Time to get a little biological. My last paper:
The fact of an organ shortage which is gripping the United States has jumped into the realm of common knowledge. We are inundated with news stories, newspaper articles and various television shows which mention or describe the organ shortage in some way. We have all heard of long waiting lists and people who have died because their names did not rise to the top of the lists fast enough. Seemingly we do have a pool from which we could draw enough organs to satisfy the needs of those on the lists; that pool being animal organs. This procedure, coined “xenotransplantation,” carries with it two large problems. The first problem can be better described in the question, “Is it even possible?” The second can be summed up in, “Is it ethical?” Of course, the second question may exhibit some domain over the first, in that if the ethical question cannot be answered or the procedure cannot be justified, then there it precludes researchers from looking into the first.
Xenotransplantation Viability
The first route to examine in the plausibility of xenotransplantation is to ponder what the existing roadblocks are in xenotransplantation. The question is, “what makes xenotransplantation difficult or impossible?” Because of the potentially vast ramifications of xenotransplantation, many scientists are currently working both to answer this question and find viable ways to work around it. Solving this problem may yield a world in which every person on an organ recipient list can get the necessary organs.
One study (Odocha and Rader 1997) proposes that xenotransplanted tissue is acted upon by cytotoxic T cells and changes in calcium concentrations enhance the lysosome activity inside the transplanted tissue, which results in xenotransplant hyperacute rejection. In their model, lysosomal acid phosphotase concentrations increased with increasing calcium concentrations to elicit the hyperacute rejection. The Odocha and Rader study then necessitates that in future xenotransplant tests calcium concentrations must not be allowed to increase to induce cell death. However, the study’s limitations mean that it gave no insight into what causes normal calcium concentrations to increase after xenotransplantation has occurred.
Another of the major barriers in pursuit of a xenotransplantation solution to the organ shortage problem is that of yet there have been no successful long-term xenotransplant procedures. While researchers test on animals, the types of animals on which they work is not standardized, in the sense that in the research there are many different model systems being examined. Some of these models include mice, others pigs and baboons, rats, or rabbits and dogs. All of these models are different and because of varying genomes between species many of these studies will have no direct impact on human xenotransplantation. Instead these studies are being done to understand further exactly what the roadblocks are which stand between xenotransplantation being a viable solution. What we know about xenotransplantation of yet is still relatively little as far as making viable transplants. Before any of these techniques can be tried on humans, we must examine further and be sure of what the immunological consequences are.
In another xenotransplantation study which involves baboon species, pig livers were implanted into the primates (Sanchez et al., 2003). This is a functional and smart technique for examining what problems there in xenotransplantation. Despite the fact that baboons are not humans, an actual xenotransplant experiment allows the researchers to examine what the effects are of the transplant. One of the added benefits to humans is that the baboon is more closely related to us genetically than are other animals including rabbits, dogs and mice. Thus, the immune response and antibody response should be more analogous.
Sanchez et al., through use of hDAF transgenic pigs which do not cause hyperacute rejection reactions, had one baboon live for four days and other live for eight days post transplantation. Their experimental design assayed the immunopathology of the transplant after death. What they found was that expression of human CD55 in the pig seems to block the complement cascade from occuring, which is important to avoid rejection. However, once the specimens made it beyond the hyperactive rejection stage, the researchers found CD4 and CD8 T cells were present, which they will further examine in the future.
Another study involving hDAF pigs was conducted with limited but impressive success (Domenech et al. 2003). The researchers implanted hDAF pig hearts into baboons and achieved a median post-surgery lifespan of 27 days. The range of lifespan was 6 to 60 days. What this study demonstrated was that treatment of GAS 914 my increase the viability of xenotransplants but not unless the amount of immunosuppressive therapy is high enough. The test group mortality rate was 100 percent when cyclophosphamide treatment was reduced by 50 percent.
What is definitely known of xenotransplantation is that approaches to suppress the immune system must be multilateral. A study of pig tissue planted in rats found that despite the addition of anti-C5, a treatment to stop the complement cascade from occuring, apoptosis still occurred and the xenotransplants were not viable (Cicchetti et al. 2002). This is an important distinction to make, and it coincides with Domenech’s findings. While allografts require immunosuppression in that the major histocompatibility antigens are not the same, the organs are being donated from the same species. Thus, with adequate immunosuppression these organs can avoid rejection. However, when donating across species, applying the same immunosuppression for human tissue no longer works. So studies like the Cicchetti study are valuable, as they contribute to the knowledge that we need more than in this case, anti-C5 to make xenografts viable.
Much of the focus involving xenotransplants is getting past the hyperacute rejection phase. In some models of transplantation, organ failure can occur literally minutes from transplantation (Onozuka et al. 2003). This makes sense insomuch as we must first get beyond the first few minutes of the transplant operation to make viable xenografts. Discovering the right kinds of drugs or treatments to avoid or delay hyperacute rejection may result in viable long-term xenografts if we can suppress the immune system much the way we do with allografts. The Onozuka study involved using glycoprotein IIb/IIIa inhibitors and prostacyclin to defer the onset of the hyperacute rejection event. They fount that there was a significant difference in the survival time between treatments, and that glycoprotein IIb/IIIa inhibitors do prolong xenograft life, however ultimately the organs failed. Onozuka et al. admitted that future treatments will need further measures to counteract the hyperacute rejection event, in conjunction with their treatments.
Hyperacute rejection works in such a way where blood is cut off to the organ, through platelet action which results in an unviable tissue mass (Onozuka et al. 2003). Hyperacute rejection can also be attributed to an endothelial attack by antibodies for xenografts (or generalized foreign tissue) which activates the complement. The complement cascade is then responsible for killing the remaining tissue.
A paper by Yamanouchi (2000) describes the living conditions necessary for pigs which may be used in xenotransplant procedures. He stresses the importance of keeping them parasite, bacteria, fungi, and virus free. Reasoning for this argument stems from that while most viruses are species-specific, occasionally some pathogens can jump from species to species. Yamanouchi points out the HIV virus as well as xenotropic murine leukemia as examples of conditions which can migrate between species. The paper also focuses on treating the pigs in their sterile environments to avoid transmission of porcine endogenous retroviruses.
Porcine endogenous retroviruses (PERVs) cannot be removed in pathogen free animals, because the retrovirus is inherited via Mendelian genetics. The retrovirus is already present in the DNA when the pigs are grown (Fiebig et al. 2003). However, most of the work on removing PERVs is being done as a preventative measure. According to the Fiebig study, we are not currently sure if PERV is pathenogenic to humans. We do know that PERVs can infect human tissue (Yamanouchi 2000). The Fiebig study focuses on developing a vaccine for PERV, but with an additional lunge into the realm of HIV study. The epitopes for both PERV and HIV are very similar when mapped out. Thus, any viable vaccine for prevention of PERV may have additional impact into the fight against HIV.
Of course, discussions involving the efficacy of xenotransplantation are not limited strictly to the scientific community. The novel, The Organ Grinders by Bill Fitzhugh revolved around Jerry Landis, a wealthy but dying business mogul. To save his life, Landis was working hard on replacing his organs with xenotransplanted ones from Baboons. While the book is a work of fiction, Fitzhugh injects enough real science to make the premise work.
In the novel, Landis’ scientists finally produce an anti-rejection drug for baboon organs. This, while still fictional, ties in quite well with what we know of rejection in transplant science. Landis’ drugs inhibit the complement pathway by specifically blocking the action of C3b. Blocking C3b would be an ideal solution because it blocks both the classical and the alternative pathway. Without the complement reaction, the body will not reject an organ through a direct attack. Of course, this doesn’t stop ADCC reactions involving natural killer cells or attack by cytotoxic T lymphocytes, but Fitzhugh cleverly included a description of the baboon hearts as having human proteins and receptors.
Fitzhugh also covered the fact that baboon organs are not large enough to sustain human life in the book. He mentioned that Landis was selectively breeding and genetically engineering to build the proper size baboons. Of course, to build to the climax of the book Fitzhugh made sure Landis forgot about the fact of natural selection and also “hybrid vigor” which resulted in not just large-enough baboons, but instead too-large baboons. Despite being pulled from fiction there is some truth to this notion. Organs must be the proper size to sustain proper function. As it turns out, pig organs are closer to the proper size for humans.
At some points in the novel, efficacy blended with ethics, which added to the tension. For example, in order to procure all of the possible organs from a single baboon they could not kill nor anesthetize the baboon before the “harvest.” Thus, the baboons were merely paralyzed by drugs and still receptive to all the associated pain of having organs removed. They were not killed by the surgery, instead they were killed after their hearts were removed.
Ethical Considerations
While xenotransplantation may seem like a perfect solution to the organ shortage problem, the ethical concerns transcend science. When science and ethics meet, personal opinions and beliefs may override the benefits of the science. The important problems involve the notion of raising animals to harvest them for their organs and a notion that human and animal organs should not mix. Additional problems exist further in even deciding who would get allografts and who would get xenografts. For example, a rift may become evident between the rich and the poor, or the old and the young.
Many of these ethical ideas were addressed in Great Britain in 1997 by their Secretary of State for Health based on a report from their Advisory Group on the Ethics of Xenotransplantation (Kennedy 1997). The group decided that the only species suitable for organ harvest was pigs. The paper explicitly noted that primates were not acceptable organ donors. A possible reason for this is that humans regularly consume pork and have a very general notion that pigs are “below” us on the food chain and thus, are less important. We do not generally consume primates, and in the scientific community view many primates more as cousins than as inferior or lesser animals.
The group also codified several ethical concerns, the first of which involved limits on the extent of genetic modification. According to the paper, transgenic pig modifications must be kept to “acceptable limits.” While it makes sense to limit the genetic modification of the pigs used for xenografts, as we ought to limit the genetic changes to ones we know are not detrimental to the pig in its lifetime, this notion is still very vague. While the paper did not explicitly say so, I would imagine that much as in America each experiment must be cleared by an animal treatment board similar to IACUC.
Possibly one of the most interesting limits outlined by the paper is that nervous tissue is not suitable for xenografts. The paper said that such tissue outlined “special ethical concerns,” upon which it did not elaborate. However, if I would imagine that the special ethical concerns involve religious notions of the sanctity of human life. What effect might implantation of pig tissue have on the human soul? While this idea may not outright be a scientific notion, nor even able to be studied scientifically, it seems to have cast a large shadow over exactly which kinds of tissue can be considered for xenografts. The notion of the location of the soul has changed in the last few hundred years, from the heart region to the brain. It seems to me that the idea that pig neural tissue should not be included into human bodies is a manifestation of the notion that neural tissue must be kept pure to keep the soul pure.
Many other factors were also addressed by the British, including plausible problems involving the public health. These problems are physiological meaning that in 1997 there was insufficient research to determine if xenografts were actually viable as transplants. As is evidenced by the first section in this paper, there are still significant problems in the viability of xenograft tissues. The second problem consisted of problems of immunology. These guidelines stipulate that in the current-to-1997 research, there was little research available to support that xenografts would not be rejected. As is the case with the physiological perspective in 1997, not much has changed relative to rejection in 2004. The first part of this paper also addressed hyperactive rejection of xenografts. The third and possibly most important notion covered is the risk of infection. As this paper has covered, there is a risk in using pig xenografts of PERV. While the exact pathogenicity is of yet unknown, it has been decided that the risk to the general populace is great. Because it is a virus of another species, the human immunological response may not be up to task, which would lead to a pandemic.
In fact, the risk of public infection and that so many lives could be saved makes this is an issue of public health also spurred a different paper considering the effect of xenotransplantation on the entire populace (Bach and Ivinson 2002). The authors determined that public input would be extremely important regarding the issue of xenotransplantation and compared it to the outright rejection by many of genetically modified foods. They stressed the importance of increasing the public knowledge of not just the benefits of the end product but also the surrounding science so they may decide for themselves if the procedure is dangerous on sound principles. They noted that the corporations that study the viability of xenotransplantation do so for profit and sometimes lose track of the fact that it is the general populace who decides if they are willing to undergo the procedures. So in the end, if the optimism of the companies does not match the optimism of the populace, then the science is wasted (from a functionalist perspective).
Furthermore, according to Welin (2000) xenotransplantation may yield new struggles for those on the recipient lists. Namely, if xenotransplants are not as good as allotransplants then there will still be people who want the allotransplants. This, he postulates, will increase the cost of procuring allotransplant organs, which means that people with money will lead better lives than those without. And he further postulates that in the case of allografts being better than xenografts, then allografts should be reserved for the young to give them the highest quality of life. This struggle may be detrimental to the idea of equality of patients, but may yet be ethically correct.
In The Organ Grinders, moral dilemmas abound. As previously mentioned, Landis killed baboons without anesthesia, to preserve the organs. This is a cruel fate for the baboons. In the novel, the benefit for the profiteers was resident in that there was no federal regulation on the treatment of the xenotransplant species. Assuming that xenotransplantation were to become reality in the coming years, to prevent maltreatment of these animals at death, the FDA should institute xenotransplant guidelines as law. Despite the primates eventually being subject to “harvesting” they should not be mistreated.
The baboons roamed free on a compound which would also not likely be the case in reality. Most pigs are grown in antigen free environments which should be the same for baboons. Trying to avoid stressing out the baboon immune system and keep the baboon pathogen free should be of utmost priority. If we grow pigs for these experiments in such an environment, then baboons should be no different. Ultimately the dilemma here is the same argument that could be made for pigs: “Should we be allowed to keep animals in captivity for our ‘harvesting?’”
Underlying these more scientific ethical dilemmas is the ethics of health care in the United States. Jerry Landis was a shameless profiteer, a social parasite, a person who thrived on money and not on actually taking care of people. His greed regarding saving his own life made him look to save those of others, but only after realizing the money-making potential. At one point he said that people would pay twice as much and say it was a deal. In the US, prescription drugs are very costly, as are most surgical procedures. At the top end of all this, pharmaceutical company CEOs and insurance company CEOs examine the bottom lines and look for ways to boost profits and thus boost stocks. The risk here is that eventually, at some point, the bottom line will become more important than saving lives and protecting people from illness. A great many would argue this is already the case. Medicine is a business, and in the US, it is big business. Big business tends to work toward the good of the stockholder as opposed to the good of the worker or the customer. Businesses claim it is the payoff for heavy investment in new and sometimes ineffective drugs and procedures, but price gouging is a reality. People like Landis are able to profit off the misery of others and often egregiously so.
As with many other areas of science, the viability of xenotransplantation is yet undetermined, or at the very least, underdetermined. We have major barriers to yet overcome, due to the increased difficulty of not just having to deal with organ rejection of human tissue but instead the added pressure of trying to avoid organ rejection of organs of an entirely different species. And yet, if the population is not willing to believe in and accept the viability of these treatments, then xenotransplantation may be an unused resource. As scientists, we tend to think that the general the good is most important and that because xenotransplantation could save so many lives that it is almost undeniable as a viable alternative to allotransplantation, but if the population does not see it that way, then the science is moot, and unfortunately so.
To me, the ethical concerns are not irrelevant, but not a satisfactory deterrent. Given the option between choosing waiting for an organ which may never come and thus death, or the option of trying a viable xenograft (assuming it is possible), I would certainly choose the xenograft. I feel that my chances with a xenograft, and possibly PERV are better than with nothing at all, and that because we could stand as a species such a huge benefit from xenotransplantation that we owe it to ourselves not to overlook this possible resource.
Works cited:
Bach, F.H., Ivinson, A.J., 2002. A shrewd and ethical approach to xenotransplantation. Trends in Biotechnology. 20 (3) 129-131.
Cicchetti, F., Costantini, L., Belizaire, R., Burton, W., Isacson, O., Fodor, W., 2002. Combined inhibition of apoptosis and complement improves neural graft survival of embryonic rat and porcine mesencephalon in the rat brain. Experimental Neurology. 117, 376-384.
Domenech, N., Diaz, T., Moscoso, I., Lopez-Pelaez, E., Centeno, A., Manez, R., 2003. Elicited non-anti-GAL antibodies may cause acute humoral rejection of hDAF pig organs transplanted in baboons. Transplantation Proceedings. 35, 2049-2050.
Fiebig, U., Stephan, O., Kurth, R., Denner, J., 2003. Neutralizing antibodies against conserved domains of p15E of porcine endogenous retroviruses: basis for a vaccine for xenotransplantation? J. of Virology. 307, 406-413.
Fitzhugh, Bill. The Organ Grinders. Reduvindae: NY. 1998.
Kennedy, I., 1997. Xenotransplantation: Ethical acceptability. Transplantation Proceedings. 29, 2729-2730.
Odocha, O., Rader, D., 1997. Extracellular calcium concentration influences lysosomal behavior in the In Vitro xenotransplant hyperacute rejection model. Transplantation Proceedings. 29, 3653-3654.
Onozuka, N., Harada, O., Kobayashi, M., Suto, T., Fukuda, A., Sudo, Y., Takaya, S., 2003. Effect of prostacyclin and glycoprotein IIb/IIIa inhibitor on hyperacute rejection in a rabbit-to-dog lung xenotransplant model. Transplantation Proceedings. 35, 531-532.
Sanchez, A., Ramirez, P., Pino, G., Chavez, R., Majado, M., Munitiz, V., Munoz, A., Palenciano, C.G., Yelamos, J., Rodriguez-Gago, M., Pons, J.A., Parrilla, P., 2003. Immunopathology of an hDAF transgenic pig model liver xenotransplant into a primate. Transplantation Proceedings. 35, 2041-2042.
Welin, S., 2000. Future of xenotransplantation: What are the ethical problems? Transplantation Proceedings. 32, 1177-1178.
Yamanouchi, K., 2000. Potential risk of xenotransplant-associated infections. Transplantation Proceedings. 32, 1155-1156.
