The tantalizing possibility of using a potentially unlimited supply of organs from animals to replace damaged human ones -- through xenotransplantation -- has, in just the past few years, jumped the divide from purely academic possibility to big-business likelihood. A half-dozen or so well-supported biotechnology companies have sprung into existence to pursue the creation of transgenic animals -- pigs with human genes, primarily -- or to develop novel antirejection strategies to support animal-organ transplants. The goal is to alleviate a desperate and growing shortage of human organs available for transplantation.
BIG BUSINESS: About 100,000 patients annually could use xenografts, says Alexion's Stephen P. Squinto.
However, the emergence of this new industry has sparked sharp opposition from animal-rights advocates, who call the move poor science, poor medicine, and an unethical exploitation of nonhuman species. They and other critics also fear that the rush to commercialize xenotransplantation may preclude a full exploration of the potential impact on health-care costs, possible alternatives to the procedure, and other issues raised.
The companies are expected to be competing for a potential marketplace that has been estimated in the billions of dollars, making the economic lure as powerful a motivation for research and development as the need to find new treatments for seriously ill patients.
"Where all of the companies will get in, initially, will be to look at terminally ill patients who really have no choice, because there is no human organ available," observes Stephen Squinto, vice president of research, molecular sciences, at Alexion Pharmaceuticals Inc., a privately held biotech in New Haven, Conn. Alexion uses a combined transgenics and antirejection biochemistry approach to xenotransplantation. "And that's not really a large market -- maybe 100,000 patients per year -- although it's an important medical need.
"But if you can provide an organ that performs as well -- if not better -- than an allogeneic [same species] organ, then you start looking at organ replacement as a treatment regimen, not necessarily for end-stage terminal disease only. If you can actually get to that point, now you've opened up and expanded, and you have a very large market."
Animal-rights proponents assert that animal organs are metabolically too dissimilar to those of humans to successfully substitute for human organs in the long term, even if the immunological barriers to xenotransplantation can be overcome. A more effective -- and cheaper -- response to the problem of organ shortages, several groups suggest, would be to find ways to increase the number of human donor organs available. Scarce health-care resources would also be better spent, they say, on promoting preventive measures for heart and liver diseases, including dietary changes and reductions in alcohol consumption.
Perhaps most worrisome, they say, is that, in the plunge toward profitable products in xenotransplantation, society may find itself financially burdened with a problematic -- if scientifically fascinating -- new medical technology without having had an adequate chance to consider less-expensive, more ethical options.
"You have companies that are investing significant amounts of money and foresee a possible windfall of profit in the future -- although, quite frankly, xenotransplantation may never work," says Peggy Carlson, research director for the Physicians Committee for Responsible Medicine, a Washington, D.C.-based nonprofit that advocates preventive medicine and alternatives to animals in research and education. "But if it does work, they see billions of dollars in profit, and when you're dealing with money, that sometimes becomes a driving force. So, could good science or ethics stop this when you have powerful monetary forces and companies behind it? I think the answer is no, unfortunately."
Scientists and others counter that, even if every potentially suitable human organ could be used for a transplant, the need would still far outstrip the supply. Animal or mechanical substitute organs, both of which are under development, are the only viable ways to meet the demand, they say. And, they point out, preventive-medicinesolutions do not answer the immediate needs of thousands of end-stage organ-failure patients -- whereas xenotransplantation might.
"We have to look and see if we can justify it economically," acknowledges John Logan, vice president of research and development for Nextran Corp. in Princeton, N.J., a wholly owned subsidiary of Baxter Healthcare Corp., Deerfield, Ill. "It's a reasonable issue to be raised. But I think we can say the following: It's a hell of lot cheaper to let someone die. If we have no intervention, that is certainly a very cheap way to do medicine.
"We've got to compare it to therapies that are currently utilized. If you look at kidney transplantation vs. dialysis, for example, kidney transplantation is a more cost-effective therapy. Not only does it improve the quality of life, it's cheaper in the long run. And I think those are the kind of economic issues that drive transplantation today and will continue to drive it in the future." Logan also notes that, if xenotransplantation researchers are successful, the abundance of available organs would likely open new treatment options currently not possible.
The key to bringing xenotransplantation to the clinic will be whether researchers can find ways to effectively neutralize an array of vigorous human-immune-system responses. When presented with a transplanted animal organ, the system mounts an aggressive, two-part effort to annihilate the foreign tissue, the first involving antibodies and the second mediated by T cells. An early, extremely potent aspect of the antibody response, known as hyperacute rejection, is seen by scientists as the main obstacle -- although not the only one -- to successful xenotransplantation. A great deal of scientific attention has been paid to these topics in the past few years; in fact, Nature Medicine devoted its entire September 1995 issue to the subject.
In hyperacute rejection, preexisting antibodies that recognize nonhuman cells target the endothelial cells lining the intruder organ's blood vessels for attack by a system of about two dozen proteins called complement proteins. Complement proteins then rupture the membranes of the endothelial cells, destroying the organ's ability to supply itself with blood, leading to its destruction in minutes or hours.
Human endothelial cells present several regulatory proteins that preclude an autoimmune version of this attack from being unleashed. These proteins have been the focus of efforts by several companies, working closely with academic scientists.
Nextran, for example, has used pronuclear microinjection to create transgenic pigs incorporating three human genes that code for complement-inhibitory proteins CD46, CD55, and CD59. Pronuclear microinjection is a proprietary transgenic technology exclusively licensed from Princeton, N.J. -- based DNX Corp., a co-owner of Nextran until selling its share to Baxter in September.
In July, Jeffrey L. Platt, a professor of surgery, pediatrics, and immunology at Duke University Medical Center, received approval to use livers from Nextran's transgenic pigs in 10 ex-vivo procedures, as aids to patients waiting for a human organ to become available. According to Platt, a major advantage to the transgenic approach is that the pig organs are able to protect themselves from complement-based rejection -- at least partially -- without the need to suppress the patient's entire complement system.
"There are a number of agents that are now available to inhibit complement that can be injected into the blood," Platt notes. "The major problem with that is that you need the complement system in order to protect you against infectious organisms."
Platt acknowledges that, in addition to hyperacute rejection, further rejection mediated by antibodies and T cells remains an issue, as does the question of basic functionality of the organs. However, he notes, immunosuppressive drugs and other tactics currently used in human-to-human transplantation, or allotransplantation, may be sufficient to allow xenotransplantation to go forward once hyperacute rejection is controlled.
FIGHTING REJECTION: Researchers hope that transgenic pigs with human genes, like this one from Nextran Corp., will make possible animal-to-human transplants without recipient immune-system rejection.
Researchers at Alexion have created a dual-acting fusion gene that incorporates the functional domains of two genes coding for the complement inhibitors DAF and CD59. With the fusion gene, the company hopes to create transgenic pigs for use as organ sources. In addition, company scientists believe they have devised a way, also through transgenic engineering, to incorporate a third gene -- the H-transferase gene -- that will biochemically alter pig organs so that they provoke a less-intense rejection response in a human host.
According to Alexion's Squinto, the enzyme coded for by the H-transferase gene is central to a strategy to counter the actions of the a-Gal epitope, a carbohydrate molecule that is part of a potent antigen presented by pig cells. Human antibodies bind to this antigen and, after a xenotransplantation, would precipitate the devastating complement attack. Company scientists discovered that the enzyme responsible for synthesizing an analogous carbohydrate in humans is able, in pigs, to "outcompete" the pig version of the enzyme. As a result, when the human gene for the enzyme is introduced into pigs, their organs present high levels of the human epitope -- in fact, the same molecule that appears on the surface of so-called universal-donor, type O human blood cells -- which engenders no antibody response.
In an August vote of confidence, Norwalk, Conn.-based U.S. Surgical Corp. bought 9.5 percent of Alexion and is providing additional research support in return for marketing rights to the transgenic pigs resulting from this approach to defeating hyperacute rejection in xenotransplantation.
Imutran Ltd., a biotechnology company in Cambridge, England, supported by Sandoz Pharma AG of Basel, Switzerland, is also developing a transgenic pig that will incorporate the genes for the complement-inhibitory proteins DAF, MCP, and CD59. This work is being done under the direction of Imutran cofounder David J.G. White, a professor of surgery at the University of Cambridge.
According to many scientists, the primary motivation behind xenotransplantation research is the growing shortage of human organs for transplantation. But some animal-rights groups say that the solution to the shortage problem is not to use animal organs, but to find ways to increase the number of human organs available.
Alan H. Berger
Alan H. Berger, executive director of the Animal Protection Institute in Sacramento, Calif., contends that a presumed-consent law, similar to those in several European countries, would go a long way toward eliminating the shortage. Under such a law, the organs of recently deceased people may be harvested for transplantation in the absence of a prior written statement of objection from the deceased.
"Is it going to fulfill our current and future needs?" Berger asks. "I don't know, but we feel it should greatly increase the number of organs available. We know that we can transplant human organs successfully. And if we know that, then why not put in a system that could increase the number of human organs available?"
People for the Ethical Treatment of Animals (PETA), based in Washington, D.C., recently launched a media campaign to encourage more people to sign organ-donor cards. The campaign features a seductive photograph of former Playboy magazine playmate Kimberley Hefner over the provocative statement: "Some people need you inside of them."
Sociologist Roger W. Evans, who heads the health-services evaluation section at the Mayo Clinic in Rochester, Minn., argues that the number of deaths each year that leave the organs appropriate for donation-head-injury victims, primarily -- is much too small to meet the need. Only about 9,600 such donors are available in the United States annually, he says, some of whose families will decline to approve donation. Even accounting for the fact that multiple organs can be harvested from each individual, there would not be enough organs to satisfy the demand, which he places at about 100,000 procedures.
"Presumed consent won't get it," Evans says. "That solution will fail."
"If everyone was an organ donor, there would be enough organs to go around," counters Megan Patterson, an assistant to the vice president in PETA's policy department. "Of course, the experimental community will argue with that, because transgenic animal organs could be a huge, multibillion-dollar business."
Another approach to the problem would be to find ways to decrease the number of people whose organs fail in the first place, some animal advocates say. Preventive medicine and other nonreductionist measures would cost society less and be more effective than high-technology interventions such as xenotransplantation, they claim.
"What is this going to do to medical health insurance rates?" asks Michael Fox, vice president of bioethics and farm animal protection for the Humane Society of the United States, headquartered in Washington, D.C. "The costs are going to be astronomical. And is it really necessary? There are at least 40 different diseases now that can be prevented or reversed by simple changes in one's diet. It deeply concerns me that U.S. and other Western governments are not encouraging people to adopt a more prudent diet that is either vegetarian or very close to it."
In fact, xenotransplantation researchers note that, because pigs are a commonly farmed animal used for food, issues of limited availability and the ethics of using their organs are largely obviated. A number of animal-rights groups, however, charge that eating meat is an equally unethical, if more widespread, use of animals and actively promote vegetarianism as an alternative.
"An argument for exploitation based on another form of exploitation is illogical," contends Patterson. "It's not our right to breed animals for our own uses."
"And there is an irony here," Fox adds. "In the old days, it was Richard the Lionheart, but now it's going to be Peter the Pigheart, and he's just been eating too much fatty sausage and hamburger and so on, and his coronary arteries are packed up. Or he destroyed his liver with too much alcohol and God knows what else. This, to me, really is absurd, when governments are ignoring [alternatives] for political reasons, because politicians are not going to get money to be reelected if they tread on the toes of agribusiness and the pharmaceutical industry."
- (The Scientist, Vol:9, #20, pg.1,10-11 , October 16, 1995)
- (Copyright © The Scientist, Inc.)