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Spotlight - Michael Glickman
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Physician-scientist Michael Glickman specializes in the treatment and study of infectious diseases. In the clinic, he cares for cancer patients with a wide variety of infections, and in the laboratory he studies the interaction between bacterial pathogens and host cells.
I came from an academic medical family, with an MD/PhD older brother and an academic physician father, which meant that a physician-scientist's lifestyle was familiar to me. From early on, I had an interest in biomedical research, but, to be honest, by the time I received my undergraduate degree I agonized over the decision of pursuing an MD/PhD. In the end, I decided against it, choosing instead to go to medical school at Columbia University College of Physicians and Surgeons in 1989.
I did a few laboratory stints during medical school, which was my way of testing to see if I was truly interested in basic science research. I worked in the laboratories of Donald Landry and Paul Rothman. Both Don and Paul were relatively junior physician-scientists who served as strong role models of how to succeed in that career path. Both went on to successful academic careers, and have provided me with a great deal of inspiration and practical advice.
An Infectious Diseases Convert
When I completed medical school in 1993, I went on to do my clinical training in internal medicine at Massachusetts General Hospital in Boston. At the time, the field of infectious diseases held absolutely no interest for me. However, as I developed into a clinically trained doctor, I became more interested in Infectious Diseases. I was surprised to see a tremendous disconnect between the way the subject was taught in medical school and the way it was practiced with patients. Caring for patients with infections was far more exciting and rewarding than I had ever expected. I was interested enough in the subject to do a subspecialty fellowship in infectious diseases. The first of the three years would be clinically focused followed by two years of laboratory research, which, for me, meant that I would finally be giving the research side of things some serious consideration.
Changing Course: NYC and Mycobacteria
The choice of where to do this fellowship was governed by two factors. The first was that my wife hated Boston and wanted to move back to New York City! And the second was, within New York, what laboratory would I work in? As a result, for my postdoctoral fellowship I decided to work with William Jacobs, a professor of microbiology and immunology at Albert Einstein College of Medicine in the Bronx. Bill is a Howard Hughes Medical Institute investigator studying mycobacteria, which are a particular type of bacteria that are the common cause of many serious human infections, including tuberculosis (TB) and leprosy.
It was a seminal time in mycobacterial research, which had, until then, lagged behind other areas of microbiology and bacterial pathogenesis. The reason for this was the absence of genetic tools to work with these organisms. Bill had spent the ten years prior to my joining his lab developing genetic tools to break down those barriers, and when I started in his lab these tools were ready to be used to answer some of the big questions. Chief among them was the molecular basis for tuberculosis disease, which remains a major cause of mortality worldwide, and the search for new antimicrobials that would shorten TB chemotherapy treatment time.
Most scientists will acknowledge that science is a competitive business, but Bill's acknowledgment of this reality took a novel form. His belief was that he was creating tools to work on an enormous global health problem, and he aggressively disseminated his tools to anyone interested, often before publication. I found it inspirational that his first priority was growing the field, in large part because of the urgency of the TB problem throughout the world.
A Practical Apprenticeship
In Bill's lab, I was surrounded by PhDs doing their postdoctoral fellowships, with years of laboratory research experience among them. Their experience came in quite handy for a relative novice like me. I benefited tremendously from them in what was really a practical apprenticeship. All my lab mates were very generous with their time, which, I think, is partly a reflection of the atmosphere that Bill created in his lab.
I know that most physician-scientists at some point wrestle with the question of whether they should devote all their energies either to clinical work or to research. They certainly each have their own challenges, but I find them to be mutually complimentary disciplines. For me, they are so intertwined that I can't imagine giving up one for the other.
I enjoyed the research end of things so much that, by the end of my three-year postdoctoral fellowship, I opted to work for another two years in Bill's lab. I was studying a novel family of enzymes involved in the biosynthesis of the cell walls of tuberculous and other mycobacteria. Through my work, I was able to show that these enzymes were important for modifying lipids on the outer surface of the bacterium, and that they were important for the disease-development process known as pathogenesis. These enzymes are a potentially important target for the development of new antibiotics against mycobacteria and other microbial pathogens that have similar enzymes.
Onto SKI
In January 2002, I joined Memorial Sloan-Kettering Cancer Center as a physician-scientist, treating patients as a member of the Infectious Diseases Service in the Department of Medicine and starting my own laboratory in the Immunology Program at Sloan-Kettering Institute (SKI).
I was recruited by Eric Pamer and Alan Houghton. Eric is the Chief of the Infectious Diseases Service and has been a major mentor for me here. For me, the process of faculty recruitment can be seen as a mirror of how an institution actually functions. How well they conduct the interview process and how they respond to your questions is usually a good reflection of how the institution will respond to you as a faculty or staff member. The way Sloan-Kettering dealt with me during recruitment was dramatically different than my recruitment experience with other institutions. Their response to my question, "I would like to do this sort of research. How can I do that here?" was met with a detailed positive response. The intellectual and physical resources available here, especially at all of the Core Facilities, are truly unmatched anywhere else.
Research Focus
As a researcher, I am a microbiologist specializing in microbial pathogenesis. This area of study is relevant to cancer because cancer patients can develop a number of infections either as complications of the cancer itself or the therapies used to treat cancer. Understanding how these infections develop and how pathogens infect host cells is important to understanding how to treat infections in cancer patients. While I am specifically working on mycobacterial infections, my work still fell within the flexible scope of SKI's research focus.
In my laboratory, we study the pathogenesis of infection with Mycobacterium tuberculosis (Mtb) through a multidisciplinary approach that includes microbial genetics, biochemistry, molecular biology, lipid biochemistry, and immunology. Our general approach to understanding strategies of mycobacterial pathogenesis is the creation and analysis of defined bacterial mutants. The long-term goal of these studies is to identify and understand bacterial molecules essential for Mtb pathogenesis that would be attractive therapeutic targets and to gain insight into the novel physiology of mycobacteria.
Our active investigations are divided into three main areas. First, we are studying M. tuberculosis cell envelope lipids as direct pathogenesis effector molecules which modify host innate immune recognition. Second, we are looking at the regulation of M. tuberculosis cell envelope composition and virulence by regulated intramembrane proteolysis (RIP). And, third, working in close collaboration with Stewart Shuman of the Molecular Biology Program, we are studying a novel bacterial DNA repair pathway called nonhomologous end-joining (NHEJ).
DNA repair in general and NHEJ specifically have been a focus of many investigators at the institution because of their relevance to cancer, and we are now studying NHEJ in a bacterium, to understand DNA repair both on a generic level and with respect to its potential relevance to infection. The canonical view of NHEJ was that the repair pathway was absent from bacteria but present in human cells (and other organisms such as yeast). Although NHEJ is absent in some commonly studied bacteria such as E. coli, we were the first to demonstrate the existence of a functional NHEJ pathway in a bacterium. We believe mycobacterial NHEJ may be particularly important for mycobacterial latency, a stage of inactive infection that is particularly difficult to treat with antibiotics. If the NHEJ pathway is important for mycobacteria to resist the host's immune system or to cause infection, then it might qualify as a target for drugs
For the RIP1 protease, we discovered that it controls the composition of the TB cell envelope, a novel mechanism of control for the bacterial cell membrane. Tuberculosis bacteria lacking RIP1 are severely attenuated in mouse models, meaning that if we inject mice with RIP1-deficient TB, the mice do not become ill and are able to clear the bacteria. We know very little of how this pathway operates, but given its importance to the disease-causing properties of TB, we very much want to understand the molecular details of the pathway.
Translational Possibilities
A new direction of our work involves antibiotic development. We are actively working with the High-Throughput Drug Screening Facility to try to identify and test compounds that we have isolated to kill mycobacteria. It turns out that a number of these compounds are successful at killing a wide range of bacteria, many of which are directly related to infections in cancer patients in the US. These compounds are candidate novel antibiotics which we are actively developing, hopefully for eventual therapeutic use.
Best of Both Worlds
Six years ago when I started at SKI, I would not have imagined that I would be doing some of this work, especially the drug screening projects. These unanticipated directions are a direct result of the rich scientific environment at Memorial Sloan-Kettering, which encourages investigators to explore new directions. This environment is, for me, one of the most rewarding things about the clinical and research parts of my job.
For some people, the wildly divergent time-scales of progress between clinical care and basic research can prove frustrating. I see people in the clinic who have serious mycobacterial infections. These people desperately need better therapies for their infections, but there is very little chance that what I am working on in my lab will develop into a treatment in time to help any specific patient. In some ways, you have to be comfortable, as a physician-scientist in my field, with the difficult concept that what you are doing in the lab will improve treatment for patients -- but that it may not positively affect an individual patient who is in your office today. I see patients who have these infections, and when they see that I also do research on infectious disease, they say, "Oh, you have a lab? Have you discovered anything new that can help me?" It is frustrating for me to have to tell them that my research will most likely not be directly and immediately available as a clinical therapy for them. It will, however, build the groundwork for understanding the underlying mechanisms of these infectious agents, which can and hopefully will lead to better therapies. I find that patients are often less frustrated than their doctors about this point and are happy to see the institution engaged in basic science discovery.
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