USC surgeon-scientist Linda Sher receives $2.7 million CIRM grant to develop and test immunologically modified and humanized swine livers

Linda Sher (Photo courtesy of Linda Sher)

In 1992, Linda Sher was part of a surgical team at Cedars-Sinai that transplanted a pig liver into a human patient for the first time in the history of medicine. The pig liver kept the patient alive for 36 hours—long enough for a human donor organ to become available, but not long enough for the surgical team to transplant it. Now, over three decades later, Sher is collaborating with Renovate Biosciences to develop a new source of organs for replacement of function and transplantation by growing human livers in pigs, supported by a $2.7 million grant from the California Institute for Regenerative Medicine (CIRM), the voter-created state agency that dispenses public funding for stem cell research.

“Given the severe organ shortage crisis, this research is important,” said Sher, who is a Professor of Clinical Surgery in the Division of Abdominal Organ Transplantation and HPB Surgery, and Chief of the Division of Clinical Research in the Department of Surgery at the Keck School of Medicine of USC. “We really need new strategies to be able to provide a timely transplant for our patients.”

Sher grew up in Brooklyn, the daughter of Jewish immigrants who were forced to flee Poland for Russia during World War II. After the war, her parents moved to Berlin, where her two older brothers were born. She is the first child in her family to be born in the U.S., where her father worked as a jeweler and her mother as a seamstress. Sher recalls that “my mother had the greatest hands, and she was very talented.”

While Sher attributes her surgeon’s hands to her mother, she traces her passion for liver transplant to famed surgeon Thomas Starzl. While still a student in New York City at the Mount Sinai School of Medicine (now the Icahn School of Medicine at Mount Sinai), she spent a few months in 1979 working in a hospital in Israel, and attended a meeting in Jerusalem where she heard a talk by Starzl, who had performed the world’s first liver transplant.

“He was one of a kind,” said Sher. “He could inspire a whole room. And I was just enamored. I knew in ‘79 that when I finished my residency, that somehow, somewhere, I was going to go work with him.”

During her residency at Mount Sinai, she spent a year doing kidney transplantation and loved it. Then she and her husband, a financial consultant, packed up their car and moved to Pennsylvania so that she could pursue a fellowship with Starzl at the University of Pittsburgh.

“It was like Camelot in Pittsburgh,” she said. “It was like he was King Arthur, and everybody came to the table—not just from the States, from all over the world. That was the biggest training ground and resulted in the dissemination of liver transplant throughout the world.”

As a fellow, she worked until a week before her daughter’s birth, and returned to the operating room 10 days after delivering her child.

“Dr. Starzl sent me on a trip on an airplane from Pittsburgh to Oregon when I was eight months and three weeks pregnant,” she said. “The times were such that I wasn’t going to say no. And when I couldn’t breathe on the airplane, they had to lower the altitude. I got to Oregon, and I got the liver out to bring back. But after that, no one would fly with me for fear that they would have to deliver the baby! It was a different world for women surgeons then, and I am happy to see it is so much better, because it’s nice to see my younger female colleagues able to better balance all the different priorities in life. And for my daughter and for my daughter’s daughter, they will have more opportunities and lifestyle choices.”

In 1988, Sher, along with several colleagues from Pittsburgh, moved to Los Angeles to join Cedars-Sinai Medical Center and start the liver transplant program. During that time, she became involved in clinical research after being encouraged by her mentor and Department Chair, Leonard Makowka, who had also trained with Starzl.

In 2001, she joined R. Rick Selby’s transplant team at USC, and since that time, has assumed the position of Professor of Clinical Surgery and Chief of the Division of Clinical Research in the Department of Surgery. Her division oversees approximately 50 clinical research studies involving surgical devices, new drugs and new treatment strategies for various surgical patients. She has also collaborated with USC scientist Keigo Machida on stem cell research projects studying alcoholic liver disease using a mouse model with a humanized liver.

The CIRM-funded project marks an entirely new direction for Sher. The opportunity arose when Makowka introduced her to a group of scientists at Renovate Biosciences who are working on the development of an immunologically modified pig with a humanized liver. Sher was brought on to test the liver at USC using a perfusion device to evaluate for rejection and ability to produce human proteins. The chair of USC’s Department of Surgery, Vaughn Starnes, encouraged her to apply for funding from CIRM to cover the work at USC.

“I wrote this major grant application over the course of almost two months,” she said. “I had a lot of help from collaborators including Drs. Barr, Kahn, Genyk, Etesami, Chopra, Akbari and Machida. It truly was a collaborative effort that resulted in the award of the grant. In addition, my research manager, Christian Romero, who has worked with me for the past 20 years, has worked closely with me to conduct the ex vivo perfusions.”

In the study, Renovate will prepare the immunologically modified pigs with humanized livers. At USC, the livers will be placed on an external device and pumped with human blood, oxygen and nutrition. The team will then assess if these livers can avoid immune rejection and perform key metabolic functions, such as producing human proteins and controlling metabolism.

“This is a three-year project,” said Sher. “At the end of the three years, I will have had a 47-year career in medicine, and I will be doing what I meant to start doing a little earlier. I will be traveling. I will be caring for my granddaughter, and I will spend more time with my husband, my family and my close friends. And I am going to enjoy the next chapter of my life.”

Mentioned in this article: Keigo Machida, PhD