The Hardest Wait
Every year in the United States and Europe, surgical transplant teams save ever more lives, yet every year the number of people who die while waiting for a donor heart, lung, liver, or kidney grows. Between 1990 and 1995 in the United States on average each year only 4,835 people became organ donors after their death, about 1 in 500 of all those who died. In most cases, the donors were young persons who died of traumatic head injury, and each could provide several organs. During 1994, about 5,000 newly dead persons provided organs for 18,000 transplant operations in the United States.
Despite all that surgery, in 1996 the official waiting list, which is maintained by the National Organ and Bone Marrow Registry, included 48,000 people who were in imminent need of a donor organ. Of these about 33,000 needed kidneys. And these numbers significantly underestimate the real need. Some cardiologists have guessed that as many as 50,000 people have sufficiently severe heart disease to qualify for transplant if a donor organ was available. To put it coldly, the people on these lists (and many more who are headed there) have little choice but to hope that fate will strike down someone else so that they can win a new lease on life. Each year in the United States more than 3,000 people who have become sick enough to claim a spot on a list die while waiting for a donor organ.
There is a severe shortage of cadaver organs in virtually every country that routinely performs transplant surgery. For example, during 1995 in Great Britain, 1,003 cadaver organs (including 36 imported from other nations) became available for surgical use. Yet, at the end of that year, there were 6,133 patients on the United Kingdom Transplant Support Service Authority's waiting list, a number that may underestimate the true need, as the criteria for being placed on that list are more stringent than comparable rules in the United States. In 1995 only 3,679 persons died from traffic accidents in all of Great Britain, and only 5,235 (much less than a third of the number in 1970) died of stroke (which is after trauma the second major source of organs).
As we live longer and as physicians learn to manage chronic heart, kidney, liver, and lung diseases better, as deaths from stroke continue to drop, as highway safety improves and alcohol-related traffic fatalities drop, and as more cyclists wear helmets, we can be certain that the waiting list for donor organs from cadavers will continue to grow.
The hope that we might someday be able to use animals as organ donors is older than transplant surgery itself. Alexis Carrell, who worked at Rockefeller University in New York and won the Nobel Prize in 1912 for his pioneering work in cell culture, spent years trying unsuccessfully to transplant organs and limbs from one animal to the other. It is said that his research inspired H. G. Wells to write The Island of Doctor Moreau, the story of a brilliant surgeon in self-imposed exile on a Pacific island who has discovered how to create chimeras of animals and humans.
With little knowledge to go on, but faced with desperate patients dying in front of them, in the years after World War II a small group of surgeons began studying organ transplantation, especially kidneys, in animals, often using dogs as their models. The first decade was devoted to grasping the outlines of the problem of tissue incompatibility. Having made modest advances, on a few occasions some research physicians attempted what, in retrospect, were operations as fantastic (and some said as foolish) as those imagined by Wells. In 1964 an American surgeon performed the first xenotransplant (the term refers to any transplantation of an organ from one species to another) when he removed a heart from a chimpanzee and placed it in the chest of a man who was about to die from heart failure. The much smaller chimp heart could not handle the circulatory load and the man died two hours later. In 1968 surgeons in the United States attempted a sheep-to-human heart transplant, and surgeons in the United Kingdom attempted a pig-to-human heart transplant. In both cases the immune system immediately rejected the foreign organ, and the patients died within hours. In 1977 South African surgeons twice transplanted baboon hearts into dying men; in both cases the patients quickly rejected the hearts and died within a few days. In 1992 Polish surgeons transplanted a pig heart into a dying man, and the smaller organ kept him alive for 20 hours.
The most famous and controversial cardiac xenotransplant was attempted in 1984 when surgeons at Loma Linda University Medical Center in California put a baboon heart into a 15-day-old infant known as "Baby Fae." This desperate measure was defended as a bridging operation, an effort to keep the child, who had an undeveloped left ventricle, alive until a human donor organ became available. By using drugs to suppress the infant's immune system, the doctors were able to keep Baby Fae alive for 20 days. During the same era there were a few similar efforts to use baboon, chimpanzee, and pig kidneys and livers as xenotransplants. In a few cases patients survived for up to 10 weeks, but in no case was anything approaching normal organ function achieved.
While the occasional heroic, some might say quixotic, emergency xeno-transplants were grabbing headlines, teams of immunologists took on the arduous task of trying to understand why recipients rejected the organs so quickly. Studies of xenotransplants from pigs to dogs revealed that the immune system of the recipient animal sometimes mounted an overwhelming attack on the donor organ that started within seconds, and often caused death in a few minutes (a response that is now well understood and called a hyperacute rejection or HAR). There seemed to be an insurmountable immunological wall that would make xenotransplants impossible. Nature had clearly never anticipated the need for xenotransplantation. Over the eons, mammals have evolved an elaborate set of genetically coded immunological defenses that will, when they recognize that the body has been penetrated by foreign tissue, unleash a massive counterattack so deadly that it carries an extremely high risk of destroying the patient.
Surgical advance in xenotransplantation depends on cracking the secrets of the immune system and then learning how to circumvent its de fenses. Beginning with studies in the mouse and moving on to other species, immunologists have gradually characterized an immensely complex set of genes that make up what has become known as the major his-tocompatibility locus. This block of genes directs the production of molecules that reside on the surfaces of circulating cells that form part of the immune system. They immediately detect any foreign organ. In humans it is called the HLA (for human leukocyte antigen) system. By 1970 scientists had found that these genes (which reside on chromosome 6) have so many variations that in combination there are more than 20,000 possible genotypes. That is why when one searches for a donor outside one's immediate family the odds are so low of finding an immunologically identical match. The dramatic increase in successful kidney transplants in the 1960s and 1970s was in large part due to a better understanding of which genes in the HLA complex must be matched in order for the operation to succeed. It is our ability to characterize the HLA type of any individual that made it feasible to create a national donor matching program.
Over the last five decades the immense effort to understand our immune system has paid off. The first human kidney transplants, which were performed at the Peter Bent Brigham Hospital in Boston in the mid-1950s, involved identical twins. Surgeons and their medical colleagues gradually branched out to transplants from brother to sister and parent to child. That is, they began by transplanting organs between genetically identical individuals and progressed to genetically similar donor-recipient pairs. As they learned more and more about how to avoid organ failure due to the response elicited by foreign HLA antigens, physicians became able to match organs between unrelated persons, thus greatly expanding the pool of potential donors.
By 1980 we knew that by matching just four particular major HLA al-leles, the odds of transplant success would substantially improve. Surgery was also greatly aided by immunosuppressive drugs, especially cyclosporin A, which became available about that time. Cyclosporin A is almost magical in its power to dampen the immune response, in effect letting us circumvent some of the problems associated with making imperfect matches between donor and recipient. Transplant teams now know that if they can find a fresh donor kidney which shares an immunological profile at the four key HLA coding sites with the potential recipient, the odds are 9 out of 10 that the kidney will be functioning well in the recipient two years af ter the surgery. For many recipients, the donor organ lasts much longer. Yet, with all this success the waiting list keeps growing and each year more people die while waiting for a transplant.
By the 1990s immunologists knew enough about how organisms react to foreign tissue to develop a visionary strategy to solve the tremendous shortage of organs. The first task was to pick a donor species and develop much deeper understanding of its immune system. Because they are far more plentiful than nonhuman primates and much less expensive to maintain, and because their hearts and kidneys are about the same size as ours, scientists chose pigs as the future source for our replacement organs. Researchers also still have much interest in baboons, which are the second most common primate (after humans) on the planet. Baboons, however, have posed difficult problems, not the least of which is that their blood types do not include a universal donor (like human type O) blood. Nevertheless, during 1994 Thomas Starzl, a pioneering transplant surgeon and researcher at the University of Pittsburgh who helped to develop cyclosporin A, transplanted baboon livers into two patients who were near death. His team was able to keep the patients alive 25 and 75 days. In effect they overcame the risk of the hyperacute rejection (HAR) that kills in minutes and the acute vascular rejection (in which the patient's immune cells attack the blood vessels of the donor organ) that kills in days, but could not defeat the acute cellular rejection mounted by the patient's T cells that develops over weeks.
The first problem to solve in either baboon- or pig-to-human transplants was to suppress the HAR, which is what so quickly killed the dogs that received the pig hearts in early surgical experiments. During the HAR, circulating cells and chemicals in the body immediately recognize the foreign organ and call an immunological "red alert." Within seconds, millions, then billions, of cells are triggering a massive counterattack. A group of proteins making up what is called the "complement cascade" almost immediately destroys the cells that line the blood vessels of the donated organ and in turn the organ itself. The patient dies from massive bleeding and anaphylactic shock.
The solution to circumventing the HAR in xenotransplants came with the ability to design transgenic animals. Two major approaches emerged: (1) manipulate early pig embryos to delete a gene that produces the key cell surface marker that human immune cells called xenoreactive antibod ies immediately recognize and attack and (2) create transgenic pigs that carry one or more human genes which regulate the production of complement and therefore can moderate the power of the complement cascade. Early work suggests that both approaches might work, but there is much to be done. For example, mice that have been born from transgenic embryos in which the gene for the Gal epitope (which codes for a key cell surface antigen by that name that antibodies recognize as foreign and attack) has been deleted provide donor organs which recipient mice do not reject, but the donor mice are blind. Scientists have successfully created transgenic pigs that carry both monkey and human genes which code for proteins to regulate complement activity (RCAs). When kidneys from these pigs were transplanted into monkeys, the organs in some survived for up to 60 days, long after the time for acute rejection. Scientists in both universities and biotech companies have launched programs to create transgenic mice, pigs, and other animals that will carry several genes in addition to the RCAs. The hypothesis and hope is that animals that receive such donor organs should initially perceive them as not too different from their "immunologic selves," and that their immunological sentries will not call in an HAR.
Since 1993 David White, a surgical researcher in Cambridge, England, has been developing a herd of transgenic pigs that contain in their genomes multiple copies of a human gene called decay accelerating factor (DAF), the earliest acting of the proteins that are critical to the HAR. When White removed hearts from these transgenic pigs and perfused them with human blood, he found that the organs sustained much less tissue damage than did hearts from ordinary pigs. He and other scientists have transplanted transgenic pig hearts heterotopically (put them into animals that have kept their own hearts) into baboons (which have RCAs quite like humans). In experiments in England and in the United States, the transgenic pig hearts have delayed the HAR and lived up to 30 hours, about 30 times longer than might be the case if a full force HAR was unleashed. On the other hand, a few control (nontransgenic) pig hearts pumped nearly that long when placed in the chests of cynomolgus monkeys. When Dr. White's team gave the recipient monkeys drugs to suppress their immune systems, they were able to keep them alive with pig hearts for 60 days.
At a company in Boston called Biotransplant, Inc., a group of scien tists led by Elliot Liebowitz, Ph.D., is developing an even more sophisticated, two-pronged strategy. In addition to breeding transgenic pigs with organs whose surface cells should be able to neutralize part of the human immune response, they are focusing on ways to alter the human recipient's bone marrow to make it pig-like. A technique that has worked in several animal species and could work in humans involves removing some bone marrow from the individual who needs the transplant, culturing the cells in laboratory flasks, using genetically engineered viruses to force the cells in culture to take up pig genes that code for key immune response proteins, and returning the altered marrow (by a simple intravenous catheter) to the patient. If it works in humans, the recipient would have an immune system that defended its body in the usual ways, except it would regard a pig organ as "self." In November of 1999, BioTransplant announced that, in association with physicians at the Massachusetts General Hospital, it had performed research with a small group of human subjects that provided proof in principle of this approach, which they call ImmunoCog-nance (TM). Their work, which was reported at the Fifth Congress on Xenotransplantation in Nagoya, Japan, triggered a $2,500,000 payment from Novartis, the giant pharmaceutical company that is funding much of the research.
Just as with human-to-human heart transplants in which success was measured at first by survival times of hours, then days, then weeks and months, and finally years and decades, success with porcine transplants will grow slowly. But grow it will. On the basis of cross-species animal-to-animal transplants, some immunologists think even now that it is scientifically permissible to try a pig-to-human heart transplant. They envision the attempt with a patient who has only hours to live and for whom no human donor heart is available. They think that by using drugs to suppress the human immune response they can prevent rejection of the transgenic pig heart for up to 30 days, enough time to justify a "bridging" operation—surgery to fend off death in hopes that a donor organ will become available. However, before that attempt is made, those who favor xeno-transplants, a loose coalition that includes millions of patients and their families as well as physicians and scientists, will have to neutralize the objections of a perhaps even larger coalition of opponents, mostly animal rights activists who question both the safety and the ethics of the entire field.
The safety and ethical issues raised by xenotransplantation first captured general public interest in 1995 when a team of AIDS researchers in San Francisco boldly proposed transplanting baboon bone marrow into human patients with the disease. It had been known for some years that the bone marrow of baboons is highly resistant to HIV infection. Even when they are directly inoculated with massive quantities of HIV, baboons do not get AIDS. The idea behind this controversial experiment was that if transplanted baboon marrow cells took hold, the bone marrow of the infected patient would become a chimera—partly composed of his own cells and partly composed of those of the baboon. If the marrow made lots of baboon T cells that are adept at fighting HIV, they might even wipe out the virus, which would constitute the world's first true cure of AIDS.
As word about the proposed baboon-to-human transplant spread, some bioethicists argued that the experiment would be unethical because the operation posed an unquantifiable, but extremely high, risk of death to the human recipient (whose immune system was severely weakened) from infection with an endogenous baboon virus or from some more usual infectious agent. But public discussion quickly turned to the much more frightening question of whether such surgery could cause an epi-demic—the result of the inadvertent transfer of some unknown baboon virus into humans. Because no one can design an experiment that offers absolute reassurance about this risk, it is a concern that is difficult to allay.
We cannot predict what will happen when a virus that has for millennia co-evolved with one host suddenly jumps into a new host, but we do know that it can be devastating. In 1967 vervet monkeys infected with the Marburg filovirus were imported into Germany. The virus infected 31 humans, and killed 7. In 1976 a shepherd in Pakistan developed a bleeding disorder that turned out to be due to a rare infection with the Crimean-Congo hemorrhagic fever virus, a bug previously thought to be unable to infect humans. Seventeen persons, mostly medical workers who had contact with the man, became infected, and four died. During 1995 in the Four Corners region of the American west there was an outbreak of han-tavirus (a virus that is routinely found in rats but does not cause them any ill effects) in humans. About one-half of the infected persons died. Even more frightening is the possibility that the flu epidemic of 1918, an illness that killed 25,000,000 people around the world in a year, was caused by a mutated form of the swine flu virus.
Frightening as they are, acute outbreaks are much easier to diagnose and contain than are epidemics in which the virus causes a devastating illness that develops slowly over a much longer period, exactly what occurred with AIDS. There is strong circumstantial evidence that the HIV epidemic began quietly in Africa when a monkey virus known as SIV crossed into humans, mutated, and adapted to its new home, and then moved on to other humans. The virus infected millions of people during the decade before we realized that a global epidemic was under way.
When the FDA was asked to permit the baboon-to-human experiment, it held a special meeting to review safety issues. The focus of attention was the baboon foamy virus, thought to be harmless to humans, and whether passaging it through a human might select for mutant strains which could become highly virulent. After the meeting, which was held on July 14, 1995, the FDA demanded that the medical team make every possible effort to use a baboon that did not carry the virus. It also required that San Francisco General Hospital beef up its containment facilities. Despite uncertainties about the risk to the public health, in August the FDA gave approval for a clinical trial involving one patient.
On December 14, 1995, Jeff Getty, an AIDS patient and activist in San Francisco, became the first human to receive a transplant of bone marrow cells taken from a baboon. The experiment did not harm Getty, and there was no evidence that he developed a viral infection of baboon origin. However, within a few weeks it was clear that the stem cells did not engraft (establish a permanent colony in his bone marrow) so the procedure should not help him in his struggle with AIDS. How could the doctors determine this? They used PCR to search Getty's blood for DNA sequences that are unique to the baboon Y chromosome. The technique, which could find just one baboon cell among 1,000,000 human cells, found none. Ironically, one reason for the engraftment failure may be that the experiment was too tentative. The transplant team may not have been sufficiently aggressive in suppressing his weak, but functioning immune system, so it might still have been strong enough to reject the baboon cells.
Meanwhile, other experimental firsts that posed risks of transmitting animal viruses into humans were being announced at a rapid clip. In April, 1995, Diacrin, Inc., a company in Massachusetts, began a trial to investi gate the safety of transplanting fetal pig brain cells into the brains of persons with advanced Parkinson disease or Huntington disease. The hope was that these immature cells would escape immune surveillance and grow to produce the dopamine that is so deficient in Parkinson patients and to replace the cells that die off in a region called the substantia nigra in Huntington patients. Scientists at Diacrin launched their human study only after showing that they had been able to deliver the fetal cells to the precise location in the brains of rats and demonstrate that the foreign cells lived and established connections with rat brain cells. Also in 1995, Duke University physicians tried to treat a patient with end-stage liver failure by passing his blood through a pig liver that was outside of, but hooked up to, his body, a living dialysis machine. Elsewhere, scientists started using encapsulated pig pancreas cells to treat severe diabetes. Others began transplanting adrenal cells from the fetal calf into the spinal cord of patients with end-stage cancer in an effort to relieve intractable pain. As word of cell xenotransplants spread, a chorus of critics both inside and outside the animal rights community emerged.
Knowing that it was their most likely means of reaching a wider constituency, animal rights groups argued both that using animals as donors was unethical and that pig xenotransplants posed a major public health risk. They warned that the porcine endogenous retrovirus (PERV), which is of the same general class as HIV and which is carried in the DNA of all pigs, could infect humans and become the next AIDS-like epidemic. In the United States, expert virologists were not worried. In 1996 the Institute of Medicine asked 60 virologists to advise it if xenotransplants posed a serious threat to humans; 59 of them said that the experimental work posed little threat and should proceed.
In England, at the time home to the world's leading xenotransplanta-tion research, a strong coalition of animal rights groups argued that even if the research did not pose a public health threat, it constituted the "ultimate exploitation of animals." The groups had an obvious political impact. In 1996, as researchers talked more and more openly about performing the first animal-to-human organ transplant, the government imposed a moratorium and convened a blue ribbon commission to assess the ethics (not the safety) of xenotransplantation. About the same time, Dr. KarlFrederich Bopp of the Health and Social Policy Division of the Council of Europe called for a moratorium throughout Europe on such work. Late in
1996 the British Advisory Group on the Ethics of Xenotransplantation advised that too little was known about the risks to ethically permit clinical trials in humans.
In 1997 U.S. officials at the FDA, confronted with mounting public concern about the risk of PERV and strong resistance from animal welfare groups, placed a clinical hold on all ten approved research programs that intended to transplant whole pig organs into humans. They required each to demonstrate the capacity to detect even the smallest signs of PERV infection in recipients. Within six months, six programs had successfully done so and had restarted. In June of 1999 the FDA Xenotransplantation Subcommittee held a public meeting as it prepared to issue final rules on the conduct of xenotransplantation research. Expert after expert testified about efforts to detect evidence of PERV infection in persons who had been exposed to porcine tissue. Together they had tested every human research subject who had received pig tissue and had found no sign of infection in anyone. In addition, they had tested 100 primates that had received pig tissue, and none of them was infected with PERV. The meeting was notable for the report that in the first half of 1999 more than 150 pig-to-primate transplants had been conducted. At the close of the meeting, Dr. Hugh Auchincloss, chair of the FDA subcommittee, announced that the FDA would give a green light to cell xenografts (experimental therapies such as using fetal pig neurons to treat Parkinson disease). The conditions under which the FDA will permit xenotransplants will be published in 2000.
In Europe, the many animal rights groups who abhor the use of trans-genic animals as spare organ factories for humans have become allies with religious groups that are troubled by the notion of transplanting animal organs into humans. Some of them believe that deep spiritual consequences flow from placing an animal heart into a human; others that such actions violate the natural order. Others worry that it would be psychologically devastating for a person to depend on an animal organ for existence.
How do people feel about the possibility of living with a baboon, pig, or some other genetically engineered animal organ in their bodies? We have only a little evidence. A survey of 1728 acute-care nurses in Australian hospitals found that more than 65% said that they would not accept a primate organ and only 19% reported that they would. The percentages were virtually identical when the same question was asked concerning pig or sheep organs. The survey did not ask whether views would differ if the donor organ contained a few human transgenes to modulate the immune response. On the other hand, Jeff Getty was eager to undergo the baboon bone marrow transplant. A survey of healthy persons may offer little insight into what most gravely ill persons would do should xenotransplantation represent the only option to avert death.
Many persons alive today because of a heart transplant tell of feeling a profound connection with the donors that they never met. Some even report feeling that the deceased individual is watching over them, almost invariably in a kind, caring way. Given the symbolism of the heart in our culture, the use of transgenic hearts, be they taken from primates or pigs, is likely to pose significant emotional issues for some recipients. How would it feel to wake up each day to listen to the beat of a baboon's heart? The question is impossible to answer, but one prediction can be confidently made. The early recipients will have to bear the burden of intense media attention. They will be forever redefined by others as the men and women who first had animal hearts placed into their chests.
Hopefully, they will benefit from the fact that we live in an era that has recognized and embraced a neurological definition of self. For most of our cultural history the heart has been regarded as the seat of emotional life. For 2000 years we have defined death as the moment at which the heart stopped. Paradoxically, it was the possibility of human-to-human heart transplants that moved technologically advanced societies to adopt a neurological definition of death. This was legally necessary to permit medical teams to harvest viable organs from brain-dead individuals for donation.
Despite how technologically advanced it may seem to save human lives with genetically engineered pig hearts, the use of transgenic organs to provide replacement organs will probably last only a decade or two. It will be superseded 20-30 years from now by the creation on demand of needed organs grown by cloning and reprogramming cells taken from the needy patient. Scientists are already trying to develop ways to clone organs from single cells. Needless to say, this scenario suggests that those who could afford access to such organs might be able to dramatically extend their life span. This may be the greatest legacy of an era that has just begun with the cloning of a sheep from a single cell.
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