The Beast In Me

Every 14 minutes, a new name is added to a waiting list for organ transplants in the US. There are more than 70,000 people on the list at present - 5,000 more than were waiting last year. But the list is merely the tip of the iceberg.

The United States Institute of Medicine has estimated that between 250,000 and 500,000 patients have sufficient heart failure to warrant cardiac replacement.

Fewer than 1 per cent of patients who need transplants are receiving them. Because no ethically acceptable policy initiatives could even come close to closing the gap between the supply and demand for organs, xenotransplantion (the transplantation of cells, tissues, and organs from one species to another) - with its potential to create a virtually unlimited supply of organs for transplant - is a technology worthy of serious consideration.

Attempts to graft animal parts to humans date to the 17th century, when a dog bone was said to have been used to repair the skull of a Russian aristocrat. But only during the past 35 years has the practice been systematically studied and clinical trials conducted.

Recent discussion has centred on two possible donor animals - baboons and pigs. Although baboon organs would not be rejected as violently, transplanting their organs carries much greater risk of viral transmission.

The animal of choice is the pig. Their organs are the right size, they breed quickly and they are domesticated animals raised in very large numbers for food.

With xenotransplantation, three basic scientific questions arise: will the animal organ do the work of a human organ? Will it be rejected by our immune system? Will it cause infection in its human host?

The principal danger posed by any transplant is rejection - the recognition by the body of a foreign invader and the activation of an immune response. The response to an animal organ is much stronger than it is to an organ from another human. While organs from non-human primates evoke a stronger reaction than a human organ, a transplant from a more distant species, such as a pig, elicits an even stronger response, termed hyper-acute rejection. Within minutes, the organ turns into a black, swollen, useless mass.

In 1992, an ingenious mechanism was devised to defeat hyper-acute rejection. Human genetic material was injected into pig embryos. The organs to be transplanted were thereby coated with human proteins and, in effect, able to trick the human immune system into mistaking them for human organs.

Hyper-acute rejection seems to have been eliminated but major hurdles remain. Principally acute vascular rejection (AVR), which appears to be related to antibody generation against the xenograft.

It is AVR that is mainly responsible for limited survival times - at present, the longest survival times in monkeys for life-supporting pig kidneys and hearts are 39 days and 78 days, respectively.

Infection continues to be a concern. A study published last summer in the journal Science went a long way toward dispelling the biggest fear surrounding xenotransplantation - the spectre of a worldwide epidemic resulting from a virus which is embedded in a pig's DNA (porcine endogenous retrovirus, called PERV) infecting human recipients of pig organs and tissues. The study followed 160 people who had been exposed to pig cells or tissue and no viral transmission was found. There remains the possibility, however, that with long-term exposure and a suppressed immune system, PERV could infect that patient at some later time.

Xenotransplantation raises moral issues. First is the question of safety, which is a medical and moral matter since the first ethical concern in medicine is to do no harm. Great vigilance with respect to viral transmission will still be required as clinical trials go forward.

There are animal welfare concerns. Because pigs are bred for food, and most people do not see a moral equivalency between a pig's life and that of a human, the central ethical imperative with respect to pigs as donors is that they be treated well and killed in a humane manner. The evidence is clear that companies that breed pigs for transplantation treat them well, especially when compared with those that breed pigs for food.

A third important ethics focus is the adequacy of the human recipient's informed consent. Such patients, in dire medical straits, may be tempted to overlook the risks of being a recipient of a pig organ. They might be burdened psychologically by having a pig organ implanted. Because of concerns about viral transmission, they - and probably their family members - would be subjected to a lifetime of surveillance, probably by public health authorities.

Finally, there is the question of allocation of resources: are there alternative strategies available, such as prevention of diseases that cause the need for transplants? Certainly prevention efforts should be strengthened, but a large number of patients suffer end-stage organ failure for reasons that are not amenable to prevention efforts. Indeed, in a somewhat paradoxical way, because of them. Fewer people are now dying of heart attacks. This leaves lots of us to grow older and eventually suffer heart failure. And, for many who will need transplants in the near future, prevention is simply too late.

If we are going to proceed with xenotransplantation, how do we do it? And more to the point, when? How much do we have to know, how successful do we have to be, in order to begin? We have to find a way to balance the unknown risk of infecting the first patients and the wider public, against the clear benefit of having a greatly increased organ supply.

People on the waiting list are dying every day. Is it reasonable - and morally sound - to say that we will not go forward with xenotransplantation unless and until we are presented with incontrovertible proof that there can be no cross-species infection?

Transplant medicine has always been extraordinarily dramatic and compelling, marked by stories of seemingly impossible dreams and heroic interventions in the face of overwhelming odds. There have been visionary pioneers, such as University of Pittsburgh surgeon Tom Starzl, who doggedly persisted to perfect liver transplantation in the face of near-universal skepticism that it could ever work.

Everyone who has received a liver transplant owes their life to Tom Starzl. But the early patients were also heroes. They took the risks and bore the burdens for the rest of us. As will the first recipients of pig organs.

The danger of the heroic posture is that it is too tolerant of risk, oblivious of danger. While medicine cannot advance without risk-taking, risk can be moderated. We need more research, before clinical trials can begin, to find strategies for overcoming the immunological problems that remain. And we must monitor rigorously to guard against disease transmission and adhere strictly to informed consent. Plenty of hurdles and moral challenges remain, but the promise for all of us is extraordinary.

Arlene Klotzko, a bioethicist and lawyer, is a consultant and writer about biotechnology. She is a visiting scholar in the Program on Medicine, Technology and Society, UCLA School of Medicine.

Copyright © 2000 SMH.

This article posted August 16, 2000.