Scientists have cleared a major barrier to transplanting organs from pigs into humans after removing threatening viruses from the animals' DNA.
The new research opens up the possibility of breeding animals to harvest their organs to meet the demand for new tissue.
Some challenges, including major ethical objections still remain, but experts said the breakthrough is a significant step towards pig-to-man transplants, also known as xenotransplantation.
The shortage of organs for transplants is one of the biggest challenges to modern medicine, and the current supply of tissue meets only a tiny amount of the total demand, the authors said. But the ability to breed pigs specifically for that purpose would allow that to be easily addressed, since they have similar organs to ours and can be bred in large numbers.
Until now, the use of pig organs in humans has been held back in large part by fears about retroviruses that are found in pigs and could prove fatal to humans, if they made their way into the body, and could then cause an epidemic as they spread from human to human. Porcine endogenous retroviruses, known as Pervs, are a permanent part of the gene and so appeared be impossible to remove.
But the researchers have now successfully removed those Pervs from the pig genome, using the CRISPR-Cas9 gene editing technique that allowed them to produce Perv-free, living pigs. That, in turn, removes one of the biggest barriers to organ transplantation from pigs to man.
“This represents a significant step forward towards the possibility of making xenotransplantation a reality,” said Darren Griffin, a professor of genetics at the University of Kent. “The chance of transmitting PERV from the pig organ to the human cells was a significant barrier and the study shows yet another application of the CRISPR-Cas9 system.
“By comprehensively demonstrating that PERV is the problem that we suspected that it may be, then providing a solution, the authors present a very elegant study. However, there are so many variables including ethical issues to resolve before xenotransplantation can take place.”
Those ethical worries are significant, and include a consideration of the harm and benefit brought to the person receiving the heart. Though scientists have eliminated the biggest barrier to safety in putting a pig’s heart into a human, there remain risks – and those risks would have to be balanced by ethical committees.
It would also be difficult to ensure that people could give proper consent to the procedure, which could be used in the most dire of circumstances.
But those objections may fade if it becomes clear that the transplants will be useful. When human organ transplantation was beginning, in the 1960s and 1970s, many opposed the idea – but those objections were put aside when it became clear how effectively transplants could keep people alive.
In the US, the government tightly regulates all xenotransplants, in large part because of fears about diseases caused by Pervs.
In the UK, such work was once regulated by a body called the United Kingdom Xenotransplantation Interim Regulatory Authority (UKXIRA), but that was disbanded in 2006 amid a recognition that activity in the industry had slowed. The British regulation would now be decided by the Human Tissue Authority, a non-departmental body of the Department of Health.
Official bodies including the World Health Organisation have warned about the danger of so-called xenotourism, where people might fly to countries with more lax regulations to receive treatment. Some companies have already conducted trials in countries including Mexico.
In the UK, it’s likely that authorities would press for caution given the grave concern about the effects of such experiments. But the significance of any potential treatment for organ failure would mean that regulators would certainly not get in the way.
“I think we would say that the regulatory approach would be proceed, with caution,” said Jonathan Montgomery, who is professor of health care law and chair of the Health Research authority as well as having served as chair of the Nuffield Council on Bioethics.
“This sounds promising. But it doesn’t yet take away the anxieties about the safety of the process.”
That would mean that ethicists would have to see far more evidence that the transplants had been safe to use in humans, for instance.
When it does come to be tested, it would be done on people that weren’t relying on it as their last resort, said Professor Montgomery. It would be too much of a risk to try it on people that didn’t have any other option, and it would be difficult to get informed and free consent from people who saw it as their only option.
Some experiments in primates suggest that a pig’s heart may not be rejected immediately, despite the vast difference between the two animals, if it is treated in the right way.
In 2015, researchers reported that they had put a pig’s kidney that had been edited to get rid of α-gal, the antigen that would cause a human to reject a pig’s heart, into a baboon. The baboon lived for 136 days.
As well as the work to put a pig’s organ into a human, some work on xenotransplantation is looking at the possibility of growing human organs inside another animal. Those organs would be genetically edited so that they would in effect be a person’s – except they would have formed inside of a pig or other animal, from which they would be extracted and then placed into the human.
And doctors already use some parts of animals, including heart values, in surgery on humans.
“Successful transplantation of tissues and organs from animals to man has been one of the goals of modern medicine for the last 20 years,” said Ian McConnell, emeritus professor of veterinary science at the University of Cambridge. “It has been seen as an important strategy to overcome the chronic shortage of human organs for transplantation in man.
“There are several medical procedures using pig tissues such as heart valves in cardiac surgery, insulin producing pancreatic cells to correct diabetes in man and corneal transplants which have been used safely in man for many years. The safe use of pig organs such as kidneys in xenotransplantation has been seen as an approach which could be used to overcome the shortage of donor organs in human transplantation.
“The use of human organs for transplantation only meets a small percentage of the total and growing number of individuals in desperate need of organ transplantation. It is a huge unmet need of modern medicine. But the use of animal organs such as pig kidneys and hearts is not without serious ethical and biosecurity concerns.”
In the first part of the new research – published in the journal Science – the scientists demonstrated for the first time that Pervs can make their way from pigs into humans, proving that there is a high risk for any transplant. But the second part looks at solving that, by using gene editing techniques to remove Pervs.
That risk of infection had been the primary thing that shut down plans to develop xenotransplantation, which has been a dream of scientists since at least the 1960s. Many companies shut down their work on the idea in the 2000s, fearing that the challenge of Pervs wouldn’t be overcome.
Historically, anxieties about the transmission of viruses have been significant because of diseases like HIV, said Professor Montgomery. That would mean any clinical research would require a “high degree of confidence” that such problems could be avoided, he said.
“The shortage of human organs and tissues for transplantation represents one of the most significant unmet medical needs,” the scientists write in the paper. “Xenotransplantation holds great promise.
“Porcine organs are considered favourable resources for xenotransplantation since they are similar to human organs in size and function, and can be bred in large numbers.”
The researchers behind the study said that they would be conducting more work to engineer the Perv-free pigs so that they could become even safer to potentially use in humans. The pigs grown in the lab could eventually serve as the foundation for animals that one day have their organs harvested for humans, they suggested in the conclusion to their paper.
"This is the first publication to report on Perv-free pig production,” said Luhan Yang, co-founder and chief scientific officer at biotech company eGenesis, which led the research.
"We generated a protocol to enable multiplex genome editing, eradicated all Perv activity using Crispr technology in cloneable primary porcine fibroblasts and successfully produced Perv-free piglets.
"This research represents an important advance in addressing safety concerns about cross-species viral transmission.
"Our team will further engineer the Perv-free pig strain to deliver safe and effective xenotransplantation."
But a number of obstacles remain, said Professor McConnell.
“At this stage this work provides a promising first step in the development of genetic strategies for creating strains of pigs where the risk of transmission of retroviruses in vivo organ transplantation has been eliminated,” he said.
“It remains to be seen whether these results can be translated into a fully safe strategy in organ transplantation. Even if organs from these gene-edited pigs could be safely used to overcome virus transmission there remain formidable obstacles in overcoming immunological rejection and physiological incompatibility of pig organs in humans.”
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