The 2018 Stanley J. Korsmeyer Award: Joseph Heitman, MD, PhD

Joseph Heitman, MD, PhD, is the recipient of the 2018 American Society for Clinical Investigation’s (ASCI) Stanley J. Korsmeyer Award for his key contributions to our understanding of how eukaryotic microbial pathogens evolve, cause disease, and develop drug resistance; and his discovery of TOR and FKBP12 as targets of the immunosuppressive chemotherapeutic drug rapamycin.

Dr. Heitman received BS and MS degrees from the University of Chicago in 1984, his PhD from Rockefeller University in 1989, and his MD from Cornell University in 1992. From 1989 to 1991, he was a European Molecular Biology Organization postdoctoral fellow at the University of Basel’s Biozentrum, in the laboratory of Michael N. Hall.

Rapamycin was first isolated from the bacterium Streptomyces hygroscopicus in the early 1970s from Easter Island soil samples collected in the 1960s, in a hunt for microbes that might provide the basis for new drugs. Although rapamycin was first developed as an antifungal agent, it was found to be a powerful suppressor of the immune system and was effectively abandoned for a time. However, researchers subsequently took up the immunosuppressive qualities of rapamycin and other drugs to transform the field of organ transplantation by making recipients less susceptible to rejecting their transplants. In addition, rapamycin was found to hinder cell growth, opening its use in the treatment of cancer and in the prevention of restenosis of coronary artery stents.

As a fellow in Dr. Hall’s laboratory, Dr. Heitman focused on the mechanism of action of rapamycin and two other immunosuppressive drugs, cyclosporin A and FK506 (tacrolimus), using Baker’s yeast, Saccharomyces cerevisiae, to study the drugs’ activity. In collaboration with Rao Movva, a scientist at Sandoz Pharmaceuticals in Basel, the researchers found that rapamycin arrested yeast cell growth in a manner similar to how it arrested growth in human T- cells, supporting the idea that the drug target was the same in both yeast and human. Their isolation and analysis of drug-resistant yeast mutants led to the discovery of FKBP12 and TOR as the targets of rapamycin. Further studies revealed the TOR pathway functions to sense nutrients and govern appropriate cellular physiological responses.

Subsequently, Dr. Heitman’s research in infectious disease has defined molecular virulence determinants and revealed novel modes of sexual reproduction and drug resistance for eukaryotic pathogenic microbes. The phosphatase calcineurin (the target of cyclosporin A and FK506) was identified as a key virulence determinant conserved across human fungal pathogens, and ongoing studies are exploring new therapeutic leads. He discovered that pathogenic microbes undergo unisexual reproduction, and has studied its impact on the evolution of eukaryotic microbial pathogens and how sexual reproduction may have originally evolved. Recent studies have unveiled novel mechanisms of antimicrobial drug resistance involving epimutations that silence drug-target genes via RNAi. Beyond his own laboratory, Dr. Heitman has provided resources and insights to advance the field of fungal genetics and genomics.

Dr. Heitman has mentored numerous undergraduates, medical students, graduate students, and postdoctoral and medical fellows, many of whom have developed independent careers in medicine and basic biomedical research. Among many others, John Perfect, Andrew Alspaugh, and William Steinbach have been key collaborators in studies on fungal pathogenesis and therapeutic exploration.

Dr. Heitman’s work has been recognized by the Gustavo Cudkowicz Memorial Prize in Immunobiology, 1991; the American Society for Biochemistry and Molecular Biology’s AMGEN Award, for significant achievements in the understanding of human disease involving studies in model yeasts defining targets and modes of action for immunosuppressive drugs, 2002; the Infectious Diseases Society of America’s Squibb Award, in recognition of outstanding achievement in the field of infectious diseases, in 2003; and a National Institutes of Health / National Institute of Allergy and Infectious Diseases MERIT award for studies on unisexual reproduction of eukaryotic microbial pathogens, 2011-2021.

Dr. Heitman is an elected fellow of the Infectious Diseases Society of America (2003), the ASCI (2003), the American Academy of Microbiology (2004), the American Association for the Advancement of Science (2004), and the Association of American Physicians (2006).

Dr. Heitman joined the faculty at Duke University School of Medicine in 1992, was named a James B. Duke Professor in 2004, and appointed Chair of the Department of Molecular Genetics and Microbiology in 2009. He was an investigator of the Howard Hughes Medical Institute from 1992 to 2005 and a Burroughs-Wellcome Scholar in Molecular Pathogenic Mycology from 1998 to 2005. He has given prominent lectures, including the American Society for Microbiology Division F Lecture (2009), the Foundation Lecture for the British Society for Medical Mycology (2010), the Karling Lecture for the Mycological Society of America (2011), and the Max Delbrück Lecture for the German Genetics Society (2017); is an editor of PLOS Genetics, mBio, PLOS Pathogens, and Fungal Genetics and Biology; and has edited seven textbooks on fungal pathogens, evolution of eukaryotic microbial pathogens, genetics, and microbiology.