Researchers have used the gene-editing technique CRISPR to modify the genome of pigs in order to eliminate genes that code for a family of viruses that could infect humans. We wouldn’t get the viruses from eating pork; no, researchers are looking into this because we could someday grow pig organs to be transplanted into humans. Now that they’ve nixed the viruses successfully, we’re one step closer to inter-species transplantation.
In the US and beyond, we have lots of people who need organs, but not enough available organs to satisfy that need. The American Transplant Association estimates that 120,000 people are waiting for organs, and 22 people die every day on the waiting list. So researchers have been coming up with strategies to close that gap, ranging from the feasible with the technology and public health resources we have now, to the seemingly far-fetched.
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One of those seemingly ridiculous ideas is xenotransplantation—transplanting tissues or organs from another animal into humans. Researchers tried it, unsuccessfully, in the early 1900s. With the advent of more sophisticated genetic modification tools in the 1990s, scientists revisited it again. Now, with CRISPR, xenotransplantation seems even closer to researchers’ grasp.
A major hurdle has seemed to be Porcine Endogenous Retroviruses (PERVs). All mammalian species (including humans) have small snips of viral DNA embedded in their genetic code and researchers feared that if pig tissues were implanted in humans, the viruses lurking in pig DNA could infect human cells. Though lab-based tests suggest this could happen, scientists have never really been sure.
In the study, published Thursday in the journal Science, a team of researchers led by scientists from eGenesis Inc, a biotech company dedicated to using CRISPR to solve the human organ shortage, conducted some preliminary tests to better understand how PERVs could affect human cells.
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“We came to the field without any bias. It’s debatable whether PERVs are a hypothetical or real safety concern,” Luhan Yang, co-founder and chief scientific officer at eGenesis and one of the study authors, tells Tonic. “We believe what we see—is there infection? How severe is the problem?”
They found that not only could pig cells infect human cells with PERVs in a petri dish, but that human cells infected with PERVs could infect other human cells that had never touched pig cells. Not good.
Having established that PERVs could plausibly pose a risk to humans, Yang and her team set about to get rid of them. They used genetic sequencing to identify 25 genes that contained PERVs, then used CRISPR to deactivate them. After tweaking the process a bit and adding some factors to help the DNA repair itself, the researchers were able to edit out the virus snippets with 100 percent efficiency.
But could animals survive with their DNA so drastically altered? To find out, the researchers transferred the altered genetic code into pig embryos, a number of which they implanted in surrogate sows. There were 37 PERV-inactivated piglets born; 15 are still alive and the oldest are four months old.
The resulting pigs are the most genome-modified animals on Earth, Yang says. And though PERVs don’t seem to serve any biological purpose, this is the first time scientists are seeing animals without them, so the researchers have to keep studying the pigs to understand what happens to them as they age.
To Jeffrey Platt, a professor of surgery, microbiology, and immunology at the University of Michigan, it’s not totally clear that PERVs would in fact present a threat to human health. “As for the problem [of PERVs], it’s unproved,” says Platt, who was not involved in the research. “If someone was skeptical, they might say they solved a problem that they don’t know is a problem.”
Ultimately, though, he thinks the study is well done and useful on a technical level. “Having more experience with targeting and modifying specific parts of the genetic material of the pig will lower the threshold to being able to, say, engineer a pig that will provide better organs or cells for people to use for medical purposes.”
Yang says she envisions the technique developed by her team being used for other medical applications like modifying T cells to fight cancer.
Scientists still have some issues to address before xenotransplantation can move to the real world; namely, both Platt and Yang agree that the human immune response to a pig organ is one of the biggest hurdles. Even the current techniques we have to suppress the immune system, such as immunosuppressant drugs that a transplant recipient typically takes, won’t be strong enough to preserve a pig organ in the human body.
“The vulnerability of the pig organ to the human immune system, and the interaction between those two, poses the biggest hurdle today,” Platt says. Yang’s team is addressing this issue and is currently working on parallel experiments; the researchers hope to publish a paper on that work later this year.
To continue editing mammalian DNA on a large scale, Yang says we’d probably need more advanced versions of CRISPR that can insert longer bits of genetic code with greater specificity. “CRISPR is great at knocking out genes. But when it comes to knocking in a specific gene, its capacity is limited,” she says.
Regulatory agencies, too, can be a roadblock, though Platt suspects regulators would be heartened by the ability to eliminate these viruses. “Knowing there is a potential solution to PERVs, if it’s a problem that needs to be solved, is great from the perspective of regulation of this field,” he says.
Neither Platt nor Yang was willing to speculate on when xenotransplantation may first be tried in the clinic. There are issues that they haven’t yet foreseen, and procedures have to become more developed before human subjects can get involved. “It’s still early days. That’s how we see it. It would be irresponsible for me to provide a timeline at this stage,” Yang says.
Progress, Platt notes, ebbs and flows. “I don’t think it’s a particularly long road [to the clinic]. We’re perceptibly closer to the end than when I started.”
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