Cross-species organ transplants set to increase

By Catherine
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Written by Catherine Bolgar*
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Almost 115,000 solid organs were transplanted in 2012, which was less than 10% of global needs, according to the Global Observatory on Donation and Transplantation. In the U.S., 18 people die daily while waiting for an organ transplant.

Xenotransplantation, or transplants from other species, could provide an unlimited supply of organs and cells. Huge strides have been made in this area in the past decade, but challenges remain.

After initially focusing on primates such as baboons and chimpanzees, researchers have turned to pigs, which grow quickly to the appropriate size and which are in abundant supply. However, the human immune system reacts more strongly to pig organs than to human organs.

If you put a human organ into a human with no anti-rejection treatment, it will survive about a week,” says David K. C. Cooper, professor of surgery at the University of Pittsburgh’s Thomas E. Starzl Transplantation Institute. “If you put a pig organ into a human, it will last five to 10 minutes. There’s a much stronger immune response.”

Sugar molecules, called galactose oligosaccharides, on the surface of cells in the pig organ provoke human antibodies into action. So scientists have been genetically modifying pigs to knock out the genes that produce the offending sugar.

That helps, but it isn’t enough. Researchers are trying to delete other genes responsible for major antigens recognized by the human immune system and to add protective human complement-regulatory proteins. Complement proteins are part of the system that destroys cells that the body has identified as being foreign. Differences in how pigs and humans control blood coagulation also is a challenge—too much coagulation and you get thrombosis, not enough and you get bleeding. Now some pigs have been modified to express human anticoagulants. A number of pigs have different combinations of added or deleted genes.

It’s becoming much more precise the way you can genetically modify the pig,” says Peter Cowan, scientist director of the Immunology Research Centre at St. Vincent’s Hospital in Melbourne and president-elect of the International Xenotransplantation Association. “The thing with xenotransplantation that you can’t do with humans is you can keep modifying the donor. You can identify new problems and can keep adapting the pig to the human recipient. In that respect, pig donors might be as good as, if not better, than human donors in the long run.”

Heart valves from ordinary pigs have been used in humans for years, with best results in older patients whose immune systems are less robust. The valves are treated with agents that protect the pig cells, and therefore injury to the cells is slow, Dr. Cooper says.

Some of the biggest hopes are transplants of pancreatic islet cells, which produce insulin. Pig islets transplanted into nonhuman primates have successfully reversed diabetes.

Sixteen humans with Type 1 diabetes received pig islets in a clinical trial in New Zealand, eight in Argentina and eight in Russia, according to Living Cell Technologies, the Australian biotech company conducting the trials. To protect against immune response, the islets were encapsulated. The patients were able to reduce, but not completely stop, their insulin doses.

The World Health Organization estimates that 347 million people worldwide have diabetes. One day, successful transplants of pig islets could let diabetics regulate their insulin levels without the need for insulin injections.

Successful pig organ transplants are farther in the future. Two baboons at the U.S. National Institutes for Health currently have pig hearts transplanted into them. One has been beating for more than a year and the other for more than two years. “That’s a big step forward,” Dr. Cooper says. However, the baboons’ own hearts are still beating alongside. “We are now asking the question of whether, if you replace the baboon heart with a life-supporting pig heart, will you obtain the same result?”

Next in order of difficulty come kidneys, livers and lungs, all of which present coagulation challenges in addition to rejection.

One of the big concerns in using animal donors is the transfer of diseases to humans. The genome of any pig individual is unique, so each pig has a different set of porcine endogenous retroviruses, or PERVs. These PERVs aren’t transmitted by infection, like other viruses, but instead within cells, from mother to child. “This is the inherent risk that pig cells realize,” says Ralf R. Tönjes, head of the “non-vital tissue preparations, xenogenic cell therapeutics” section at the Paul-Ehrlich-Institute in Langen, Germany. “We have the tools and diagnostic techniques to screen the pigs for the presence or absence of infectious PERVs.”

In addition, “all the exogenous germs have to be excluded from any donor pig used for xenotransplantation,” Dr. Tönjes says. “This is the law. Any bacteria, viruses and fungi we know that could be harmful for the recipient have to be excluded by the proper screening program realized by the preclinical breeding facility. We’re talking about bacteria like staphylococcus and viruses like herpes. It’s a real, real effort.”

Pigs offer advantages in terms of germs. “You’re actually less likely to get a virus going from pig to human than from chimpanzee to human because of the distance between the species,” Dr. Cowan says.

The donor pigs can be raised in controlled, clean facilities, and constantly screened for pathogens. With human donors, “in many cases you don’t know what the donor has. There are some viruses that if you just recently got infected won’t show up in tests before an organ is transplanted,” he says. Except for cases where someone is donating a kidney or part of his liver, human donors are dead, and doctors can’t ask about medical conditions.

Working on multiple fronts—genetic modifications to donor pigs, new immunosuppressants and anti-inflammatory drugs—researchers hope to get to a point where transplants from pigs survive as long as transplants from humans.

If we resolve the remaining problems, the impact of xenotransplantation would be immense,” Dr. Cooper says. “Xenotransplantation could offer cures for millions of people world-wide with conditions like diabetes, Parkinson’s or corneal blindness, as well as organ failure.”

*For more from Catherine, contributors from the Economist Intelligence Unit along with industry experts, join The Future Realities discussion.




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