| Now scientists create a sheep that's 15% human (27/3/2007) | |
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1.Now scientists create a sheep that's 15% human EXTRACT: Dr Patrick Dixon, an international lecturer on biological trends, warned: "Many silent viruses could create a biological nightmare in humans. Mutant animal viruses are a real threat, as we have seen with HIV." (item 1) --- 1.Now scientists create a sheep that's 15% human [image caption: Chimera: sheep have 15 per cent human cells and 85 per cent animal cells] Scientists have created the world's first human-sheep chimera - which has the body of a sheep and half-human organs. The sheep have 15 per cent human cells and 85 per cent animal cells - and their evolution brings the prospect of animal organs being transplanted into humans one step closer. Professor Esmail Zanjani, of the University of Nevada, has spent seven years and GBP5million perfecting the technique, which involves injecting adult human cells into a sheep's foetus. He has already created a sheep liver which has a large proportion of human cells and eventually hopes to precisely match a sheep to a transplant patient, using their own stem cells to create their own flock of sheep. The process would involve extracting stem cells from the donor's bone marrow and injecting them into the peritoneum of a sheep's foetus. When the lamb is born, two months later, it would have a liver, heart, lungs and brain that are partly human and available for transplant. "We would take a couple of ounces of bone marrow cells from the patient,' said Prof Zanjani, whose work is highlighted in a Channel 4 programme [Animal Farm] tomorrow. "We would isolate the stem cells from them, inject them into the peritoneum of these animals and then these cells would get distributed throughout the metabolic system into the circulatory system of all the organs in the body. The two ounces of stem cell or bone marrow cell we get would provide enough stem cells to do about ten foetuses. So you don't just have one organ for transplant purposes, you have many available in case the first one fails." At present 7,168 patients are waiting for an organ transplant in Britain alone, and two thirds of them are expected to die before an organ becomes available. Scientists at King's College, London, and the North East Stem Cell Institute in Newcastle have now applied to the HFEA, the Government's fertility watchdog, for permission to start work on the chimeras. But the development is likely to revive criticisms about scientists playing God, with the possibility of silent viruses, which are harmless in animals, being introduced into the human race. Dr Patrick Dixon, an international lecturer on biological trends, warned: "Many silent viruses could create a biological nightmare in humans. Mutant animal viruses are a real threat, as we have seen with HIV." Animal rights activists fear that if the cells get mixed together, they could end up with cellular fusion, creating a hybrid which would have the features and characteristics of both man and sheep. But Prof Zanjani said: "Transplanting the cells into foetal sheep at this early stage does not result in fusion at all." --- 2.Gods and Monsters chimera: 1. a. a fire-breathing she-monster in Greek mythology having a lion's head, a goat's body, and a serpent's tail b. an imaginary monster compounded of incongruous parts ON APRIL FOOLS' DAY 1998, within hours of reading U.S. patent application No. 08/993,564, the Honorable Bruce Lehman did something no other commissioner of patents had done in the 200-year history of America's oldest government agency. He stepped before a cluster of microphones and announced that the patent would never be approved. No half-human "monsters" would be patented, Lehman declared angrily, or any other "immoral inventions." Legal scholars -- accustomed to an office bound by statute to remain silent until patents are approved or rejected -- were shocked. Forgoing the traditional 18-month review period, Lehman had issued a marching order to his staff to reject a patent application they had barely read, rather as if a judge had instructed a jury that the defendant was guilty before the trial began. Furthermore, to support his decision, Lehman cited an 1817 court ruling that excluded inventions "injurious to the well-being, good policy, or good morals of society." But patent law had long since been amended to say that if an applicant could claim constructive use for a patent, he or she could not be denied simply because there might be dangerous or unethical uses of the invention. "Even attorneys who worshiped the system were horrified," recalls former patent examiner Peter di Mauro, who has since left the agency. Research biologists and biotech executives also felt blind-sided, hearing in Commissioner Lehman's outburst a threat to the hard-earned clearance they had won from the Supreme Court 18 years earlier to patent "anything under the sun made by man" -- even living organisms. Strange as it may seem, the inventor, Dr. Stuart Newman, a soft-spoken developmental biologist and professor at New York Medical College in Valhalla, New York, completely agreed with Lehman that his invention defied the boundaries of human morality. It's why he filed for the patent. And it's why, six years later, as the biomedical community holds its breath, he and the Patent Office remain locked in a legal battle that may redefine what we mean by "human." Newman's patent application is for an intriguing biotechnological contrivance called a chimera [ki-mir-a]. According to Greek mythology, a chimera was a part-lion, part-goat, part-serpent creature that terrorized Lycia until it was slain by the hero Bellerophon. If biotech continues to run amok, warns Newman, such inventions of legend and allegory could actually be invented. Created by injecting the embryonic stem cells of one or more species into the embryo of another species and then allowing that embryo to continue development in the womb of either species, a biological chimera is a way to hybridize two or more species that won't cross sexually. The exact results are largely unpredictable except for the certainty that the chimera will contain cells of each species proportionate to the numbers placed in the embryo. A creature made from an equal number of cells from two species could look like one species but contain the genes, organs, and intelligence of the other. Newman seeks to patent "chimeric embryos and animals containing human cells." And while his application cites innocuous biomedical uses for human/ animal chimeras -- such as toxicological research and the potential for growing rejection-proof human organs in pigs or other creatures -- taken to its most extreme but not necessarily impossible end, the technology could be used to manufacture soldiers with armadillolike shielding, quasi-human astronauts engineered for long-range space travel, and altered primates with enough cognitive ability to ride a bus, follow basic instructions, pick crops in 119 degrees, or descend into a mine shaft without worrying their silly little heads about inalienable human rights and the resulting laws and customs that demand safe working conditions. At first blush, what Newman seeks sounds quite like many patents already obtained by university laboratories and biotech corporations to insert human genes into mice and other mammals, creating what is known as a "transgenic" animal. But cross-pollinating using whole cells containing the entire genomic sequence is a profoundly different and even more morally charged process, and Newman's invention presents the Patent Office with a serious legal and political quandary that could earn the agency enemies either way it might rule. Granting a patent for a half-human chimera would throw religious, bioethical, animal-rights, and constitutional activists into high dudgeon. And the biotech industry would boil over the approval of what is clearly a preventive patent. But decline it and the agency is in court, eventually the highest court in the land. The last time that happened the Patent Office lost its case. Thus far, however, Commissioner Lehman and his successors have decided that foiling Newman is worth the risk. And Newman, a man accustomed to disappointing reversals in and outside his laboratory, has fought back, claim by claim, for six years, because he knows that with a patent in hand he can delay what he regards as a deeply offensive technology for the 20-year life of the patent. Opposed to genetically altering human beings and patenting living organisms, Newman (who's supported in this endeavor by techno-gadfly Jeremy Rifkin) sees in the chimera the manifestation of all he finds immoral about biotech. The technology exists to make chimeric embryos "tomorrow," he says, and a chimera of two similar species (say human and chimp) that could survive into adulthood probably isn't far off. "This is the prize. The more you can humanize animals genetically, the better they are for research models and as sources of transplantable tissues." With such goals in mind, six Canadian and American biologists gathered November 13, 2002, at the New York Academy of Sciences to debate in private whether or not to proceed with chimeric research involving human cells. While two of the scientists raised questions about the ethics of such research, the rest felt that while it could admittedly lead to outcomes "too horrible to contemplate," chimeras still offered enough medical promise to proceed. Dr. Newman has since notified all six that if they proceed in developing chimeras, they will be in violation of his pending patent, and litigation will follow. News of the meeting, immediately reported in Nature, threw the Patent Office into an even deeper bind. "This goes way beyond the jurisdiction of the agency," Deputy Commissioner Stephen Kunin said. "We're being dragged into a controversy which, from our perspective, we don't need to be part of." In truth, the Patent Office made itself part of this controversy almost two decades ago when it began granting patents for genetically altered mammals. At that moment, it placed itself and the patent process at the intersection of science, commerce, and religion, and in Stuart Newman's line of fire. THE PATENT ACT OF 1793, drafted by Thomas Jefferson, and subsequent case law stipulated that nature, in any of its forms or manifestations, could not be patented. But in the late 1920s, research agronomists approached Congress and argued that man-made plant hybrids were not really products of nature, but rather existed as a consequence of human manipulation and were thus, in Jefferson's carefully chosen words, "a new composition of matter." The 1930 Plant Patent Act soon allowed for new varieties of plants that reproduced asexually to be patented. Molecular biology soon produced other techniques for creating new organisms and genetically altering existing ones. But most required sexual reproduction and were thus deemed "natural." Then on June 16, 1980, the U.S. Supreme Court surprised both sides in an obscure patent case by ruling 5-to-4 that a General Electric scientist named Ananda Chakrabarty could patent genetically modified bacteria that produced enzymes capable of breaking down crude oil. In its opinion, the majority concluded that Chakrabarty's bugs, with their vibrant cells and shimmering DNA, were "a human-made invention...with markedly different characteristics from any found in nature." They were new compositions of matter, and were, for the life of the patent, the sole property of General Electric, which, fearful of releasing such an engineered life-form into the environment, never used them. Soon, thousands of life-form patent applications were before the Patent Office, which rapidly evolved from an agency opposed to patenting life-forms to an outright booster of the practice. Biotech scientists, executives, and their attorneys surmised that if whole organisms were now patentable, then surely inert pieces of them-genes and gene sequences-would be as well. A 1986 patent for corn genetically manipulated to produce tryptophan-the chemical the human body uses to make serotonin-widened the opening. In 1987, the Patent Board of Appeals rejected a process to produce bigger oysters through pressure as "too obvious" but noted that involvement of a multicellular animal was not itself a bar to patentability. On the strength of that decision, Patent Commissioner Donald Quigg called a press conference and announced that all "multicellular living organisms, including animals," were patentable. He did make a specific exception for human beings, a restriction mandated, Quigg said, by the 13th Amendment, which prohibits their ownership. Few realized how much wider the Quigg decision had opened the pathway to life-form patenting until a year later, when after a five-year court battle, the Patent Office issued Patent No. 4,736,866 to Harvard biologists Philip Leder and Timothy Stewart for mice transgenically engineered to develop tumors. The famous OncoMouse® was born, and DuPont, which funded the research, holds the exclusive license to it and all its progeny, though the National Institutes of Health is using the mice for cancer research with the understanding that any commercial application it develops belongs to DuPont. The OncoMouse® was the first complete, living, breathing mammal to be patented in the United States, but it was not the last. Scores of transgenic mammalian patents have since been approved, including those for cows and sheep modified to produce medicinal milk ("factory pharming"), rats with a propensity to develop in-flammatory diseases, and a mouse whose cells contain the gene for human insulin. When Newman filed in 1997, his was among 15,000 biotech patents applied for that year. By 2002 the number had nearly doubled. Most are approved, many of them conflicting with existing patents, leaving previous owners no recourse but the courts, which thrills patent attorneys. And, despite Quigg's 13th Amendment stipulation, applications to patent human genes also increase, even genes for which there is no known purpose or product. And they are approved. When objections are raised to this practice, particularly by scientists, the Biotech Industry Organization argues that the United States would lose its "global competitive advantage" if a patent slipped away. "Few people realize," one newspaper article notes, "that a genetic 'land grab' is taking place on a scale that rivals 19th-century colonialism." IF NEWMAN'S PATENT seems the stuff of fancy or Planet of the Apes, consider that a sheep/goat chimera was made back in 1984. It's called a "geep." When fully grown, it looks a little like a sheep with features of a goat, or vice versa, and the cells of each are fairly evenly scattered throughout the geep. In a chimera, the two sets of cells remain distinct (unlike in a hybrid such as a mule, where all the cells are hybridized "mule cells"), ensuring that a geep will accept skin grafts from either the sheep or the goat whose cells it owns without stimulating an immune response. And it can be used to test the toxic effects of chemicals on both sheep and goats. Thus a part-human chimera, even one without obvious human characteristics or rights, could be used to test for human carcinogens and mutagens without the safeguards currently required for clinical trials. In his application, Newman says "the cells composing the embryo may contain one or more transgenes." With such a refinement, chimeric technology could one day be used to engineer specific tissue characteristics of one species into the organs of another. That would be the first step toward growing transplantable human organs inside other animals, a product of enormous commercial interest to biotech companies like Advanced Cell Technology (ACT), which looks on with envy and distress as Newman does battle with the government. A Boston-area company, ACT is already inserting human DNA into cow embryos to produce and patent human stem cells. It is also attempting to design and breed pigs that will look, smell, and behave like pigs in a feedlot but possess hearts, livers, kidneys, and pancreases so humanlike in size, shape, function, and tissue type that people will not reject them after transplantation. Either way the Patent Office rules on Newman's application is bad news for ACT. Approval means Newman owns the technology they need to advance their chimeric research, and ACT executives know that such an activist is unlikely to license it to them or anyone else. Rejection by the Patent Office sends a chilling signal through the entire biotech industry that the government has found a moral boundary beyond which it is unwilling to tread. This may explain why ACT's high-profile vice president of scientific and medical development, Robert Lanza, told me that he supports Newman's effort "100 percent" but added, "While I am opposed to creating chimeric animals, I do not approve of tying up any technology that could save lives." ALTHOUGH IT IS NOW THE EXPLICIT GOAL of the Patent Office to complete patent reviews within 24 months, Newman's patent is still officially pending, six years after it was filed. On four occasions patent inspectors have rejected his application, but with objections so vague and specious that Newman and his attorneys have been able to argue it back to life, only to be rejected again on new grounds. When the agency objected to using human embryonic cells to help create a chimera, for example, Newman's lawyers pointed out it is legal to abort 100-percent-human embryos, and would make no sense to grant part-human embryos greater protection. But one objection survives each exchange-that the chimera itself would be too humanesque. All the recipes in Dr. Newman's application call for using human embryonic cells and stem cells, and describe methods likely to raise the ire of anyone who believes that human life begins at conception or that human cells are more sacred than those of other creatures. Newman's chimera could end up looking, feeling, and behaving somewhat like a human being. That so troubled patent inspector Deborah Crouch, the first of four examiners to work the case, that she coined an intriguing expression to justify rejection. "Since applicant's claimed invention embraces a human being," she wrote, "it is not considered to be patentable subject matter." Newman and the Patent Office have spent much of the subsequent six years grappling with the meanings of "embrace" and "human." To make matters more bizarre, while Newman and his lawyers argue against the embraces-a-human assessment, Newman in fact agrees with it. He knows at least four ways to make a chimera, but he has no intention of ever making one, with or without human cells and features. So as not to disseminate technology he considers dangerous, his application includes only techniques to make chimeras that can be found in existing literature, which gave examiners another excuse to reject his patent-lack of originality. Newman responded that it is not the method for which he seeks a patent but the "unique application" of using human cells and, of course, the final product. What that product would be, exactly, is at least as much the stuff of philosophy as science. Place a human gene or gene sequence in a pig or dog and you haven't really moved either animal very close to being human as we understand it. But place the same genes in a chimpanzee, whose DNA is so similar to a human's that only a full genomic scan can tell them apart, and you could create something almost human, something that perhaps begins to resemble or "embrace" a human. This would be even more likely if you made a new creature by combining embryonic cells, rather than just the genes, from two or more species, as in Newman's chimera. "Different people would draw the line between nonhuman and human at different places," says Newman. "The problem is, the material continuity among all living organisms is such that no matter where you choose to draw it, based on whatever philosophy and belief system, the technology will eventually enable crossing that line." Pull back from the molecular level and the answer to the question "What is human?" is fairly obvious. Bruce Lehman echoed Justice Potter Stewart's famous definition of obscenity when asked what he thought would constitute a chimeric human. "I'm quite certain that when we see one of these, we'll know it," he told the Washington Post a few weeks after issuing his summary rejection in 1998. But with a chimera's ability to hide distinct human features, even intelligence, inside another species, the definition of humanity could be blurred beyond recognition. Now that he's stepped down from the Patent Office, Bruce Lehman can talk about pending patents, and so in August 2002 we met a few blocks from the U.S. Capitol in his modest office at the International Intellectual Property Institute, an organization he created after leaving office with a $1 million grant from the Bush administration. IIPI promotes the installation of patenting systems in every country of the world. As a private citizen, Lehman is free to reveal his true motivations for stifling Newman's patent, and as a patent evangelist he's happy to expound on the vital role intellectual-property laws play in industrial development, economic globalization, and the commercialization of biotech inventions. And he is more than willing to rebuke bio-Luddites such as Newman, whom he regards as anti-science. "Stuart Newman is promoting an effort that will make it difficult to engage in biological research and commercialize the fruits of that research," says Lehman. "It's not funny or cute; it is profoundly wrong. Every attempt to stop science has been characterized by darkness." Lehman says he was acting on the concept of ordre public, a European legal restriction against immoral inventions that does not exist in American patent law. Nevertheless, he believes that every American public official should be responsible for defending ordre public whether or not it is required by statute. Yet Lehman also told me that had Advanced Cell Technology, Geron Corp., or almost any biotech firm applied for the same patent Newman did, he would not have stood in their way. And though he spoke of "monsters" when he first reacted to Newman's patent, Lehman now says he does "not believe there should be a prohibition against a human patent." It was not the specter of half-human chimeras or even patenting whole human beings that revolted him, he now says. "I was just deeply offended by anyone attempting to use the U.S. Patent Office to make a point, or to stop the advancement of science. I refused to make it easy for him." Whatever his motives, by violating the agency's rules and issuing a premature and emotional ruling, Lehman may have given Newman adequate justification to appeal a rejection. By law, inventors are entitled to revise their applications and reapply as often as they wish in pursuit of approval. But Newman and his lawyers have decided that if the agency persists in rejecting the invention, they will appeal the decision all the way to the Supreme Court. NEWMAN AND HIS ATTORNEYS have had only one audience with patent examiners. The "interview" occurred in January 2001, when the case was transferred to a new examiner. "They really didn't know what to make of us," recalls his attorney at the time, Patrick Coyne, who says they talked through the "embracing" issue and tried to explain to the new examiner why the invention was "original." For the moment, Patent officials seem content to leave Newman's application in limbo while they strategize their next move. They're faced with four options: They can withdraw all their objections and grant a patent; they can withdraw legal and scientific objections and reject the invention because it "embraces a human"; they could drop the embraces-a-human complaint and reject the patent for lack of originality or utility; or they could stand their ground on all objections and let the courts decide. There are vexing questions at work here, both moral and legal. Should new organisms be created? Should any organisms be patented? And should humans or anything remotely resembling humans be created or patented? While it is really only the business of the Patent Office to deal with the second question, Newman's initiative could eventually force the entire federal government—executive, legislative, and judicial branches—to consider the others. In their third response to Newman, sent in August 2000, patent officials acknowledged, "In the absence of clear legislative intent and guidance from the courts, it is incumbent on the Office to proceed cautiously." That is tantamount, contends attorney Coyne, to admitting that the agency has been granting life-form patents for more than 20 years without congressional authority. Newman hopes this means that Congress and the courts may soon be forced to reconsider the entire patent law, which was last rewritten in the early 1950s, long before the biotech era began. "They're asking themselves how far they can go," Newman says. "They seem set upon turning down the application as an act of prudence and letting me take it to the Board of Patent Appeals and beyond." Patent Appeals is an interagency court where inventors and patent examiners can haggle before administrative judges over what is or is not feasible, novel, and useful about an invention. But in this case, it is also a place to decide whether to grant a handful of biotech companies control over the genetic blueprint of evolution and open the larger debate over what is and is not human. For while Congress and the courts have made clear that humans are not patentable, they've never defined the term "human." It's hard to gainsay any legal mind, especially on the current Supreme Court, but if the court does eventually hear the case, some arguments and counterarguments can be anticipated. One justice might argue, for example, that chimeric mice possessing human brain cells are still mice, much as the Patent Office decided that the Onco- Mouse®, with its array of human genes, was a mouse -period. Bring a cage full of the brainy little squeakers before any court and the point will be obvious. They're rodents. However, another justice would surely observe that if human cells become scattered throughout the entire body of a gorilla, a primate that is genetically 98 percent human, and the chimera looks pretty much like a gorilla, but with some obvious human traits-blue eyes, for example, or a more functional opposing thumb-perhaps the inventor has created something that resembles, approaches, or, in the awkward language of an ambivalent patent examiner, "embraces" a human being. And if the gorilla grows up with an ability to use its larynx, tongue, and lips well enough to articulate a few simple words, "I love you," for example, one might even grant the invention personhood. Partly in anticipation of human/animal chimeras, legal scholars and bioethicists have already begun to challenge the strictly human view of personhood. "Personhood doesn't come from coded sequences," asserts University of Pennsylvania bioethicist Arthur Caplan, "nor does it require human anatomy. It's really defined by what goes on in a brain. A dolphin, for example, could conceivably acquire enough additional intelligence to warrant personhood." What, then, for "human rights"? And what rights are left for, say, humans in persistent vegetative states who Caplan and a growing number of his peers say might one day be considered to have lost their personhood and thereby their right to life? Save the dolphin with its humanesque reasoning and kill the vegetative patients by harvesting their organs for sick humans, or even for a part- human chimera? But the real issue here is not with chimps, dolphins, mice, or any of their rights to personhood, but with our notion of humanity and how it is challenged by chimeras, which threaten either to erase taboos we still embrace, like bestiality, or reintroduce practices we'd hopefully sloughed off, like slavery. Could one animal cell make a being suitable for ownership, forced labor, and medical experimentation, just as "one drop" of black blood once did? What becomes of human empathy if there are chimeric, quasi-human "flesh robots" performing human tasks, or if there are two, three, four, or more genetically separate hom-inid species of self-conscious, intelligent, soulful beings on the planet, perhaps one being genetically enhanced to be stronger, faster, brighter than today's humans, with enough chromosomal conflicts to prevent crossbreeding with "lesser" humans? Will genetically enhanced humans lay claim to the Bill of Rights and exclude all others, or write their own Bill of Superhuman Rights? Will they regard the gene poor much as many European whites once regarded dark-skinned humans-as lesser, subhuman or nonhuman? And will the gene poor, the "naturals," be forced by fate, law, or judicial decree to accept their genetic lot in life? And who will parent the chimeras? These are questions that Stuart Newman believes must be answered before a patent is considered for a human/primate chimera, and before a future court is forced by chimeric technology to determine the legal status of pigs with brains powerful enough to render them self-conscious. So he continues to fight for approval to devise creatures he hopes are never made. Mark Dowie discovered this story about the paradox of the chimera patent while researching a longer article on the patenting of life-forms. Dowie is a former publisher and editor of Mother Jones and teaches graduate course in scientific writing at the University of California, Berkeley. --- 3.Pig-human chimeras contain cell surprise Pigs grown from fetuses into which human stem cells were injected have surprised scientists by having cells in which the DNA from the two species is mixed at the most intimate level. It is the first time such fused cells have been seen in living creatures. The discovery could have serious implications for xenotransplantation - the use of animal tissue and organs in humans - and even the origin of diseases such as HIV. The adult pigs that had received human stem cells as fetuses were found to have pig cells, human cells and the hybrid cells in their blood and organs. "What we found was completely unexpected. We found that the human and pig cells had totally fused in the animals' bodies," said Jeffrey Platt, director of the Mayo Clinic Transplantation Biology Program. Nuclear mix The hybrid cells had both human and pig surface markers. But, most surprisingly, the hybrid cell nuclei were found to have chromosomal DNA that contained both human and pig genes. The researchers found that about 60 per cent of the animals' non-pig cells were hybrids, with the remainder being fully human. Importantly, the team also found that porcine endogenous retrovirus (PERV), which is present in almost all pigs, was also present in the hybrid cells. Previous laboratory work has shown that while PERVs in pig cells cannot infect human cells, those in hybrid cells can. The discovery therefore suggests a serious potential problem for xenotransplantation. The work also suggests a possible route of infection for other viruses that have crossed from animals to humans. "Perhaps HIV managed to jump from primates to humans through infected blood from a bite, which allowed the stem cells from the two species to fuse," Platt told New Scientist. "When the genes recombined, perhaps the virus was reawakened." Body plan Chimeric animals containing human cells have been created before. New Scientist reported in December on the growing of human liver cells in sheep. The work, by Esmail Zanjani and colleagues at the University of Nevada, Reno, aims to provide human tissue for transplantation into people. "The new work is certainly very interesting," Zanjani told New Scientist. "But the question is how widespread and how many of these hybrid cells were found? If they are very rare - and we haven't found any in our experiments - then I don't think it is that important." Zanjani says it is "possible" that HIV had spread to humans through a type of human-primate cell fusion, but adds that much more research needs to be done. In Platt's experiments, the human stem cells were injected into the pig fetuses about a third of the way through gestation. In Zanjani's work, the cells were injected about halfway through. The injections must be given after the body plan of the fetus has developed, but before the immune system is active. The former ensures the animals look like normal pigs and sheep. The latter prevents the human stem cells being rejected. Journal reference: Federation of American Societies for Experimental Biology Journal (DOI: 1096/fj.03-00962fje) |
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