Xenotransplants

Xenotransplant experiments began in earnest during the 1960s but have proved equally unsuccessful, with none of the grafts surviving long-term. In one high profile case, surgeons at the Loma Linda Medical Centre in California transplanted a baboon’s heart into a 2-week old girl called Baby Fae. She died 21 days later. In 1995 an American AIDs patient received a transplant of baboon bone marrow but again the graft failed. Paradoxically the patient felt better although this was attributed to the irradiation and cocktail of drugs that were part of the treatment. The idea of using baboon bone marrow to replace that of the patient’s, arose from the fact that baboons are resistant to infection by HIV (Lancet, February 17, 1996, 457).

It is not surprising that xenotransplants has proved such a failure since graft rejection is far more of a problem when animal rather than human organs are transplanted into a person. As transplant surgeon and animal researcher Roy Calne explained, “… the difference biologically between animals and man is very great” (Cambridge Evening News, August 1, 1988).

However, xenotransplant research continues, the usual justification being that there are insufficient human organs to fulfil current transplant needs.

UK research

The severe problems of graft rejection arise because of tissue differences between animals and people. In an attempt to overcome this hurdle, the Cambridge-based company Imutran genetically engineered pigs to carry a human protein. Imutran produced its first transgenic pig in 1992 and later transplanted organs from these animals into primates. In 1996 the company announced the results of experiments in which kidneys were grafted into 7 monkeys (New Scientist, 1996 August 31, 10). One of the animals survived for 7 weeks and the tests were said to be successful since none of the kidneys were rejected within minutes of the operation – the usual outcome.

(NB In 1996 Imutran was taken over by Sandoz, the pharmaceutical company which supplies the transplant drug, cyclosporin.)

Apart from Imutran’s experiments – centred at Cambridge University several – other UK labs were trying to overcome the problems of xenotransplantation. These labs included:

• St. Mary’s Hospital, London
• St. Thomas Hospital, London
• Royal Postgraduate Medical School, London, in collaboration with the Babraham Institute, Cambridge
• University of Glasgow
• Worcester Royal Infirmary

Not all the research uses living animals; some involves test tube experiments with cells and tissues. But the number of institutes involved indicates that much effort is being directed towards xenotransplant development. Furthermore, there is no shortage of funds. For instance, the British Council for the Prevention of Blindness funded experiments at Addenbrookes Hospital and the University of Cambridge in which guinea pig corneas were transplanted into rats (M. Chatterjee et al, Transplantation Proceedings, 1996, vol. 28, 731). At the Worcester Royal Infirmary, the Diabetes Foundation sponsored research in which pig pancreatic tissue was transplanted into ‘nude’ mice (K. A. Heald et al, Transplantation Proceedings, 1996, vol. 28, 824). Other xenotransplant research has been funded by the British Heart Foundation, the National Kidney Research Fund, and Baxter Healthcare.

In addition, Cambridge University collaborated with overseas  laboratories, for instance in the US and Germany, to investigate xenotransplants.

Objections to xenotransplants – effects on the animals

If xenotransplants become a clinical reality, there is the prospect of “biological factories” in which animals are bred solely as a source of organs for human spare-part surgery. Apart from the “donor” animals, other creatures already suffer and die to develop the techniques, as the following examples show:

• At Addenbrookes Hospital in Cambridge, hearts were surgically removed from anaesthetised rabbits and grafted onto the necks of baby pigs taken from their mothers shortly after birth. Most of the piglets rejected the transplant within 2 hours but four animals, receiving anti-rejection treatment, survived longer, in one case for nearly 19 hours (P. S. Johnston et al, Transplantation, 1992, vol. 54, 573-576).
• In another example from Addenbrookes, hearts were transplanted from hamsters into rats, survival times depending on the anti-rejection treatment employed. Most animals died from infection or graft rejection (R. I. R. Hason et al, Transplantation Proceedings, 1993, vol. 25, 421-422).
• Research by Imutran, described earlier, in which transgenic pig kidneys were transplanted into 7 monkeys (and which were deemed successful), led to progressive anaemia in the 4 animals that lived the longest. Another died of a kidney blockage, whilst two others died at 8 days from “acute vascular rejection” (New Scientist, 31 August 1996, 10).

Objections to xenotransplants – the human dangers

Cross species transplants carry a potentially devastating risk in that a currently unknown animal virus could trigger a new plague when it passes to human beings. During the development of polio vaccines, thousands of people were inoculated with a vaccine contaminated with live SV40 virus. This originated from the monkey kidney cells used during the manufacture of the vaccine (L. Hayflick, Science, 1972, May 19, 813-814). The Marburg agent, a hitherto unknown virus, was also found and killed several of those handling the monkey tissues (L. Hayflick, Laboratory Practice, 1970, vol. 19, 58-62). Today, scientists suspect that the AIDs epidemic originated from a monkey virus.

It is known that baboons (used as tissue donors in the U.S.) carry several viruses that have the potential to infect humans. These include STLV, carried by 40% of the baboon population, which can cause cancer in this species. There will be similar problems if pigs are used as the donor species. Historically, pig viruses have proved hazardous for people. The outbreak of flu which killed more than 20 million people in 1918 and 1919 probably spread to humans from pigs (New Scientist, 1997, March 29, 20). And test tube studies have shown that pig viruses will replicate in human cells (A. Dorling et al, Lancet, 1997, March 22, 867-871). So this is not a theoretical problem.

Even if an animal virus is harmless to its host species, it may be hazardous to other animals, including people. Also, there is the possibility that harmless viruses (say, one from a pig and one present in people) will combine to produce a lethal outcome. Another danger is that it may take a decade (as often happens in AIDs cases), before a new virus produces clinical effects, by which time xenotransplant recipients could have passed the virus to other members of the community, for instance by sexual contact. Xenotransplants put everyone at risk, not just those who receive animal organs.

There are other problems with xenotransplants. For example, will the donor organs age at the same rate as the rest of the human body? And how will animal organs interact with the drugs that patients will have to take?

Alternatives to xenotransplants

Resources consumed by xenotransplant research programmes could be more productively spent exploring other ways of improving the supply of human organs. When Belgium introduced an “opt-out” scheme (where organs are presumed to be available after death unless otherwise indicated), the number of donors increased markedly (New Scientist, 1994, July 18 24-29).

It also has to be remembered that transplants are often not the only means of treatment. For instance, between 1984 and 1986, 50 patients were referred to a California teaching hospital as candidates for “urgent cardiac transplantation”. While waiting for their operation, they were given intensive drug treatment with vasodilators and diuretics. As a result, 41 were then able to be discharged. Only 16 of these patients were still assessed as in need of a heart transplant! One year later, of the 25 patients who stayed on drug therapy, 17 remained in reasonable health despite once being assessed as “urgent” cases for the operation (British Medical Journal, 1989, April 22, 1124).

Another possibility is to explore lifestyle changes (vegan diet/exercise/psychological treatments) that have already been shown to reverse advanced coronary heart disease (D. Ornish et al, Lancet, 1990, July 21, 129-133). In addition health policy and research priorities could be directed more towards preventing disease, thereby obviating the need for so many transplants and allowing those still in need to receive the human organs that are available. An unlimited supply of animal organs would generate an ever greater demand for spare-part surgery, diminishing still further the vital role of preventative medicine. Researchers have already argued that “an inexhaustible supply of [animal] tissue would improve the chances of developing realistic therapies for other diseases, for example diabetes mellitus and Parkinson’s disease” (A. Dorling et al, Lancet, 1997, March 22, 867-871).

Xenotransplants – the debate

In the US, xenotransplants from animals to people are permitted: official guidelines recommend that donor animals should be screened for disease, But as Jonathan Allan of the Southwest Foundation for Biomedical Research in Texas has pointed out, “there is no way to screen for viruses that have yet to be discovered” [J. Allan, Nature Medicine, 1996, vol. 2, 18-21]. Because of the fear of infection, Allan believes that xenotransplants should be banned [New Scientist, 1997, March 1, 6].

In Britain, a government inquiry chaired by Ian Kennedy concluded that xenotransplants are too risky and must not be carried out until questions of safety and effectiveness have been resolved by further research. The report states that “xenotransplantation does not offer an easy or early solution to the chronic shortage of human organs for transplant” [New Scientist, 1997, January 18, 6].

Nevertheless the Kennedy report, like the earlier enquiry by the Nuffield Council on Bioethics, regards the use of pig organs as ethically justified. Kennedy believes the use of primates is unethical but the assumption seems to be that since pigs are killed for food, they can also be killed as transplant donors. Animal Aid’s view is that a civilised society should be trying to reduce exploitation, not extend it to new areas.

It might be assumed that patients suffering from organ failure would be enthusiastic supporters of xenotransplantation. Indeed, a questionnaire from the British Kidney Patient Association, giving “a full explanation of the process of xenotransplantation with transgenic pigs”, found that 78% of dialysis patients would be willing to accept a pig’s kidneys. The BKPA states that, like UK kidney patients, it is “enthusiastic and supportive” of the xenotransplant programme [E. Ward, Lancet, 1997, June 14, 1775].

In contrast, an Australian survey of patients suffering from kidney failure revealed that only 42% would be willing to accept an animal organ. A slight majority (44-45%) were unwilling. This survey was prompted by the finding that 66% of acute-care nurses were opposed to xenotransplantation [P. J. Mohacsi et al, Lancet, 1997, April 5, 1031].

It cannot be said therefore, that it is a case of the animal rights movement versus the medical community. There are clearly ethical, scientific and medical concerns about xenotransplants from all sides.

In 2016, the prospect of using animals, specifically pigs, in order to supply organs for transplantation into humans, once against surfaced. It was reported in the media how a team in the US were conducting research with human stem cells which were injected into pig embryos, in an attempt to produce human-pig chimeras. (Gene-editing was to be used to make the embryo grow without its pancreas and then human stem cells injected into the embryo with the aim of growing a ‘human’ pancreas.)

These chimeric embryos were being allowed to develop to 28 days when they would be killed and the tissue analysed. The researchers hoped that this would ‘lead to a pig embryo which develop normally but the pancreas will be made almost exclusively out of human cells and could be compatible with a patient for transplantation.’

There were fears that some human cells could migrate and possibly reach the embryonic brain, thereby making it more ‘human’.

Animal Aid is morally opposed to the use of animals as ‘bioreactors’ – to use them in such a way, whatever the possible benefit for humans, is immoral. However, we also have scientific concerns – there are clear scientific reasons why this technology will not produce the promised results. It is claimed that, although grown in a pig, the ‘harvested’ organ, with its human cells, can be grafted into a human patient, function effectively and not be rejected by the person’s immune system.

However, careful reading of the scientific literature around this topic makes it clear that a ‘human’ organ cannot be grown in a pig and remain wholly human. If it were to do so, the pig would reject it as foreign. Equally, when the hybrid organ is grafted into a human, that human’s immune system will, if not immediately, then over time, set out to destroy and reject what it recognises as foreign.’