Every day, billions of your cells receive signals that induce them to commit suicide. This form of cell death, which scientists call apoptosis, is a controlled, normal process that rids the body of old, diseased and malfunctioning cells. However, when unhealthy conditions surrounding the cell cause abnormal signaling and also induce apoptosis, it aggravates disease and contributes to organ failure.

"Apoptosis emerged as a key mechanism of cell death around the time I was setting up my lab about 20 years ago," says Dr. Gores who, at that time, had just returned from specialized training at another institution. He was sent by Mayo Clinic under a scholarship for promising physician scientists. "For two years I did nothing but study and image cells and think about how they die. I came back with ideas that were relevant to organ preservation for the liver transplant program."

Dr. Gores has been involved with the Mayo Clinic Liver Transplant Program since it began in 1985. His interest in liver biology was encouraged by his former mentor and colleague, Nicholas LaRusso, M.D., a Mayo Clinic gastroenterologist and scientist in whose laboratory Dr. Gores trained. Dr. Gores, suspecting that apoptosis contributes to liver injury in many acute and chronic liver diseases, launched a quest to understand its pathways in liver cells. He hoped to discover mechanisms that could regulate liver cell apoptosis, mechanisms that could ultimately become new therapies. His quest is well under way.

How death receptors pull the trigger

Dr. Gores has conducted pioneering studies that demonstrate how specific proteins, called death receptors, trigger the demise of liver cells. Death receptors sit on the cell surface and join with binding proteins, called ligands. Next they join forces to boost the strength of the death signal, forming clusters on the cell’s surface. As soon as they penetrate the cell membrane they form a complex of "death domains," which act like a magnet attracting specific cellular proteins into a clump that scientists call the Death Inducing Signaling Complex (DISC). The DISC includes an important member of the family of proteins called caspases. When the caspase is activated, it breaks down components of the cell that are critical for its structure and function. The cell then shrivels up, ready to be dispatched by a macrophage.

"As it turns out, the liver is particularly susceptible to death receptors," says Dr. Gores. "They are remarkable proteins because if you trigger them under the right circumstances, the liver just falls apart."

A new chapter in the story of bile constituents

In pioneering studies, the Gore lab discovered that bile constituents secreted by the liver can trigger apoptosis and that the pathway involves death receptors. It was an important discovery because of its implications in potential treatments for cholestasis, a major problem in liver disease.

Cholestasis is a condition where bile backs up from the system of tiny canals and ducts leading to the common bile duct and the gall bladder, where it is stored. The ducts may be physically blocked by a gallstone or tumor, or the cause may be a physiologic disturbance where bile is improperly manufactured or its secretion impaired. Bile acids are produced by the liver from cholesterol and become increasingly concentrated when they are stored in the gall bladder.

"It was well recognized that bile acids could be toxic to the liver but the story didn’t fit well," says Dr. Gores. "We identified a molecular pathway showing that they actually triggered a death receptor, which led to apoptosis."

In his groundbreaking study, Dr. Gores showed that toxic bile acids increase cell surface death receptor proteins and reduce the recruitment of a protein that inhibits apoptosis to the DISC, thus enhancing caspase activation (Journal of Clinical Investigation, January 1999).

"What was important about this study was it demonstrated that inhibition of the death-receptor signaling and their cascades may prove useful in lessening liver injury during cholestasis," says Dr. Gores.

The next step was to sort out which of these molecules would provide the safest and most effective molecular target. The Gore lab has since partnered with biotech companies to test the inhibitors of these proteins, especially caspases, in human trials.

"The caspases and proteases are really the piranhas of this cascade—they just tear up the cell," says Dr. Gores. "We are helping industry with trial design, concept and rationale."

In related work, the Gore team has played a pivotal role in testing the use of caspase inhibitors for organ preservation. The difference in temperatures of a donor liver — from cold storage to its transplantation — are known to induce apoptosis in some cells. A multi–center clinical trial, which Dr. Gores helped organize, suggested that a caspase–inhibitor drug could prevent injury during liver transplantation (American Journal of Transplantation, Jan 2007).

Linking obesity and liver disease

The rising incidence of obesity and diabetes in Western countries poses increasing health risks for many diseases and health conditions, including liver disease. For this reason, nonalcoholic fatty liver disease (NAFLD) has become a growing problem affecting all age groups, including children. The Gores lab has been on the forefront in this area by providing insight into how fatty acids, which are elevated in metabolic syndrome, can attack the liver. In 2003, they published a pivotal paper showing that apoptosis is a major mechanism of disease pathogenesis in the metabolic syndrome, suggesting that fatty liver disease may sensitize liver cells to death ligands, which promote an external pathway to apoptosis (Gastroenterology, Aug 2003).

"In obesity, high levels of circulating free fatty acids can induce cell death, injury and apoptosis in the liver," says Dr. Gores. "Several drug companies are now interested in using caspase inhibitors to treat liver disease in the metabolic syndrome."

Wanted: Dead and alive

Much of Dr. Gores’ work complements that of long–time collaborator Scott Kaufmann, M.D., Ph.D. However, as a cancer researcher, Dr. Kaufmann is trying to kill cells rather than keep them alive. Their common interest in understanding death signal pathways diverges in its goals.

"All cancer cells have to develop some mechanism to prevent cell death," says Dr Gores. "Dr. Kaufmann wants to amplify and induce cell death and we’d like to apply his work to cancers involving the liver."

Dr. Kaufmann’s lab was instrumental in helping to understand how anticancer drugs act by inducing apoptosis in cancer cells. One of his projects focuses on the pathways and mechanisms involved in caspase activity.

A very distinguished investigator

Dr. Gores’ research is supported by three National Institute of Health grants. It runs the gamut from lab studies in single cells and animals to participation in human trials. His lab is internationally recognized for its accomplishments in uncovering the mechanisms of apoptosis in liver tissue and, as the locus for the best and brightest in the field to come and learn their trade.

In 2008, Dr. Gores’ peers awarded him Mayo’s top honor for its researchers by naming him a Mayo Clinic Distinguished Investigator.

"Mayo has been unique in allowing me to develop both a clinical and an investigative career," says Dr. Gores. "What you do in the clinic helps put the disease in clinical context so that you understand what you’re trying to attack. I really believe that unraveling these mechanisms will provide new treatment strategies. I wouldn’t be surprised to see the caspase inhibitors in the clinic within five years."

— Yvonne Hubmayr, December 2008