second series of operations, baboon kidneys were transplanted into six patients. All six patients died. The longest lasting kidney functioned for 60 days. In 1984, a baboon heart was transplanted into a patient known as "Baby Fae." She died after 20 days. In 1993, livers from two baboons were transplanted into patients suffering from hepatitis B. One liver functioned for 55 days. The patient died after 70 days. The second liver lasted only 26 days.
An attempt to graft whole bone marrow from a baboon into a 56-year old patient in Pittsburgh also ended in failure and death.
By genetically altering animal donors, scientists hope they can eventually side step the rejection mechanism. The aim is to modify is known as a "complement" in the donor's immune system. The complement releases deadly toxins when it comes in contact with the complement of another species. With a short period of time, the toxins destroy the grafted organ or tissue. But if a pig or other animal donor could be modified to have a complement resembling a human complement, that aspect of the rejection process would be short circuited, hence the introduction of human genes to the donor animal's DNA. One technique for doing this is called "micro injection." A fertilized egg is extracted from a mouse or a pig, and one or two human genes is injected into the pronucleus.
The animal adopts those characteristics and passes them on to its heirs.
A number of companies are currently developing genetically altered animals.
Genetically engineered animals, cut through the elaborate requirements that have to be fulfilled before human testing can begin. "It is a tool," says a scientist working in the field."It allows you to get more qualified 'go-no-go" answers earlier. You can have higher confidence in betting on your winners, or you can eliminate the losers at an earlier stage, and save a lot of money." The bottom line, is that "you can get miracle cures into the market place quicker so that everyone can benefit."
Ultimately, though, it is xeno transplantation, the use of animal tissue and organs for human needs, which has captured the imagination of surgeons?
Although baboons and primates appear to be obvious candidates as transplant donors since they are closer to humans, there are also strong drawbacks. One is supply. There are only a few thousand baboons currently being kept in captivity for medical purposes in the US--hardly enough to satisfy the demands for transplants. The baboons who are available, are also far from being clean laboratory specimens. There is a very real danger that a transplant from a baboon could introduce a lethal new virus into the human race. The virus might not be detectable for years, much like AIDS. That is a prime concern in the Getty case. Says the FDA's Noguchi, "Ironically, you are the most concerned if the bone marrow is a success. The virus could remain latent for several years. It is if the experiment succeeds that we will have to be the most careful."
Scientists would much prefer to make a transplant from a domesticated animal like the pig instead. Although pigs carry viruses too (swine influenza is an example), they are genetically different enough to make it less likely that a virus will accidentally enter into the human system. Also, since pigs reproduce more rapidly than primates, it is easier to raise them under stricter laboratory conditions. In contrast, baboons roam in packs, are far harder to control and often pass viruses among themselves. Another advantage of the pig is that a variety of heart sizes are available which match human dimensions. At present anywhjere from 50,000 to 100,000 pig heart valves are being used throughout the world. Most function relatively reliably over at least a ten year period. Dr. Leonard Bell, CEO of Alexion, a transgenic startup, points out that 90 million pigs are slaughtered for food in the U.S. each year. Pigs are not only far more abundant, but there is much less sensitivity about using a pig's organs than there is in using a primate's. "It's an easy decision," says Bell,"would you rather have a meal on your table, or be alive?"
Bell, a clinically experienced cardiologist, is skeptical about the use of baboons. "The wide range applicability of primate transplantation studies," he notes,"is extremely limited. In that regard, it has to be seen more as a scientific experiment than a wide ranging therapy." These considerations have raised a number of questions about the Getty operation. In an unusually blunt letter to the New York Times, Dr. Murry Cohen, co-chairman of a Virginia-based organization calling itself the Medical Research Modernization Committee, denounced the Getty transplant as insane. "This represents not scientific progress," wrote Cohen, "but medicine and Science gone mad. With no potential for success, the procedure must be called an experiment."
Suzanne Ildstad, a transplant surgeon at the University of Pittsburgh, says she conceptualized the approach while she was studying how to "harvest" bone marrow at the Fred Hutchinson Cancer Center in Seattle. She had developed an interest in xenotransplant because of the acute shortage of donor organs, and she had carried out increasingly successful work at grafting highly mismatched bone marrow. While she was working at Hutchinson, a colleague remarked that baboons made terrible animal models for working with AIDS because their immune system refused to become infected. In fact, the colleague remarked, most primates were bad models for working with AIDS. "A light bulb went off," says Ildstad. "It was an unexpected potential application of our work."
Ildstad dismisses questions about the limited supply of baboons. "You don't sacrifice humans who donate bone marrow," she says. "It is not necessary to sacrifice the animal to obtain numbers of cells." new techniques, Ildstad adds, allow the harvesting of baboon bone marrow cells from the baboon's blood while the baboon is kept alive. For the Getty operation, Ildstad is gambling that by carefully selecting the cells to transplant and by preparing them in advance, she can avoid the hyper acute rejection that could normally be expected to follow. A number of experiments using new techniques show that it is possible to graft tissue from one species to another and have the recipient survive longer than it might have otherwise. But in Ildstad's testing, the animals eventually ¨did die.
Her last experiment had resulted in engrafting 15% of the marrow for six months, but after that it trailed off and the human bone marrow stopped functioning. Ildstad's team ran out of funding before it could carry out new experiments. To a number of physicians, it seems like sketchy data to proceed with an experiment on a human being. The fear in some quarters is that a failure will set back the entire field of xenotransplantation, and could eventually rule out the use of baboons indefinitely.
Stephen Rose, who heads AIDS funding at the National Institute of Health, was quoted by the Lancet as saying: "Having seen her data--there is no data--she never got engraftment. There are no underlying data to make me believe this is going to be successful."
The Lancet also reported that one reason that the operation is not being carried out in Pittsburgh is that the institutional medical review board there has grown more cautious since the failed transplant of baboon whole bone marrow two years ago.
That operation was carried out in Pittsburgh by Camilio Ricordi.
Although most experts are skeptical that the experiment will work with Getty, he is considered an informed adult, and that is why he was given the green light by the FDA's Noguchi and others. Noguchi says it is not necessary for full clinical studies to have been carried out before this type of procedure is tried. At a 2-day meeting of the Biological Response Modifiers Advisory Committee in Bethesda, Maryland on July 13, the committee voted unanimously, with only one abstention, to let the operation proceed. Says Noguchi, "The bulk of the panel felt that a risk was there, but that it was small. " The risk that had Noguchi and others concerned was that transplanting baboon cells in Getty might carry a virus that would suddenly unleash an epidemic similar to AIDS or the Ebola virus.
The abstention at the Bethesda conference came from Dr. Jonathan Allan, an expert on baboon viruses at the Southwest Biomedical Foundation in San Antonio, Texas. The foundation is the largest source of baboons for medical use in the world. The danger is that with his immune system nearly destroyed by AIDS and further obliterated by radiation treatments to enable the transplant to take hold, Getty might prove the perfect host for a new disease. "If you transplant an organ from a baboon to a human," says Allan,"you are going to transplant whatever microbes are present in that organ into the human. Once you introduce a virus into a human, it becomes almost impossible to get it out. You are fulfilling the first half of the equation for starting a new epidemic."
Allan points out that it is now nearly impossible to find healthy baboons for transplants. "We have exhausted our supply of adult baboons who do not carry viruses," he says. "There are no other adult baboons that we can use to carry out these experiments. " The baboon used for the Getty transplant, in fact, carries one virus as opposed to four which were carried by the baboon originally selected. Allan points out that the 3,000 baboons at the foundation travel in herds of 400 to 500, so viruses spread easily among them. "It's like plucking them out of Africa," he says. "The bottom line is that you are not going to make a dent in the organ shortage by using baboons, and you may unleash a new epidemic. It is a no-win situation." A major complaint of Allan is that until now discussions of animal transplants have involved surgeons, but have not incorporated the infectious disease experts who should be examining the issue as well. In contrast to Allan's point of view, Dr. Robert Michler, head of cardiothoracic surgery at Columbia Presbyterian Medical Center in New York points out that there have already been numerous xenotransplant operations involving primates. Some of the patients have survived for at least a few weeks, and there have been no cases of dangerous viruses emerging from the operation.
Although overruled by the committee, Allan stirred some genuine concern.
"I don't think he was being overcautious," says Noguchi, "and I don't think the committee can discount his concerns either. his basic thesis is that once you get a retrovirus into the population, it is very difficult to eradicate it. No one can dispute that basic concept."
Allan is not the only one to raise the issue. Dr. Ronald Desrosiers, professor of microbiology at Harvard Medical School, is even more adamant. "You are taking a large number of cells out of a baboon and you are intentionally placing them into a human," says Desrosiers. "There is a reasonable chance that you are going to be transmitting a virus. It is a scary, worst-case scenario, but it is not a totally unrealistic one."
Desrosiers adds: "You can say that you will screen the baboons, but you can only screen for viruses that you know about, which is probably a very small minority of all the viruses that baboons carry. I think it is probably safe to say that 99% of the viruses baboons carry have not been discovered yet."
"The decision would have been more difficult if there was a chance that the bone marrow transplant would work," Desrosiers concludes. "But the chance of that bone marrow taking and working in a human is zero. There is no chance that the experiment is going to work. It has never been done, even in an animal system."
How true that analysis is will be become evident over the next few months. Even if the Getty operation succeeds though, the future points to future transplants from hyper controlled genetically engineered pigs and sheep.
But even that will raise troubling ethical questions about just how far we should go to fight against the natural process of human mortality. The Humane Society's Jonathan Balcombe notes: "The world is beginning to collapse as an organism because there are so many humans and we take such a toll. We have to begin to move away from an exploitative view of other life. We need to start thinking more of ourselves as stewards of the planet. Raising animals as spare parts for human transplants moves us in the opposite direction."
Whether one agrees with Balcombe, traditional ideas about the differences between animals and human beings are going to require quite a bit of rethinking.