By David McNamee
Recently, Medical News Today reported on a breakthrough in xenotransplantation - the science of transplanting functional organs from one species to another. Scientists from the Cardiothoracic Surgery Research Program of the National Heart, Lung and Blood Institute (NHLBI) demonstrated success in keeping genetically engineered piglet hearts alive in the abdomens of baboons for more than a year.
While that is a sentence that might sound absurd, or even nightmarish to some, xenotransplantation is a credible science involving the work of leading scientists and respected organizations like the NHLBI and the Mayo Clinic, as well as large private pharmaceutical firms such as United Therapeutics and Novartis.
What is more, xenotransplantation is not a new science, with experiments in cross-species blood transfusion dating as far back as the 17th century.
Why transplant the organs of animals into living humans?
The reason why xenotransplantation is a burning issue is very simple: because of a crippling shortage of available organs for patients who require transplants, many people are left to die.
US Government information on transplantation reports that an average of 79 people receive organ transplants every day, but that 18 people die each day because of a shortage of organs.
The number of people requiring an organ donation in the US has witnessed a more than five-fold increase in the past 2 decades - from 23,198 in 1991 to 121,272 in 2013. Over the same period, the number of people willing to donate has only doubled - 6,953 donors in 1991, compared with 14,257 donors in 2013.
Although some researchers are attempting to solve this shortage by developing mechanical components that could assist failing organs, these devices are considered to increase the risk of infection, blood clots and bleeding in the patient.
Stem cell research is also actively pursuing the goal of growing replacement organs, but despite regular news of breakthroughs, the reality of a functional lab-grown human organ fit for transplant is a long way off.
As the NHLBI's Dr. Muhammad M. Mohiuddin, who led the team responsible for the baboon trial, explained:
"Until we learn to grow organs via tissue engineering, which is unlikely in the near future, xenotransplantation seems to be a valid approach to supplement human organ availability. Despite many setbacks over the years, recent genetic and immunologic advancements have helped revitalized progress in the xenotransplantation field.
Xenotransplantation could help to compensate for the shortage of human organs available for transplant."
Xenotransplantation's eccentric history
The earliest known example of using animal body parts to replace diseased or faulty components of human bodies dates back to the 17th century, when Jean Baptiste Denis initiated the clinical practice of animal-to-human blood transfusion.
Perhaps predictably, the results were not successful and xenotransfusion was banned in Denis' native France.
Fast forward to the 19th century and a fairly unusual trend for skin xenotransplantation had emerged. Animals as varied as sheep, rabbits, dogs, cats, rats, chickens and pigeons were called upon to donate their skin, but the grafting process was not for the squeamish.
Medical records show that, in order for the xenosurgeons of the time to be satisfied that the donor skin had vascularized (developed capillaries), the living donor animal would usually have to be strapped to the patient for several days. However, the most popular skin donor - the frog - was typically skinned alive and then immediately grafted onto the patient.
Despite several reputed successes, modern physicians are skeptical that these skin grafts could have been in any way beneficial to the patient.
The first corneal xenotransplantation - where the cornea from a pig was implanted in a human patient - took place as early as 1838. However, scientists would not look seriously again at the potential for xenotransplantation until the 20th century and the first successes in human-to-human organ transplantation.
In 1907, the Nobel prize-winning surgeon Alexis Carrel - whose work on blood vessels made organ transplantation viable for the first time - wrote:
"The ideal method would be to transplant in man organs of animals easy to secure and operate on, such as hogs, for instance. But it would in all probability be necessary to immunize organs of the hog against the human serum. The future of transplantation of organs for therapeutic purposes depends on the feasibility of hetero [xeno] transplantation."
These words have been described as "prophetic" because Carrel is describing the exact line of research adopted by xenotransplantation scientists a century later.
A few years later, another leading scientist, Serge Voronoff, would also predict modern science's interest in using the pancreatic islets of pigs to treat severe type 1 diabetes in human patients. However, other xeno experiments by Voronoff have not endured critical reappraisal quite so well.
Voronoff's main scientific interest was in restoring the "zest for life" of elderly men. His attempt to reverse this element of the aging process was to transplant slices of chimpanzee or baboon testicle into the testicles of his elderly patients.
Incredibly, this surgery proved quite popular, with several hundred operations taking place during the 1920s in both the US and Europe.
By the 1960s, despite limited availability, the transplantation of kidneys from deceased to living humans had been established by French and American surgeons.
Dialysis was not yet in practice and given that, in the absence of an available donor kidney, his renal failure patients were facing certain death, the Louisiana surgeon Keith Reemtsma took the unprecedented step of transplanting animal kidneys. He chose chimpanzees as the donor animals, due to their close evolutionary relationship with humans.
Although 12 of his 13 chimpanzee-to-human transplants resulted in either organ rejection or infectious complications within 2 months, one patient of Reemtsma continued to live and work in good health for 9 months, before dying suddenly from acute electrolyte disturbance. Autopsy showed that the chimpanzee kidneys had not been rejected and were working normally.
Experiments in the xenotransplantation of essential organs continued in living patients until the 1980s - without lasting success. However, the procedures attracted widespread publicity, with some attributing a subsequent rise in organ donation to the failed attempt to transplant a baboon heart into a baby girl in 1983.
Where does research currently stand?
Despite the more obvious similarities between humans and other primates, pigs are now considered to be the most viable donor animal for xenotransplantation.
Despite diverging from humans on the evolutionary scale about 80 million years ago, whole genome sequencing of the pig has shown that humans and pigs share similar DNA, while the pig's organs - in size and function - are anatomically comparable to humans.
However, perhaps the main advantage of the pig as donor is in its availability - potentially providing an "unlimited supply" of donor organs. If transplantation is viable, pig donors would provide an immediate solution for the organ shortage problem.
Xenotransplantation optimists also believe that the process can improve on the existing success rate of transplantation of human organs. By keeping the pigs healthy, regularly monitored for infection, and alive right until the point when the required organs are excised under anesthesia, the adverse effects associated with transplantation from deceased donors - such as non-function of organs or transmission of pathogens - would be much less likely, this group argues.
However, there are still significant scientific barriers to the successful implementation of xenotransplantation.
The company United Therapeutics - who moved into xenotransplantation research after the daughter of CEO Martine Rothblatt was diagnosed with pulmonary hypertension, a condition with a 90% shortage rate of available lung donors - claim to be making progress with eliminating these barriers.
MedIcal News Today spoke to Rothblatt, who once claimed that the company will have successfully transplanted a pig lung into a human patient "before the end of the decade."
"For a first clinical trial, which was my goal, I think we are on track," she told us. "I said our goal by end of decade is to transplant a xeno lung into a patient with end-stage lung disease and bring them safely back to health."
As well as pioneering lung xenotransplants, the company has ambitions of making pig kidneys, livers, hearts and corneas available for human transplant.
"All are years away, but lung may well be most difficult," admits Rothblatt. "We call it the canary in the coal mine."
In order to make pig lungs compatible with humans, Rothblatt has estimated that 12 modifications need to be made to the pig genome that will prevent rejection. She claims United Therapeutics have now succeeded in making six of these genome modifications.
Also, it was United Therapeutics' genetically modified piglets that provided the world record-beating pig hearts for the NHLBI study in baboons.
Opposition to xenotransplantation
However, science is not the only obstacle to xenotransplantation. Despite clearing all steps of the research with ethics committees at every step, Rothblatt - who has a doctorate in medical ethics - admits there will be unforeseeable regulatory dilemmas and ethics conversations before xenotransplantation can be accepted into clinical practice.
In 2004, the UK's Policy Studies Institute conducted the first major survey of public attitudes towards potential solutions for the organ shortage crisis. The public perception of xenotransplantation was shown to be overwhelmingly negative.
Indeed, response to animal-to-human transplantation was so hostile that some respondents demanded that it be removed as an option on the survey. Although many respondents considered xenotransplantation unethical, the major concern was that animal viruses could infect humans and spread into the population.
Following the survey, an intriguing debate over the ethics of xenotransplantation took place in the pages of Philosophy Now. Making the case against xenotransplantation, Laura Purdy - professor emerita of philosophy at Wells College in Aurora, NY - commented that "the xeno debate proceeds as if saving lives is our top moral priority." She argues that, from this perspective, it suggests that the lives lost down the line as a result of perfecting xenotransplantation do not count.
"What about the 11 million babies and children who die every year from diarrhea, malaria, measles, pneumonia, AIDS and malnutrition?" she questioned. "What about the half-million women who die every year during pregnancy and childbirth when simple measures could save most of them?"
We asked Prof. Purdy why the fact that people die from matters unrelated to transplantation issues would morally preclude science from attempting to also solve the issue of organ donor shortages.
"I agree that, other things being equal, saying that people are dying from other causes doesn't show why we should not also tackle this cause," she replied.
"But once one has taken on board the larger risks to society, both from the research as well as the deployment of the technology, as well as the probability that this is merely a bridge technology that, hopefully will be made obsolete by future developments (such as partial or whole artificial hearts) or advances in public health (making headway against diabetes) and the probability that both research and implementation will be very expensive, that seriously erodes the case for proceeding.
Resources for health are far from infinite. There is a great deal that we could be doing now to advance human health that does not have these downsides - why not focus more there?"
Whether public attitudes toward xenotransplantation have mellowed in the decade since the Policy Studies Institute's survey is not currently known.
However, as the technology advances and the likelihood of implementation draws closer, so too must the public conversation over the perceived rights and wrongs of animal organ transplantation advance in order to hold the science accountable.
Do you have a view on this issue? If so, use our comments box to join the debate.