840.119:Xenotransplantation

Xenotransplantation: The production of porcine organs for use in humans.

State of the Art

By definition, xenotransplantation is: the surgical transfer of cells, tissues, or especially whole organs from one species to another.

Xenotransplantation consists of scientists searching for methods to produce in animals organs suitable for transplant into people. A new source of hearts and other organs could save or improve the lives of thousands of people waiting for the limited supply of available human organs. When looking at alternatives, pigs appear to be the best choice. This is because the pig is compatible in size and physiology of humans.

Although xenotransplantation has been around for over hundreds of years, successes have been few and far between. The use of pig organs began approximately ten to fifteen years ago. One common procedure is the transplanting of pig heart valves into humans. Some scientists believe it may take five to seven years before whole organ xenotransplantation of pigs-to-humans becomes reality. According to David Ayares, chief operating officer and vice president of research at PPL, "We're now ready to go into pivotal pig-to-primate trials and need to show in excess of 90-day survival before regulatory authorities approve human trials".

Because the size of pig organs is similar to that of humans, they are considered one of the best sources for transgenic transplants. In addition they are easily bred in large numbers. First, though, they must be made compatible to humans, specifically the removal of a surface sugar protein not present on human cells, which causes the human body to reject the pig organ. The advantage of using biotechnology is that the pigs can be genetically modified to have inactivated copies of the gene to correct the rejection or infection problems.

The sugar protein, a 1,3 galactosyl epitope (determining factor) triggers immune-system rejection in transplant to humans. Progress has been to overcome this problem by genetically modifying the pigs and inactivating these genes. Once a genetic change is introduced into a population, "donor animals" can be bred easily by conventional techniques.

Xenotransplantation is important because every day more people are added to the waiting list for organs. Clinical transplantation has become one of the preferred treatments for end-stage organ failure since the introduction of chronic immunosuppressive drugs in the mid-1980's. Xenotransplantation is one of the novel approaches to dealing with the limited supply of human organs. Over sixty percent of people on the list die before they can recieve an organ. In one study, out of 140 patients referred for heart transplant only about twenty-five received the heart they desperately needed. It is estimated that out of the 80,000 people who need a transplant each year, only 24,000 recieve an organ. The rest must either continue to look for other alternatives or keep waiting. Sadly, many people die while they are still waiting.

The major barrier to progress in pig-to-primate organ transplantation is the presence of terminal 1,3 galactosyl (Gal) epitopes on the surface of pig cells. Humans have lost the corresponding Gal activity in the course of evolution and therefore produce preformed natural antibodies to the epitope. These are responsible for rejection of pig organs.

Another issue that desperately needs looking into is the possibility that human cells may be vulnerable to infection by potentially dangerous viruses carried by pigs. The pig pancreatic islet cells produce a variant of a virus called porcine endogenous retrovirus.

Objectives

The focus of this page is to explain the scientific approach being taken to achieve sucessful pig to human organ transplantation.

Scientific Approach

The technique is progressing at a fairly rapid pace. There have been successful transplants from pigs to sheep. The next step is transplanting from pigs to baboons, which are much more closely related to humans.

Unaltered porcine organs transplanted into other mammals do not last very long. In the article "Xenotransplant" it was said that "Without extremely high levels of immunosuppressive drugs, pig organs seldom last half an hour." By bioengineering pigs to lack certain genes or replace them with human genes it is possible to greatly increase the life of the organ after transplantation. This has been proven in research where the gene for a certain sugar enzyme was deleted from the pig. The hearts of the pigs were then placed in the abdomens of eight baboons. Of these eight baboons five lived between 2-6 months with the aid of immunosuppressants.

Some companies used cloning techniques to produce piglets with organs more likely to be accepted by humans in a transplant operation. The genetically modified pigs lacked one of the two copies of a gene that makes a sugar called alpha-1,3 galactose, the substance that triggers the immune system rejection in transplants to humans. Tissues from these pigs are "completely devoid" of the pig sugar that spurs the rejection. Scientist took skin cells from a pig fetus that already had one copy of the relevant genes knocked out and deactivated the second copy of the gene in the cells.

This pig heart is being infused with blood plasma containing antibodies from a sheep to help it resist rejection when it is implanted into a sheep. (PHOTO COURTESY UNIVERSITY OF NEBRASKA MEDICAL CENTER)

Impact (Potential)

Because there are too many people in need of organ transplants and not enough organs being donated, thousand die each year while they wait. The table below shows the number of people on the National Transplant Waiting List waiting for a specific organ. Using the liver for an example, there are there are 7,551 women waiting for a liver and 10,356 men, just in this country, and just for a liver.

Table 1. Number of Individuals on the National Transplant Waiting List as of May 2001

If we were able to take the organs from another animal, in this case the pig, to transplant into humans successfully we may be able to overcome the deficit and save thousands of lives. In addition, with genetic engineering we may be able to make these organs better for transplanting than human organs. The organs may last longer than those transplanted from humans as well as perform better. While we are unable to manipulate the human genome it is possible to do experiments with animals that can be applied to humans.

Associated Risks

There are several risks associated with pig to human transplantations. There are some diseases that can be transferred from pigs to humans. Pigs have a very promising future due to their tissues being relatively free of potentially toxic agents. While many diseases are species specific there are some that can be transferred. One specific example is porcine endogenous retrovirus. Porcine endogenous retrovirus is dormant in pigs. Doctors feel, however, it is possible that transplanting the organs into humans could reactivate the virus. It has been shown in laboratory conditions that the virus can be transferred from pig to human tissues.

Other risks include the possibility of rejection. There are galactose α-1,3-galactose residues on the surface of pig cells that are not present in humans. Because the human immune system doesn’t recognize these residues they will try to destroy the pig cells.

Another major concern is the possiblilty that animal virus residing in a xenograft recipient may become airborn, infecting thousands of people and potentially causing a viral epidemic.

• PERV- virus that is dormant in pigs. Transplanting organs into humans may reactivate it. Lab experiments show that transfer from pigs to humans is possible o It may make it easier for viruses to cross the species barrier • Viral Epidemic Pandemic- Virus could become airborne, because we don’t have antigens against this virus (there is no human equivalent) Thousands of people might die before a vaccination could be created. • Rejection- ,3 galactose is present on pig cells but not on human cells. Because it is not recognized,the human immune system will attempt to destroy it.

Ethical Issues

There is much controversy about using pig organs for transplant. Some people feel that we don’t have a right to kill other animals just to aid our own ends. A specific example is PETA, a very outspoken animal rights group.

Others feel that by putting the organs of a different species of animal into our bodies we will be losing some of our humanity. Individuals view their internal bodies as an extension of their identities, and soon after the xenotransplantation, some patients will realize the consequences of their actions on their self-concepts. Having an animal's organ in one's body has the potential to decrease our self-image despite intense counseling on the neutrality of this occurrence.

Some people view xenotransplantation as an involuntary form of human experimentation violating US laws and UN charters. We can’t know the exact effects the organ will have until it is transplanted. And because it may cause diseases to cross the species barrier, people may unwillingly be subjected to new diseases that they wouldn’t otherwise contract.

Xenotransplatation is more expensive than human-to-human transplantation (roughly $300,000 per operation, not including the hidden costs of breeding, housing, feeding, medicating, testing, transporting, rendering, and disposing of the waste and remains of herds of transgenic animals) making it unaffordable for most people. While some people are trying to make life better for us, there are others who’s only goal is making money. Companies may develop monopolies over artificially engineered and created species, allowing them to charge even more for the organs. As the process is refined these costs will hopefully decrease.

Currently, the wealthy and powerful get first access to transplants. We need to allocate organs as per top priorities. There is hope that using pig organs we will be able to change this, letting those who need a transplant the most recieve an organ first.

References

Baker, Monya. "Xenotransplant". Technology Review. 108 (5) 2005. 86.

http://education.guardian.co.uk/higher/biologicalscience/story/0,,627038,00.html

http://www.uq.edu.au/oppe/PDFS/Xenotransplantation.pdf

Lai, Liangxue. "Production of α-1,3-Galactosyltransferase Knockout Pigs by Nuclear Transfer Cloning". Science. 295 (5557) 2002. 1089.

Naik, Gautam. "Health and Technology: Cloned Piglets May Aid Organ Hunt---PPL Therapeutics Makes Gain in Effort to Improve Translants' Success Rate". The Wall Street Journal. New York, N.Y.: Aug 23, 2002. pg A8.

Winslow, Ron. "Scientists Clone Pigs, Lifting Prospects of Replacement Organs for Humans". The Wall Street Journal. New York, N.Y.: Aug 17 2000. pg A6.

http://net.unl.edu/newsFeat/med_eth/me_xeno.html

http://www.crt-online.org/wrong.html

http://www.technologyreview.com/read_article.aspx?id=17596&ch=biotech

http://dictionary.reference.com/browse/xenotransplantation