Reengineering Life

A Startup Is Making Thousands of Gene-Edited Pigs Because Humans Need Their Organs

Scientists are using CRISPR to address the global organ shortage

Photo illustration source: Damien Meyer/Getty Images

Reengineering Life is a series from Future Human about the astonishing ways genetic technology is changing humanity and the world around us.

More than 109,000 people are currently waiting to get a donor organ in the United States. Last year, however, only 39,718 total transplants were performed. Thousands of people will die before they can get the lifesaving transplants they need.

To meet this need, some researchers are attempting to genetically engineer pigs to make their organs suitable for people. Previous efforts to transplant whole animal organs into people have failed, but the gene-editing tool CRISPR could bring the idea closer to reality.

Pig organs aren’t naturally compatible with human bodies. To make them a better fit, scientists at a Chinese biotech startup co-founded by Harvard genetics pioneer George Church, PhD, have used CRISPR to make 42 simultaneous modifications across 13 genes in pigs. The company, Qihan Biotech, has been experimenting with different edits since its formation in 2017. This latest version, which it dubs “pig 3.0,” is the most extensively edited yet.

The edits are meant to prevent immune rejection, blood clotting, bleeding, and infection in transplant recipients. The idea is to trick a person’s immune system into recognizing a transplanted pig organ as a human one. The company reported its results in the journal Natural Biomedical Engineering on September 21.

“This is a tour de force,” Jay Fishman, MD, associate director of the transplant program at Massachusetts General Hospital, who was not involved in the study, told Future Human. “We have a shortage of organs for transplantation. We now have the tools to manipulate animal organs in ways to try to make these organs work.”

Given their similar organ size and function to humans, pigs have long been seen as a promising source for human organ transplants. But there are two major hurdles to putting pig organs into people: rapid immune rejection and the possibility of infection.

Pig cells have molecules on their surface called antigens that look foreign to the human immune system. As a result, any pig organ transplanted into a person would trigger a severe immune response, leading to swift rejection. Pig heart valves have been routinely transplanted into people for decades, but the pig tissue is “fixed” using chemicals so that the cells are no longer alive.

Last year, doctors overcame this immune issue when they transplanted genetically engineered pig skin onto a human burn victim for the first time. The pigs were specially bred to prevent their skin from being rejected. Though the pig skin grafts are meant to be temporary and are eventually replaced with skin from a person’s own body, they’re seen as a key step toward human clinical trials that use whole pig organs.

Another potential hurdle for pig-to-human organ transplants is the fact that pigs harbor a family of innate viruses in their DNA known as porcine endogenous retroviruses, or PERVs. These viruses could be passed to a person during a transplant, but their risk to humans is still unclear.

In 2017, Church and others, including Luhan Yang, PhD, who worked in Church’s lab, reported the first CRISPR’d pig prototype: a PERV-free pig. The second version, pig 2.0, had immune system edits. Pig 3.0 combines all these edits.

“They are pretty healthy,” Yang, now CEO of Qihan Biotech, told Future Human in an interview. “So far, they look normal in terms of their physiology, fertility, and reproduction capability.” According to blood tests, the edited pigs’ livers, hearts, and kidneys are functioning normally.

The company, which is based in Hangzhou, has produced about 2,000 of the 3.0 pigs in China. Some have been allowed to mate, and the resulting offspring also carry the same genetic modifications as their parents.

The question now is whether these modifications actually make the pig organs more suitable for human transplant. “The leap of faith that we’re supposed to make is that these now will produce organs that are functional in humans,” Fishman says. “But we don’t know that yet.”

Before the edited pig organs can be used in people, they must first be tested in monkeys, humans’ close relatives. Qihan Biotech has carried out “dozens” of pig-to-monkey organ transplants, Yang says. The company is focusing on the kidney, because the need is so great, but is also carrying out multi-organ transplants to study how other pig organs fare in monkeys. The latest edits have resulted in less severe immune reactions in monkeys compared to the company’s previous pig prototypes, according to Yang. She declined to say how long the transplanted monkeys have survived.

In 2016, researchers at the U.S. National Institutes of Health announced they were able to keep a pig heart alive in a baboon alive for more than two years — breaking all previous records.

Yang and Church are also co-founders of eGenesis, Qihan Biotech’s partner company in Boston, which has produced more than 100 edited pigs, according to MIT Technology Review. But research on monkeys is expensive and controversial in the United States, and Chinese regulations are friendlier to research on nonhuman primates.

Fishman says the fact that the pigs seem healthy and fertile and have normal-sized litters is a good sign that the genetic manipulations didn’t harm the pigs. But CRISPR isn’t perfect: One of its well-known side effects is that it can make so-called “off-target” edits — unintended edits to other places in the genome. Some of these small DNA changes are probably harmless, but others could have health consequences.

When Yang and her team used genome sequencing to look for off-target effects in the edited pigs, they found several unintended insertions and deletions. These inadvertent edits occurred in “noncoding” genes — those that don’t provide instructions for making proteins the body needs. Scientists once dismissed this part of the genome as “junk DNA” but are now realizing that these regions may have important functions.

Muhammad Mohiuddin, MD, director of the cardiac xenotransplantation program at the University of Maryland School of Medicine, who was not involved with the work, tells Future Human that extensive gene modifications could lead to abnormalities in the animals’ organs.

He also says it’s possible that different genetic modifications will be needed for different organs. “We should be careful to avoid altering more genes than those that are absolutely necessary to avoid unknown risks.”

Former staff writer at Medium, where I covered biotech, genetics, and Covid-19 for OneZero, Future Human, Elemental, and the Coronavirus Blog.

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