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Pig organs may provide radical solution to organ shortage

by Alexandra Taylor Published on 20th Oct 2015

by Alexandra Taylor Published on 20th October 2015

The prefix “xeno-“ has a Greek root meaning “strange” or “foreign.” In human-to-human organ transplants, there is always a risk of the recipient body fighting off a perceived invasion by an unknown entity. With xenotransplantation, the transfer of organs or tissues between species, this risk is intensified. Thousands of people in the US die each year waiting for organ transplants. Many organs that become available go to waste. Lungs and hearts can only be used after a few hours on ice. The current shortage has scientists searching for substitutes, but 3-D printed organs are still a few decades off.

“Until we learn to grow organs via tissue engineering, which is unlikely in the near future, xenotransplantation seems to be a valid approach to supplement human organ availability,” Dr. Muhammad M. Mohiuddin of the National Heart, Lung, and Blood Institute (NHLBI) told the American Association for Thoracic Surgery (AATS). “Despite many setbacks over the years, recent genetic and immunologic advances have helped revitalize progress in the xenotransplantation field.”

The Past

Xenotransplantation has been around almost as long as human-to-human organ transplants. While the field has been quiet the past few decades, recent advances have highlighted animal-to-human transplant as a viable alternative to the current organ crisis. In the near future, it is possible that patients suffering from end-stage liver, lung, and heart failure will start receiving organ transplants from pigs.

Despite having diverged on the tree of life roughly 80 million years ago, pigs and humans share many genetic similarities. The organs of young pigs are close to the appropriate size for human transplant. Pigs are widely available, and the methods for raising them are well known. By modifying the porcine genome to make it more compatible with humans, researchers hope that pig organs will provide a long-term transplant solution. Primate studies have shown preliminary success: this summer, NHLBI reported a baboon surviving with a pig kidney for 136 days; Mohiuddin says a baboon has survived with a pig heart for almost two and a half years.

Xenotransplantation as a concept dates back centuries. Blood transfusions between humans and animals took place as early as the 1600s. Human-to-human organ transplants started in the 1950s, and animal-to-human transplants followed the decade after. One woman lived for nine months with a chimpanzee kidney in the 1960s. Pig valves have long been used in heart transplants, but these are stripped of their cells, making them much less complicated.

A famous case occurred in 1984, when newborn “Baby Fae” died three weeks after receiving a baboon heart. While primates seem like a natural choice for xenotransplantation, their genetic proximity to humans intensifies the risk of spreading disease between species, a danger known as zoonosis. Primates reproduce slowly and poorly in captivity, and are largely endangered. They are too expensive to breed on a wide scale, and scientists have little experience modifying the primate genome. Raising primates for slaughter also brings up an ethical dilemma that society has circumvented for pigs, which are already bred for food.

Revivicor

Martine Rothblatt is a well-known American entrepreneur and the CEO of Revivicor, a regenerative medicine company based in Blacksburg, VA. Rothblatt’s daughter suffers from pulmonary arterial hypertension, an often-fatal condition for which she is likely to need a lung transplant in the future. Motivated by her daughter’s condition, Rothblatt entered the biotech sphere by founding United Therapeutics in 1996. According to their website, their Pipeline initiative aims to provide an “unlimited supply of transplantable organs.” Rothblatt hopes to achieve the first pig-to-human lung transplant within the next decade.

Revivicor has been working with famed geneticist Craig Venter since last year, when Rothblatt invested $50 million in his company, Synthetic Genomics. Venter’s team has been tasked with editing the genomes of pig cells, which Revivicor then breeds into piglets by cloning. Venter is famous for being among the first scientists to sequence the human genome, and the first to introduce a synthetic genome into a cell. On the topic of xenotransplantation, he told the World Post, “It’s not trivial to do but it is such a key medical need that we are giving it a go.”


Revivicor has their work laid out for them. Genes that are incompatible with human physiology must be knocked out of the genome. Human genes are added in. Once the organ has been transplanted, targeted immunosuppressants are administered to avoid rejection. In 2003, Revivicor cofounder Dr. David Ayares became the first to overcome the most immediate hurdle to xenotransplantation, known as hyperacute rejection (HAR), by engineering pigs that lacked an aggravating sugar molecule usually found in their blood vessels. The more compatible the pig genome, the less severe the course of immunosuppression needed. “We are adding the human genes to the pig so you have the organ repressing the immune response, rather than have to give a whopping dose of immune suppressants,” Ayares told MIT Technology Review.


Revivicor is working with transplant surgeons to determine which genes should be added. Their pig genomes are currently “humanized” with five genes—soon to be eight—which allay the immune response. For example, the protein thrombomodulin is added in to make antibody attachment sites appear more human, preventing clotting. Rothblatt told Technology Review, “We’re turning xenotransplantation from what looked like a king of Apollo-level problem into just an engineering task.”

National Heart, Lung and Blood Institute

Last August, the NHLBI in Bethesda, Maryland, reported having kept a pig heart alive in a baboon for over a year. Baboons in the experimental group received hearts with three modifications: two genes were knocked out that coded for sugar, and one gene coding for human thrombomodulin was added. The hearts were heterotopic, meaning they were joined to the circulatory system, but did not pump blood. The baboon’s natural hearts remained intact, while the transplanted organs were inserted into the baboons’ abdomens. At the time, the average survival of the group that received the human gene-modified hearts was 200 days, with the longest living for over 500 days. This summer, Mohiuddin reported that a baboon had survived for 945 days.

This study helped researchers determine which immune suppressant was most effective, which will serve as a starting point for future trials. Next, researchers will develop hearts with seven modifications, replacing the baboon’s actual hearts using the predetermined immunosuppressant method.

“Based on the data from long-term surviving grafts, we are hopeful that we will be able to repeat our results in the life-supporting model,” Dr. Mohiuddin told the AATS. “This has potential for paving the way for the use of animal organs for transplantation in humans.”

Like NHLBI, Revivicor is also focusing on hearts before developing lungs. Because it contains so many blood vessels, lung tissue is in constant contact with the immune system, a fact that could require unreasonable levels of suppressive therapy. Testing can run at about $100,000 per transplant, but Rothblatt has a personal stake in the matter and remains undaunted. Researchers at the University of Maryland are studying pig lungs flooded with human blood as a means towards this end.

Complications

Aside from rejection, several unknowns surround the concept of xenotransplantation in humans. The body temperature of a pig is about two degrees Celsius higher than that of a human. Hearts must be taken from pigs when they are young to be the appropriate size, but it is unclear whether the hearts will continue to grow once implanted. Pigs have a lifespan of about fifteen years, which could cause their organs to wear out much more quickly than a human transplant. Human organs produce hormones that pig transplants would be unable to mimic.

Perhaps the most pressing barrier is the danger of cross-species infection. The effects of zoonosis are heightened by immunosuppressive therapy, since the body’s capacity to fight off infection is limited. Many infectious agents can be eliminated through rigorous sanitary measures. Food and water must be sterilized, and mammalian protein must be eliminated from the diet to prevent prion disease.

Viruses pose a larger threat. Certain viruses, such as swine flu, are already known to pass between pigs and humans. Retroviruses, which integrate their own DNA into the DNA of their host, pose a risk as well. They could lie undetected in the genome beyond the length of a clinical trial. The most widespread of these is porcine endogenous retrovirus, or PERV, which is present in all pigs. Certain forms of PERV can infect human cells. Further study is needed to determine what risk, if any, PERV poses to humans.

Genome Breakthrough

At the beginning of this month, Dr. George Church of Harvard Medical School announced serious progress in combatting PERV. Dr. Church and his team altered 62 genes in pig cells using the futuristic genome-editing technique CRISPR. Only one CRISPR molecule was required to snip all the viral DNA from the pig genomes, which the cells then replaced with their own DNA. The edited cells were 1000 times less likely to infect human kidney cells.

At an October 5 meeting on gene editing at the National Academy of Sciences, Dr. Church reported having successfully created pig embryos with inactivated PERV sequences. He hopes to start implanting PERV-negative pig embryos that are compatible with the human immune system into surrogate mothers sometime next year. His team is currently working to make this process as inexpensive as possible.


Looking Forward

Public and private advances are turning what once sounded like science fiction into a viable future for organ transplantation. Even if pig organs are unable to meet the needs of an entire human lifespan, they could serve as a “bridge” therapy to tide a patient over until a suitable human organ becomes available. As with any risky procedure, the benefits of receiving a pig organ transplant must be weighed against the dangers of infection. Targeted immune therapy and developments in genome editing may mean clinical trials are not so far off.

In the United States, xenotransplantation in humans would require the approval of the Food and Drug Administration (FDA). The guidelines for this practice are set to be revised in March. Unknown obstacles may arise once clinical trials are under way. As Dr. Joshua Bloom of the American Council on Science and Health has mentioned, “In many ways, this is similar to drug discovery. Just when you think you’ve solved one problem, ten others pop up, always unanticipated… In medical research, almost all rides are bumpy.”