Alternative ways of meeting demand

The heated debate on both the potential benefits and dangers of xenotransplantation threatens at times to overshadow the fact that the use of animal organs is not the only possible response to the chronic shortfall between the demand for human organs and the supply.

The growing waiting list for human organs in the United States (see figure) mirrors the upward trend worldwide. The number of transplant patients is relatively small in public health terms, compared with say the 500 million cases of malaria worldwide. But the costs of individual operations are such that transplants constitute a billion-dollar market, which in turn is fuelling intense commercial interest in xenotransplantation.

Demographic trends suggest that the demand for organ transplants is set to increase further, particularly as many of the diseases that result in organ failure — such as renal failure caused by diabetes — are age-related. Meanwhile, a decline in traffic accidents due to improved safety is resulting in a drop in the most reliable source of organ donors, accident victims.

Transplant statistics alone give a misleading impression of the scale of the problem, as many more individuals might seek treatment if an unlimited supply of organs were available. David Sachs, of Harvard Medical School, estimates that more than 400,000 people in the United States could benefit from heart transplants; yet the official waiting list for hearts in 1996 was just 3,698.

Xenotransplantation is not the only means of alleviating this shortage. Boosting the low rates of cadaveric donations — which vary from 27 per million inhabitants in Spain and 21 in the United States to 5 in Greece — would go some way towards this goal. Countries such as Austria, which have ‘presumed consent’ laws that do not require next of kin to be notified or to give their consent to organ donations from the newly dead, generally have higher donation rates than countries such as the United States where informed consent is required.

Donation rates also seem to be highly sensitive to public attitudes. Transplant centres often experience sharp drops in donations following media coverage of such events as the kidnapping of children for organs or the use of organs from executed prisoners.

Shortly before Christmas, US Vice-President Al Gore and Donna Shalala, Secretary of Health and Human Services, launched a campaign to increase donation rates.

Policy changes, such as encouraging prevention of heart disease or encouraging more donations, may go some way to alleviating the shortage of organs. But there is a broad consensus that these will not be sufficient, and that only science can ultimately improve the situation.

Xenotransplantation, if it proves feasible and safe, seems to offer a panacea. Apart from the risks of spreading animal diseases to the human population, it would otherwise bring a quality control to transplantation that is currently lacking, as organs could in principle be prepared in advance in large numbers, individually screened for infectious disease agents.

Alternative research routes

But other research avenues may also have an impact on the organ shortage. One is to improve the success rate of transplant operations, as many of those on the waiting lists are for repeat procedures to replace failed transplants. Although survival rates of allotransplants have been greatly improved by the introduction of the immunosuppressant cyclosporin, chronic rejection remains a major cause of loss of allotransplants, for example, according to Paul Herrling, research director of Novartis. The company has 200 scientists working on this problem.

Artificial organs and human cells and tissues provide other alternatives to xenotransplantation, and would avoid the risk of xenozoonoses. Novartis is about to market an artificial skin, Apligraf, based on cultured human cells, for example, while stem cells extracted from umbilical cord blood offer a promising alternative to bone marrow transplants (see Nature 382, 99; 1996).

Herrling says Novartis only intends to use xenotransplants where no alternatives are currently available, such as for hearts and livers. Similarly, the company only intends to proceed with clinical trials in the first instance for life-saving indications. It would not, for example, test kidneys where alternatives such as dialysis exist, he says.

Research to create next generation artificial hearts is also under way, although reliable devices are still some way off. More complex organs, such as artificial livers and lungs, remain even more distant possibilities. Another promising alternative in the long term, in particular for cell and tissue implants, would be to graft tissues derived from human embryonic stem (ES) cells. In principle these could be cultured to provide large quantities of a range of differentiated tissues such as nervous tissue or muscle.

The therapeutic potential of such cells led the French national bioethics committee to recommend last year that a ban on human embryo research be lifted for research in this area. But the culture of human ES cells has so far proved impossible. Even the culture of animal ES cells — although more straightforward — is still in its infancy.

ES cells also have a potential drawback in that they may give rise to cancers. But interest in their transplant potential was nonetheless raised last summer, when John Gearhart, a researcher at the Johns Hopkins University School of Medicine in Baltimore, told the International Congress of Developmental Biology in Snowbird, Utah, that his group had achieved growth of human ES stem cells in vitro for several months.

Ronald McKay, head of the laboratory of molecular biology at the US National Institute of Neurological Disorders and Stroke, is using ES cells in a rat model to generate large quantities of dopaminergic neurons to treat Parkinson's disease. He believes that, in the long term, culture of human ES cells will have a major impact on transplant biology.

“I think we will be able to graft cells, and if one knows enough about kinetics and control mechanisms of cellular differentiation then you will be able to restore organs to health,” he predicts. “It might sound like science fiction but it seems plausible; reconstructing organs is a natural extension of developmental biology.”

McKay argues that transplantation is still in the “hunter-gatherer” phase, and that the way ahead is the “settled agricultural” phase, namely establishing banks of well characterized cells with strict quality control. Animal experiments suggest that ES cells could be engineered to be accepted by the immune system and to generate ‘universal donor’ tissues acceptable to all patients.

One attraction of such cells is that only a few embryos would be needed to seed banks of cells without needing new abortion material. But several US scientists argue that the strength of political opposition to abortion in the United States means that such research is unlikely to be encouraged.

Figure 1

The growing US waiting list for human organs is fuelling demand for transplants of animal organs.