Division of Bioengineering and Environmental Health, Massachusetts Institute of Technology, Cambridge, MA 02139-4309, USA
Dr Ronald (Ron) Glenn Thurman, Professor of Pharmacology and Nutrition, and Director, Laboratory of Hepatobiology and Toxicology at the Department of Pharmacology, University of North Carolina at Chapel Hill died on July 14, 2001 at the age of 59. For over 30 years Ron Thurman was an outstanding investigator in the fields of hepatic metabolism, alcoholic liver injury, non-genotoxic liver carcinogenesis and toxicology. With his untimely death, his great family of colleagues and friends lost a most productive and creative researcher, teacher and mentor. His major research focus was on the liver and his many discoveries provided key insights into the critical role that cellcell interactions play in pathophysiology of liver disease. The research findings on molecular and cellular mechanisms of liver carcinogenesis, inflammation, fibrosis and cirrhosis provide the foundations to better understanding of a variety of dreadful human diseases and will continue to have profound influences in the areas of medicine, pharmacology, toxicology and nutrition.
Ron was born November 25, 1941 in Carbondale, Illinois, a small and quiet town in the rural Midwest. He was the only child in Glenn and Melba Thurman's family and grew up with a zest for knowledge and discovery. His interest in biology and chemistry developed gradually but steadily through a mix of successful and failed chemical and medical experiments that at one time destroyed the laundry room. Ron began his official productive and memorable career in science with a BSc degree in Pharmacy from the St Louis College of Pharmacy and a PhD degree in Pharmacology from the University of Illinois Medical College.
Ron made an excellent choice for his postdoctoral mentor when he joined the laboratory of Dr Britton Chance, a world-known expert in Biophysics, Physical Chemistry and Radiologic Physics, at the Johnson Foundation of the University of Pennsylvania in 1968. In Dr Chance's laboratory, Ron studied the liver metabolism of ethanol as well as oxidationreduction changes in perfused rat liver as a model for biochemical and toxicology research. The mutual interest in the subject of mixed function oxidation in perfused rat liver brought a productive and successful collaboration with the laboratory of Dr Roland Scholz at the University of Munich. Ron was awarded a highly prestigious Alexander von Humboldt Fellowship to continue in-depth research on the control of mixed function oxygenation in the perfused liver and he spent 2 years with Dr Scholz in Munich from 1969 to 1972. A Research Career Development Award from the National Institute on Alcohol Abuse and Alcoholism further rewarded the outstanding career of the young scientist and Ron returned to the University of Pennsylvania as an Assistant Professor in 1972. He continued studies of pathways of ethanol metabolism in perfused rat liver with an emphasis on the role of hydrogen peroxide and catalase in hepatic microsomal ethanol oxidation as well as pathways responsible for the adaptive increase in ethanol utilization following chronic treatment with ethanol.
In 1977, Ron was recruited from the University of Pennsylvania to the University of North Carolina at Chapel Hill, where he began what would prove to be an exciting quarter of a century of discoveries, collaborations and mentorship. His life was that of a scientific brilliance and achievement, enormous productivity, hard work, courage, persistence and unparalleled enjoyment of life. In fact, just a few weeks before his untimely death, Ron celebrated his 400th paper to be referenced on PubMed and was full of ideas and will to push that number much higher. His research was thoughtful and hypothesis-driven. His unique mentoring style with weekly meetings with each laboratory member (technicians, undergraduate and graduate students, or `postdocs') was coupled with a constant awareness of progress of all of his many research projects taught his co-workers a great lesson in determination, efficiency and success. Yet, his style was far from micromanagement of the laboratory affairs. He was masterfully developing independent and creative thinking in every one of a several dozen medical and graduate students, nearly 40 postdoctoral fellows and many laboratory assistants and undergraduate students who enjoyed having Ron as their mentor. He was the Mentor who would guide you in a way that one would be capable of formulating a hypothesis, designing and conducting the experiments and completing the process with a manuscript. He actively encouraged his trainees to participate in grant writing and laboratory management; skills that he knew would be absolutely crucial for ones successful scientific career. He was an exceptionally successful fundraiser himself and he was willing to share his expertise with others. Naturally, almost all of his trainees went on to outstanding careers in medicine, academic and governmental research and the pharmaceutical industry.
Ron approached the complex entity of liver disease in a focused, rational and precise manner. Over the years, Ron's body of work established key concepts that guide research on liver disease in laboratories throughout the world. His three major research focus areas were alcoholic liver injury, liver preservation for transplantation and liver carcinogenesis. In the past 10 years he broadened his scientific expertise to the studies on the mechanisms of chronic graft rejection, arthritis and effects of nicotine on lipid metabolism. Regardless of the topic, he was extremely well educated in all scientific areas and was able to sustain excitement of his co-workers by constantly bringing novel and creative ideas to the table.
The biggest achievement of Ron's research career, perhaps, is his novel concept that cellcell interactions in liver, namely between Kupffer cells, the resident hepatic macrophages that account for <5% of liver cells, and parenchymal cells, that encompass >90% of liver, play a critical role in the mechanisms of many diseases of this organ (13). For instance, Ron's seminal contributions established the role of lipopolysaccharides (LPS)-stimulated Kupffer cell activation in the pathogenesis of alcoholic steatohepatitis. Most recently, using an intragastric ethanol-feeding model in rats and mice, his laboratory defined key genetic components in alcoholic steatohepatitis. Knock-out mouse and viral gene delivery studies demonstrated critical roles of the Kupffer cell-derived tumor necrosis factor (TNF)-, ICAM-1, oxidants, as well as of endotoxin receptor CD14 and Toll-like receptor 4 in alcoholic liver injury. The concept, which emerged from Ron's work, was simple but unexpected: alcohol drinking promotes LPS translocation across the gut mucosa. The chronic exposure to LPS causes Kupffer cell activation and the release of cytokines, free radicals and other inflammatory mediators, which then culminates in hepatocellular injury and likely fibrosis as well. This concept is now widely accepted and will guide alcohol research for many years to come.
In the area of liver carcinogenesis, Ron's emphasis was on non-genotoxic compounds, namely chemicals that belong to a broad class of peroxisome proliferators. These compounds are potent rodent carcinogens that act as tumor promoters by increasing cell proliferation; however, their precise mechanism of action is not well understood. A number of years ago, Ron was first to hypothesize that Kupffer cell-derived oxidants, such as superoxide, may play a role in initiating production of mitogenic cytokines that leads to hepatocyte proliferation and the ultimate development of liver tumors. Indeed, active and continuous research of his laboratory demonstrated that peroxisome proliferators activate Kupffer cells both in vitro and in vivo, and by using Kupffer cell inhibitors such as methyl palmitate and dietary glycine it was shown that these cells are responsible for hepatocyte proliferation by mechanisms that involve TNF- and possibly other mitogens. Moreover, peroxisome proliferators activate the transcription factor nuclear factor (NF)-
B, one of the major regulators of mitogenic cytokines in Kupffer cells. Importantly, activation of NF-
B by peroxisome proliferators was shown to be oxidant-dependent, leading to the hypothesis that oxidants of Kupffer cell origin play a novel signaling role in the mechanism of action of this class of non-genotoxic compounds. Peroxisome induction, hepatomegaly, cell proliferation and tumors caused by peroxisome proliferators require the peroxisome proliferator-activated receptor (PPAR)
. However, PPAR
is not involved in mitogen production by Kupffer cells because it is not expressed in this cell type. How PPAR
is involved in liver tumor remains unclear and Ron's latest research on this topic was to uncover the precise mechanism of how both Kupffer cell mitogens and parenchymal cell PPAR
are involved. This project was so dear to his heart that he decided to devote a year of his precious time to serve as a Visiting Professor in the Institute for Cancer Research at the University of Vienna, Austria in 1999 and 2000. He certainly enjoyed his fruitful collaborations with Prof. Rolf Schulte-Hermann and his many colleagues as well as he enjoyed the wealth of the cultural life that Vienna has to offer. This was so much Ron, combining exciting research, teaching and collaborations, and at the same time enjoying great culture and history, all the necessary ingredients of the life that he wanted to live.
I wanted to conclude by emphasizing two of the greatest lessons that he taught all others and me. First lesson is to formulate the hypothesis before doing all of the experiments. It may sound simple, but this skill is hard to master when one is just learning about science. Ron was successfully achieving this `shift in thinking' in his trainees by having only one comment to all exciting results and experiments that we would share in our weekly meetings: `So what?' And this was the toughest question to find an answer to, but at the same time it was the best way to spark creative and critical thinking. Second lesson was that successful science is collaborative in nature. Once, he returned from one of many invited lectures and shared a story with us. One of the graduate students at the university that he went to asked him to define a secret of a successful scientific career in a single word. His answer was, `Collaborations'. I am sure that some may disagree with this, but I am certain that all of those many academic, governmental and industrial scientists who had a privilege of being involved in joint research with him really enjoyed it. He truly believed that a personal ego must not dominate a creative mind.
Ron Thurman was an outstanding scientist, a caring and supportive mentor for his students and postdocs, a man of highest integrity and a great friend to all who knew him. Ron clearly had an unmatched impact on the lives and careers of so many people; he will be remembered. Although his untimely death prevents Ron from pursuing the research he loved so dearly, his many students, protégés and collaborators will continue the work and inspire others to the standards of excellence that Ron not only met but demanded.
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