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Xeno Transplantation

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Xenotransplantation
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  E arly morning, sometime in thenear future. A team of surgeonsremoves the heart, lungs, liver,kidneys and pancreas from a donor,whereupon a medical technician packsthese organs in ice and rushes them to anearby airport. A few hours later theheart and liver land in one city, the twokidneys in another, and the lungs andpancreas arrive in a third. Speedily con-veyed to hospitals in each city, these or-gans are transplanted into patients whoare desperately ill. The replacementsfunction well, and six people receive anew lease on life. Back at the donor cen-ter, surgeons repeat the procedure sev-eral times, and additional transplantstakeplace at a score of facilities distrib-uted around the country. In all, surgicalteams scattered throughout the U.S.conduct more than 100 transplant op-erations on this day alone. How could so many organ donorshave possibly been found? Easily — byobtaining organs not from human ca-davers but from pigs.Although such amedical miracle is not yet possible, weand other researchers are taking definitesteps toward it. Our efforts are drivenby the knowledge that the supply of hu-man organs will always be insufficientto satisfy demand. Within just the U.S.,thousands of patients await transplantsof the heart, liver, kidney, lung and pan-creas, and millions struggle with diseasesthat may one day be curable with otherkinds of donations. Notably, hemophilia,diabetes and even Alzheimer’s and Par-kinson’s diseases might well be treatedusing transplanted cells. So the pressureto devise ways to transplant animalcells and organs into patients — “xeno-transplantation” — steadily mounts. Blending Species T he thought of combining parts fromdifferent species is not at all new.Greek lore of more than 3,000 years agofeatured centaurs — creatures that werehalf man, half horse — and the Chimera,a combination of lion, goat and serpent.As early as 1682 a Russian physician re-portedly repaired the skull of a wound-ed nobleman using bone from a dog.But it was not until after the turn of the20th century that doctors attempted withsome regularity to graft tissues from an-imals into humans. For instance, in1905 a French surgeon inserted slices of rabbit kidney into a child suffering fromkidney failure. “The immediate results,”he wrote, “were excellent.” Neverthe-less, the child died about two weeks later.During the next two decades, severalother doctors tried to transplant organsfrom pigs, goats, lambs and monkeysinto various patients. These grafts allsoon failed, for reasons that seemed puz-zling at the time. Before the pioneeringinvestigations of Nobel laureate Sir Pe-ter Medawar at the University of Lon-don during the 1940s, physicians hadlittle inkling of the immunologic basisof rejection.So, with only failures to show, mostdoctors lost interest in transplantation.But some medical researchers persevered,and in 1954 Joseph E. Murray and hiscolleagues at Peter Bent Brigham Hos-pital in Boston performed the first trulysuccessful kidney transplant. They avoid-ed immunologic rejection by transplant-ing a kidney between identical twinbrothers (whose organs were indistin-guishable to their immune systems). Sub-sequently, Murray and others were ableto transplant kidneys from more distant-lyrelated siblings and, finally, from un-related donors, by administering drugs tosuppress the recipient’s innate immuneresponse.Medical practice has since grown toinclude transplantation of the heart,lung, liver and pancreas. But these ac-complishments have brought tragedywith them: because of the shortage of donated organs,most people in needcannot be offered treatment. Of the tensof thousands of patients in the U.S. ev-ery year deemed good candidates for atransplant, less than half receive a do- Xenotransplantation After struggling for decades with a shortage of donated organs from cadavers, transplant surgeons may soon have another source to tap by Robert P. Lanza, David K. C. Cooper and William L. Chick 54S cientific A merican  July 1997 Xenotransplantation ORGANS that are now in high demandand in short supply for transplantationinclude ( from left to right  ) the heart, kid-ney, liver, lungs and pancreas.     S    T    E    V    E    J    O    H    N    S    O    N    A    N    D    L    O    U    F    A    N    C    H    E    R Copyright 1997 Scientific American, Inc.  nated organ. The shortfall will becomeeven more dire once doctors perfectmethods to treat diabetes by transplant-ing pancreatic islet cells, which produceinsulin. Islet replacement is simplerthantransplanting the whole pancreas, but itmay require harvesting cells fromsever-al donors to treat each patient.Fortunately, scientists did not entirelyabandon the possibility of using animaltissues in patients after human organtransplants came into vogue. During the1960s, medical researchers continuedto investigate exactly why organs trans-planted between widely different spe-cies fail so rapidly.A major cause, theylearned, is that the recipient’s bloodharbors antibody molecules that bindto the donated tissues. (These antibod-ies are normally directed against infec-tious microbes but can also respond tocomponents of transplanted organs.)The attachment of these antibodies thenactivates special “complement” proteinsin the blood, which in turn trigger de-struction of the graft. Such hyperacute rejection of foreigntissue — which begins within minutes or,at most, hours after the surgery — de-stroys the capillaries in the transplantedorgan, causing it to hemorrhage mas-sively. Although this reaction presentsan imposing barrier to xenotransplan-tation, recent experiments suggest thatscientists may yet overcome it.For example, in 1992 David J. G.White and his colleagues at the Univer-sity of Cambridge managed to create“transgenic” pigs, bearingon the innerwalls of their blood vessels proteinsthatcan prevent human complement pro-teins from doing damage. They did thisby introducing into pig embryos a hu-man gene that directs the production of a human complement-inhibiting pro-tein [see “Transgenic Livestock as DrugFactories,” by William H. Velander,Henryk Lubon and William N. Dro-han; Scientific American,  January].White and his co-workershave not yettested how tissues from these pigs farein a human host, but organs from suchgenetically engineered pigs have func-tioned for as long as two months inmonkeys, because the pig cells that arein direct contact with the host’s im-mune system are able to quash the firstwave of attack.Other methods may also serve tothwart hyperacute rejection. In 1991one of us (Cooper), along with severalother investigators, identified the specificmolecular fragments, or antigens, on Xenotransplantation S cientific A merican  July 1997 55 TRANSPLANTS OF TISSUES from animals to humans (xenotransplants) have beenattempted experimentally using a variety of donor animals, from frogs to baboons andpigs. Most efforts quickly failed. But doctors may soon perfect ways to transplant or-gans, such as the heart, from specially bred pigs.     S    T    E    V    E    J    O    H    N    S    O    N    A    N    D    L    O    U    F    A    N    C    H    E    R Copyright 1997 Scientific American, Inc.  pig tissues that human antibodies tar-get. The cells lining pig vasculature haveon their surfacesantigens made up of aparticular sugar group. So it may be pos-sible to breed (or indeed to clone)a lineof genetically engineeredpigs that lackthis troublesome sugar group.One plan would eliminate the enzymethat adds the sugar in the first place. Al-ternatively, scientists could provide pigswith a gene specifying an enzyme thatwould replace the problematic sugarwith some other carbohydrate structure.For example, they could give pigs thegene for an enzyme that replaced exist-ing antigens with the human type Oblood group antigen, which does notelicit an immune response. Or, in princi-ple, the offensive groups could be re-moved by introducing into a pig thegene for an enzyme that degrades theundesirable sugar.Yet another strategy to prevent hy-peracute rejection would be to alter therecipient’s immune system so that it can-not destroy the transplanted tissue. Forexample, using standard apparatus,doctors can remove from the patient’sblood all the antibodies to pig tissue. Itis also possible to deplete the comple-ment proteins temporarily or otherwiseinterfere with their activation. Remark-ably, animal studies suggest that if sur-geons transplant a pig organ while thepatient’s immune system is so sup-pressed, the organ may — for reasons thatremain largely mysterious — achieve ac-commodation, a state that enables it tosurvive even after the host’santibodiesand complement return to normal levels.The transplanted organ then continuesto work despite a distinct lack of toler-ance from the host’s immune system.Unfortunately, researchers have notyet managed to induce accommodationreliably in animals undergoing xeno-transplantation. But Guy Alexandreand his colleagues at the University of Louvain Medical School in Belgiumhave achieved it in certain patients whoreceived human organs from donorswith incompatible blood types — a situa-tion that, like xenotransplantation, nor-mally sparks hyperacute rejection. Fostering Tolerance I nvestigatorsstudying xenotransplan-tation are optimistic that, with somecombination of these methods, immedi-ately harmful immune reactions can beovercome. Yet grafts of animal tissuesin patients would still fall prey tomoredelayed forms of immune rejection,which can take days or weeks to devel-op. In particular, the so-called cellularimmune response to grafts from animalsis likely to be at least as strong as the ro-bust attacks that white blood cells of theimmune system often mount against or-ganstransplanted from one person toanother. Avoiding such delayed reactionsmight require massive doses of immu-nosuppressive drugs, such as cyclospor-ine, to be given indefinitely, and the risksof toxicity, infections and other compli-cations would be excessive.Newly devised immunosuppressiveagents should help, but it would clearlybe more desirable if the human bodycould be induced to accept animal tis-sues without requiring ongoing drugtherapy. That happy condition mightseem impossibly difficult to arrange. Buthope springs from the observation thatlong-term organ acceptance, or immuno-logic tolerance,has occurred spontane-ously in a few people who have receivedhuman organs. Doctors of these patientswere able to reduce, and ultimately elim-inate, the normal regimen of immuno-suppressive drugs.Though still an elusive goal, the in-duction of immunologic tolerance is anarea of vigorous research, and advancesare sure to come. Curiously, it may ulti-mately prove easier to achieve tolerancewith xenotransplantation than with tra-ditional organ transplants. Donated hu-man organs need to be procured urgent-ly under emergency conditions,but ani-mal organs would be available ondemand. That flexibility might give phy-sicians adequate time toreprogram theimmune system of the recipient.One way to create tolerance involvesmodifying the immune system of the pa-tient with bone marrow cells from thedonor animal. (Bone marrow is thesource of all components of the blood,including the white blood cells of theimmune system.)Once introduced, thedonated cells spread and mature, creat-ing a “chimeric” immune system that ispart donor, part recipient. The aim is toalter the patient’s immune system so thatit does not recognize as foreigneitherthe donated cellsor subsequently trans-planted tissues from the same animal.Following this strategy, David H.Sachs and his colleagues at Massachu-setts General Hospital injected bonemarrow cells from donor pigs (alongwith substances to stimulate prolifera-tion of the cells) into baboons. Theseanimals had undergone a course of ra-diation to deplete their immune systemstemporarily and prevent rejection of thepig bone marrow cells. The researchersalso filtered from the blood of the ba-boons those antibodies directed againstpig tissues and administered a brief course of immunosuppressive drugs. Al-though the baboons’ immune systemseventually killed most of the transplant-ed cells, some pig DNA survived in oneof the baboons for almost a year. Whatis more, an important component of thischimeric baboon’s immune system — theaggressive killer T  cells — no longer re-acted to the pig cells as foreign.Such research may yield ways to pre-vent immune rejection of organs trans-planted from animals, buttruly effec-tive measures are probably still someyears away. Another scheme for evad-ing rejection is, however, already under-going clinical trials: immunoisolation.Following this approach, physiciansphysically sequester transplanted tissuewithin a membrane thatallows small Xenotransplantation 56S cientific A merican  July 1997 HYPERACUTE REJECTION of a pig organ transplanted into a patient would verylikely occur in minutes. It ensues after antibodies bind to the linear sugar chains liningpig blood vessels ( left  ). But tissues from pigs genetically engineered to carry the angularsugar groups found in people with type O blood should not elicit such reactions ( right  ). CELLMEMBRANEHUMANSUGARCHAINANTIBODYANTIBODYPIGSUGAR CHAIN     J    E    N    N    I    F    E    R    C .    C    H    R    I    S    T    I    A    N    S    E    N Copyright 1997 Scientific American, Inc.  ANIMAL TISSUES were trans-planted into a person for the firsttime when a doctor repairedthe skull of an injured Russiannobleman using a piece of skullfrom a dog. The surgery was said to have been successful,but the Russian Church threatened the nobleman with ex-communication, prompting him to have the graft removed.FROG SKIN was often graftedonto patients’ skin in an at-tempt to heal burns or skin ul-cers. One British army sur-geon claimed to have per-formed hundreds of theseprocedures with good results.SERGE VORONOFF, an émigré doctorin Paris, began transplanting tissuesfrom the testicles of monkeys into el-derly men. He claimed that these sex-ual rejuvenation treatments instillednew vigor, but experts were skeptical.FIRST CARDIAC TRANSPLANT attempted to put a chim-panzee heart into a human. The pioneering effort,conducted by James D. Hardy at the University of Mis-sissippi, failed within two hours because the heartproved too small to support the patient’s circulation. Episodes in the Historyof Xenotransplantation     D    A    N    E    R    I    C    K    S    O    N    L    A    U    R    I    E    C    A    M    P    B    E    L    L     T   o   n   y    S    t   o   n   e    I   m   a   g   e   s     C    O    U    R    T    E    S    Y    O    F    J    A    M    E    S    D .    H    A    R    D    Y    C    O    R    B    I    S  -    B    E    T    T    M    A    N    N CHIMPANZEE KIDNEYS weretransplanted into 13 patientsby Keith Reemtsma, a profes-sor of surgery at Tulane Uni-versity in Louisiana. One of his patients survived for a fullnine months after the opera-tion (even returning to her job as a schoolteacher) be-fore succumbing to a severe electrolyte imbalance. Remark-ably, the animal kidneys she had received (  photograph )showed no signs of rejection on inspection at autopsy.CHRISTIAAN BARNARD ( right  ), wellknown for performing the first suc-cessful human heart transplant adecade earlier, tried to use baboonand chimpanzee hearts as tempo-rary backup pumps in two patientswith hearts that did not functionproperly after cardiac surgery. Butthe animal organs, being too smalland subject to rejection, failed tohelp the patients survive.BABY FAE, born prema-turely with a malformedheart, received a heartfrom a baboon. Despitethe use of the new immu-nosuppressive drug cy-closporine, the infant livedonly 20 more days.     L    O    M    A    L    I    N    D    A    U    N    I    V    E    R    S    I    T    Y    M    E    D    I    C    A    L    C    E    N    T    E    R LIVER TRANSPLANTS from ba-boons to humans, conducted atthe University of Pittsburgh,proved a mixed success. Onepatient survived for more thantwo months with the animal liv-er. But the massive immunosup-pression necessary to avoid re- jection eventually brought onfatal infection.JEFF GETTY received immunecells from a baboon in an at-tempt to combat his severeAIDS. Although the baboon cellsdied quickly, his condition mys-teriously appeared to improve.CLINICAL TRIAL using pig fetal nerve cells in pa-tients with Parkinson’s disease indicated some suc-cess. The injected pig cells survived in the brain of at least one person for more than seven months.     W    I    D    E    W    O    R    L    D    P    H    O    T    O    S    U    N    I    V    E    R    S    I    T    Y    O    F    P    I    T    T    S    B    U    R    G    H    M    A    R    K    R    I    C    H    A    R    D    S     C   o   n    t   a   c    t    P   r   e   s   s    I   m   a   g   e   s     C    O    U    R    T    E    S    Y    O    F    K    E    I    T    H    R    E    E    M    T    S    M    A    J    O    H    N    D    I    N    S    M    O    R    E     D    i   a   c   r    i   n ,    I   n   c . 1682Late1800s19201964198419771995199219971963 to 1965 Copyright 1997 Scientific American, Inc.
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