The baby baboon is wearing a mesh smock and appears to be sitting upright. “This little lady… looks pretty philosophical, I’d say,” says Eli Katz, who shows the animal photo via a Zoom call. The little baboon is the first to receive a heart transplant from a young gene-edited pig says the chief medical officer of biotech company eGenesis, and the study aims to pave the way for similar transplants in human babies.
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The Cambridge, Massachusetts-based company has developed a technique that uses the CRISPR gene-editing tool to make around 70 changes to a pig’s genome. These changes should allow the organs to be successfully transplanted into humans, the team says. eGenesis hopes to transplant pig hearts into babies with severe heart defects as early as next year. The goal is to give them more time while they wait for a human donor heart.
Before this can happen, the eGenesis team wants to practice on twelve baby baboon. So far, two operations of this type have been carried out. While none of the animals survived more than a few days, the company, along with other players in the space, is still optimistic. Many recipients of the first liver transplants would not have survived then either, but thousands of people have benefited from such transplants since then, says Robert Montgomery. Babies with congenital heart defects are “a very good population to focus on,” he says, “because so many of them [sonst] die”.
Editing risk
In the United States alone, more than 100,000 people are waiting for an organ transplant. About 17 of them die every day. Researchers are investigating several saving avenues, such as bioprinting organs and growing new organs in people’s bodies. Animal organ transplantation is another potential alternative to meet the need.
The idea of using organs and tissues from animals, known as xenotransplantation, is not new. The first attempts were made as early as the 17th century. There were newer attempts in the 1960s and again in the 1990s. Many experiments used organs from monkeys and baboons. But by the early 1990s, the consensus was that pigs are the best donor candidates, says Montgomery.
Primates are precious because they are intelligent animals that experience complex emotions. Only a small number may be used for human research, and they are slow to reproduce anyway. Also, they are more likely to transmit harmful viruses. Much is known about the rearing and husbandry of pigs, and their organs are about the right size for humans.
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However, organ transplantation between animals of different species is not entirely straightforward. Even organs from another person can be rejected by the recipient’s immune system. Animal tissue contains many more components that our immune system considers “foreign”. This can also lead to the organ being attacked by immune cells. There is also a chance that a virus could be transmitted with the organ. Even if a donor animal is not infected, it has what is known as “endogenous retroviruses” – genetic code for ancient viruses that were built into its DNA a long time ago.
These viruses do not cause any problems in their animal hosts. But in other species, they could eventually trigger an infection. “There is a risk that viruses that are endemic to animals will evolve and become deadly in humans,” says Chris Gyngell, a bioethicist at the Murdoch Children’s Research Institute in Melbourne, Australia.
70 gene edits
This is exactly the risk the eGenesis team wants to counter with CRISPR. “You can use CRISPR-Cas9 to inactivate the 50 to 70 copies of the retrovirus in the genome,” said Mike Curtis, President and CEO of eGenesis. The changes prevented retroviruses from replicating, he says.
The company also used further gene editing to switch off some pig genes whose protein products trigger harmful immune responses in humans. Finally, it added seven human genes that it believes make the organ less likely to be rejected by the recipient’s immune system. Overall “we produce [Organ-]donors with over 70 edits,” says Curtis.
The eGenesis team carries out these edits on so-called pig fibroblasts. These are cells found in connective tissue. It then removes the cell nuclei containing DNA from the processed cells and inserts them into pig egg cells. After their fertilization with sperm, the resulting embryo is placed in the uterus of an adult pig. Finally, the cloned piglets are delivered by caesarean section. “It’s the same technology that was used to clone Dolly in the 1990s,” says Curtis, referring to the famous sheep, which was the first animal to be cloned from an adult cell.
eGenesis has approximately 400 cloned pigs housed at a research facility in the American Midwest. It does not want to reveal the exact location because the facilities have already been the target of animal welfare protests. Early last year, the company set up a “clean” facility to manufacture human-sized organs. Anyone entering them must shower and wear protective clothing to avoid bringing germs that could infect the pigs. The 200 pigs currently at the center live in groups of 15 to 25, Curtis says, “It’s basically like a very clean house. We control all the feed that comes in and we have waste control and an airflow control. There is no mud.”
The pigs whose organs are not used are closely examined, Curtis says. The company needs to understand how the many genetic changes it makes affect an animal throughout its life. The team also wants to know if human genes continue to be transcribed over time. Some of the pigs are over four years old, Curtis says. “Things are looking good so far,” he concludes.
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