For half a century, doctors have said human organ transplants will someday be replaced by xenotransplantation, or putting animal organs into people.
But xenotransplant attempts have largely failed, making it seem like the goal will never be realized.
“The running joke is that the future of transplantation is xenotransplantation, and always will be,” said Dr. Robert Redfield, a transplant surgeon at UW Hospital.
But Redfield is teaming up with Dhanu Shanmuganayagam, a UW-Madison expert in using pigs as models of human disease, on a new xenotransplant initiative at the university. With $300,000 in start-up funding from a biomedical research foundation, they plan to create pigs customized to patients in need of kidneys, pancreases or other organs, and ultimately transplant porcine parts into patients.
There’s a reason for renewed interest in the field, not only at UW but around the country: CRISPR, a gene-editing tool discovered in 2012. The “molecular scissor” allows researchers to remove genes that can cause immune rejection or transmit potentially dangerous viruses from animals.
“CRISPR makes it much more viable,” said Shanmuganayagam, who has been using the technique to create pigs tailored to children with neurofibromatosis, an inherited condition that can cause disfiguring tumors.
With more than 125,000 Americans on the waiting list for organs, and fewer than 35,000 transplants performed each year, there is a great need for additional organs, Redfield said. Organs from some deceased human donors don’t last long because they are not in prime condition, he said.
“Xenotransplantation is a potential solution to both of those problems,” Redfield said. “Pigs could be an unlimited supply.”
The University of Alabama and the University of Maryland are among the institutions that are further along in the quest than UW-Madison. The two universities received nearly $34 million combined from the Maryland biotech company United Therapeutics for xenotransplant programs.
But UW-Madison has three pig labs in Madison and the Swine Research and Teaching Center, a 1,500-pig facility near Arlington. The campus is home to the Wisconsin National Primate Research Center, through which Redfield and Shanmuganayagam hope to transplant pig organs into rhesus monkeys before applying to conduct clinical trials in humans.
Dr. Hans Sollinger, a UW Hospital transplant surgeon who transplanted pig kidneys into baboons in 2000, with little success, said UW-Madison is in a position to make a significant contribution to the rejuvenated field.
“It’s a different world now,” Sollinger said. “The chances for success, although not tomorrow or even next year, are quite a bit better.”
A brief history
Xenotransplant research has been going on since shortly after the first successful human-to-human kidney transplants were done in the 1950s.
In the 1960s, Dr. Keith Reemtsma of Tulane University in Louisiana transplanted chimpanzee kidneys into 13 people. Most of the organs failed within eight weeks, but one lasted nine months, according to a history of xenotransplantation published in 2015 in the International Journal of Surgery.
In 1984, Dr. Leonard Bailey of Loma Linda University in California gained national attention after transplanting a baboon heart into an infant known as Baby Fae, who died after three weeks.
Eight years later, Dr. Thomas Starzl of the University of Pittsburgh transplanted baboon livers into two patients, with one recipient surviving 70 days.
Improved immunosuppression drugs and new animal cloning techniques spurred more interest in xenotransplantation, including in the Madison area.
In 1996, the blood of a 17-year-old patient at UW Hospital was cleaned through a pig liver until a human organ was found for transplant. Infigen, a spin-off from DeForest-based ABS Global, in 2000 produced cloned pigs, which the company said held promise for use in transplants.
The same year, Sollinger transplanted pig kidneys into 10 baboons through a national program sponsored by the company Novartis. The procedures failed within three weeks, Sollinger said, and Novartis stopped the program the next year.
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Infigen shut down in 2004 as research in the field stalled.
CRISPR, which stands for “clustered regularly interspaced short palindromic repeats,” has revived interest.
Last year, researchers from Harvard University and China announced they had used CRISPR to create newborn pigs without porcine endogenous retroviruses, or PERVs. Removing the potentially dangerous viruses would eliminate one hurdle to pig-human organ transplants.
A University of Alabama researcher last year reported transplanting kidneys from pigs into baboons after using CRISPR to genetically modify the pigs. The organs lasted more than seven months.
“Just like we keep cars and planes and buildings going forever with an unlimited supply of building parts and machine parts, why can’t we create an unlimited supply of transplantable organs to keep people living indefinitely?” Martine Rothblatt, CEO of United Therapeutics, said during a TED media organization interview in 2015.
Pigs designed for patients
Shanmuganayagam, who with Redfield started UW-Madison’s xenotransplant initiative last year, aims to make an initial version of a “humanized” pig within a few months.
Using the patented Wisconsin miniature swine that he helped develop, Shanmuganayagam plans to knock out four to six genes, “the things that really make a pig a pig.”
Eventually, he and Redfield plan to add in genes associated with a transplant recipient’s immune system, creating an individualized pig for each patient.
The first clinical goal, and the focus of funding Redfield received from the Hartwell Foundation, is to use insulin-producing islet cells from pig pancreases in people with Type 1, or juvenile, diabetes. Transplants of kidneys and other organs are also envisioned.
Trials in monkeys won’t start until the researchers have a better idea of which genes to eliminate and add in the pig. “There are going to be a lot of forks in the road,” Shanmuganayagam said.
Some people who develop organ failure can wait a few years before getting transplants, such as kidney patients sustained by dialysis. Pigs could be designed as organ donors when the patients first become ill and be available before the people’s conditions deteriorate too much, Redfield said.
“That’s a significant window to be able to create something that’s personalized,” he said.
Organs from living human donors have boosted kidney and liver transplant rates in recent years, and are generally of good quality. But only a small proportion of the population is open to being living donors and qualifies, and the surgery poses risks to donors, Redfield said.
“If you could replace that with made-to-order organs, where you don’t have to put other human beings in harm’s way, that’s a relatively attractive solution,” he said.
The researchers don’t anticipate much public opposition to using pigs as organ donors if it will reduce human suffering and prolong lives.
People consume pigs, and pig tissue is used in some human heart valve surgeries, hernia repairs and skin grafts, with pig antigens removed to minimize immune rejection in a way that can’t be done with organs.
“We’re competing with death,” Redfield said. “I think the vast majority of people will be OK with it.”