Neil Kaplowitz, MD
Professor of Medicine; Chief, Division of Gastroenterology, Liver Diseases; USC Associates/Thomas H. Brem Chair in Medicine

Dr. Neil Kaplowitz is the USC Associates-Brem Professor of Medicine, Garrie-Budnick Chair in Liver Disease and chief, division of gastrointestinal and liver disease in the Department of Medicine. He is also the director of the NIDDK-sponsored USC Research Center for Liver Disease. His major research focus is in liver diseases and the effects of drugs and alcohol on the liver. His laboratory studies the convergence of signal transduction, mitochondrial dysfunction, oxidative stress, ER stress and cell death pathways in the pathogenesis of liver injury in cell and animal models.

What initially attracted you to liver function and liver diseases?

As I developed an interest during medical school in the regulation of biochemical and physiological processes in the liver (see below), I naturally wanted to link this research with human illness, particularly what I was seeing in the hospital — both initially as a trainee and later as a faculty member. Physician-scientists have a unique perspective in having a deep appreciation of clinical relevance and important issues that we face in diagnosis and treatment. Although my research focus has been largely laboratory-based, the hospital work and bedside teaching has always kept my laboratory research goals focused on clinical relevance. So my specialization in hepatology has evolved simultaneously with my research interests.

As a clinician, what attracted you to research?

Career paths are heavily influenced by great teachers who present complex information in a lucid fashion, providing insight. For me, as a medical student, there were two: Severo Ochoa, a physician-scientist and Nobel laureate who taught biochemistry by explaining the experimental approaches to the great discoveries of the time (e.g., Kreb’s cycle and genetic code), and Norman Javitt, also a physician-scientist. He taught about metabolism and transport of bilirubin and bile acids, as well as the physiological basis of bile secretion and the mechanisms of cholestatic jaundice. This introduction, along with the challenge of diagnosis and treatment of an organ not readily accessible to direct examination and a rich center of unexplored biochemistry and physiology, fascinated me. If I had had similar experiences with neuroscientists, cardiologists or nephrologists, who knows what would have happened. After Norman Javitt’s lectures in year 2 of medical school, I asked him if I could do research with him. He suggested that I might work on porphyria, a group of genetic metabolic diseases that manifest due to defects in the pathway to heme synthesis. Norman and a dermatology collaborator were seeing a number of cases of photosensitive protoporphyria and this was not an area Norman had investigated. So, I went to the library and read everything I could and came back to him with an idea that lead to a year of research during medical school and a publication in the New England Journal of Medicine. From there, I just built on the logical progression from porphyrins (pyrroles) to heme (cytochrome P450s and drug metabolism) to its breakdown to bilirubin. I later worked again with Norman during a GI fellowship. Again, he made another important suggestion, namely that I determine if the liver cytoplasmic proteins that bind bilirubin also bind bile acids. I set out to do this, but was quickly diverted by the discovery that the binding proteins were glutathione (GSH) S-transferases, which are enzymes of detoxification. This led me into the field of toxicology and drug toxicity, initially studying the biochemistry and regulation of these enzymes and GSH itself. Ultimately, one thing builds on another, as I became more and more focused on oxidative and organelle-derived stress responses, signal transduction, and mitochondrial dysfunction in the pathogenesis of cell death in animal models of liver disease. Norman placed the seed and I went with it wherever it would logically take me. I try to do the same for my mentees.

What other areas of research have you collaborated and how have these collaborations advanced or influenced your own research?

I have had a longstanding collaboration with the Fernandez-Checa lab in Barcelona, since he moved from my lab at USC in 1993. We share common interests in the dysregulation of mitochondrial GSH and the role of ER stress in the pathogenesis of alcoholic liver disease. This has been mutually beneficial, advanced our independent work and provided novel insights that extend beyond alcoholic liver disease. We work together at USC every summer, supported by one of the funded projects of the Southern California Research Center for ALPD grant based at the Keck School.

Over the years, I have frequently found interesting challenges, and tried to develop new insights in my areas of clinical interest — drug-induced and alcoholic disease — through collaborations at the Keck School with colleagues such as the late Telfer Reynolds, and Andrew Stolz, as well as outside the Keck School with the drug-induced injury clinical research group of Andrade and Lucena in Malaga, Spain, and NIDDK Drug-Induced Liver Injury Network and an NIAAA-sponsored Southern California Alcoholic Hepatitis Network. In addition, as consultant for pharmaceutical companies, I have mainly assisted in identifying and understanding the mechanism of hepatotoxicity of drugs in both preclinical and clinical development. All of these clinical collaborations have led to publications and provide new insights, which I have taken under consideration in advancing my own laboratory research. In one case in particular, the initial consultations on antisense molecules developed by ISIS Pharmaceuticals directed at potential therapeutic targets in liver disease have led to a decade-long collaboration, which has greatly advanced my research on the role of signal transduction and cell death pathways in the pathogenesis of liver injury in animal models. The key is that my curiosity is aroused in any context, including the clinical setting, and I enjoy trying to learn something new.

What do you think will be the next big advance in your field, and what do you think the Keck School can do to position itself to be a leader in this area?

Two of the most common liver diseases, hepatitis B and C, will be diminishing due to the great advances in therapy. The remaining common causes of cirrhosis are fatty liver disease (linked to obesity and diabetes) and alcoholic liver disease. We have great strength in basic and clinical research in alcoholic liver disease, but lag in fatty liver disease. Although we have considerable strengths in diabetes and obesity at USC, we need to strengthen both our basic science research in lipid metabolism and our clinical research in the hepatological aspects of this major disease through several key recruitments. Ultimately, a multidisciplinary approach with visionary leadership of a senior clinician-scientist in this field would position us to play a major role. We need a well-supported registry of patients, lipidomics, biobanking and clinical trials on biomarkers of progression and treatment.

Liver immunology is a key area that needs to be developed. We are learning that the regulation of the adaptive immune system plays a role in the pathogenesis of viral, autoimmune, transplant rejection and drug-induced liver disease. Dysregulation of immune tolerance, specifically in the liver, may explain a great deal about the pathogenesis of idiosyncratic drug-induced liver disease — a major cause of acute liver failure and failure of drugs in development and post marketing. We have a great deal of strength in innate immunity, but to face the challenges of immune-mediated liver disease, a key recruitment of an established investigator in liver-specific adaptive immunity and its translational applications would be critical to position USC to advance this field.

Other important emerging areas include prevention and individualized treatment of liver cancer and the prevention or reversal of fibrosis and cirrhosis. We have outstanding investigators at the forefront of these areas. Major advances in stem cell and regenerative medicine are likely to occur over the next decade, which will provide rescue of acute liver failure and repair of cirrhosis. The Eli and Edythe Broad CIRM Center for Regenerative Medicine and Stem Cell Research at USC provides an exceptional base for advancing this field. However, an established scientist who can lead a basic and translational liver program is missing and would be critical for us to be in the forefront of the applications of this promising field to liver disease.

We have a wonderful mix of basic science and clinical research in liver disease at USC, arguably among the best in the nation. However, several key recruitments — along with appropriate resources — would strategically position us to leap ahead and be at the forefront of the emerging areas likely to lead to new advances in the prevention and treatment of liver disease.

What advice would you give to junior faculty about being competitive in receiving grant funding?

First, one needs to be in a supportive environment that provides strong, dedicated mentorship, protection of time for research, and access to routine and cutting edge technologies through center and institutional core facilities. Second and even more importantly, the science needs to be strong with respect to its importance or novelty, the availability of convincing preliminary data, and some published track record that attests to the feasibility of the proposed work. Third, it is critical to remain focused and not over extend. Thus, one has to place his or her work in context, convince the reviewers that it is important to conduct the work and that it will significantly advance the field, that he or she has the capability of completing what is proposed (based on preliminary data and collaborative resources available), and that it will dig deep in one place rather than scratching the surface in multiple places. Ultimately, the quality of the science and novelty will prevail.