Posted by Ellen on February 06, 2002 at 14:26:32:
A Shrewd and Ethical Approach to Xenotransplantation
by Fritz H. Bach and Adrian J. Ivinson
This article will also appear in Trends in Biotechnology.
Posted February 1, 2002 · Issue 119
Policies surrounding xenotransplantation, and many other emerging high-technology interventions, must balance opportunity and risk. Whereas traditional stakeholders, such as the researcher community, government agencies, and the commercial sector, readily contribute to the debates that influence policies, the voice of the public is seldom heard. Not only does this raise ethical concerns, but also it might ultimately prove to be shortsighted. Before any country settles unilaterally on comprehensive policies governing the practice of xenotransplantation, well-informed public opinion needs to be taken into account.
The tension between individual and societal rights is the basis of an age-old philosophical debate. That debate becomes all the more urgent and complex with the introduction of ever more potent modern technologies that offer potential benefits to individuals counterbalanced by potential risks to society. The widening of the debate is occasioned by the growth and increasing prominence of a powerful and essential group: the stakeholders. This group, which includes but is not limited to the commercial sector, governments, nongovernmental organizations, and global organizations, brings a variety of vested interests to the debate, not least the huge profits to be made developing and selling technologies. This extended conflict between individuals, society and the stakeholders is exemplified by the case of clinical xenotransplantation - the transplantation of organs, tissues or cells from another species (probably pigs) to humans.
There are many tens, if not hundreds of thousands of individuals each year who could benefit from a transplant. Yet, given the shortage of human organs available for transplantation, many patients wait in vain. The United Network for Organ Sharing (the U.S. organization that maintains the nation's organ transplant waiting list under contract with the Department of Health and Human Services) has shown that in the United States alone, the gap between organs available and organs needed each year currently stands at 50,000 and is growing at a rate of 5,000-10,000 per year. However, if pigs could be used as donors, there would, in principle, be an unlimited supply of organs, tissues and cells.
Leaving aside the still formidable challenge of rejection of pig organs by nonhuman primates, the preclinical model, the promise of xenotransplantation, has given rise to a new ethical dilemma. As with all mammals, pigs harbor many viruses or ghosts of viruses, some active, some latent, and others represented only by a partial genetic sequence embedded in the pig genome. Although it is difficult to assign precise numbers to the risk, many infectious disease experts agree that it is possible that pig-endogenous retroviruses (PERVs) could be transmitted to a human xenotransplant recipient. In part, this possibility rests on a 1997 demonstration that, under specific in vitro conditions, PERVs can infect human cells , and last year's demonstration that PERVs carried in xenotransplanted tissue is transcriptionally active and infectious across the pig-mouse species barrier . Given the possibility that PERVs could be transmitted to a human xenotransplant recipient, it is further possible that such an infection could be passed from a patient to close contacts and even to the general population. Although scientists, physicians and others disagree (often vehemently) on the magnitude of such a risk , few dismiss the risk and many agree that it is sufficient to require very serious concern (see Stoye, J.P. Xenotransplation: Panacea or Poisoned Chalice?). Unfortunately, because of the absence of data that would allow us to estimate the likelihood of such an event, this side of the debate has stagnated for a few years, awaiting definitive evidence one way or the other. In the meantime, the dilemma between individual patient benefit and societal risk is a significant and difficult issue that needs to be addressed.
And adding to this seemingly intransigent problem are the pressures brought to bear by the various stakeholders for whom economic considerations are at the forefront. The economic considerations are considerable - in 1996, perhaps the period of peak optimism and excitement for the commercialization of xenotransplantation, the investment specialist firm Salomon Brothers estimated that by 2010 xenotransplantation could be part of a $6 billion market. Although the high-tech xeno sector has since cooled significantly, many biotech companies have invested heavily in xenotransplantation and are eager to see their investment pay off. How then should we proceed? Who is to decide whether xenotransplantation is desirable given our current limited knowledge of the risks? And, if we are to proceed, under which conditions?
The answer is, in part, clear. In most societies there are elected or otherwise designated bodies charged with such decisions. In the United States, for example, the government's Food and Drug Administration (FDA) plays a crucial role. But should the FDA or any equivalent national authority be given almost complete authority in such decisions? When dealing with the threat of infectious agents, it is wise to remember that viruses and other agents do not respect national borders. In this respect the decisions of one country might impact others.
The concept of informed consent for individual patients has become a central tenet of Western medicine. When faced with medical decisions, the patient is informed of the various options and the relative risks and advantages of each. This information is provided in a balanced and authoritative manner. Although physicians offer guidance and support, the decision on how to proceed belongs to the patient. With information in hand, the patient consents to a chosen course. But crucially, the "informed" precedes the "consent." For the medical profession, to do otherwise would be unethical.
Why then should we not apply the principle of informed consent to entire communities when it is the community as a whole that is being exposed to the risk? At the very least, informed representatives of the public should be given an opportunity to participate actively and meaningfully in the decision about whether and under what conditions society is exposed to the risk. If it is unethical to foist a particular medical risk on a patient, is it not equally unethical to expose the public to a risk without first considering their opinion? Although we have focused on the potential biological risk to the public, there are other threats to be considered. Some are deeply offended by the thought of putting human genes into pigs (as in the development of transgenic pigs the organs of which are less likely to be rejected by a primate) whereas others do not want to see pig organs in people. (Both groups might worry about compromising the species barrier.) For some, xenotransplantation is yet another high-cost medical procedure that widens the gulf between the "haves" and "have nots," and threatens to consume precious health-care resources that would otherwise have been directed to many more people in need of less expensive interventions.
We have previously argued that the public is the most neglected participant in the discussion about xenotransplantation . Whereas the recognized stakeholders have well-developed mechanisms through which they can be heard and patients have advocacy groups promoting their equally legitimate needs, the public has no ready entrée to the discussion and as a result is seldom heard. Of course some governmental bodies do host "public" meetings that anyone can attend. But this is a far cry from a well-organized mechanism through which opinion is actively sought from members of an informed public.
Critics may counter that there are no appropriate tools for meaningful public consultation - to which there are two rejoinders. First, if indeed there are no such facilities, then we must develop them. Just as we would not accept the defense that a physician failed to inform his or her patient of all the medical options and associated risks available to them because of the lack of a nearby consultation room, neither can we accept that public consultation is impossible. Second, a great deal of progress has in fact been made towards effective consultation of an informed public. Methods such as Citizen's Juries, Consensus Conferences and Citizen Foresight were developed for just this purpose and have been used widely by many groups including the government, national research institutes, physician groups and nongovernmental organizations. Indeed the question of xenotransplantation has been considered by a Citizen's Jury assembled by the University of Calgary. Less formal approaches are also valuable, including town hall meetings, and most recently the Internet is opening up the possibility of virtual meetings involving people of diverse backgrounds.
Regardless of the particular approach taken, if public engagement of this sort is to be effective, it is crucial that participants are well informed by balanced and authoritative data. All sides of the issue must be presented without any attempt by the moderators to elicit a given response or steer the discussion. The public participants must arrive at their own conclusions.
The practice of public engagement does not mean that the few public representatives set policy. The responsibility for final decisions and ensuing polices should not be ceded to the few tens, hundreds or even thousands of individuals consulted. Such groups cannot be representative of the whole population and were not elected to represent the population. For that, in many countries there are political representatives to whom we delegate such decisions. Instead, the value of public engagement is in providing those with ultimate authority a further angle from which to view their decisions. In this way, the public's voice is added to those of the traditional stakeholders.
In some countries, such as Denmark, public involvement in national and local policy decisions is routine and public participation has become a civic duty. In many others, including the United States, although the principle and desirability of public participation has been recognized, it has not been acted upon. Thus, whereas meetings of the FDA are open to the public, it is expecting a lot for all but the most committed members of the public to find out where and when such meetings are to be held and then to make (and fund) their own way to Washington, D.C. to participate in a meeting often frontloaded with stakeholder agendas. Equally important, there is no effort made to assure that the participants in these meetings are well informed and have access to the people and other resources needed to answer their questions. (This is a criticism that applies equally to the well-meaning attempts by some to gauge public opinion on complex science by way of questionnaires or opinion polls.)
Although the future of public engagement on issues of science and technology is by no means assured, there are promising signs. Some researchers, governmental, and nongovernmental organizations and advocacy groups are turning more of their attention to the issue. Perhaps most welcome are the early signs that the commercial sector is also recognizing the need to involve the public as evidenced by the recent experience with genetically modified (GM) foods. GM foods are a classic case of potential risk and potential opportunity. Whereas some argue that GM technology can revolutionize our ability to grow more and better food in places that need it the most, others are concerned with individual safety, environmental safety, and the dominance of multinational companies. For better or for worse, the marketing of GM foods has met strong opposition. The commercial sector recognized a potentially powerful technology and dived headlong into development and commercialization, fully expecting to be applauded for its efforts. Yet in many parts of the world there was outright rejection of GM technology. Whereas scholars have argued long and hard about why GM was rejected by so many, it soon emerged that public opinions had formed in a relative vacuum of objective information. (A 1999 international marketing poll  asked the general public to respond to the statement: "Ordinary tomatoes do not contain genes, while genetically modified ones do." Across Europe, 35% answered "true" and 30% "don't know." The equivalent numbers for the United States were 10 and 45.) Ignorance of the true risks and opportunities gave way to anger and fear.
Could public involvement in the development of GM technology have helped? The answer is almost certainly yes, as suggested by Hendrik Verfaille, the president of Monsanto, perhaps the biggest commercial player: "We thought we were doing some great things. A lot of other people thought we were making some mistakes. We were blinded by our own enthusiasm. We missed the fact that this technology raises major issues for people - issues of ethics, of choice, of trust, even of democracy and globalization. As we tried to understand what had happened, we realized that we needed to hear directly from people about what they thought, what their concerns were and what they thought we ought to do. If we are to close the gap between those who believe in the benefits and those who have concerns, then something has to change."
The experience of Monsanto demonstrates that not only is public consultation the ethical approach, but it also makes sound business sense. Returning to the example of xenotransplantation, several countries in Europe have maintained a moratorium, or the equivalent thereof, on xenotransplantation. Meanwhile, the FDA has indicated a willingness to entertain protocols for xenotransplantation and has given permission for certain trials of cellular xenotransplantation. Although we cannot predict the outcome of these trials, we do not want to see the future of xenotransplantation dictated by the uninformed fears or enthusiasms of any group, including the public. There is still time to seek meaningful public engagement on this question and in so doing to set the precedent for how we will tackle questions surrounding cloning, engineering weather patterns, nanotechnology and the myriad other technological opportunities that are coming our way.
Susan Wolsborn is Web designer of HMS Beagle.
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Xenotransplantation: Regulatory Challenges - reviews progress made by the U.S. Public Health Service and the Food and Drug Administration to balance the potential risks and benefits. From Current Opinion in Biotechnology, 2001, 12:3:312-316. Full text available from BioMedNet.
Xenotransplantation, Endogenous Pig Retroviruses and the Precautionary Principle - considers public health issues related to xenotransplantation. From Molecular Medicine Today, 2001, 7:2:62-63. Full text available from BioMedNet.
Xenotransplantation: Is the Risk of Viral Infection as Great as We Thought? - discusses the likelihood of animal virus transfer. From Molecular Medicine Today, 2000, 6:5:199-208. Full text available from BioMedNet.
Prospects for Xenotransplantation - reviews recent advances in clinical applications. From Current Opinion in Immunology, 2000, 12:5:563-568. Full text available from BioMedNet.
Recent Advances in Xenotransplantation - focuses on strategies used to eliminate hyperacute rejection. From Current Opinion in Immunology, 1999, 11:527-531. Full text available from BioMedNet.
PHS Guideline on Infectious Disease Issues on Xenotransplantation - reflects comments received on the September 1996 draft, as well as scientific and international policy developments on the technology. From the U.S. Food and Drug Administration.
United Kingdom Xenotransplantation Interim Regulatory Authority - offers background, publications, and meeting information.
Public Consultation on Xenotransplantation - includes background information and policy discussions. From the Canadian Public Health Association.
Porcine Possibilities - examines whether transgenic technology can reduce the risk of xenotransplantation. From the October 16, 2000 issue of The Scientist.
Cloned Pigs May Help Overcome Rejection - a recent report from Science magazine. Registration required for full text.
Focus on Xenotransplantation - a special feature from Nature Medicine.
Xenotransplantation: State Of The Art: Update 1999 - a review of current research efforts and difficulties. From the April 15, 1999 issue of Frontiers in Bioscience.
Animal-to-Human Transplants: The Ethics of Xenotransplantation - examines the ethical concerns raised by this technology. From a report by the Nuffield Council on Bioethics.
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