Seminar - Mehmet Orman

Mehmet A. Orman

Post-Doctoral Research Fellow
Memorial Sloan Kettering Cancer Center, NY

Characterizing the Physiology of Persister Cells

Abstract

Phenotypic heterogeneity is a common mechanism by which populations of living organisms survive adverse environmental conditions. For example, persister cells observed in various organisms including bacteria and cancer cells are rare, phenotypic variants which have the ability to tolerate extraordinary levels of drugs. Once the therapeutic agent is removed, persisters can resume growth and establish a population that exhibit drug-sensitivity identical to original populations, which distinguishes them from drug-resistant mutants. Elimination of persisters is desired to cure relapsing diseases; however, persister physiology has remained elusive, and this has hindered progress toward eradicating this detrimental phenotype. In this context, this talk highlights the central role of metabolism in persister formation, and demonstrates its potential to provide anti-persister strategies. Using a fluorescent measure of metabolic activity, fluorescence-activated cell sorting, and persistence assays, we provided the first direct measurement of bacterial persister metabolism. We discovered that within nutrient-depleted conditions, where persisters are abundant, they rarely arise from the subpopulation having the lowest redox activity. We dissected this phenotype with genetic, biochemical, and flow cytometric techniques and discovered that inhibition of respiration within this nutrient-depleted phase is an effective means to prevent persister formation. We determined that loss of stationary phase respiratory activity prevented self-digestion, including digestion of membranes, endogenous proteins and RNA. This yielded a subpopulation of bacteria that were more capable of translation, replication, and concomitantly cell death when exposed to antibiotics. Overall, this research program demonstrates a novel strategy to eliminate persisters arising from nutrient-depleted, non-growing populations.

Bio

Mehmet obtained his B.S. and M.S. degrees from the Chemical Engineering Department at Middle East Technical University in Ankara, Turkey in 2007, and his Ph.D. in Chemical and Biochemical Engineering from Rutgers University in 2011. Previously, he was a postdoctoral research associate at the Chemical and Biological Engineering Department at Princeton University, until 2015. He then joined the Memorial Sloan Kettering Cancer Center, the world’s leading cancer research center, as a research fellow to gain more insights within the cancer research field. 

In his research, he utilizes systems biology, metabolic engineering, and molecular genetic tools to understand biological problems that impose a huge burden on the health care system. His diverse research interests include: understanding inflammation induced-hypermetabolic state; characterizing the physiology of reversible drug tolerant phenotypes; and studying DNA repair mechanisms in cancer cells. To date, he has contributed to 29 peer-reviewed journal publications and book chapters, and he has more than 20 conference publications/presentations. His pivotal research proposal in persistence has recently received the best possible impact score of 10 from the NIH for the K22 Career Transition Award, which supports tenure-track assistant professors within the first two years of their academic career with $250,000 direct cost.