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Xenotransplantation Georg Kallert February 14, 2002 Xenotransplantation • Transplanting animal organs and tissues into human • “Excitement” – Provide organs to all the patients who need them • “Controversy” – Infectious agents from the donor animals might be passed to the organ recipients and the population at large Transplant Organs • More than 75,000 Americans are waiting to receive human organs (est. 180,000 globally), but less than 1 in 3 will get one • Some countries have allowed the sale of organs from executed prisoners • Scientists have been experimenting for many years with animal transplants, especially from primates • Globally, the market for transplant organs is estimated at $6 billion Transplant Organs from Pigs • Scientists are now focused on using pigs as a source for transplant organs • Why pigs? – available in large numbers – their organs are similar in size and nature to those of humans (especially miniature pigs) Recent News • Two firms that are researching organ transplants from pigs have each announced that they cloned female miniature pigs without a specific gene that causes immune rejection in humans • Important milestone: first pigs to be cloned with a removed gene, as cloning pigs with added genes has been done in the past • The pigs are missing one of the two genes needed for making an enzyme for sugar production Knockout Pigs • Piglets without one gene for -1,3-galactosyl transferase, yet since they have the other gene, they are still producing this enzyme -1,3-galactosyl transferase • This enzyme enzyme catalyses the synthesis the sugar, -1,3-galactosyl, or alpha-gal • This sugar is on the pig cell’s surface and is easily detected as foreign by human antibodies • If the pig cells with alpha-gal were inserted in the human body they would be killed immediately How was the Gene removed? • Used a "gene trap" vector, a piece of DNA containing snippets complementary to the target gene • Vector was moved to Nucleus using electricity • Odds of a successful insert were 1 in 5 million • The modified fetal cells were fused with oocytes whose chromosomes had been removed • Implanted the embryos into sows that had just come into heat Remaining Obstacles • Produce a male litter with one gene and mate them to with the female litter to get piglets with no genes for -1,3-galactosyl transferase – Takes up to 18 months, not guaranteed – Pigs without any gene for the enzyme may die, but mice with the double knockout did not • Treat any further immunes responses • And prevent the spread of viruses across species from transplants, xenozoonosis Immune Responses • Hyperacute rejection (in minutes) – Destroys blood vessels in organ, cuts off oxygen – Alpha-gal is the main cause, but other sugars exist • Delayed xenograft rejection (in days) – Build-up of antibodies and killer cells in the organ – Little data to determine effect of absence of alpha-gal • T-cell-mediated chronic rejection (months-years) – Presence of alpha-gal does not effect this barrier – Medicine used in human transplants would not work – Inject donor pig’s thymus cells develop tolerance PERV • Porcine endogenous retroviruses are present in the genome of all pigs • They could spread to donors and then all humans • Researchers state their cloned pigs consistently test negative for transmission of PERV to human cells in vitro • Cultured human cells can be infected by PERVs released from cultured pig cells • But, humans receiving pig tissues or blood plasma have never been affected • Three possible explanations for this protection Defense #1 • PERVs lack the “equipment” to infect human cells in vivo • However, immunodeficient mice have been infected by PERVs in experiments with transplanted islet cells – Believe that rodent viruses and retroviral elements may have combined with PERV to allow infection – This could happen with humans Defense #2 • Human cells lack the proper receptor for binding or the machinery to allow PERVs to replicate – If this is the case, then PERVs will pose little or no threat Defense #3 • The body’s immune system, T-4 cells and antibodies • Even when immune system is suppressed for transplant, PERVs could still be eliminated • Experiment to try: do PERVs infect mice with functional immune systems Role of the Antibodies • As the virus envelope is made of cell membrane it would also contain the alpha-gal sugar • Human antibodies would attack it just as they attack a pig cell • However, altered pigs could yield the virus without alpha-gal, and the antibodies may not detect it Ethics • Should we be tampering with animals? • Should we be putting animal parts in humans? • Do the researcher’s cloned pigs really have no PERV DNA? • Is it worth exposing the entire human population to dangerous viruses? • Should xenotransplantation be a “last resort” or the “best option?” • What are humans with animal parts? Polling Data • In a 1998 study, more than 75% of Americans would consider a xenotransplant for a loved one if no human organs were available • However 75% of Americans admit to knowing very little about xenotransplantation • Opposition is greatest among the most informed • Most worried about compatibility, not viruses • Preferred primate donors, as opposed to pigs • Spiritual leader approval was important • Europe: only 36% saw it as morally acceptable Conclusions • By removing the gene for the enzyme an important hurdle has been crossed • Immunological barriers still remain • Virus risks are not yet fully understood • Even though there is ban on non-human primate transplants, pig clinical trials may be allowed • So human trials may be just four years away Bibliography Butler, Declan. “Poll reveals backing for xenotransplants.” Nature 391, 315 (1998). -----. “Xenotransplant experts express caution over knockout piglets.” Nature 415, 103 - 104 (2002). Kaiser, Jocelyn. “Cloned Pigs May Help Overcome Rejection.” Science 295, Issue 5552, 25 (2002) L. Lai et al. “Production of -1,3-Galactosyltransferase Knockout Pigs by Nuclear Transfer Cloning.” Science 295, Issue 5557, 1089-1092 (2002) Platt, Jeffrey L. “Xenotransplantation: New risks, new gains.” Nature 407, 27 - 30 (2000). Stolberg, Sheryl Gay. “Breakthrough in Pig Cloning Could Aid Organ Transplants.” New York Times, Jan. 4 (2002) Q&A