Distinguished Investigator

A conversation with Mayo Clinic's Gregory Gores, M.D.

Gregory Gores, M.D.

Liver disease no more: Research that translates into new treatments for patients

ROCHESTER, Minn. — It's been almost seven years since Bil Musgrave, a 53–year–old man from Chandler, Indiana, received a cancer diagnosis. It was bile duct cancer, a deadly diagnosis that usually claims the lives of its victims soon after diagnosis.

Giving up is not in Mr. Musgrave's nature, so he turned to Google where he found a news release about new research findings by Gregory Gores, M.D., a gastroenterologist at Mayo Clinic in Rochester. It was a live–saving move because that news release led Mr. Musgrave to Dr. Gores, a physician he credits with saving his life. Mr. Musgrave created a Web site detailing his experience with cancer at www.bileductcancer.org.

Dr. Gores, an expert in liver cancer and liver injury, was named a Distinguished Investigator for Rochester in 2008 in recognition of his body of work. On receiving Mayo's highest honor for its investigators, Dr. Gores said: "It is really a tremendous honor to be recognized as someone who has contributed to the institution in such an important way. In a way, this marks the pinnacle of my Mayo career, at least, to date. I hopefully will continue to earn the award over time by furthering my research."

The Centers for Disease Control and Prevention says that approximately 27,530 people die each year from chronic liver disease. About 17,000 Americans are currently waiting for liver transplants, but only about 38 percent of those will receive a new liver.

Dr. Gores began his gastroenterology research at Mayo Clinic in 1983 when he was accepted into the gastroenterology research training program under Nicholas F. LaRusso, M.D., and Laurence Miller, M.D., now deputy director for research in Arizona.

During his interview for the research training program, Dr. Gores met with Dr. LaRusso, who admittedly was not impressed. He couldn't have known it then, but 25 years later Dr. LaRusso would nominate Dr. Gores for 2008 Distinguished Investigator.

"Over the years, Greg has made a remarkable number of significant contributions in the areas of basic research, patient–oriented research and disease–oriented research. He has achieved world–wide recognition in his field for his work," Dr. LaRusso wrote in his nominating letter.

Dr. Gores was raised on the Fort Berthold Indian Reservation in North Dakota. He was a good student, so his father suggested he pursue a career in medicine — he agreed and never strayed from that path. In medicine, Dr. Gores found that he was fascinated by the science of liver injury.

Q. Why did you decide to specialize in liver diseases?

A. I had a lot of difficulty determining what specialty I would pursue. It was Dr. Rollie Dickson who encouraged me to go into GI, but I had already been accepted into the cardiology program at the University of Wisconsin. I declined and took a gamble that I would somehow get into the GI training program at Mayo where I could pursue research. I was fascinated by the science of liver disease and always wanted to work on liver injury.

Q. After completing the training program at Mayo, you went to the University of North Carolina where you delved deep into research. Why was North Carolina a draw?

A. When I started my research back in 1983–85, we didn't know much about liver injury. Cell death, per se, was a topic only investigated by a small group of pathologists. It wasn't on the radar screen, but I ended up joining a group in Chapel Hill (North Carolina) who were studying cell death. They had special imaging technology called single cell fluorescent microscopy. With this technology we could quantify changes in calcium and pH levels in cells, which we suspected were wreaking cellular havoc.

Q. In the 1980s, with the advent of cyclosporine, livers were transplanted into patients with greater success than ever before. Cyclosporine gave rise to the first true clinical application of liver transplantation. This changed the course of liver transplantation forever with more patients living longer. What contributions did you make in this area?

A. I returned to Mayo in 1988, which was three years after Mayo started a liver transplant program. I was the second fellow to rotate onto the liver transplant program. In those days, organ preservation was very precarious. Livers were stored in a solution on ice and it was a gamble that it would survive well enough to be put it back into a patient. It was a big concern in the transplant community. The timing was good for me because as a fellow I could focus on improved preservation of livers for transplantation.

Q. In the meantime, scientists were learning more about cell death, also known as apoptosis, and soon after, you made one of the most important discoveries of your career.

A. Yes, I very quickly started to learn that these toxic compounds in bile, called bile acids, actually induced apoptosis (cell death). We were one of the first to show that bile acids caused apoptosis. We were subsequently able to show the mechanisms by which they do that, one being the stimulation of death receptors on the surface of the cell. This was the first of our significant achievements.

Q. Then, one year later in 2000, you published findings that sparked a surge of interest in research in this area.

A. In a series of experiments, we identified a lysosomal disruption as a key pathway in apoptosis. The research is important because it identifies a new organelle (a subunit of cells called the lysosome) and a new protease (enzyme) contributing to cell death pathways. Understanding how the lysosomal pathway works is an important part of understanding apoptosis.

Q. In your research, you're not quite trying to evade apoptosis, but in fact you are trying to strike a healthy balance of cells on the surface of the liver to protect the liver. How does this work?

A. We focus on how receptors on the cell surface induce liver damage. It's very intriguing. Receptor initiated events get rid of cells, but if it is exaggerated, it causes tissue damage. The problem is that the receptors are there to get rid of unwanted and damaged cells, such as cancer cells. If it is over–accentuated, it can cause liver damage. These pro–death pathways can become over–stimulated by bile acids, cholestasis (a condition in which little or no bile is secreted from the liver), by the immune system or by fat. So, while the cell death process (apoptosis) drives liver injury and scarring, the liver responds by trying to evade the damage by evading apoptosis, which can drive cancer. The concept is straightforward: too much apoptosis will lead to liver injury and too little will drive a cell to carcinogenesis.

Q. More recently you've delved into studying the effects of metabolic syndrome on the liver — in other words, how fatty acids can damage the liver. What have you discovered so far?

A. This work could lead to new treatments for fatty liver disease. We published our first work in this area in 2006 in which we show that fatty acids induce apoptosis in hepatocytes — the most dominant liver cell subtype in the liver. If we can identify new pathways by which the liver is damaged by the metabolic syndrome (a combination of medical conditions such as cardiovascular disease and diabetes), our research could point to the need for a different therapeutic approach. There are currently few treatments, but there are some drugs under study that block cell death as a mechanism to treat fatty liver disease. It's a different strategy than treating insulin resistance.

Q. You seem to have an interest in exploring complex, rare diseases, in particular bile duct cancer. Why is this?

A. In the late 1990s, Dr. LaRusso encouraged me to begin work in bile duct cancer because no one was really doing much work in the area and it was very important to some of the patients we saw at Mayo Clinic with primary sclerosing cholangitis, of which about 10 percent get bile duct cancer. At the same time Frank Prendergast, M.D., Ph.D., who was director of the Cancer Center, provided us resources to work in the area. I developed a transplant protocol with radiation oncology to look at the transplantation of these patients. Then, Scott Kaufmann, M.D., Ph.D., a cancer biologist who studies ways to induce cell death of cancer cells, was recruited to Mayo Clinic. I knew a lot about cell death as a damage mechanism and by working together, we've been able to focus on cancer biology to eventually improve patient care.

Q. What's next in your career?

A. I'll continue to see patients to determine their eligibility for transplantation, but now, in terms of research, I would really like to define how fatty acids in the metabolic syndrome injure the liver, and continue to define new therapies, concepts and pathways for that disease and bile duct cancer.

— Reprinted with permission from Inside Mayo Clinic Research