Double lung transplant surgery, carried out in 2007 at the Department of thoracic surgery, Foch hospital, Suresnes, France (Image: Foch/Phanie/Rex Features)
by Andy Coghlan
IN THE not too distant future, a person in need of a heart transplant could be offered a pig's organ. That's the hope of a group that met in China last week to agree global guidelines for the first clinical trials of "xenotransplants".
The meeting of clinicians, researchers and regulators in Changsha, Hunan province, which was organised by the World Health Organization, resulted in the so-called Changsha Communiqué - a document that should eventually guide global regulation of xenotransplants.
It sets out principles for research, recommends how the WHO and individual countries should monitor such research, and includes guidelines for trials (see "Trials and transplants"). Perhaps most importantly, with human organs in desperately short supply, it reflects how far research has come since a decade ago, when some of the problems associated with xenotransplants seemed insurmountable.
For example, one big concern related to porcine endogenous retroviruses (PERVs). These are dormant viral DNA present in the pig genome that researchers feared would reawaken in an organ transplanted into humans, who, unlike pigs, might not be able to keep the viruses dormant. Pigs have now been genetically engineered either to lack PERVs entirely or to carry RNA interference molecules primed to sabotage any that become active. "Most of us now agree the risk is quite manageable," says Megan Sykes of Massachusetts General Hospital in Boston, who attended the meeting.
The first pig tissue to find its way into humans probably won't be an organ, but insulin-producing islet cells from the pancreas, to treat people with diabetes. Two years ago, Bernard Hering's team at the University of Minnesota in Minneapolis reported injecting unaltered pig islet cells into the livers of diabetic monkeys, along with immunosuppressive drugs. The monkeys were able to go without insulin injections for the duration of the 100-day experiment (Nature Medicine, vol 12, p 301). Hering is now in discussions with the US Food and Drug Administration (FDA) about how to proceed with a human trial.
David White and his colleagues at the Robarts Institute in London, Ontario, Canada, are also talking to the FDA about a possible trial next year. To make islet cells less likely to be rejected, White mixes them with Sertoli cells from pig testes, which contain a molecule that seems to damp down attacks by human T-cells. White explains that Sertoli cells are equipped with the cellular machinery to protect sperm, which would otherwise be vulnerable to attack by the immune system because they have half the chromosomes of other cells.
Rafael Valdés-González of the Children's Hospital of Mexico in Mexico City, who first pioneered the Sertoli cell technique, has already tested it in a small number of people and claims that one patient is still insulin-independent as a result (Clinical Transplantation, DOI: 10.1111/j.1399-0012.2007.00648.x).
Also some grounds for optimism come from a handful of trials of pig islet cells in countries where regulation is less tight. In Russia, the New Zealand company LCT claims to have had some success treating five patients with pig islet cells, which they disguised from the immune system by encapsulating them in alginate, a substance from seaweed that allows nutrients and hormones to diffuse in and out but prevents contact with immune cells. Last month, LCT won authorisation to begin a trial in New Zealand.
Sykes hopes that success with initial islet trials will bring greater public acceptance of xenotransplantation, leading to the really exciting prospect of transplanting full organs. These naturally pose greater problems, though, mainly because they must be hooked up to a blood supply and so face the full force of the immune system.
In 2002, researchers at Revivicor, a company based in Blacksburg, Virginia, found a possible way around this. Their "knockout" pigs lacked the gene for the alpha-gal protein - the molecule that indicates the presence of foreign cells to the human immune system. Other Revivicor researchers have inserted "complement regulator" genes into pig organs, which prevented monkey antibodies from attacking them.
One problem that is proving more difficult to solve is clotting. "We think antibodies bind to blood vessels of the pig graft, and these activate coagulation factors," says David Cooper, a pioneer of xenotransplantation at the University of Pittsburgh Medical Center in Pennsylvania who collaborates with Revivicor.
To deal with this, two groups have produced pigs carrying human genes for anti-clotting substances. Revivicor has inserted a gene for a protein called tissue factor pathway inhibitor, which neutralises tissue factor, a key trigger of clot formation. And at the University of Melbourne in Australia, Anthony d'Apice and his colleagues have bred pigs that make human CD39, a protein that stops platelets from aggregating into clots. The hope is that these substances will only be produced locally, preventing clots in the transplanted organ but not disrupting vital clotting elsewhere (Transplant Immunology, DOI: 10.1016/j.trim.2008.10.003).
Even with these interventions, powerful immunosuppressant drugs would still be needed, weakening the body to other invaders, including cancer. To minimise this problem another idea is taking shape: engineer the organ to make its own immunosuppressant. CTLA-4 Ig, for example, prevents T-cells being switched on, and is already used as an immunosuppressant for transplant patients.
Revivicor is now combining all these ideas in one animal by engineering pigs that make CTLA-4 Ig and an anticoagulant in specific organs, have the alpha-gal knockout and make the complement regulator throughout their bodies. D'Apice also claims to have created a pig with four added genes.
Because of the potential success of such experiments, guidelines are essential now. Peter Doyle, a delegate at the meeting and former secretary of the now-defunct UK Xenotransplantion Interim Regulatory Authority says: "Xenotransplantation has the potential to treat millions of people, but the threatened dangers are worrying unless it's properly regulated globally."
Trials and transplants
Global regulation of trials needed to monitor for dangers such as viruses
Trials banned in all countries incapable of effective regulation
All trials and recipients must be registered
Trial regulation must include scientific and ethical assessment, and "involve the public"
First recipients of xeno-organs must be carefully selected to ensure they and their families accept lifelong vigilance for any signs of novel disease
All source animals should be kept in closed colonies free from pathogens
"Compelling justification" needed for trials, including adequate evidence of safety and efficacy from animal studies