Xenotransplantation
BMJ 2000; 320 doi: https://doi.org/10.1136/bmj.320.7238.868 (Published 25 March 2000) Cite this as: BMJ 2000;320:868All rapid responses
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EDITOR-Your recent correspondence on xenotransplantation 1 illustrates differences of approach and perception to essentially the same data. Clinicians traditionally evaluate the risk-benefit ratio for patients, not the public. Xenotransplantation, by raising the issue of xenozoonoses spreading from recipients to the general public, extends the risk-benefit calculus to the public, which does not directly benefit from this experimental therapy but may be put at risk. If we base our decisions on traditional risk-benefit analysis we would favour patients, perhaps at the expense of the public. If we base them on the currently trendy “precautionary principle” we would tend to pay more attention to the public interest and perhaps burden needy patients.
Heavy industry investment and potential investigator conflicts of interest mean that we must try to balance opportunity with possible opportunism. The public and non-experts are confused. They are aware of the existence of potential problems, but have little sense of the details. Given the imperative to explore potentially important therapeutic options in the face of some as yet undefined level of public risk, how can we proceed? Based on my experience with the World Health Organization (WHO)2 and other international xenotransplantation related groups3, I believe we need to ask three key questions:
1.How do we engage the public in a meaningful way to inform, educate and consult?
Several recent xenotransplant guidelines, including those from the WHO2, have recognized this need. A small group of experts met at Meech Lake in Canada last summer to begin exploring this difficult question, for which it was realized that there were no real answers yet. To move forward, an international working group has been formed3. It has commissioned white papers from internationally recognized experts; national consultative committees are being formed and skeptics are being converted.
At the same time, we have formed a WHO electronic discussion group on the Internet4, with the help of Health Canada and OECD, and this is about to finish the first round of discussions based upon the recommendations from the WHO report. Hopefully, more people will become involved in these “practical ethics” endeavors.
2.What kind of consent process is appropriate for potential xenotransplant recipients?
This is a subject of immediate concern and the United Kingdom Xenotransplant Interim Regulatory Authority is to be congratulated for taking the lead in producing a discussion document addressing it5. Dying and very sick patients are easily convinced to accept experimental therapy, but will they and their contacts and sexual partners agree to the kinds of invasive investigations, limits to freedom and very real dangers to confidentiality that the proposed guidelines entail? Will they refuse to cooperate once they are well, or if the graft fails? We have proposed a kind of “Ulysses contract”6 model that might be applicable, but there is still some work to be done to address the human rights and legal issues involved.
3.Are there any types of limited clinical studies that can answer important scientific questions while substantially minimizing the risk to the public?
It is necessary to consider moving forward very cautiously because moratoria, by removing the subject from consideration, can be harmful and also because of the substantial danger that, because of financial considerations and desire for primacy, clinical experiments may be performed in countries or centres incapable of ensuring safety or ethics.
There is, for example, a need to see if tissues / organs from “humanized”, transgenic pigs will indeed be protected from hyperacute rejection in human recipients, as they seem to be in primates. Extracorporeal perfusion of transgenic pig livers will go some way towards answering this question, and it may now be time to allow this in a very few “centres of excellence” under rigidly controlled safety conditions and where experienced investigators have declared any competing interests, are willing to let the public know what they seek, and are willing to submit results, whether positive or negative, for peer review and publication as soon as they become available. Similarly, transgenic pig islets, perhaps enclosed in immuno-isolating biomaterials to allow egress of insulin but not of viruses, should be considered. Indeed, such limited experiments have already been permitted in the United States and in Australia, but in Europe and the rest of the world there is still lack of consensus as to what to do next.
We are certainly not ready to proceed to large-scale clinical trials, particularly of vascularized whole organs. We are still learning how to assess the infection risks. We certainly have to be cautious, but by asking nuanced, action-oriented questions, we may be able to proceed cautiously and re-assess the situation at every stage.
A.S. DAAR
D. Phil (Oxon), FRCP (Lond), FRCS, FRCSEd
Professor of Surgery, Sultan Qaboos University
Hunterian Professor, Royal College of Surgeons of England
Member, Ethics Committee of the Human Genome Organization
The author has no competing interests.
1.LETTERS.Xenotransplantation David K C Cooper, Carl G Groth, Ian F C McKenzie, Emanuel Goldman, Alix Fano, and Harold Y Vanderpool
BMJ 2000; 320: 868 [Full text]
2. Daar AS (1999). Animal-to-human organ transplants-a solution or
a new problem? World Health Bulletin. Vol.77 (1) 54-81. The WHO report can be found at http://www.who.int/emc-documents/zoonoses/docs/whoemczoo982.pdf Accessed April 28,2000
3. http://www.xenoproject.org/
4. http://www.who.int/emc/diseases/zoo/meetings/xenodg.html Accessed April 28,2000
5.
http://www.doh.gov.uk/pub/docs/doh/surveil.pdf
Accessed April 28,2000
6. Daar AS (1999) Xenotransplantation: informed consent/contract and patient surveillance. Biomedical Ethics 4(3): 87-91
Competing interests: No competing interests
Re: Xenotransplantation: three questions to advance the discourse: A response
EDITOR:
A.S. Daar, in his letter "Xenotransplantation: three questions to advance
the discourse" (April 28, 2000) describes the Precautionary Principle as
"trendy," which might lead some readers to dismiss it out of hand. That
would be too bad, as the Precautionary Principle raises issues that tend
to be obscured by alternative approaches to decisionmaking. Disregarding
it may systematically discount legitimate interests, rendering decisions
morally questionable.
He also suggests that moratoria remove subjects from consideration
and may thus be harmful. However, moratoria can buy time for full and
democratic discussion about whether or how to proceed. This seems
especially important where the stakes are high, and where it may take
awhile to consider the significance of new findings, such as the Paradis
et al. study (Khazal Paradis, Gillian Langford, Zhifeng Long, Walid
Heneine, Paul Sandstrom, William M. Switzer, Louisa Chapman, Chris Lockey,
David Onions, The XEN Study Group, and Edward Otto, "Search for Cross-
Species Transmission of Porcine Endogenous Retrovirus in Patients Treated
with Living Pig Tissue, Science, Vol. 285 (1999):1236-41).
Should researchers go forward with any kind of trials before
resolving the difficult moral and political questions about the civil
rights of research subjects and their associates? Because infections might
not show up for many years, going forward in the absence of policy seems
particularly dangerous. If no infections do appear in the short run, it
may erroneously be assumed that xenotransplantation is safe, and society
may be unprepared if infections do develop later. The argument that
research will migrate to less regulated environments undermines all
national attempts at regulation and shows how much we need international
cooperation.
Laura Purdy, Ph.D
University of Toronto Joint Centre for Bioethics
Competing interests: No competing interests