As an MD-PhD student at Einstein, George Wu, M.D.-Ph.D. ’76, learned about a unique receptor on the surface of liver cells that brings proteins inside the cell. At the time, it was just one more fascinating aspect of the liver, an organ that, as Dr. George Wu puts it, “has so many properties and activities essential for life. There are artificial hearts and kidneys, but no artificial liver. It’s too complex.”
Flash forward nearly 40 years. Dr. George Wu, who retired in 2020 after serving as director of the Division of Gastroenterology-Hepatology and Herman Lopata Chair in Hepatitis Research at the University of Connecticut Health Center, has harnessed that same cell-surface receptor as a means of importing mitochondria, which are factories of energy, into liver cells to help them regenerate. The method could offer patients with cirrhosis, hepatitis C and other diseases an alternative to liver transplantation, or at least bridge them until a liver donor can be found. Dr. George Wu and his wife and collaborator, Catherine “Cathy” H. Wu, Ph.D., a University of Connecticut Health Center professor, have published widely on gene therapy, gene regulation, gene delivery, cell culture and transfection (artificial introduction of DNA or RNA into cells through means other than viral infection). They hold 11 patents related to this approach, including two that they’ve licensed to biotech companies. Now the Wus, who met at Einstein when Dr. Cathy Wu was a postdoctoral fellow there, are making a generous gift to the school that will endow the MD-PhD program’s directorship.
“We have a debt of gratitude that goes back to what’s really at the heart of Einstein’s program – the concept of the physician-scientist,” says Dr. George Wu. In most MD-PhD programs, he says, students tend to focus on either clinical training – to pay off loans – or on research, but not both. “But at Einstein, which had one of the earliest MD-PhD programs, the focus has always been on applying research knowledge to problems in the clinic, simultaneously training experts in both research and clinical medicine. The culture was translational before that term for the process became popular. So, we weren’t just earning degrees as either a clinician or a researcher. We were trained to fulfill both roles in a complementary combination, each discipline feeding the other.”
Right Place, Right Time
During the mid-1970s, as molecular biology was coming into its own, Einstein faculty were particularly active in exploring those synergies.
In research on the liver, Professor Irwin Arias, director of Einstein’s division of gastroenterology, was in the midst of describing the genetic defect causing neonatal jaundice and building the nation’s first multidisciplinary liver research center (the Marion Bessin Liver Research Center), which included many physician scientists. But Arias and other Einstein leaders were also keenly focused on patients.
“There were M.D.s, Ph.D.s, and M.D.-Ph.D.s of many various backgrounds working together using different approaches,” Dr. George Wu says, adding that Dr. Arias told his students and residents, “You have to understand how to apply basic knowledge to medicine and vice versa,” as he made rounds.
Other professors made the dry stuff of textbooks come alive by drawing on examples from the violent crime that dominated New York City’s headlines in those days. Professor Leslie Wolfson, in neurology, used examples of wounds to the various regions of the brain and spinal cord to illustrate how the connections affected different parts of the body.
“Drs. Sam and Ora Rosen were a wonderful duo, teaching the principles of glucose and lipid metabolism in the management of diabetes,” he says.
And still others used their pets to pique a student’s interest. The gastroenterologist Professor Irmin Sternlieb owned a Bedlington terrier, a breed with a genetic mutation that causes toxic copper overload, a condition similar to Wilson’s disease in humans.
“I stopped him one time on campus to ask, ‘what kind of dog is that?’,” Dr. Cathy Wu says. “He was only too glad to explain!”
Breaking New Ground
Still, for all the excitement at that time, it was early days in treating liver disease.
“When I entered the field, no one wanted to work on hepatitis C,” Dr. George Wu recalls. “The treatments then had only a 15 percent success rate, with intense side effects – it was like using a sledgehammer, and you had to follow patients very closely, acting like a cheerleader in addition to being a physician.”
“But through fundamental knowledge of the structures required for hepatitis C viral replication, and by using test tube and culture models, novel agents have since been developed to eliminate the virus from the blood. The success rate is now 95 percent, with virtually no side effects,” he shares.
When Drs. George and Cathy Wu met at Einstein, he was working on his Ph.D. studies with the late Professor Samuel Seifter. Her sister was a research assistant in Dr. Seifter’s lab. She brought her cat into the Seifter lab to get a free shot – a popular benefit in those days for students with pets – on a day when he was working there. It turned out their parents already knew one another, although they had not met previously. They married in 1975 while still at Einstein and even lived for a year in the old student dormitory.
The Wus initially worked together on collagen, which at that time was understood only as a component in connective tissue. Dr. George Wu was writing his doctoral thesis on its role in scar tissue formation in cirrhosis, while Dr. Cathy Wu was identifying different liver collagen types and the circumstances under which they are made.
“I knew the clinical concerns, and she knew the animal work and how to create protocols,” Dr. George Wu says. “We’re a good team, but her rule has always been, ‘Don’t talk science at home.’ I do anyway, but she ignores me.”
In 1983, the Wus moved to the University of Connecticut Health Center and, drawing on their understanding of how scarring and other damage occurs, switched their focus to the repair of liver cells via targeted delivery of different substances. They developed and patented a method for importing small molecules that would protect cells against the toxicity of chemotherapy in liver cancer, though the technique hasn’t been used because most chemotherapies are toxic to cells in multiple organs.
Subsequently they were able to deliver genes and DNA to cells in culture and in animal models, but the resulting expression of new genes lasted only for short periods.
Finally, about five years ago, they hit on the idea of transplanting coated mitochondria to liver cells. Mitochondria are organelles that convert glucose into the energy cells need to survive. The Wus’ strategy was to coat the mitochondria with the protein recognized by receptors on the surface of liver cells.
“Potentially, transplanted mitochondria could replicate themselves, which would enable them to repair damaged cells,” Dr. George Wu explains. “And in theory that would make unnecessary multiple exposures, reducing the chance of autoimmune issues in patients.”
The Wus have since demonstrated the feasibility of that approach – the first-ever instance of targeted delivery of coated mitochondria to the liver in animals – prompting Mitrix Bio Inc. to license the method and retain Dr. George Wu as a consultant.
“We’re still far from having a product,” Dr. George Wu cautions. “We need to do more with toxicology and immune reaction studies. But hopefully we can develop a treatment for acute liver failure – that is, for people who, because of viruses or drug overdoses, have been left without enough liver to survive. Down the road, we could potentially adapt our method to other cells types, organs and disorders. For example, if we could introduce mitochondria into muscle cells, we might be able to use the technology to treat damaged hearts or skeletal muscle tissue.”
Building on Einstein’s Legacy
Of course, the Wus would love to see Mitrix Bio, Inc. succeed – “we don’t have another 50 years,” Dr. Cathy Wu says – but they are equally anxious for their work to serve as an important building block for further important advances. That’s clearly part of their thinking in making their gift to Einstein’s MD-PhD program, where, in one additional twist to their story, their personal connection has roots that go beyond their student days.
In 1989, a patient at Einstein named Herman Lopata – the inventor of the holograms that prevent credit card fraud – was dying of liver failure from hepatitis B. He stipulated in his will for endowed chairs to be given to liver experts at three institutions, to be identified by national searches. One chair went to a researcher at Einstein; another to a researcher at Fox-Chase Cancer Center in Philadelphia; and the third went to Dr. George Wu at the University of Connecticut.
“The chair has been a huge help to our work,” Dr. George Wu says. “The funds don’t go to my salary, which is paid for by grants, but instead to research. In effect, I had a mini-grant each year that I had discretion over. That’s enabled us to pursue the work on mitochondria and hire post-docs if NIH funding lapsed.”
The Wus’ gift honors Herman Lopata and, even more broadly, speaks to the sense of community at Einstein that his generosity typifies. Over the years, Drs. George and Cathy Wu have built a global network of former Einstein classmates, post-docs and students. Those connections have enabled them to travel to Egypt on Dr. George Wu’s recent Fulbright Scholar award; recruit editorial board members for peer-reviewed journals; train the children of ex-colleagues; and attend a Croatian wedding of a recent former Ph.D. candidate.
“It’s like a family,” Dr. George Wu says.
“That’s what Einstein is, and that’s what we learned there,” Dr. Cathy Wu adds. “We all work together, and we all help each other – even now, when we don’t see each other much anymore.” – Joe Levine
