Lucy Gross
In recent years, there has been a tremendous shortage of organs for transplantation all over the world. Between 1991 and 2000, the number of people waiting for transplants increased by 41 percent, yet over these same years, the number of donors decreased by 10 percent.[1] As of 2010, ten people on the vital organ transplant waiting list were dying each day in the United States.[2] This problem has only worsened in the last five years, but cross-species transplantation (xenotransplantation) of organs, tissues, and cells offers hope.[3] Despite the biological, immunological, and ethical issues, the development of xenotransplantation will be beneficial to science and our society in the long run.
Although the earliest claim of xenotransplantation dates back to 1501, when an Iranian surgeon replaced a portion of sick bone with some of that of a dog,[4] xenotransplantation became popular in the early 17th century with blood transfusions from animal to humans in France and England.[5] Nearly two centuries later, skin transplantations from sheep, rabbits, dogs, cats, rats, chickens, and ideally frogs were performed, but none were successful or permanent. During that same period, the first corneal xenotransplantation was performed from a pig to a human in 1838. Due to the failure of the corneal transplant, along with many others, the practice petered out and only became popular again in the 1960s because of Dr. Keith Reemtsma, who believed “nonhuman primate kidneys might function in human recipients.”[6] He went on to perform thirteen transplants, but most failed within 4 to 8 weeks from either rejection or infectious complications. One patient lived for nine months before dying from acute electrolyte disturbance.[7] Another surgeon experimenting with xenotransplantation during this time was James Hardy, who transplanted a chimpanzee heart, but unfortunately, it was too small “to support the circulation.” It was rejected within hours.[8] Later, in the 1980s, a baboon heart was transplanted into a girl, and the graft went into acute rejection twenty days later. Due to issues related to rejection, xenotransplantation did not gain interest again until the 1990s.[9] Xenotransplantation has continued to evolve quickly since then, and scientists are trying to navigate certain obstacles that cause rejection of the organ or harm to come to the human.
Besides increasing the sheer number of organs available to a nearly unlimited supply, xenotransplantation is also beneficial because a number of allotransplantations occur after brain death of the donor. This has detrimental effects that could lead to rejection or lack of function of the organ. For xenotransplantation, doctors would be able to harvest the organs from an animal while it is still alive, which would also pose ethical controversy with such groups as PETA. If a culture does not allow allotransplantation, then xenotransplantation would allow them to receive an organ,[10] such as Japan, which in the last two decades turned over a thirty year ban on organ transplantation.[11] Finally, unlike with allotransplantation, scientists are able to manipulate the genes and proteins of the donor animals.[12]
Through the years, many different animals have been used for xenotransplantation, but in recent years, pigs have become the ideal donor species compared to nonhuman primates. This decision was made because humans know very little of breeding nonhuman primates in captivity. They also have very few offspring. Many of the considered species are endangered, thus the interest in chimpanzees for xenotransplantation plummeted in the 1960s when they were listed as an endangered species.[13] Due to the fact that humans are more genetically related to nonhuman primates than pigs, it is more likely that the transmission of infectious disease would occur.[14] In addition, the slaughtering of pigs for consumption has been sewn into our country’s history for centuries. As a result, people would have less moral and ethical issues with slaughtering pigs than nonhuman primates, which makes them a great candidate for being the donor species. The other benefits of using pigs for xenotransplantation include quick maturation, large litters produced, and organs similar in size to humans’. Our close long-term relationship to pigs decreases the likelihood that genetically-engineered pigs would pass on infectious agents.[15] That is as long as they are kept under particular conditions and monitored frequently, which will be regulated by government bodies. When tested on nonhuman primates, the pig cardiac graft survival rate was around eight months, and the kidney rate was around three months.[16]
The biological barriers that scientists are considering for successful transplantation are the longevity of the donor pig organs, considering that the normal lifespan is around fifteen years, and a 4°C higher body temperature in pigs than humans.[17] Another issue is that the porcine insulin pathway, which regulates glucose homeostasis, works in humans, but “not all porcine hormones are effective across the species barrier.”[18]
While some immunologic barriers have been solved recently, others are even more complicated to fix than the physiological ones in situations of xenotransplantation. The result of the organ not being immunologically compatible with the human host is hyperacute rejection (HAR), which happens within hours of the transplantation and occurs because an individual’s antibodies are attacking the donor organ’s αGal antigens, which are not produced in humans. Fortunately, for the most part, the problem of HAR has been solved.[19] The present issue to overcome is acute humoral xenograft rejection (AHXR), which presents itself around a day after transplantation and continues to destroy the organ over the next days.[20] Scientists are working to add human anticoagulant genes into genetically engineered pigs, along with other genes to regulate the human inflammatory response.[21]
When developing xenotransplantation for nonhuman trials now and clinical trials in the future, governing bodies must consider the many ethical issues that are connected to the controversial topic, such as those related to the donor species, biotechnology industries, public opinion, and public health and safety. Public health must be addressed before clinical trials begin because a pig retrovirus could infect a human through xenotransplantation, which could be passed on to an individual in contact with the recipient, leading to an epidemic.[22]
One of the largest issues that doctors and scientists face is the public’s opinion of transplantation, especially related to animals. As mentioned above, due to their usage in our society, there is less controversy around doctors testing with pig organs than primate organs due to being less similar to humans evolutionarily. Another ethical issue with nonhuman primates is the idea of right for these animals since they have such complex social behaviors.[23] Scientists must weigh and compare the potential risks and benefits when considering xenotransplantation.
Another ethical issue that needs to be addressed is whether biotechnology industries can sell these genetically engineered pigs’ organs for a profit, which would only allow a select few be able to afford a xenotransplanatation. Individuals do not need to pay for organs for allotransplantation besides the cost involved in their procurement, so this poses an issue that must be considered.
At a stage when the advancements are sufficient for a successful transplant, the view of xenotransplantation by the public could determine the future of the practice, depending on if people willingly participate in clinical trials, which will potentially be greatly shaped by the media.[24] Gender and education level seem to affect an individual’s view on xenotransplantation. In a study done by Dr. John Hagelin, it was found that women take greater issue with the use of animals in xenotransplantation, worrying about the animals’ well-being, compared to men.[25] He also concluded that those who supported xenotransplantation also had “higher formal education,” but this could just be due to those with higher education levels having a “decided and differentiated opinion” on any issue.[26]
Along with education and gender, religion also plays a critical role in transplantations between pigs and humans and just in general. Of the major three monotheistic religions, two, Judaism and Islam, disallow the consumption of pigs let alone the addition of them into one’s body. Along the same lines, Hinduism requires that the body is whole to pass into the afterlife. Buddhism, on the other hand, believes that any kind of organ transplant should be decided by the individual’s morals and ethics.[27]
Over the last 300 years and even within the last twenty, scientists and doctors alike have taken large strides toward a successful xenotransplantation, and with the technology and the increased attainability of genetically engineered pigs, success is likely in the near future.[28] Biological and immunological issues will be solved, and it will be interesting to see if previous issues of ethics and morals will disappear with the possibility of saving thousands of lives per year. Besides working to address these problems, scientists are also observing the non-whole organ transplantation from pigs to nonhuman primates. When receiving a transplantation of neuronal cells from a pig, nonhuman primates with a model of Parkinson’s disease showed improvement of locomotor function.[29] Other diseases that have been shown to be improved by non-organ transplantation are diabetes, neurodegenerative disorders, and chronic pain control.[30] Within the next few decades, there will be a major influx of trials with xenotransplantation, and it will become more popular within medicine than allotransplantation because the benefits of the procedure far outweigh the risks.
[1] Mohantha D. Dooldeniya and Anthony N. Warrens. “Xenotransplantation: where are we today?” Journal of the Royal Society of Medicine 96 (Mar 2003):111-117.
[2] U.S. Department of Health and Human Services. “Xenotransplantation.” U.S. Food and Drug Administration. Last modified January 4, 2010. Accessed February 18, 2015. http://www.fda.gov/BiologicsBloodVaccines/Xenotransplantation/.
[3] David K. C. Cooper, “A brief history of cross-species organ transplantation.” Baylor University Medical Center Proceedings 25, no. 1 (January 2012): 49-57.
[4] Jack-Yves Deschamps, Françoise A. Roux, Pierre Saï, and Edouard Gouin. “History of xenotransplantation.” Xenotransplantation 12, no. 2 (March 2005): 91-109.
[5] Dooldeniya and Warrens.
[6] Cooper.
[7] Ibid.
[8] Ibid.
[9] Nature Biotechnology. “Xenotransplantation.” Nature Biotechnology. 2000. http://www.nature.com/nbt/journal/v18/n10s/full/nbt1000_IT53.html
[10] Cooper.
[11] Isabel Stenzel Byrnes and Kirsten Incorvaia,“Organ Donation” The Power of Two, 2011, http://www.thepoweroftwomovie.com/organ-donation/.
[12] Dooldeniya and Warrens.
[13] Ibid.
[14] Institute of Medicine (US) Committee on Xenograft Transplantation: Ethical Issues and Public Policy. Xenotransplantation: Science, Ethics, and Public Policy. Washington, D.C: National Academies Press (US), 1996.
[15] Tushar Samdani, “Xenotransplantation.” Medscape. Sept. 9, 2014. http://emedicine.medscape.com/article/432418-overview#showall
[16] Cooper.
[17] Dooldeniya and Warrens.
[18] Ibid.
[19] Emanuele Cozzi, Erika Bosio, Michela Seveso, Marta Vandori, and Ermanno Ancona. “Xenotransplantation—current status and future perspectives.” British Medical Bulletin 75-76, no. 1 (February 2006): 99-114.
[20] Dooldeniya and Warrens.
[21] Petra Rattue, “Xenotransplantation From Genetically Engineered Pigs” Medical News Today. October 21, 2011. http://www.medicalnewstoday.com/articles/236387.php
[22] C. Smetanka and D.K.C. Cooper, “The ethics debate in relation to xenotransplantation.” Scientific and Technical Review of the Office International des Epizooties (Paris) 24, no. 1 (2005): 335-342.
[23] Samdani.
[24] Smetanka and Cooper.
[25] John Hagelin, “Public opinion surveys about xenotransplantation.” Xenotransplantation 11 (2004): 551–558.
[26] Ibid.
[27] Samdani.
[28] Cooper.
[29] Rattue.
[30] Nature Biotechnology.
