We are searching data for your request:
Upon completion, a link will appear to access the found materials.
It is being said that organs can be obtained for transplant from the pigs. What is special about pigs that we are using them? Why can't we use monkeys or chimpanzees with whom we share a more recent common ancestor?
Monkeys and many other primates are too small to provide organs that will provide the needs of a human host. The fact that primates are so close to humans physiologically is not always a win as transplanted organs will bring diseases into the host that can be quite dangerous.
Besides, because even human human transplants induce immune rejection of organs. Its typical that immune suppressants will be a lifetime treatment for the patient.
Finally, the cost of a pig organ is negligible and their organs are about the right size, and I would bet that activists don't protest pig transplants nearly as much as primate donors.
Growing human organs for transplantation with new proof-of-concept
In a new paper published in Stem Cell Reports, Bhanu Telugu and co-inventor Chi-Hun Park of the University of Maryland (UMD) Department of Animal and Avian Sciences show for the first time that newly established stem cells from pigs, when injected into embryos, contributed to the development of only the organ of interest (the embryonic gut and liver), laying the groundwork for stem cell therapeutics and organ transplantation. Telugu's start-up company, Renovate Biosciences Inc. (RBI), was founded with the goal of leveraging the potential of stem cells to treat terminal diseases that would otherwise require organ transplants, either by avoiding the need for transplants altogether or creating a new pipeline for growing transplantable human organs. With the number of people who suffer from organ failures and the 20 deaths per day in the U.S. alone purely from a lack of available organs for transplant, finding a new way to provide organs and therapeutic options to transplant patients is a critical need. In this paper, Telugu and his team are sharing their first steps towards growing fully transplantable human organs in a pig host.
"This paper is really about using the stem cells from pigs for the first time and showing that they actually can be injected into embryos and only go to the endodermal target organs like the liver, which is very important for delivering safe therapeutic solutions going forward," says Telugu. "This is an important milestone. It's a pipe dream in a way because a lot of things need to work out between here and full organ transplantation, but this paper sets the stage for all our future research. We can't really just go and start working with humans in work like this, so we started with pig-to-pig transfer in this paper, working with the stem cells and putting them back into other pigs to track the process to make sure it is safe for liver production as proof-of-concept."
Telugu and his team pitched this work at UMD Bioscience Day on behalf of his company, RBI, and received the Inventor Pitch Award and the UMD Invention of the Year Award in 2018. In order to protect the intellectual property, Telugu worked with the UMD Office of Technology Commercialization (OTC) to secure patents and open the work up for additional fundraising to carry this technology through the preclinical and clinical stages. The Maryland Stem Cell Foundation provided some funding to advance this work, and Telugu is thankful that Maryland funds technologies in the human stem cell space.
"There are many terminal cases where people need some sort of an organ replacement, like organ failure and degenerative diseases that cannot be cured by drugs," explains Telugu. "The traditional paradigm is to find a donor organ, but as of today there are still thousands of patients waiting for transplants, and there is no keeping up with the demand. Researchers have thought for a long time that stem cells could help solve this problem, and these stem cells have the ability to go into a specific organ as opposed to those that go into any lineage. In this case, you can differentiate the cells and place them where they are needed to help rescue a diseased organ, eliminating the need for transplant or at least buying the patient some time. Just making the human liver and collecting them early from a neonatal piglet, the hepatocyte [liver] cells alone are a $3 billion opportunity per year. And in the future, we can move into organ transplantation, first with the liver, and then looking at other organs of interest like the pancreas and lungs."
According to Telugu, this has distinct advantages over other methods that researchers are currently using to create donor organs in pigs, since the organs Telugu and his team are working with are actually of human origin and are therefore more likely to be accepted when transplanted. "Transplant rejections are pretty common even between humans and humans," says Telugu, "and if it is such a problem normally, you can imagine how an organ from a pig could be difficult to accept and may not essentially perform the same functions. Pig proteins may not function the same, so that remains a huge barrier for other methods that are not actually growing fully human organs like ours."
This work has the potential to solve a major problem in the treatment of organ failure and other degenerative diseases, which is what Telugu and his work is all about. "Being a veterinarian by training, we always look at the problem and try to find solutions to them," says Telugu. "Most animal scientists operate by looking for solutions, so integrating research and entrepreneurship to get this to the market where it is needed is essential. We are one of the few groups on the planet that are working in this space, and we have a great team of embryologists here at Maryland to do this work. We are uniquely positioned to accomplish this with both genome editing and stem cell biology expertise, and being able to prove the concept with this paper is a great first step towards our goals."
What's at Stake?
Transplants of animal organs to humans is performed at the expense of the animal in question. Animal rights advocates believe that sacrificing animals for the benefit of human lives is not morally acceptable, whether for the use of their organs or for research necessary to study the immunological factors that cause organ rejection.
Humans are not without risk in this issue either. The effects that latent animal viruses could have on human organ recipients are not fully understood. Opponents of xenotransplantation fear that these viruses, when introduced into a human system, might cause epidemics of diseases to which we have no immunity and for which we have no readily available cures.
Pigs, for example, are currently the best candidate animal species for culturing organs for humans. These animals are also carriers for a retrovirus called porcine endogenous retrovirus (PERV).
The PERV virus has been shown to infect human cells, but the consequences of infection have not yet been determined.
Some opponents of xenotransplantation believe that animals are not the solution. These challengers contend that biotech companies are only concerned with making money from their ability to clone animal cells and create genetically modified organisms (GMOs).
The GMOs specifically targeted in the arguments are genetically modified pigs known as "knockouts" that lack the alpha-galactosyl transferase enzyme (known as alpha 1,3-galactosyltransferase)—the organs of these knockout pigs do not have the xenoantigen synthesis ability that causes organ rejection.
Surgeons Smash Records with Pig-to-Primate Organ Transplants
With the financial aid of a biotechnology executive whose daughter may need a lung transplant, U.S. researchers have been shattering records in xenotransplantation, or between-species organ transplants.
The researchers say they have kept a pig heart alive in a baboon for 945 days and also reported the longest-ever kidney swap between these species, lasting 136 days. The experiments used organs from pigs “humanized” with the addition of as many as five human genes, a strategy designed to stop organ rejection.
The GM pigs are being produced in Blacksburg, Virginia, by Revivicor, a division of the biotechnology company United Therapeutics. That company’s founder and co-CEO, Martine Rothblatt, is a noted futurist who four years ago began spending millions to supply researchers with pig organs and has quickly become the largest commercial backer of xenotransplantation research.
Rothblatt says her goal is to create “an unlimited supply of transplantable organs” and to carry out the first successful pig-to-human lung transplant within a few years. One of her daughters has a usually fatal lung condition called pulmonary arterial hypertension. In addition to GM pigs, her company is carrying out research on tissue-engineered lungs and cryopreservation of organs. “We’re turning xenotransplantation from what looked like a kind of Apollo-level problem into just an engineering task,” she says.
Some researchers agree with Rothblatt that the latest results mean pig-to-human transplants are plausible. “I think it’s possible it should be considered,” says Leo Bühler, a Swiss transplant surgeon in Geneva. He said he would transplant a genetically engineered pig’s organ into a patient today, were the patient’s situation desperate enough.
And there are desperate cases. In fact, thousands of people die each year while waiting on transplant lists. Donated human organs are scarce, and many that become available don’t end up helping anyone. That is because a heart or kidney lasts only a matter of hours packed in ice, so organs can’t reach any but the closest patients.
“We want to make organs come off the assembly line, a dozen per day,” says Rothblatt. In 2011 her company paid about $8 million to take over Revivicor, and she has outlined plans for a facility able to breed 1,000 pigs a year, complete with a surgical theater and a helipad so organs can be whisked where they are needed.
The problem with xenotransplantation is that animal organs set off a ferocious immune response. Even powerful drugs to block the immune attack can’t entirely stop it. In a famous 1984 case, a California newborn known as “Baby Fae” received a baboon heart. But it lasted only three weeks before failing. The human body reacts even more strongly to pig tissue, since pigs are genetically more distant. All human tests of pig organs have ended quickly, and badly. A Los Angeles woman who got a pig liver in 1992 died within 34 hours. The last time a doctor transplanted a pig heart into a person, in India in 1996, he was arrested for murder.
Researchers continue to work with pigs because they’re in ready supply, and the organs of young pigs are about the right size. In order to beat the rejection problem, researchers began trying to genetically modify the animals. One major step came in 2003 when David Ayares, a cofounder of Revivicor, created pigs whose organs lacked a sugar molecule that normally lines their blood vessels. That molecule was the major culprit behind what’s called hyperacute rejection, which had almost instantaneously destroyed transplanted pig organs.
Removing the sugar molecule helped. But it wasn’t enough. Tests in monkeys showed that other forms of organ rejection still damaged the pig tissue, albeit more slowly. To combat these effects, Ayares’s team has made pigs with more and more human genes. For instance, one gene that’s been added produces the human version of thrombomodulin, a molecule that prevents clotting in blood vessels. Although pigs have their own version of thrombomodulin, it’s the wrong shape and doesn’t work correctly with human blood.
“We are adding the human genes to the pig so you have the organ repressing the immune response, rather than have to give a whopping dose of immune suppressants,” says Ayares. By next year, some of the pigs will have as many as eight added human genes. These genetic changes make their organs more compatible with a human body, but the animals still look and act like normal pigs.
Genetically engineering the pigs isn’t easy. It’s challenging to insert human genes and difficult to get them to function correctly. “You try to put all your genes into one parcel so they go to one place in the genome,” says Bruno Reichart, a professor at the University of Munich, who leads a German consortium developing transgenic pigs. “It’s very cumbersome. Creating a good pig is really like winning the lottery.”
In the United States, leading transplant surgeons have been meeting with Revivicor every few months to plan what genes they’d like to see added next. Since last year, some of the genetic engineering has been carried out in collaboration with Synthetic Genomics, a California company started by DNA sequencing entrepreneur J. Craig Venter. Rothblatt invested $50 million in Venter’s company in 2014, and it has begun designing and building genetic add-ons and inserting them into pig cells. It is left to Revivicor to produce piglets from these engineered cells, using cloning.
Some people involved in the project are more circumspect than Rothblatt about how fast it can succeed. “Every time you relieve one rejection issue, another one comes in behind. You peel back one layer and there is another layer underneath,” says Sean Stevens, who runs the mammalian synthetic biology program for Synthetic Genomics. “No one is so naïve as to think, ‘Oh, we know all the genes—let’s put them in and we are done.’ It’s an iterative process, and no one that I know can say whether we will do two, or five, or 100 iterations.”
Yet surgeons credit the genetically enhanced pigs with some recent successes. Muhammad Mohiuddin, a transplant surgeon and researcher at the National Heart, Lung, and Blood Institute, in Bethesda, Maryland, says a heart from one of Revivicor’s pigs lasted two and a half years inside a baboon. This milestone, reached last month, surpassed a previous record of 179 days, achieved by Massachusetts General Hospital. Also this summer, transplant experts at the University of Pittsburgh said they’d kept a baboon alive with one of Revivicor’s pig kidneys for more than four months. That set a record for the longest “life-sustaining” xenotransplant between a pig and a primate.
The heart transplants were not life-sustaining but “heterotopic”—the pig heart was attached to the baboon’s circulatory system and was able to beat, but it didn’t have to do the work of pumping blood, since the baboon’s own heart remained in place. Mohiuddin says the pig heart gave out only when he decided to stop giving the baboon the novel immune-blocking drugs he had used. “We believe it could have gone on forever,” he says. “I would say 60 percent of the improvement was due to the organ, and 40 percent due to better drugs.”
Reichart calls the survival of these pig hearts “a major breakthrough.” He says, “It gives us all hope that cardiac xenotransplantation works. These hearts remained normal—it’s amazing.” However, he doesn’t think anyone should be forecasting when a transplant into humans could occur. That is because surgeons still need to completely replace a baboon’s heart with one from these pigs and show it keeps the animal alive. “It wouldn’t be serious to give a time line for use in humans,” he says.
Mohiuddin says he’ll soon begin trying to replace baboon hearts entirely. The organs he used before had three genetic alterations, but the next ones will have seven. “If they survive, then we can consider clinical trials,” he says. The first human recipients would be expected to be special cases, like someone who needs an organ as a “bridge” until a human donor becomes available.
Lung transplants will be harder, since lungs are permeated with blood vessels and heavily exposed to the immune system. So far, transplants last only a matter of days, says Rothblatt. She has been financing research at the University of Maryland, where pig lungs are being perfused with human blood in the laboratory as a way of measuring the immune response. “She wants genetically modified lungs for personal reasons, due to personal grief,” says Reichart. “I think that is a great thing, but lungs are very difficult.”
Transplant surgeons say one of the largest obstacles they face is the immense cost of carrying out xenotransplant experiments. A single transplant surgery costs $100,000 and involves eight people. Then there’s the cost of keeping the primates, the red tape of animal regulations, and limited government grants. That’s where Rothblatt’s personal interest and her fortune have made a difference, they say. “She is the one that has rejuvenated the field,” says Mohiuddin. “She has the money and a personal attachment. She wants to get it done fast.”
Cooper, D. K., Gollackner, B., & Sachs, D. H. (2002). Will the pig solve the transplantation backlog? Annual Review of Medicine, 53, 133–147.
Gaj, T., Gersbach, C. A., & Barbas, C. F., 3rd. (2013). ZFN, TALEN, and CRISPR/Cas-based methods for genome engineering. Trends in Biotechnology, 31(7), 397–405.
Platt, J. L., Fischel, R. J., Matas, A. J., Reif, S. A., Bolman, R. M., & Bach, F. H. (1991). Immunopathology of hyperacute xenograft rejection in a swine-to-primate model. Transplantation, 52, 214–220.
Lai, L., Kolber-Simonds, D., Park, K. W., Cheong, H. T., Greenstein, J. L., Im, G. S., et al. (2002). Production of alpha-1,3-galactosyltransferase knockout pigs by nuclear transfer cloning. Science, 295, 1089–1092.
Phelps, C. J., Koike, C., Vaught, T. D., Boone, J., Wells, K. D., Chen, S. H., et al. (2003). Production of alpha 1,3-galacto-syltransferase-deficient pigs. Science, 299, 411–414.
Tseng, Y. L., Kuwaki, K., Dor, F. J., Shimizu, A., Houser, S., Hisashi, Y., et al. (2005). alpha1,3-galactosyltransferase gene-knockout pig heart transplantation in baboons with survival approaching 6 months. Transplantation, 80, 1493–1500.
Petersen, B., Frenzel, A., Lucas-Hahn, A., Herrmann, D., Hassel, P., Klein, S., et al. (2016). Efficient production of biallelic GGTA1 knockout pigs by cytoplasmic microinjection of CRISPR/Cas9 into zygotes. Xenotransplantation, 23(5), 338–346.
Lutz, A. J., Li, P., Estrada, J. L., Sidner, R. A., Chihara, R. K., Downey, S. M., et al. (2013). Double knockout pigs deficient in N-glycolylneuraminic acid and galactose a-1,3-galactose reduce the humoral barrier to xenotransplantation. Xenotransplantation, 20, 27–35.
Butler, J. R., Paris, L. L., Blankenship, R. L., Sidner, R. A., Martens, G. R., Ladowski, J. M., et al. (2016). Silencing porcine CMAH and GGTA1 genes significantly reduces xenogeneic consumption of human platelets by porcine livers. Transplantation, 100(3), 571–576.
Byrne, G. W., Du, Z., Stalboerger, P., Kogelberg, H., & McGregor, C. G. (2014). Cloning and expression of porcine β1,4N-acetylgalactosaminyl transferase encoding a new xenoreactive antigen. Xenotransplantation, 21, 543–554.
Estrada, J. L., Martens, G., Li, P., Adams, A., Newell, K. A., Ford, M. L., et al. (2015). Evaluation of human and non-human primate antibody binding to pig cells lacking GGTA1/CMAH/beta4GalNT2 genes. Xenotransplantation, 22, 194–202.
Niemann, H., Verhoeyen, E., Wonigeit, K., Lorenz, R., Hecker, J., Schwinzer, R., et al. (2001). Cytomegalovirus early promoter induced expression of hCD59 in porcine organs provides protection against hyperacute rejection. Transplantation, 72, 1898–1906.
Costa, C., Zhao, L., Burton, W. V., Rosas, C., Bondioli, K. R., Williams, B. L., et al. (2002). Transgenic pigs designed to express human CD59 and H-transferase to avoid humoral xenograft rejection. Xenotransplantation, 9, 45–57.
Cozzi, E., Bhatti, F., & Schmoeckel, M. (2000). Long-term survival of nonhuman primates receiving life-supporting transgenic porcine kidney xenografts. Transplantation, 70, 15–21.
Kuwaki, K., Knosalla, C., Dor, F. J., Gollackner, B., Tseng, Y. L., Houser, S., et al. (2004). Suppression of natural and elicited antibodies in pig-to-baboon heart transplantation using a human anti-human CD154 mAb-based regimen. American Journal of Transplantation, 4, 363–372.
McGregor, C. G., Davies, W. R., Oi, K., Teotia, S. S., Schirmer, J. M., Risdahl, J. M., et al. (2005). Cardiac xenotransplantation: Recent preclinical progress with 3-month median survival. Journal of Thoracic and Cardiovascular Surgery, 130, 844–851.
Mohiuddin, M. M., Corcoran, P. C., Singh, A. K., Azimzadeh, A., Hoyt, R. F., Jr., Thomas, M. L., et al. (2012). B-cell depletion extends the survival of GTKO.hCD46Tg pig heart xenografts in baboons for up to 8 months. American Journal of Transplantation, 12, 763–771.
Zhou, C. Y., McInnes, E., Copeman, L., Langford, G., Parsons, N., Lancaster, R., et al. (2005). Transgenic pigs expressing human CD59, in combination with human membrane cofactor protein and human decay-accelerating factor. Xenotransplantation, 12, 142–148.
Bach, F. H., Winkler, H., Ferran, C., Hancock, W. W., & Robson, S. C. (1996). Delayed xenograft rejection. Immunology Today, 17, 379–384.
Khalpey, Z., Yuen, A. H., Kalsi, K. K., Kochan, Z., Karbowska, J., Slominska, E. M., et al. (2005). Loss of ecto-5′-nucleotidase from porcine endothelial cells after exposure to human blood: Implications for xenotransplantation. Biochimica et Biophysica Acta, 1741, 191–198.
Wheeler, D. G., Joseph, M. E., Mahamud, S. D., Aurand, W. L., Mohler, P. J., Pompili, V. J., et al. (2012). Transgenic swine: Expression of human CD39 protects against myocardial injury. Journal of Molecular and Cellular Cardiology, 52, 958–961.
Van’t Veer, C., Golden, N. J., Kalafatis, M., & Mann, K. G. (1997). Inhibitory mechanism of the protein C pathway on tissue factor-induced thrombin generation. Synergistic effect in combination with tissue factor pathway inhibitor. Journal of Biological Chemistry, 272, 7983–7994.
Petersen, B., Ramackers, W., Tiede, A., Lucas-Hahn, A., Herrmann, D., Barg- Kues, B., et al. (2009). Pigs transgenic for human thrombomodulin have elevated production of activated protein C. Xenotransplantation, 16(6), 486–495.
Miwa, Y., Yamamoto, K., Onishi, A., Iwamoto, M., Yazaki, S., Haneda, M., et al. (2010). Potential value of human thrombomodulin and DAF expression for coagulation control in pig-to-human xenotransplantation. Xenotransplantation, 17, 26–37.
Mohiuddin, M. M., Reichart, B., Byrne, G. W., & McGregor, C. G. (2015). Current status of pig heart xenotransplantation. International Journal of Surgery, 23, 234–239.
Cowan, P. J., Roussel, J. C., & d’Apice, A. J. (2009). The vascular and coagulation issues in xenotransplantation. Current Opinion in Organ Transplantation, 14, 161–167.
Iwase, H., Ekser, B., Hara, H., Phelps, C., Ayares, D., Cooper, D. K., et al. (2014). Regulation of human platelet aggregation by genetically modified pig endothelial cells and thrombin inhibition. Xenotransplantation, 21(1), 72–83.
Ahrens, H. E., Petersen, B., Herrmann, D., Lucas-Hahn, A., Hassel, P., Ziegler, M., et al. (2015). siRNA mediated knockdown of tissue factor expression in pigs for xenotransplantation. American Journal of Transplantation, 15, 1407–1414.
Holzknecht, Z. E., Coombes, S., Blocher, B. A., Li, W., Zhou, Q., et al. (2001). Immune complex formation after xenotransplantation: Evidence of type III as well as type II immune reactions provide clues to pathophysiology. American Journal of Pathology, 158, 627–637.
Hai, T., Teng, F., Guo, R., Li, W., & Zhou, Q. (2014). One-step generation of knockout pigs by zygote injection of CRISPR/Cas system. Cell Research, 24, 372–375.
Taylor, F., Peer, G., Lockhart, M., Ferrell, G., & Esmon, C. T. (2001). Endothelial cell protein C receptor plays an important role in protein C activation in vivo. Blood, 97, 1685–1688.
Burdorf, L., Rybak, E., Zhang, T., Riner, A., Braileanu, G., Cheng, X., et al. (2013). Human EPCR expression in GalTKO.hCD46 lungs extends survival time and lowers PVR in a xenogenic lung perfusion model. Journal of Heart and Lung Transplantation, 32(Suppl.), 137.
Loboda, A., Jazwa, A., Grochot-Przeczek, A., Rutkowski, A. J., Cisowski, J., Agarwal, A., et al. (2008). Heme oxygenase-1 and the vascular bed: From molecular mechanisms to therapeutic opportunities. Antioxidants and Redox Signaling, 10, 1767–1812.
Petersen, B., Ramackers, W., Lucas-Hahn, A., Lemme, E., Hassel, P., Queisser, A. L., et al. (2011). Transgenic expression of human heme oxygenase-1 in pigs confers resistance against xenograft rejection during ex vivo perfusion of porcine kidneys. Xenotransplantation, 18, 355–368.
Lee, E. G., Boone, D. L., Chai, S., Libby, S. L., Chien, M., Lodolce, J. P., et al. (2000). Failure to regulate TNF-induced NF-kappaB and cell death responses in A20-deficient mice. Science, 289, 2350–2354.
Oropeza, M., Petersen, B., Carnwath, J. W., Lucas-Hahn, A., Lemme, E., Hassel, P., et al. (2009). Transgenic expression of the human A20 gene in cloned pigs provides protection against apoptotic and inflammatory stimuli. Xenotransplantation, 16, 522–534.
Fischer, K., Kraner-Scheiber, S., Petersen, B., Rieblinger, B., Buermann, A., Flisikowska, T., et al. (2016). Efficient production of multi-modified pigs for xenotransplantation by ‘combineering’, gene stacking and gene editing. Scientific Reports, 6, 29081.
Davila, E., Byrne, G. W., La Breche, P. T., McGregor, H. C. J., Schwab, A. K., Davies, W. R., et al. (2006). T-cell responses during pig-to-primate xenotransplantation. Xenotransplantation, 13(1), 31–40.
Sullivan, J. A., Oettinger, H. F., Sachs, D. H., & Edge, A. S. (1997). Analysis of polymorphism in porcine MHC class I genes: Alterations in signals recognized by human cytotoxic lymphocytes. The Journal of Immunology, 159, 2318–2326.
Lilienfeld, B. G., Crew, M. D., Forte, P., Baumann, B. C., & Seebach, J. D. (2007). Transgenic expression of HLA-E single chain trimer protects porcine endothelial cells against human natural killer cell mediated cytotoxicity. Xenotransplantation, 14, 126–134.
Maeda, A., Kawamura, T., Ueno, T., Usui, N., Eguchi, H., & Miyagawa, S. (2013). The suppression of inflammatory macrophage-mediated cytotoxicity and proinflammatory cytokine production by transgenic expression of HLA-E. Transplant Immunology, 29, 76–81.
Laird, C. T., Burdorf, L., French, B. M., Kubicki, N., Cheng, X., Braileanu, G., et al. (2017). Transgenic expression of human leukocyte antigen-E attenuates GalKO.hCD46 porcine lung xenograft injury. Xenotransplantation, 24, e12294.
Lilienfeld, B. G., Garcia-Borges, C., Crew, M. D., & Seebach, J. D. (2006). Porcine UL16-binding protein 1 expressed on the surface of endothelial cells triggers human NK cytotoxicity through NKG2D. The Journal of Immunology, 177, 2146–2152.
Lin, Y., Vandeputte, M., & Waer, M. (1997). Contribution of activated macrophages to the process of delayed xenograft rejection. Transplantation, 64, 1677–1683.
Ide, K., Ohdan, H., Kobayashi, T., Hara, H., Ishiyama, K., & Asahara, T. (2005). Antibody- and complement-independent phagocytotic and cytolytic activities of human macrophages toward porcine cells. Xenotransplantation, 12, 181–188.
Oldenborg, P. A., Zheleznyak, A., Fang, Y. F., Lagenaur, C. F., Gresham, H. D., & Lindberg, F. P. (2000). Role of CD47 as a marker of self on red blood cells. Science, 288, 2051–2054.
Barclay, A. N., & Brown, M. H. (2006). The SIRP family of receptors and immune regulation. Nature Reviews Immunology, 6, 457–464.
Ide, K., Wang, H., Tahara, H., Liu, J., Wang, X., Asahara, T., et al. (2007). Role for CD47-SIRPalpha signaling in xenograft rejection by macrophages. Proceedings of the National Academy of Sciences of the United States of America, 104, 5062–5066.
Tena, A., Kurtz, J., Leonard, D. A., Dobrinsky, J. R., Terlouw, S. L., Mtango, N., et al. (2014). Transgenic expression of human CD47 markedly increases engraftment in a murine model of pig-to-human hematopoietic cell transplantation. American Journal of Transplantation, 14, 2713–2722.
Tena, A. A., Sachs, D. H., Mallard, C., Yang, Y. G., Tasaki, M., Farkash, E., et al. (2016). Prolonged survival of pig skin on baboons after administration of pig cells expressing human CD47. Transplantation, 101(2), 316–321.
Jung, S. H., Hwang, J. H., Kim, S. E., Young, K. K., Park, H. C., & Lee, H. T. (2017). The potentiating effect of hTFPI in the presence of hCD47 reduces the cytotoxicity of human macrophages. Xenotransplantation, 24, e12301.
Tonjes, R. R., & Niebert, M. (2003). Relative age of proviral porcine endogenous retrovirus sequences in Susscrofa based on the molecular clock hypothesis. Journal of Virology, 77, 12363–12368.
Ericsson, T., Oldmixon, B., Blomberg, J., Rosa, M., Patience, C., & Andersson, G. (2001). Identification of novel porcine endogenous betaretrovirus sequences in miniature swine. Journal of Virology, 75, 2765–2770.
Blusch, J. H., Patience, C., & Martin, U. (2002). Pig endogenous retroviruses and xenotransplantation. Xenotransplantation, 9, 242–251.
Specke, V., Rubant, S., & Denner, J. (2001). Productive infection of human primary cells and cell lines with porcine endogenous retroviruses. Virology, 285, 177–180.
Denner, J. (2008). Recombinant porcine endogenous retroviruses (PERV-A/C): A new risk for xenotransplantation? Archives of Virology, 153(8), 1421–1426.
Lee, J., Webb, G., Allen, R., & Moran, C. J. (2002). Characterizing and mapping porcine endogenous retroviruses in Westran pigs. Journal of Virology, 76(11), 5548–5556.
Dieckhoff, B., Karlas, A., Hofmann, A., Kues, W. A., Petersen, B., Pfeifer, A., et al. (2007). Inhibition of porcine endogenous retroviruses (PERVs) in primary porcine cells by RNA interference using lentiviral vectors. Archives of Virology, 152, 629–634.
Ramsoondar, J., Vaught, T., Ball, S., Mendicino, M., Monahan, J., Jobst, P., et al. (2009). Production of transgenic pigs that express porcine endogenous retrovirus small interfering RNAs. Xenotransplantation, 16, 164–180.
Yang, L., Güell, M., Niu, D., George, H., Lesha, E., Grishin, D., et al. (2015). Genome wide inactivation of porcine endogenous retroviruses (PERVs). Science, 350(6264), 1101–1104.
Ekser, B., Kumar, G., Veroux, M., & Cooper, D. K. (2011). Therapeutic issues in the treatment of vascularized xenotransplants using gal-knockout donors in nonhuman primates. Current Opinion in Organ Transplantation, 16, 222–230.
Graham, M. L., & Schuurman, H. J. (2013). The usefulness and limitations of the diabetic macaque model in evaluating long-term porcine islet xenograft survival. Xenotransplantation, 20, 5–17.
Mohiuddin, M. M., Singh, A. K., Corcoran, P. C., Thomas, M. L., III, Clark, T., Lewis, B. G., et al. (2016). Chimeric 2C10R4 anti-CD40 antibody therapy is critical for long-term survival of GTKO.hCD46.hTBM pig-to primate cardiac xenograft. Nature Communications, 7, 11138.
Byrne, G. W., Du, Z., Sun, Z., Asmann, Y. W., & McGregor, C. G. (2011). Changes in cardiac gene expression after pigto-primate orthotopic xenotransplantation. Xenotransplantation, 8, 14–27.
Brenner, P., Mayr, T., Reichart, B., Guethoff, S., Buchholz, S., Dashkevich, A., et al. (2017). 40 Days survival after orthotopic cardiac xenotransplantation of multi-transgenic pig hearts in a pig-to-baboon model with CD40mAb or CD40L costimulation blockade and xenograft preservation using steens cold blood cardioplegia perfusion. Transplantation, 101(5(Suppl 3)), 65.
Vial, C. M., Ostlie, D. J., Bhatti, F. N., Cozzi, E., Goddard, M., Chavez, G. P., et al. (2000). Life supporting function over one month of a transgenic porcine heart in a baboon. Journal of Heart and Lung Transplantation, 19, 224–229.
Higginbotham, L., Kim, S., Mathews, D., Stephenson, A., Breeden, C., Larsen, C., et al. (2016). Late renal xenograft failure is antibody mediated: Description of the longest-reported survival in pig to-primate renal xenotransplantation. American Journal of Transplantation, 16(Suppl 3), 68.
Iwase, H., Hara, H., Ezzelarab, M., Li, T., Zhang, Z., Gao, B., et al. (2017). Immunological and physiological observations in baboons with life-supporting genetically engineered pig kidney grafts. Xenotransplantation, 24, e12293.
Barth, R. N., Yamamoto, S., LaMattina, J. C., Kumagai, N., Kitamura, H., Vagefi, P. A., et al. (2003). Xenogeneic thymokidney and thymic tissue transplantation in a pig-to-baboon model: I. Evidence for pig specific T-cell unresponsiveness. Transplantation, 75(10), 1615–1624.
Iwase, H., Liu, H., Wijkstrom, M., Zhou, H., Singh, J., Hara, H., et al. (2015). Pig kidney graft survival in a baboon for 136 days: Longest life-supporting organ graft survival to date. Xenotransplantation, 22(4), 302–309.
Shah, J. A., Navarro-Alvarez, N., DeFazio, M., Rosales, I. A., Elias, N., Yeh, H., et al. (2016). A bridge to somewhere: 25-day survival after pig-to baboon liver xenotransplantation. Annals of Surgery, 263(6), 1069–1071.
Ramirez, P., Chavez, R., Majado, M., Munitiz, V., Muñoz, A., Hernandez, Q., et al. (2000). Life-supporting human complement regulator decay accelerating factor transgenic pig liver xenograft maintains the metabolic function and coagulation in the nonhuman primate for up to 8 days. Transplantation, 70(7), 989–998.
Cantu, E., Balsara, K. R., Li, B., Lau, C., Gibson, S., Wyse, A., et al. (2007). Prolonged function of macrophage, von Willebrand factor-deficient porcine pulmonary xenografts. American Journal of Transplantation, 7(1), 66–75.
Bush, E. L., Barbas, A. S., Holzknecht, Z. E., Byrne, G. W., McGregor, C. G., Parker, W., et al. (2011). Coagulopathy in α-galactosyl transferase knockout pulmonary xenotransplants. Xenotransplantation, 18(1), 6–13.
Addressing Potential Risk of Infection
The transfer of infectious diseases between animals and humans, or cross-species infection, remains an important area of study even though risks have been reduced. In 1997, it was reported that two of four variants of the porcine endogenous retrovirus (PoERV) could infect cultured human cells in test tubes. An endogenous retrovirus is a type of virus that exists as part of the DNA of all mammals and is passed down to offspring over successive generations without causing harm. This earlier report does not indicate if viral transfer would occur as a result of a transplant or whether, if it did happen, it would cause any disease.
Xenotransplantation opponents voice concerns regarding the unpredictable nature of microorganisms. They point to existing human viruses suspected to have originated in animals -- human immunodeficiency virus, simian immunodeficiency virus and bovine spongiform encephalopathy (BSE), in which people developed Creutzfeldt-Jakob Disease, the human equivalent to BSE. They express concern that xenotransplantation puts society as well as the individual recipient at risk for disease.
In August 1999, the results of a study were announced which found no evidence of PoERV infection among 160 people who had previously received medical treatment with living pig tissue. A number of patients in the study did show evidence of circulating pig cells, but no evidence of PoERV infection, potentially demonstrating that pig tissue can survive long-term in the human body with no ill effects. Among the patients included in the study were a few individuals who had been pharmacologically immunosuppressed and therefore presumed to be at greater risk of infection. Another study, conducted by the Mayo Clinic, will test pork slaughtering and processing workers to determine whether PoERV is transferred to people who have a history of extensive exposure to swine tissues and fluids. At this time, there is no evidence that PoERV has been transmitted in vivo or that it poses a risk to humans however, researchers are proceeding with caution to address these outstanding safety concerns. If PoERV’s are found to pose a risk, strategies are being developed that may provide a solution to the problem.
What meaning does this have now that monarchs don't do much?
As can be seen in these maps, marriages were important parts of international diplomacy in Early Modern Europe. The connections of the Protestant (England, Germany, and Bohemia) and Catholic (Spain, Italy, France, and Austria) worlds allowed leaders to call upon kin and allies during wartime.
Today, royal weddings are mostly fodder for tabloids. European monarchs don't really do anything. There are probably more important reasons why the UK and Greece haven't gone to war lately than the fact that Queen Elizabeth II married a Greek noble.
Dr. Benzell suggests that the takeaway is a reminder that leaders are people too:
"The most important lesson is that the individual identities of leaders matter. So often international relations 'realists' take the hard-line view that it is power, strategy, and interests that are the only important factors in international politics. The world is a big game of Risk or Diplomacy, with every country acting optimally given it's resources and objective 'victory conditions.' But what this research emphasizes is that leaders are people with families, and many of them care about their families more than national strategic imperatives! Diplomats ignore the personal interests and desires and friendships and dalliances of leaders at their peril."
Pig To Human Transplantation Getting Closer
Experiments using pigs genetically engineered for compatibility with the human immune system have raised hopes that cross-species transplantation could soon become an option for patients with diabetes and other currently incurable diseases. However, many scientific hurdles remain before the ultimate goal of inducing long-term tolerance of animal tissues and organs in human recipients, according to a special paper in the July 15 issue of the journal Transplantation, published by Lippincott Williams & Wilkins, a part of Wolters Kluwer Health.
"The potential benefits of successful xenotransplantation to large numbers of patients with very differing clinical conditions remain immense, fully warranting the current efforts being made to work towards its clinical introduction," concludes the article. The lead author is Dr. David Cooper of Thomas E. Starzl Transplantation Institute, University of Pittsburgh Medical Center.
Dr. Cooper and colleagues review progress to date with a strain of pigs genetically engineered in the hope of addressing chronic shortages of organs and tissues for transplantation. The animals lack the gene responsible for "alpha-1,3-galactosyltransferase" (GT)&mdashan enzyme normally present in the pig vascular system. Humans have natural, preformed antibodies to GT, resulting in immediate (acute) rejection of any pig-to-human transplant.
The fact that these genetically engineered "GT-knockout" pigs lack GT removes one obstacle to cross-species transplantation, or xenotransplantation, between pigs and humans. Apart from the possible transplantation of organs such as the kidney or heart, pigs are also viewed as a potentially invaluable source of islet cells&mdashthe insulin-producing cells of the pancreas&mdashfor use in transplantation as a treatment for type 1 diabetes.
Preliminary studies have reported encouraging results with transplantation of organs from GT-KO pigs into nonhuman primates. Hearts transplanted from GT-KO pigs into baboons have survived for several months, without the need for intensive drug treatment to suppress the recipient animal's immune system.
However, many obstacles remain to be overcome before exploratory studies of xenotransplantation from GT-KO pigs to humans can begin. The transplanted hearts do not show the pattern of acute, overwhelming rejection typical of cross-species transplantation. However, there is evidence of another type of rejection, characterized by blood clots developing in the small blood vessels.
This suggests a possible "coagulation dysregulation" between pigs and primates. New approaches will be needed to address the problem: either improved approaches to immunosuppressant drug therapy or further genetic manipulation of the donor animals. Studies may also explore techniques of inducing immune tolerance between the animal donor and human recipient before the transplantation procedure is done&mdashan approach that is not generally possible in human-to-human transplantation.
The development of GT-KO pigs has been a significant advance toward making xenotransplantation a reality. However, "these organ-source pigs have not proved the 'quantum leap' that had been hoped, and there are clearly other immunologic problems that require resolution before a clinical trial can be initiated," according to Dr. Cooper and colleagues. More research is needed to identify the nature of the human antibodies to GT, and perhaps to further modify the GT-KO pigs to overcome the observed blood clotting problems.
"Advances in these areas might allow the initiation of clinical trials of xenotransplantation, at least for cell or islet transplantation or for the use of a pig organ to 'bridge' a patient until a human organ is obtained," Dr. Cooper and coauthors write. They conclude, "The potential benefits of successful xenotransplantation to large numbers of patients with very differing clinical conditions remain immense, fully warranting the current efforts being made to work towards its clinical introduction."
Clinical Pig Kidney Xenotransplantation: How Close Are We?
Patients with ESKD who would benefit from a kidney transplant face a critical and continuing shortage of kidneys from deceased human donors. As a result, such patients wait a median of 3.9 years to receive a donor kidney, by which time approximately 35% of transplant candidates have died while waiting or have been removed from the waiting list. Those of blood group B or O may experience a significantly longer waiting period. This problem could be resolved if kidneys from genetically engineered pigs offered an alternative with an acceptable clinical outcome. Attempts to accomplish this have followed two major paths: deletion of pig xenoantigens, as well as insertion of "protective" human transgenes to counter the human immune response. Pigs with up to nine genetic manipulations are now available. In nonhuman primates, administering novel agents that block the CD40/CD154 costimulation pathway, such as an anti-CD40 mAb, suppresses the adaptive immune response, leading to pig kidney graft survival of many months without features of rejection (experiments were terminated for infectious complications). In the absence of innate and adaptive immune responses, the transplanted pig kidneys have generally displayed excellent function. A clinical trial is anticipated within 2 years. We suggest that it would be ethical to offer a pig kidney transplant to selected patients who have a life expectancy shorter than the time it would take for them to obtain a kidney from a deceased human donor. In the future, the pigs will also be genetically engineered to control the adaptive immune response, thus enabling exogenous immunosuppressive therapy to be significantly reduced or eliminated.
Keywords: clinical trial genetically-engineered kidney nonhuman primates patients pigs selection xenotransplantation.
Copyright © 2020 by the American Society of Nephrology.
Percentage survival of patients with…
Percentage survival of patients with ESKD by treatment modality in 2010 (modified from…
Reported maximum survivals of nonhuman…
Reported maximum survivals of nonhuman primates with life-supporting pig kidney grafts, 1989–2017. Details…
Macroscopic appearances of a wildtype…
Macroscopic appearances of a wildtype ( i.e. , genetically unmodified) pig kidney transplanted…
Rapid development of thrombocytopenia (consumptive…
Rapid development of thrombocytopenia (consumptive coagulopathy, a reliable indicator of graft rejection/failure) in…
(A) Pig kidney graft survival…
(A) Pig kidney graft survival in baboons receiving either conventional (tacrolimus-based group A)…
(A) Human IgM (left) and IgG (right) antibody binding to wildtype (WT), GTKO,…
Increases in the lengths of…
Increases in the lengths of the kidneys in four baboons with genetically engineered…
20 Americans Die Each Day Waiting for Organs. Can Pigs Save Them?
Group 3 Created with Sketch.
Thanks to genetically engineered pigs, the donor-organ shortage could soon be a thing of the past.
Group 3 Created with Sketch.
By TOM CLYNES NOV. 14, 2018
Anchoring a row of family photos in Joseph Tector’s office is a framed, autographed picture of Baby Fae, the California newborn who made headlines in 1984 when she received a baboon’s heart to replace her own malfunctioning organ.
It’s inscribed “To Joe” by Leonard L. Bailey, the surgeon who turned to the monkey heart as the only option to keep his patient alive. Bailey snapped the picture about five days after the operation, while Stephanie Fae Beauclair was sleeping. A strip of surgical tape runs down the center of her chest from neck to diaper, marking the incision line where her rib cage was pulled apart to make the swap. Baby Fae would die less than three weeks later.
It’s an unsettling image to come upon while glancing over snapshots of someone’s dutifully smiling children. But to Tector, who was 19 at the time of Baby Fae’s surgery, the cross-species organ transplant was the most inspiring thing he𠆝 ever heard of. “I remember where I was when the news broke,” he says. 𠇊t that moment I knew exactly what I wanted to do with my life.” What he wanted to do with his life, though he may not have articulated it precisely this way, was to become a surgeon-scientist trying to crack the problem of xenotransplantation — the placing of animal organs into human bodies.
Should you ever find yourself in need of a replacement for a vital organ, your ability to receive one will depend on some factors that have nothing to do with how badly you need that heart or lung or pancreas. Your age and blood type will figure, as will your ability to afford the immunosuppressant drugs and lifelong care needed to keep the organ functioning. If your lucky day ever comes, it will come only because someone else had an extremely unlucky day: A healthy and immune-compatible donor will have died in a way that leaves a healthy target organ unscathed.
But there is a chance that your lucky day will never come — that you’ll become one of the 20 Americans who die each day waiting for an organ. Indeed, forces that improve American health in other ways threaten to make the shortage of transplant organs even more acute: Safer vehicles cut into supply longer life spans exacerbate demand. Even though 58 percent of adults in the United States have registered as donors, demand still outpaces supply and most likely always will.
While Tector worked his way through medical school, his hero Bailey continued his pioneering research in cross-species organ transplants, conducting dozens of transplants in and among baboons, sheep and goats. Large primates such as apes and chimpanzees, however closely matched they may be to us genetically, turned out to be a poor option for a sustainable organ-donation solution they breed slowly and are in many cases endangered. But there is one abundant and quick-breeding species that in crucial respects bears an almost uncomfortable resemblance to humans: Sus scrofa domesticus, the common pig. Pigs gestate in less than four months, reach sexual maturity in five or six months and produce large litters. A 150-pound pig is uncannily humanlike in organ size and function.
Alas, in terms of our immune systems, pigs and humans are very different. A surgeon can’t just sew a pig organ into a human and expect it to work, because of molecular incompatibilities that developed since our ancestry diverged about 90 million years ago. Scientists have spent the decades since Baby Fae’s baboon-heart transplant working to comprehend the mechanisms that guide the human immune system to distinguish friend from foe, and to persuade it to regard the pig as friend.
Tector did in fact turn himself into one of those scientists: He is the director of the University of Alabama at Birmingham’s Xenotransplant Program. And today, 34 years after Baby Fae’s death, he and others on the xenotransplantation frontier believe they are on the cusp of delivering on Bailey’s promise, of creating a future in which designer swine, raised in pathogen-free indoor farms, will serve as spare-parts factories for our ailing, aging bodies.
“The joke about xenotransplantation is that it’s always just around the corner, and it always will be,” says Parsia Vagefi, the chief of surgical transplantation at the University of Texas Southwestern Medical Center in Dallas. 𠇋ut recent progress has been so remarkable that for first time it feels like we’re on the verge of a definitive solution to the organ crisis.”
One consequence of xenotransplantation being always just around the corner is that pigs have been quietly insinuating their way into our bodies for some time now. Their pancreas glands have been used to make some types of insulin, and their intestinal tissue has been used to make the blood thinner heparin. Cardiac surgeons reach for pig heart valves to replace leaky and hardened human plumbing, and eye surgeons have affixed pig corneas to damaged human eyes. But a major organ — something that beats or filters or secretes just as well as it did for its donor — presents far greater challenges. Unless the recipient’s immune system is effectively deceived or suppressed, the incoming organ is destined for a very fleeting second act.
Since the 1980s, the immunologist David Sachs, then with Harvard University and now with Columbia University Medical Center, has been exploring ways to overcome the immune-system incompatibility at the heart of the xenotransplantation challenge. At some point deep in our evolutionary past, humans and other Old World primates switched off genes that produce the alpha-1,3-galactosyltransferase (alpha-gal) enzyme, which is still functional in most other species that have immune systems. Because the alpha-gal antigen is common in the environment, we produce antibodies against alpha-gal when we encounter it in our guts as babies. These anti-gal antibodies are a big part of the reason we reject ordinary pig tissue after transplantation. Sachs figured that if he could eliminate alpha-gal from the pig genome, problem solved.
The 1996 birth of Dolly the sheep gave Sachs an opening. Using a similar cloning method, he was able to slip a mutation that eliminated this enzyme into a line of specially inbred miniature swine. The new gal knockout (GalT-KO) pigs boosted the survival of pig organs in primates from minutes to weeks, a huge breakthrough. But weeks is not life alpha-gal problem solved turned out not to fully solve the immune-rejection problem.
At around this time, the Swiss biotechnology giant Novartis, the maker of the immunosuppressant drug cyclosporine, began pouring funding into promising xenotransplantation research at university and private labs. “We were in the transplant wards, so we understood how devastating it is to have patients withering away waiting for an organ that never became available,” says Geoff MacKay, who was on the executive team responsible for Novartis’s transplant immunology programs at the time. According to MacKay, Novartis put “north of $1 billion” into xenotransplantation research.
But in 1998, a research team at Massachusetts General Hospital detected porcine endogenous retroviruses (known by the memorable acronym PERVs) scattered throughout the pig genome. In the age of mad cow disease and on the heels of the AIDS epidemic, there was, Sachs says, 𠇊 lot of anxiety about the possibility that we might be introducing a new pandemic, another AIDS virus or something.” Funding dried up.
In 2013, a 27-year-old Harvard graduate student named Luhan Yang co-authored a study that demonstrated how the genome-editing tool known as Crispr-Cas9 could slice through mammalian genes and edit sequences to remove some characteristics and alter others. Yang had been a science superstar in her native China as a high school senior, she brought home a gold medal from the International Biology Olympiad. “In my home country,” she says, “millions of people need organ transplants, and most of them will die before they can get one. According to Buddhism, it’s good to die with a full body, so there’s very little donation culture.” This, Yang decided, would be the challenge she would turn Crispr’s newly demonstrated power to addressing.
Yang assembled a team and co-founded the biotech company eGenesis with the renowned bioengineer George Church, her mentor at Harvard they quickly raised $38 million in seed capital. But it soon became evident that it would take more than a handful of gene edits to knock the endogenous viruses out of the pig genome. “The initial data was very discouraging,” Yang says. “The cells either died or only had very low targeting efficiency.” In 2015, Yang’s team finally succeeded in snipping out all 62 copies of the PERV gene in pig-kidney cells growing in lab dishes — an accomplishment that still holds the record for the most single-cell modifications.
It worked in a petri dish, but it was still unclear whether a viable pig could be produced after such extensive editing. Working with collaborators in Denmark and China, Yang’s team developed a technique to edit genetically normal cells from a living pig, then embed the DNA-containing nuclei of these modified cells into egg cells taken from the ovaries of a normal pig. A few months later, the team witnessed the birth of the first pig born without the endogenous viruses. They named it Laika, after the first dog in space.
With the PERV gene knocked out of their pigs, Yang and her team are experimenting with knocking in dozens of human genes to make the organs more humanlike: Some would buffer the pig tissue from assault by the human immune system others would tweak its coagulation system to diminish the risk of clotting.
The ability to manipulate so many genes in one interaction has opened up myriad possibilities for researchers and quickened the pace of innovation. But Crispr gene editing can be imprecise: It can sometimes clip DNA in the wrong spot, potentially wiping out tumor-suppression genes in pig donors or, worse, human recipients. Tector’s strategy is to use as few gene edits as he can — he has settled on a triple-knockout pig — to minimize but not eliminate the rejection risk, then employ available immunosuppressive drugs to bridge the smaller compatibility gaps. “There are so many unknowns about genetic engineering that regulators are going to want to go into this in a stepwise fashion,” he says. “The simpler we can make it, the better.”
Catalyzed by Crispr, what had looked like a moonshot half a decade ago is starting to look more like a very methodical gold rush. Pharmaceutical upstart United Therapeutics, founded by the satellite-radio entrepreneur Martine Rothblatt, has helped rejuvenate the field, sinking millions into promising programs. Rothblatt has said she anticipates livering hundreds of organs a day.” Pigs from a subsidiary of the company, Revivicor, were used by a team in Maryland to keep a pig heart beating in a baboon for 945 days.
After years of setbacks, the past two years have seen a cascade of record-breaking xenotransplants using primate models, and researchers are working with regulators to prepare for clinical trials with humans. The first pig-to-human skin graft using live cells is set to take place this month in Boston. At the same time, Tector is readying a clinical trial in which he will install his triple-knockout pigs’ kidneys in dialysis patients who are unlikely to be considered for human-donor organs.
If that experiment fails, the recipients can return to dialysis. If it succeeds, it will, like most approaches on the horizon, be in no small part from the influence of a heavy regimen of immunosuppressant drugs whose substantial side effects are tolerated by transplant patients as part of the trade-off required to stay alive. Immunosuppressant drugs have advanced tremendously over the past few years, but many eminent xenotransplantation scientists regard the 𠇋rute-force immunotherapy” approach as stopgap until researchers perfect a more elegant approach called tolerance induction — essentially a re-education campaign for the immune system that convinces it to perceive the incoming organ as “self.”
The farm looks, at first glance, much like any number of other hilltop farms in central Massachusetts. Only when you get out of the car do you begin to notice the peculiarities: the cinder-block barn’s bricked-in windows, the security fencing, the monster-breath sound of industrial fans pulling air through superfine HEPA filters. This is what’s known as a designated pathogen-free pig facility, and it’s where David Sachs, the Columbia University immunologist who created the GalT-KO pig back in the late s, maintains a herd of about 100 pigs specially inbred to be optimized for tolerance-induction research.
The buildings are biosealed and pressurized to protect their porcine inhabitants from environmental pathogens such as viruses, fungi and bacteria. Inside are animal pens, a meticulously organized laboratory and an operating room. To keep the animals pathogen-free, selected pigs are born inside the facility via cesarean section and then maintained as a closed herd. Subsequent generations will be bred from the progenitor animals inside the facility, a little more than an hour’s drive from Massachusetts General Hospital’s Transplant Center.
Sachs sought out his original pigs from herds whose ancestors had escaped from European settlers in the southern Rocky Mountains and the Andes. Domestic swine can grow to more than 1,000 pounds, but centuries in the harsher climate had selected out the smaller pigs that proved better able to survive the mountain winters. Their miniaturized bodies, and the organs inside, are about the same size as a human’s. After more than 20 generations in captivity, each newborn pig here will be genetically very similar to the others in its generation. “These pigs,” Sachs says, 𠇊re very likely the most inbred large animals on Earth.”
That genetic uniformity, as well as the absence of pathogens, makes his pigs ideal for an impending study in which researchers will try to induce tolerance by adding part of the recipient’s immune system to that of the donor, via bone-marrow and stem-cell transplants, before the transplant operation. The “mixed chimera” experiment is modeled on a human-to-human experiment in which seven out of 10 patients were able to be taken off immunosuppressants permanently. “We’ve shown that it’s possible between humans,” Sachs says. “There’s a high likelihood of it being good for xenotransplants too.”
When I visited the facility, the newest member of Sachs’s herd had been born just eight days earlier. As I watched this perky, roly-poly creature nose a ball around its small enclosure, I was suddenly struck by the recognition of what I was looking at: a Sus scrofa domesticus that might someday become, in a strange and partial way, a Homo sapiens. The organs inside this little pig — or perhaps more realistically, those of its progeny — could someday find their way inside me or you or one of our descendants. If so, we will be much the better off for it, even if we cannot say the same for the pig.
Tom Clynes is an author and a photojournalist who covers adventurous science and environmental issues. His most recent book is “The Boy Who Played With Fusion.”