ON MARCH 15th 2024, a dark brown, gene-edited pig was driven from its home in the Midwest to a medical facility on the outskirts of Boston, Massachusetts. It had never before been outside the clean room in which it had spent its year-long life. The next day the pig had its kidneys removed. One was for research; the other was transplanted into a man called Richard Slayman. It was the first pig-to-human kidney transplant with a living patient. In the operating theatre at Mass General Hospital, after the surgical team were finished, invited attendees spontaneously clapped.
Xenotransplantation has been a dream for decades; now six people in America, so sick they were granted special permission, have received kidneys and hearts from pigs carefully crafted for their role as organ donors: a few porcine genes had been switched off, and several human genes added, to avoid the human body rejecting the organs. Only the two most recent recipients are still living; owing to their dire condition the first four, including Slayman, died within months. But clinical trials with healthier recipients are set to start this year. With more than 100,000 Americans waiting on a new organ, xenotransplantation is a leading example of how editing animals could benefit human society. But it is far from the only one.
It makes sense that the agriculture industry would toy with gene-edited animals; it is long-held practice to breed livestock that grow better and faster. CRISPR editing follows the same path. Japanese regulators have approved several CRISPRed fish; in America the Food and Drug Administration (FDA) has given the nod to cattle that grow better in hot temperatures. But many scientists are focused more on improving health than increasing meat. Beyond giving people new organs, gene-edited animals could prevent the spread of diseases and possibly eradicate some of them.
This work is well under way for animal infections, probably because there is an obvious market for hardier livestock breeds. In 2023 Recombinetics, a gene-editing company in Minnesota, created a calf in a lab in Iowa which had been edited for protection against bovine diarrhoea virus, a pathogen dangerous to cows (and costly to farmers). Then in 2024 Genus, a genetics company outside London, established a line of gene-edited pigs immune to a virus sometimes referred to as “pig AIDS”, which is responsible for as much as $1.2bn per year in production losses in America.
Animals can also be edited to protect humans. Take bird flu, a virus with obvious pandemic potential. If the spread in poultry could be stopped, it would limit human exposure and give the virus fewer opportunities to mutate. In 2023 Helen Sang, a biologist at the Roslin Institute in Scotland, used CRISPR in an attempt to edit protection against bird flu into chickens.
Fowl play
To replicate in a host cell, bird flu hijacks a protein belonging to a family of three, where the two other proteins are inactive. Switching off the gene responsible for making that protein should give the chickens immunity. That is exactly what Dr Sang’s team did.
But things did not go quite to plan. Although the chickens seemed protected at first, the virus quickly mutated so that it could exploit the other proteins that had previously been useless to it. In the end, the team had to knock out all three genes to shut down infection, and it is unclear if the chickens can thrive when thus diminished. It was a lesson to scientists, says Dr Sang, to be careful about entering an arms race with a pathogen that humans might lose.
Scientists are thus trying to make sure that they win. Parts of New England are blighted by Lyme disease, a bacterial infection. People contract it from ticks that pick it up from white-footed mice. Kevin Esvelt, a bioengineer at MIT, has long wanted to release (initially on an uninhabited island) edited mice which cannot carry Lyme, and so lower the risk to humans. But it is not straightforward to prevent the Lyme bacterium from developing resistance.
Be careful about entering an arms race with a pathogen
Dr Esvelt begins by exposing mice to a protein from the bacterium’s surface—think something like the coronavirus’s spike protein. He waits for them to produce antibodies against it, then edits a new generation of mice to produce those antibodies from birth. He has previously edited one kind of antibody into normal lab mice, and says he has figured out how to edit white-footed mice, too. But he needs to edit in multiple antibodies to insure against resistance long-term. “To resist, [the Lyme disease bacterium] would need to acquire, presumably, at least four separate mutations all at once,” he says. “Which, by my calculations, is pretty unlikely to occur for at least 100 years.”
While compelling, his approach is limited to smaller animal populations. To be effective the immune animals must largely replace the original population. That simply cannot be achieved if the original population amounts to millions and millions of individuals—as is the case with the malaria mosquito.
Malaria tops the list of infectious diseases that scientists want to get rid of. It infects more than 250m annually around the world and in 2023 killed 600,000. It is caused by a parasite carried by the Anopheles mosquito. Even if scientists edited and released tens of thousands of such mosquitoes, it would hardly make a dent in the global population, says Alekos Simoni from Target Malaria, a research non-profit group with headquarters at Imperial College London.
Instead some scientists are working on another weapon, something called a gene drive: a bit of DNA that propagates through the generations at higher-than-normal rates. The idea goes back decades but the advent of CRISPR made it seem much more doable. To make a gene drive, scientists put the desired edit—say, one that makes offspring infertile—into a gene, alongside the code for CRISPR itself. Animals have two copies of each gene and when they reproduce, their offspring gets one of them. If only one copy is edited, there is an even chance the edit is passed on. But if CRISPR is installed next to the edit, it copies itself to the other gene copy right away. When the organism reproduces, the edit (and the CRISPR) is then certain to be passed on. Within just a few generations, the majority of individuals in a population will carry it.
There are two sorts of malaria drives: one that makes mosquitoes immune to the parasite and one that makes second-generation mosquitoes infertile, something which, in lab experiments, can sink a population (see chart). Target Malaria has bet on the latter kind. The former is the focus of Transmission Zero, a programme also run out of Imperial College London.
Activists have repeatedly called for a United Nations moratorium on gene drives (so far unsuccessfully). The most obvious concern is unintended effects on the ecosystem, such as the drive accidentally spreading to other populations. Though researchers try hard to minimise ecological harms, ultimately the consequences will not be known until the edited animals are released. The issue of resistance (in the mosquito or the pathogen, depending on the drive) remains, too. That means organisations may have to put in multiple drive edits at once or build an arsenal of back-up drives. Target Malaria postponed field trials, initially expected in 2026, to prepare for exactly this. Dr Simoni now expects trials to start within five years.
Some pigs are more equal than others
If any of the anti-malaria gene drives get off the ground, it will be the biggest gene-editing intervention in animals so far. But the most complex sort, outside of custom-made lab animals, will probably remain the organ-donor pigs. Donor pigs from the xenotransplantation company Revivicor, which is behind the first xenotransplantation trial, receive about ten edits all in all. eGenesis, the company behind Slayman’s transplant, has gone further. Its co-founder George Church, a biologist at Harvard University best known for wanting to edit elephants into mammoths, believes the pig organs can be made immune to viruses. Already he has removed a kind of virus built into the pig genome (which may or may not pose a threat to humans) with a whopping 59 additional edits. In future he is hoping to build in even more protection.
Judging by the sum of those ambitions, animal editing will find wider use—first in agriculture, then in medicine, then possibly in the wild. Genus expects their virus-resistant pigs to gain approval from the FDA this year and hit the market in 2026. eGenesis hopes to start its own pig-organ trial. But elsewhere producers of gene-edited animals will have to wait. In England market approval for edited plants is expected to be streamlined from this year under the Precision Breeding Act—but not yet for animals. That cheers some who worry the technology could be misused, for example by propping up factory farms, on which resistant animals might be used as an excuse not to improve conditions. Scientists are even discussing whether to edit livestock animals to feel less pain. Many more uncomfortable questions will no doubt spring up. ■