Joseph Heitman | |
---|---|
Nationality | American |
Occupation(s) | geneticist, microbiologist, and molecular biologist |
Awards | Edward Novitski Prize (2019) |
Academic background | |
Alma mater | University of Chicago, Cornell and Rockefeller Universities |
Doctoral advisor | Peter Model, Norton Zinder |
Other advisors | Michael N. Hall |
Academic work | |
Discipline | Microbiology,Genetics,Infectious Diseases |
Sub-discipline | Mycology,Genomics,Evolution,Molecular Biology |
Institutions | Duke University School of Medicine |
Notable students | Christina M. Hull (postdoc 2000-2003) |
Joseph Heitman is an American physician-scientist focused on research in genetics,microbiology,and infectious diseases. He is the James B. Duke Professor and Chair of the Department of Molecular Genetics and Microbiology at Duke University School of Medicine. [1]
Joseph Heitman grew up in southwestern Michigan and attended Portage Northern High School. [2] He completed a dual Bachelor of Science–Master of Science program in chemistry and biochemistry at the University of Chicago from 1980 to 1984. [3] There he began his research career,working in the laboratories of organic chemist Josef Fried,biochemist Kan Agarwal,and bacteriologist Malcolm Casadaban. [2] [4] In 1984,he began a dual MD–PhD program at Cornell Medical College and Rockefeller University,working on DNA repair in bacteria with Peter Model and Norton Zinder. [3] In 1989,after receiving his PhD from Rockefeller University,Heitman took a leave of absence from medical school to serve as an EMBO-sponsored long-term fellow at the Biozentrum University of Basel working with Michael N. Hall and Rao Movva applying yeast genetics to understand the mechanisms of action of immunosuppressive drugs. [3] [5] This work led to the discovery of the cellular growth regulator TOR for which Michael Hall was awarded the Albert Lasker Award for Basic Medical Research in 2017. [6] [7] In 1992,Heitman finished medical school and moved to Duke University to set up his own laboratory in the Department of Molecular Genetics and Microbiology. [3] [4] He was an investigator with the Howard Hughes Medical Institute from 1992 to 2005 and a Burroughs Wellcome Scholar in Molecular Pathogenic Mycology from 1998 to 2005. [8] He became Chair of the Department of Molecular Genetics and Microbiology in 2009. [3] Since 2019,Heitman has been co-director of the Canadian Institute for Advanced Research's Fungal Kingdom program along with co-director Leah E. Cowen. [9]
Heitman's research has been recognized with prestigious awards and funding opportunities,including funding by the Howard Hughes Medical Institute from 1992 to 2005,and an National Institutes of Health MERIT Award from 2011-2021. [8] [10] Several awards have recognized his research accomplishments,including the ASBMB AMGEN Award (2002),the IDSA Squibb Award (2003) (now called the Oswald Avery Award),the Stanley J. Korsmeyer Award (2018) (for key contributions to understanding how microbial pathogens evolve,cause disease,and develop drug resistance and discovery of TOR and FKBP12 as targets of rapamycin),the Rhoda Benham Award (2018),the Edward Novitski Prize (2019) (honoring work on human fungal pathogens and identifying molecular targets of widely used immunosuppressive drugs,a seminal contribution to discovery of TOR,which regulates cell growth in response to nutrients),the American Society for Microbiology's Award for Basic Research (2019),and the Distinguished Mycologist Award from the Mycological Society of America (2021). [11] [12] [13] [14] [15] [16] [17] Heitman is an elected fellow or member of the Infectious Diseases Society of America (2003),American Society for Clinical Investigation (2003),American Academy of Microbiology (2004),American Association for the Advancement of Science (2004),the Association of American Physicians (2006),the American Academy of Arts and Sciences (2020) [18] [19] ,the National Academy of Sciences (2021) [20] [21] ,the German National Academy of Sciences Leopoldina (2021) [22] ,and the National Academy of Medicine (2024). [23] [24]
Heitman's research has largely focused on studies of model and pathogenic fungi to address unsolved problems in biology and medicine. Pioneering research with the model budding yeast Saccharomyces cerevisiae discovered TOR and FKBP12 as the targets of the immunosuppressive and antiproliferative drug rapamycin,now widely used in organ transplantation and cancer chemotherapy. [25] [26] Later studies elucidated key features of how the TOR signaling pathway senses nutrients to control cellular responses. [27] Studies were conducted on the dimorphic transition of Saccharomyces cerevisiae from budding yeast cells to pseudohyphae,elucidating nutrient sensing signaling cascades governing this morphological transition involving GPCR-cAMP-PKA signaling cascades controlling gene expression,and discovering a novel role for the ammonium permease/Rh antigen homolog Mep2 as a transceptor for nitrogen source availability. [28] [29] [30] [31] [32] [33] [34]
Heitman's research program has also focused extensive studies on the pathogenesis,sexual cycle,and novel drug targets of the pathogenic fungus Cryptococcus . [3] His group described a previously unknown form of sexual reproduction in Cryptococcus species,known as unisexual reproduction,which involves both selfing sexual reproduction (homothallism) of isolates grown on their own without a mating partner,as well as sexual reproduction and recombination involving cell-cell fusion between individuals of the same mating type followed by meiosis and sporulation. [35] [36] Studies conducted in parallel defined and illuminated evolution and function of fungal mating-type loci,illustrating parallels with sex chromosome evolution of plants and animals,including the discovery and characterization of the homeodomain proteins Sxi1alpha and Sxi2a,which coordinately control cell type identity and sexual reproduction. [37] [38] [39] [40] [41] [42] Heitman's group has also had a long-standing interest in fungal evolution,describing how cellular processes such as sexual recombination and RNA interference are changed in different fungal lineages,as well as the expansion of the geographic range of the emerging pathogen Cryptococcus gattii . [3] [36] [43] [44] [45] [46] [47] [48]
Joseph Heitman has served as co-editor of seven textbooks spanning microbiology,genetics,infectious diseases:The Fungal Kingdom,ASM Press October 2017,editors:Joseph Heitman,Barbara J. Howlett,Pedro W. Crous,Eva H. Stukenbrock,Timothy Yong James,and Neil A.R. Gow.; [49] Sex in Fungi:Molecular Determination and Evolutionary Implications,ASM Press 2007,editors:Joseph Heitman,James W. Kronstad,John W. Taylor,and Lorna A. Casselton.; [50] Cryptococcus:From Human Pathogen to Model Yeast,ASM Press 2011,editors:Joseph Heitman,Thomas R. Kozel,Kyung J. Kwon-Chung,John R. Perfect,and Arturo Casadevall.; [51] Molecular Principles of Fungal Pathogenesis,ASM Press 2006,editors:Joseph Heitman,Scott G. Filler,John E. Edwards Jr.,and Aaron P. Mitchell.; [52] Human Fungal Pathogens,Cold Spring Harbor Laboratory Press,2015,editors:Arturo Casadevall,Aaron P. Mitchell,Judith Berman,Kyung J. Kwon-Chung,John R. Perfect,and Joseph Heitman.; [53] Evolution of Virulence in Eukaryotic Microbes,Wiley Press June 2012,editors:L. David Sibley,Barbara J. Howlett,and Joseph Heitman.; [54] and Yeast as a Tool in Cancer Research,Springer Press,2007,editors:John L. Nitiss and Joseph Heitman. [55]
Joseph Heitman serves as an editor for journals including PLOS Pathogens , PLOS Genetics , mBio , Fungal Genetics &Biology ,and Frontiers Cellular and Infection Microbiology | Fungal Pathogenesis, [56] [57] [58] [59] [60] and from 2006 to present on the editorial boards for the journals Current Biology , Cell Host &Microbe ,and PLOS Biology . [61] [62] [63]
Yeasts are eukaryotic,single-celled microorganisms classified as members of the fungus kingdom. The first yeast originated hundreds of millions of years ago,and at least 1,500 species are currently recognized. They are estimated to constitute 1% of all described fungal species.
Basidiomycota is one of two large divisions that,together with the Ascomycota,constitute the subkingdom Dikarya within the kingdom Fungi. Members are known as basidiomycetes. More specifically,Basidiomycota includes these groups:agarics,puffballs,stinkhorns,bracket fungi,other polypores,jelly fungi,boletes,chanterelles,earth stars,smuts,bunts,rusts,mirror yeasts,and Cryptococcus,the human pathogenic yeast.
Saccharomyces cerevisiae is a species of yeast. The species has been instrumental in winemaking,baking,and brewing since ancient times. It is believed to have been originally isolated from the skin of grapes. It is one of the most intensively studied eukaryotic model organisms in molecular and cell biology,much like Escherichia coli as the model bacterium. It is the microorganism which causes many common types of fermentation. S. cerevisiae cells are round to ovoid,5–10 μm in diameter. It reproduces by budding.
Candida albicans is an opportunistic pathogenic yeast that is a common member of the human gut flora. It can also survive outside the human body. It is detected in the gastrointestinal tract and mouth in 40–60% of healthy adults. It is usually a commensal organism,but it can become pathogenic in immunocompromised individuals under a variety of conditions. It is one of the few species of the genus Candida that cause the human infection candidiasis,which results from an overgrowth of the fungus. Candidiasis is,for example,often observed in HIV-infected patients. C. albicans is the most common fungal species isolated from biofilms either formed on (permanent) implanted medical devices or on human tissue. C. albicans,C. tropicalis,C. parapsilosis,and C. glabrata are together responsible for 50–90% of all cases of candidiasis in humans. A mortality rate of 40% has been reported for patients with systemic candidiasis due to C. albicans. By one estimate,invasive candidiasis contracted in a hospital causes 2,800 to 11,200 deaths yearly in the US. Nevertheless,these numbers may not truly reflect the true extent of damage this organism causes,given new studies indicating that C. albicans can cross the blood–brain barrier in mice.
Cryptococcus is a genus of fungi in the family Cryptococcaceae that includes both yeasts and filamentous species. The filamentous,sexual forms or teleomorphs were formerly classified in the genus Filobasidiella,while Cryptococcus was reserved for the yeasts. Most yeast species formerly referred to Cryptococcus have now been placed in different genera. The name Cryptococcus comes from the Greek for "hidden sphere". Some Cryptococcus species cause a disease called cryptococcosis.
Cryptococcus neoformans is an encapsulated yeast belonging to the class Tremellomycetes and an obligate aerobe that can live in both plants and animals. Its teleomorph is a filamentous fungus,formerly referred to Filobasidiella neoformans. In its yeast state,it is often found in bird excrement. Cryptococcus neoformans can cause disease in apparently immunocompetent,as well as immunocompromised,hosts.
The mating of yeast,also known as yeast sexual reproduction,is a biological process that promotes genetic diversity and adaptation in yeast species. Yeast species,such as Saccharomyces cerevisiae,are single-celled eukaryotes that can exist as either haploid cells,which contain a single set of chromosomes,or diploid cells,which contain two sets of chromosomes. Haploid yeast cells come in two mating types,a and α,each producing specific pheromones to identify and interact with the opposite type,thus displaying simple sexual differentiation. A yeast cell's mating type is determined by a specific genetic locus known as MAT,which governs its mating behaviour. Haploid yeast can switch mating types through a form of genetic recombination,allowing them to change mating type as often as every cell cycle. When two haploid cells of opposite mating types encounter each other,they undergo a complex signaling process that leads to cell fusion and the formation of a diploid cell. Diploid cells can reproduce asexually,but under nutrient-limiting conditions,they undergo meiosis to produce new haploid spores.
Fungi are a diverse group of organisms that employ a huge variety of reproductive strategies,ranging from fully asexual to almost exclusively sexual species. Most species can reproduce both sexually and asexually,alternating between haploid and diploid forms. This contrasts with most multicellular eukaryotes,such as mammals,where the adults are usually diploid and produce haploid gametes which combine to form the next generation. In fungi,both haploid and diploid forms can reproduce –haploid individuals can undergo asexual reproduction while diploid forms can produce gametes that combine to give rise to the next generation.
Cryptococcus gattii,formerly known as Cryptococcus neoformans var. gattii,is an encapsulated yeast found primarily in tropical and subtropical climates. Its teleomorph is Filobasidiella bacillispora,a filamentous fungus belonging to the class Tremellomycetes.
In enzymology,a sterol 14-demethylase (EC 1.14.13.70) is an enzyme of the cytochrome P450 (CYP) superfamily. It is any member of the CYP51 family. It catalyzes a chemical reaction such as:
Pathogenic fungi are fungi that cause disease in humans or other organisms. Although fungi are eukaryotic,many pathogenic fungi are microorganisms. Approximately 300 fungi are known to be pathogenic to humans;their study is called "medical mycology". Fungal infections are estimated to kill more people than either tuberculosis or malaria—about two million people per year.
A killer yeast is a yeast,such as Saccharomyces cerevisiae,which is able to secrete one of a number of toxic proteins which are lethal to susceptible cells. These "killer toxins" are polypeptides that kill sensitive cells of the same or related species,often functioning by creating pores in target cell membranes. These yeast cells are immune to the toxic effects of the protein due to an intrinsic immunity. Killer yeast strains can be a problem in commercial processing because they can kill desirable strains. The killer yeast system was first described in 1963. Study of killer toxins helped to better understand the secretion pathway of yeast,which is similar to those of more complex eukaryotes. It also can be used in treatment of some diseases,mainly those caused by fungi.
A fungus is any member of the group of eukaryotic organisms that includes microorganisms such as yeasts and molds,as well as the more familiar mushrooms. These organisms are classified as one of the traditional eukaryotic kingdoms,along with Animalia,Plantae,and either Protista or Protozoa and Chromista.
The meiotic recombination checkpoint monitors meiotic recombination during meiosis,and blocks the entry into metaphase I if recombination is not efficiently processed.
The bZIP intron RNA motif is an RNA structure guiding splicing of a non-canonical intron from bZIP-containing genes called HAC1 in yeast,XBP1 in Metazoa,Hxl1 or Cib1 in Basidiomycota and bZIP60 in plants. Splicing is performed independently of the spliceosome by Ire1,a kinase with endoribonuclease activity. Exons are joined by a tRNA ligase. Recognition of the intron splice sites is mediated by a base-paired secondary structure of the mRNA that forms at the exon/intron boundaries. Splicing of the bZIP intron is a key regulatory step in the unfolded protein response (UPR). The Ire-mediated unconventional splicing was first described for HAC1 in S. cerevisiae.
Vomocytosis is the cellular process by phagocytes expel live organisms that they have engulfed without destroying the organism. Vomocytosis is one of many methods used by cells to expel internal materials into their external environment,yet it is distinct in that both the engulfed organism and host cell remain undamaged by expulsion. As engulfed organisms are released without being destroyed,vomocytosis has been hypothesized to be utilized by pathogens as an escape mechanism from the immune system. The exact mechanisms,as well as the repertoire of cells that utilize this mechanism,are currently unknown,yet interest in this unique cellular process is driving continued research with the hopes of elucidating these unknowns.
Arturo Casadevall is a Bloomberg Distinguished Professor of Molecular Microbiology &Immunology and Infectious Diseases at the Johns Hopkins Bloomberg School of Public Health and Johns Hopkins School of Medicine,and the Alfred and Jill Sommer Professor and Chair of the W. Harry Feinstone Department of Molecular Microbiology and Immunology at the Johns Hopkins Bloomberg School of Public Health. He is an internationally recognized expert in infectious disease research,with a focus on fungal and bacterial pathogenesis and basic immunology of antibody structure-function. He was elected a member of the National Academy of Sciences in 2022.
The Gal4 transcription factor is a positive regulator of gene expression of galactose-induced genes. This protein represents a large fungal family of transcription factors,Gal4 family,which includes over 50 members in the yeast Saccharomyces cerevisiae e.g. Oaf1,Pip2,Pdr1,Pdr3,Leu3.
Kaustuv Sanyal is an Indian molecular biologist,mycologist and Director of Bose Institute in Kolkata. He is a professor at the Molecular Biology and Genetics Unit of the Jawaharlal Nehru Centre for Advanced Scientific Research (JNCASR). He is known for his molecular and genetic studies of pathogenic yeasts such as Candida and Cryptococcus). An alumnus of Bidhan Chandra Krishi Viswavidyalaya and Madurai Kamaraj University from where he earned a BSc in agriculture and MSc in biotechnology respectively,Sanyal did his doctoral studies at Bose Institute to secure a PhD in Yeast genetics. He moved to the University of California,Santa Barbara,USA to work in the laboratory of John Carbon on the discovery of centromeres in Candida albicans. He joined JNCASR in 2005. He is a member of the Faculty of 1000 in the disciplines of Microbial Evolution and Genomics and has delivered invited speeches which include the Gordon Research Conference,EMBO conferences on comparative genomics and kinetochores. The Department of Biotechnology of the Government of India awarded him the National Bioscience Award for Career Development,one of the highest Indian science awards,for his contributions to biosciences,in 2012. He has also been awarded with the prestigious Tata Innovation Fellowship in 2017. The National Academy of Sciences,India elected him as a fellow in 2014. He is also an elected fellow of Indian Academy of Sciences (2017),and the Indian National Science Academy (2018). In 2019,he has been elected to Fellowship in the American Academy of Microbiology (AAM),the honorific leadership group within the American Society for Microbiology. He was awarded the J.C. Bose National Fellowship in 2020.