Animal-to-human transplants and public health:
Who pays, and with what?
Toshi Knell
Toshi Knell is a former industrial designer, now full-time writer (published by, amongst others, Quadrant and Elsevier Science)
specialising in science and nature, politics and economics. She is a fellow of the Salzburg Seminar.
Pig to human organ transplant trials are proposed by
Australia’s National Health and Medical Research Council (NHMRC) in its Guidelines for Xenotransplantation.
Introduction
Organ demand outpaces human cadaveric supply at an increasing rate. There are 500 kidney transplantations annually in Australia. In the US alone, an estimated 80,000 people on organ transplant waiting lists enjoy an estimated 1 in 5 chance of receiving an organ. Ageing populations and increasingly unhealthy, sedentary lifestyles in OECD countries provide a future demand for organs and cells that is the subject of much concern, especially as it is worth "tens of billions of dollars" to the health product industry.
Animal organs and cells offer the promise of on-demand supply. Genetically modified animals, "humanized" to decrease the massive rejection that the human body puts up to other species on an immediate and continuous basis, is being proposed to treat organ failure and chronic conditions such as Parkinson’s disease, dialysis needs, hepatitis C liver failure and type I diabetes.
Pigs are being proposed by the NHMRC for human transplantation "trials" of both single cells and organs; but already, mice are being used to culture human stem cells and as carriers for human cells in many other experiments. Many experiments have been and are now being conducted in a worldwide situation marked by a lack of regulations, public knowledge and democratic informed consent. Sue Cartledge, editor of Hospital & healthcare, editorialised the situation in Australia in October 2002.
There has been a huge amount of public discussion in recent weeks about … human embryonic stem cells…. Almost invisible but with equally as far reaching implications, and possibly greater risks to those not directly involved, is the issue of xenotransplanation … The meeting I attended was in a small room in a CBD hotel; there were sufficient chairs for about 20 people. Fortunately that was the number who turned up; probably because, like me, they had had very little advance warning…. there were a couple of animal rights activists and a smattering of medical media. No mainstream media, no members of the general public.
In fact, in speaking to the supposed experts, health professionals including physicians, and legislators, I found a high degree of ignorance in their respective fields concerning this issue. "Xeno-" and "-zoonose" were both terms that needed definitions supplied (commonly understood definitions: xeno-referring to foreign, thus animal to people: zoonoses being diseases passed by animals to people, and xenozoonoses being passed from xenotic procedures). Legislators did not know how this decision-making process works, nor whose portfolio xenotechnology falls into. It seems to be in some sort of crack with the health portfolio being so big.
As to openness, there were a number of arguable assertions and claims made by the Committee in the Sydney meeting, which was adjourned by them promptly at the two-hour mark, no opportunity being given to reply. In reply to requests for transcripts of the public meetings and open disclosure of submissions, the NHMRC has said that these will not be disclosed but will be considered by the Council, which has taken an advocacy position. Informed consent has not been considered to be democratic informed consent though the community bears the risks and burdens of benefits that are only envisaged to be enjoyed by a few (if the procedures ever work efficaciously, which they have not to date).
Risks
Nature (August 17, 2000) editorialised this issue writing "the public consequence could be catastrophic … Animal viruses can also change unpredictably when they jump the species barrier." The Bovine Spongiform Encephalitis (BSE or "Mad Cow Disease") Inquiry levied much criticism for allowing disease to jump the species barrier, a topic that came up 222 times in the report.
Peter Collignon, Canberra Clinical School, Sydney University, Director Infectious Diseases Unit and Microbiology, the Canberra Hospital, wrote:
What if we were trying to design the ideal experiment in which a new virus that would infect humans would be cross-transmitted from pigs to humans? We would be hard pressed to come up with a better experiment than what is planned to be done with xenografts (and on a massive scale)…. Once established into a new human host, human to human transmission has occurred for many of these agents (HIV, influenza, hepatitis B, SV40).
The most discussed risk of disease is posed by Porcine Endogenous Retroviruses (PERVs). This is how the Council of Europe describes this risk.
The special interest in retroviruses is based on their ability to integrate into the genome of infected cells. Retroviruses are RNA-viruses, which use a viral enzyme, the reverse transcriptase (RT) to transcribe the single-strand RNA into double-strand DNA, which then will be integrated as provirus. So called exogenous retroviruses such as HIV-1 infect specific target cells and integrate into the genome of these cells. Proviruses will therefore not be found in other cells of the organism. If, however, a retrovirus infects an oocyte or a sperm cell, which gives rise to a new organism, every cell of the body will contain the integrated provirus. Such retroviruses are termed endogenous. Endogenous retroviruses may, on one hand, be expressed as infectious virus particles, and on the other they will be transmitted like normal genes to the progeny.
The humanised pig is also a zoonosis problem. The known problem of animal handlers contracting zoonoses increases when there is a level of both secrecy and commerciality. This means that infected animals and their handlers could be a problem hidden from the public for some time. A problem that the New York Times reported took eleven months before being cracked down on for an animal tissue supplier in the US.
The Centers for Disease Control (CDC), Atlanta, considers the xenogeneic risks too high in xenotechnology. The CDC raises a new point at odds with the Council’s assurance that "we have lived with pigs for thousands of years."
The short life expectancy of the average swine minimizes the opportunity to observe clinical manifestations that might result from infections with agents characterized by long periods of clinical latency such as retroviruses or prions.
If the pig’s life span is a problem, imagine the problem with rodents, yet they are commonly used now as hosts.
Xenotechnology exposes the species to an historically unprecedented level of species mixing and epidemiology outcome unknowns at a time when we still do not have the social structures and science to cope with the rising disease burden that we have. In no country considering xenotechnology could there be considered to be a health care system that citizens think works well enough, and that is at present stress levels.
We now know that blood banks and hospitals have become vectors for disease. The US Red Cross is examining its own response to xenograft recipients and they are looking at the narrowest definition of risk in terms of blood donors. Thus, infection could be also be spread by the health agencies’ response to risk.
Disease has different periods of dormancy, different levels of physical manifestations and different methods of transmission, including respiration. This means that the number of people infected would be totally unknown. For example, in the current West Nile fever pandemic in North America, health authorities are experiencing a classic post-mortem learning curve regarding symptoms and manifestations, with 80% of carriers still being labelled asymptomatic. How can we consider, therefore, that carers and immediate contacts are the only ones of possible concern (as blood banks are contemplating), and use terms like "stakeholders" (as the NHMRC does) with xenotransplantation? If, for instance, respiration is a method of transmission, an aeroplane would be an ideal vehicle for the modern Typhoid Mary. With delayed outcomes the impact could be much greater than Mary’s.
A new "breakthrough", genetically modified miniature swine (bred to decrease human rejection response), was announced in January 2003. As to Porcine Endogenous Retroviruses, the president of the company announced that the PERVs "seemed" to have been screened out. The Council was also positive in the public meeting in Sydney as far as the technical ability to screen out PERVs.
The Council of Europe explains that PERVs cannot be eliminated, nor can a myriad of other possible pathogens:
In order to obtain pathogen free animals for xenotransplantation, known bacteria, fungi, parasites and viruses including exogenous retroviruses may be eliminated by (i) selection of uninfected animals, (ii) by treatment with antibiotics and antiparasitical reagents or (iii) by vaccination of the animals. To achieve this, animals have to be tested for the presence of all microorganisms listed in Tab. 3, 6, 7, 11 and 12. At present an additional risk comes from unknown microorganisms which may not be detected, and from endogenous retroviruses, which cannot be eliminated.
If the technology were efficacious and the assurances of promoters able to be taken, then xenotransplanation could be better considered a possible medical "trial" procedure. Yet both are questioned. In the UK, in the zoonotically hot days of 2000, a meeting was described hosted by their authority.
Authority member John Dark, a Newcastle heart transplant surgeon, told the audience that research involving the implementation of transgenic pig organs into primates…. had yielded ‘disappointing’ results and had lead up a ‘blind alley’… Another UKXIRA member, Professor Herb Sewell, an immunologist…said he could not see progress ‘within a ten year time scale, if at all.’
The Council considers that non-therapeutic transplantation is unethical. Yet the lack of any reliably documented fundamental improvement in the health of any recipient to date and the low life expectancy to date (measured in days, not years) means that xenotransplantation in humans is experimental not therapeutic.
Cost vs. benefit
If we look at a prospective xenograft recipient, the public is footing the bill for what is seen to be a private-only procedure as the costs are exorbitantly high. Thus, only the wealthy will have this as a choice. The whole community, however, is subjected to the disease impact and costs and for the "surveillance" (NHMRC term) part of this process. It is unstated as to who will pay and what the surveillance will be but certainly the burden of public health monitoring and notification for public health purposes will fall on the taxpayer. The benefactors, however, are private - the small percentage of our species that could have access to this procedure and the companies that are selling it. In terms of capitalist theory, this is the inverse of user pays. It turns dry, rightist economics on its head. And as for a socialist system, it fails utterly, as it puts the individual and private corporation above society as a whole. This is that society pays for the bulk of the "research" and pays in disease risk and burden in both the research and the commercial stages.
But let’s say that xenotransplants go ahead. What are we going to do about monitoring? Is monitoring optional as the NHMRC suggests: "While it is expected that…most patients will adhere to the request for lifelong monitoring, individual recipients may withdraw their consent." In our free society, we are not contemplating quarantining the recipient or contacts, yet the disease risk is not defined narrowly when understood. And what do we do with the genetic burden aspect?
Liability: corporate, federal and state, sovereign
To a group of people who are not able to perform normal procedures now because of risk, the possible liability ramifications are immense.
Conclusion
On grounds of efficacy, safety, public risk and public cost, the technology is at least worth a great deal more public informing and discussion. This is a transitional technology that leaves a permanent genetic legacy and social burden. As the NHMRC Guidelines say, "As for other areas of medical research, an overriding consideration for xenotransplantation research is that it should serve the common good."
This technology fails to serve the public good and has many detrimental impacts on the public.
Recommendations
• A process that could lead to democratic, informed consent needs to be implemented.
• An international approach is crucial as disease knows no borders.
• Other avenues, some very promising, should be fully explored. For instance, human stem cells do not need other animals to be cultured, as experiments in Singapore prove. Other developments include artificial blood, artificial tissue and a large range of mechanicals.
• "Implied consent" for organ donation should be proposed, as it could significantly improve human donor rates (Spain’s doubled on implementation of this change and their rates are now as high as five times Australia’s)
• A moratorium on current work is advisable, until there is informed consent.
References (further references available on request)
-- "Draft guidelines and discussion paper on xenotransplantation: Public Consultation 2002" Xenotransplantation Working Party, NHMRC
-- "Provisional surveillance summary of the West Nile virus epidemic" Journal of the American Medical Association, January 14, 2003
-- "The cloning of a special little pig has been done" The Times of India, January 13, 2003
-- "Pig organ use a step closer" Melbourne Herald Sun, Jan 12, 2003
-- "The BSE Inquiry: The Inquiry into BSE and variant CJD in the United Kingdom"
-- "Xenografts: Are the risks so great that we should not proceed?", Peter Collignon and Laura Purdy (bioethicist, professor of philosophy, Wells College), Microbes and Infections 3, 2001, Éditions Scientifiques et Médicales Elsevier SAS
-- Pig bits OK for people: body "Researchers should be allowed to transplant parts from genetically modified pigs into human beings in controlled experiments, a national advisory body says…." The West Australian, 8 July, 2002
-- "Experts back animal to human transplants" ABC News, 8 July, 2002 www.abc.net.au/news/2002/07/item20020708071346_1.htm
-- "Genetic transplants under threat from disease: Interview: Professor Ron Trent - Chairman of the NHMRC Gene Advisory Panel", ABC Country Hour, 18 Aug, 2000
-- "... Council has agreed to give the procedure the ‘thumbs-up’... We speak to Kerry Breen, Chairman…" ABC Radio National , 9 July 2002 www.abc.net.au/rn/talks/brkfast/stories/s601975.htm
-- The 4th National Symposium on Biosafety. PHS Perspective on Xenograft Transplantation, Louisa Chapman, MD, Medical Epidemiologist, CDC, Atlanta
-- "State of the Art Report on Xenotransplantation (2000)", Council of Europe
-- The Emergence of Zoonotic Diseases (2002) National Academy Press, Washington DC
-- Public Health Emergencies; Environmental Issues, Missouri State Emergency Management Agency, August 1999
-- "Public consultation needed on xenotransplants" Helen Gavaghan, The Scientist, Feb 22, 2002
-- "Recall is ordered at large supplier of implant tissue" New York Times, August 15, 2002
-- "Interview with a Humanoid’, by Nicholas Kristof, New York Times, July 23, 2002
-- Bernard Vallat, Director General, OIE Proceedings: Joint WHO/FAO/OIE Technical Consultation on BSE: public health, animal health and trade, 11-14 June, 2001
-- "Few who are infected show signs of illness" USA Today, Aug 7,2002
-- Infectious Diseases of Mice and Rats (1991), Institute for Laboratory Animal Research, National Academy Press, Washington DC
-- Red Cross "Comment to FDA on draft guidelines Precautionary Measures to possible risk of transmission of zoonoses by blood and blood products from Xenoplantation Product Recipients and their contacts"
-- "Killer flu can result from a single mutation" New Scientist, 25 August, 2002
-- "GE Free New Zealand Submission to the Parliament Select Committee on Finance and Expenditure regarding the Hazardous Substances and New Organisms (Genetically Modified Organisms) Amendment Bill by Pat Clark." www.gefree.org.nz/RciRep/9.html
-- "Recall is ordered at large supplier of implant tissue" New York Times, August 15, 2002
-- "Xenotransplantation: Reply to the Government’s response, from the Institute of Biology and British Electrophoresis Society" Institute of Biology www.iob.org
-- "What’s wrong with xenotransplantation", Campaign for Responsible Animal Transplantation www.crt-online.org/wrong.html
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