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Ending the Transplant Organ Shortage

Genetic engineering could save thousands of lives
Animated image organ delivery boxes on a infinite track


ccording to the federal Health Resources and Services Administration, more than 100,000 people in the United States are waiting for organ transplants, and 17 die each day. The vast majority — around 88,000 — need kidneys. Now, a research team at the Miller School may have developed a solution — transplanting donor organs from genetically modified pigs — that could shorten the wait and save countless lives.

The team leader, Alfred Tector, M.D., professor of transplant surgery in the DeWitt Daughtry Family Department of Surgery, is part of an intergenerational effort to improve organ transplants. His father, Alfred “Cy” Tector, M.D., was a pioneering heart surgeon in Wisconsin. The younger Dr. Tector has vivid memories of learning about heart transplants from his dad.

“I first got interested around 1984,” Dr. Tector said. “I used to follow my dad around the hospital where he had his transplant program. But I noticed most of the people waiting for transplants were dying.”

Dr. Tector’s father did everything he could to help his patients, including inventing new devices and being the first in Wisconsin to implant the Jarvik artificial heart. But the math wasn’t their friend — there just weren’t enough donor organs to meet the need.

However, another promising source has gone mostly untapped: mammalian organs, or xenotransplants. In 1984, “Baby Fae” received a baboon heart and survived for around a month. The technology was crude, but the possibilities were tantalizing.

Now, Dr. Tector and colleagues are poised to make xenotransplantation a reality — not with primates but with pigs. Advanced gene editing and other techniques are making these organs more acceptable to the human immune system. In the next few years, this technology has great potential to alleviate chronic organ shortages.

The Potential of Pigs

On a technical level, organ transplants have become routine. However, the lack of transplantable organs has created a severe bottleneck. Porcine xenotransplants could be the solution. Pigs grow rapidly, and their organs are quite similar to those in humans.

“The pigs we are developing could potentially be used for kidney, liver, heart, lung or pancreas transplants,” Dr. Tector said. “The challenge has been the human antibody response.”

Human antibodies bind to sugars on pig organs, leading to rapid rejection. To fix this, Dr. Tector’s team is using CRISPR-Cas gene editing to delete the offending sugars. By eliminating these antigens, the group could initially open up xenotransplantation to about 30% of waiting kidney patients.

Research Associate Professor Jose Estrada, D.V.M., Ph.D., has been working on xenotransplantation for more than 17 years. His goal is to make safe organs for human transplant, and as gene editing techniques have evolved, that job has gotten easier.

“With the first pig we produced, we used a technique called homologous recombination to edit its genome,” Dr. Estrada said. “To produce one pig with this system took between two and three years. Now, using CRISPR-Cas, we can make similar modifications in months or no more than a year. It makes a huge difference.”

CRISPR-Cas is a two-molecule system that offers a fast and relatively easy gene editing tool. First developed in 2012, the CRISPR molecule acts as a guide, leading the protein complex to the gene of interest. The Cas molecule (often Cas9) acts as molecular scissors, cutting the gene.

Advanced gene editing and other techniques are making these organs more acceptable to the human immune system.

Drs. Tector and Estrada are removing the genes that lay down antigenic sugars. Without them, the organs more closely resemble human versions. Patients will still need to take anti-rejection drugs, but their new organs likely won’t face the body’s destructive antibody response.

The group starts by editing porcine skin cell DNA. From there, the most promising cells are isolated and their nuclei removed. These nuclei, and their all-important genetic material, are then placed in egg cells and implanted. Around 114 days later, the engineered pigs emerge. The results have been quite promising.

“We have knocked out three genes responsible for human immunological rejection,” Dr. Estrada said. “We are also knocking out histocompatibility genes (SLA 1 and 2) to make the organs more tolerable in the human body.”

A Phased Approach to Human Patients

The team is continuously refining their methods. Recently, they finished developing crossmatch testing to give these xenotransplants the highest chances of success. This process alone took 10 years.

“That’s a big advantage,” Dr. Tector said. “It allows us to select the patients who have the best chance to do well, so we don’t lose people or transplant them unnecessarily when they’re not going to benefit.”

The researchers are now working with the U.S. Food and Drug Administration to rigorously test these xenotransplants before moving to human patients. Dr. Tector envisions a phased approach in which early patients are given pig organs as temporary stopgaps on the way to human transplants. In following years, the team hopes to carefully extend the time patients continue with their xenotransplants. Eventually, they will be used permanently.

While kidneys are the first step, Dr. Tector’s team is also pursuing liver xenotranplants. Pig livers pose a different biological problem than kidneys: They tend to destroy human platelets, dramatically increasing the risk of patients bleeding out. However, the researchers have identified the genes associated with this complication and are studying possible solutions.

The group hopes to engineer better tolerated organs to expand the number of patients who might benefit from xenotransplants. In the distant future, they envision an even more exciting, personalized approach: engineering animals that are precisely compatible with individual patients.

“If time allows, we could, hypothetically, produce a specific pig for each patient,” Dr. Estrada said. “It would be as closely crossmatched as we could make it. That is one of our long-term goals.”