杏吧原创

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Few people know more about transplanting animal organs into humans than . 鈥淚 think this is the beginning of a complete revolution in transplantation,鈥� he says.

Cooper, a surgeon and researcher at Harvard Medical School, is referring to the creation of pigs genetically modified to make their organs more suitable for xenotransplantation 鈥� the use聽of organs from other animals in humans. A series of such transplants has made recent headlines. Late in 2021, two teams transplanted pig kidneys into people who were brain-dead in experiments lasting just a few days. Then, in January, a pig heart was transplanted into 57-year-old David Bennett, who聽is聽said to be slowly recovering聽with聽no signs of聽organ聽rejection by his body.

The next step is to carry out聽clinical trials 鈥� Bennett鈥檚 transplant was permitted on compassionate grounds as a last resort, rather than as part of a trial. But Cooper, who wasn鈥檛 involved in these recent transplants, is confident that the approach will succeed. In fact, he thinks that with further development, organs from modified pigs will be better than donated human organs.

鈥淭his is the first time in 70 years of organ transplantation that we鈥檙e able to modify the donor, as聽opposed to just suppressing the recipient,鈥� he says. 鈥淎nd the more you can do to the donor organ, the聽less you have to do to the recipient. So I think the day will come, in not too many years, when聽we don鈥檛 need to give the recipient any treatment at all.鈥�

In 1968, Cooper was present at聽the first heart transplant done in the UK, where he trained as a surgeon. He later worked in South Africa under Christiaan Barnard, who did the first ever heart transplant. Cooper then moved to聽the US where, since the 1990s, he has focused on developing xenotransplantation to increase the number of available organs.

There is no doubting the need聽for more organs. In the US聽alone, there are . Many in need of聽a kidney will wait more than five years, and nearly half will die聽while waiting or get taken off聽the list because they become too frail, he says.

As early as the 1960s, there were聽attempts to transplant chimpanzee and baboon organs into people. However, primates aren鈥檛 a suitable source of organs for numerous reasons, including the ethics. So, instead, most researchers turned to pigs, which聽multiply rapidly and grow fast enough that organs can be harvested within months of birth.

Unaltered pig organs can鈥檛 be put in people because they trigger a strong immune response that destroys the organ within minutes or hours. The main cause of this hyperacute rejection is a sugar on聽the surface of pig cells known as Gal for short. In 2005, Cooper and his colleagues reported that聽deleting the gene for the enzyme that attaches Gal when pig organs are transplanted into baboons. So the problem of聽hyperacute rejection has long聽been solved, he says.

It isn鈥檛 the only issue, however. Biological mismatches between donor and聽recipient can also lead to transplanted organs being slowly rejected over聽time despite the use of immunosuppressive drugs. They聽can also lead to聽blood聽vessel聽damage.

Still some obstacles

To try to prevent these issues, several groups and companies around the world have been making more genetic changes to聽the pigs they work with. The heart and kidneys used in the recent transplants came from pigs聽created by a US company called Revivicor. In these animals, four聽genes have been inactivated, including the gene for Gal, and聽six聽human genes have been added. Other teams have made even more extensive changes.

To make further progress, these teams now need to do clinical trials to see if these modified
pig organs can survive for long enough to justify their use.

So why haven鈥檛 such trials got the go-ahead? Researchers are stuck in a bit of a catch-22. The US聽Food & Drug Administration (FDA) wants them to demonstrate consistent survival for at least a year when, for example, a baboon gets a pig kidney transplant, says Cooper. But organs modified to work in humans don鈥檛 usually survive this long in monkeys.

鈥淲e鈥檝e almost reached the end聽of the road with the animal models because they鈥檙e no longer representative of the human situation,鈥� he says.

Cooper doesn鈥檛 think that putting pig organs into brain-dead people for a few days tells us anything new scientifically, because the key questions are now聽all about long-term survival.

He says he was surprised that the FDA allowed Bennett鈥檚 heart transplant to proceed, but he is聽hopeful it is a sign that the regulator will authorise clinical trials soon. It makes most sense to聽start with kidneys, because if聽anything goes wrong people can聽go on dialysis.

鈥淚f we are proposing a small trial聽in patients with kidney transplants, and they know we have the backup of dialysis if necessary, I think they will probably accept to go ahead with聽it,鈥� says Cooper.

Another obstacle is setting up a聽clean facility for raising gene-edited pigs, to ensure they are free聽from diseases. Revivicor has one, but other groups are only getting started. 鈥淧robably the most important thing preventing some groups from going into the clinic now is that they don鈥檛 have access聽to pigs under these clean聽conditions,鈥� says Cooper. 鈥淚t鈥檚 quite time consuming and聽expensive to care for pigs under these strict conditions.鈥�

The genetic modifications made to pigs so far probably aren鈥檛 enough to prevent their organs being slowly rejected, says Cooper, as already happens with human organs. 鈥淰ery rarely do you have a聽patient who, 10 years later, hasn鈥檛 got some signs of what we call chronic or low-grade rejection, and it鈥檚 a major cause of having to聽retransplant patients. I think we鈥檙e likely to get that low-grade rejection more quickly in a xenograft.鈥�

Even if pig organs initially don鈥檛 last as long as human ones, they could still be used to keep people alive and well until a human organ聽becomes available.

The time that transplanted organs survive might also be聽extended by new immunosuppressing drugs, developed to treat conditions such聽as arthritis. 鈥淲e鈥檙e testing one here at Massachusetts General Hospital with very good results in聽monkeys,鈥� says Cooper.

These drugs aren鈥檛 yet approved, but have been shown to be safe in trials. This is why the FDA has allowed one of these experimental聽 drugs, currently called KPL-404, to聽be given to Bennett.
In the longer term, Cooper thinks further genetic changes can聽mean immunosuppressive drugs won鈥檛 be required at all.

While trials of pig kidney and heart transplants might begin soon, it will be a while yet before it happens with other major organs. 鈥淭he liver and the lungs are way behind the kidney and the heart,鈥� says Cooper. 鈥淲e have a pretty good idea what the problems are,聽but they鈥檙e complex. We will certainly need more genetic manipulations of the pig in order to overcome those problems.鈥�

And the possibilities go way beyond organs. For instance, modified pigs could provide an聽unlimited supply of insulin-producing islet cells for curing diabetes. 鈥淪ome people say, well,聽you鈥檙e exchanging the need聽for insulin with the need for聽immunosuppressive therapy. And that is quite correct,鈥� he says.聽鈥淏ut within a few years, you聽probably won鈥檛 have to give聽any immunosuppression, or聽very little.鈥�

Other possibilities that look promising include treating Parkinson鈥檚 disease with dopamine-producing cells, damaged eyes with corneal transplants and burns with skin grafts. 鈥淎nd we鈥檝e been testing red blood cell transfusions. I think eventually all red blood cell transfusions will be pig red blood cells,鈥� says Cooper. 鈥淪o xenotransplantation will revolutionise medicine, actually, not just transplantation.鈥�