Lalita Ramakrishnan

Lalita Ramakrishnan FRS FMedSci (born 1959)[2] is an American microbiologist who is known for her contributions to the understanding of the biological mechanism of tuberculosis.[3][4][5] As of 2019 she serves as a Professor of Immunology and Infectious Diseases at the University of Cambridge, where she is also a Wellcome Trust Principal Research Fellow and a practicing physician.[6] Her research is conducted at the Medical Research Council Laboratory of Molecular Biology (MRC LMB), where she serves as the Head of the Molecular Immunity Unit of the Department of Medicine embedded at the MRC LMB. Working with Stanley Falkow at Stanford, she developed the strategy of using Mycobacterium marinum infection as a model for tuberculosis.[7][6] Her work has appeared in a number of journals, including Science, Nature, and Cell.[1][8][4] In 2018 and 2019 Ramakrishnan coauthored two influential papers[9] in the British Medical Journal (BMJ) arguing that the widely accepted estimates of the prevalence of latent tuberculosis -- estimates used as a basis for allocation of research funds -- are far too high.[10][11]

Lalita Ramakrishnan

FRS FMedSci
Lalita Ramakrishnan at the Royal Society admissions day in London, July 2018
Born1959 (age 61–62)
Baroda, India
Alma materBaroda Medical College (BM)
Tufts University (PhD)
AwardsMember of the National Academy of Sciences (2015) and Fellow of the Royal Society (2018)
Scientific career
FieldsMicrobiology
Immunology
Infectious diseases[1]
InstitutionsUniversity of Cambridge
University of Washington
ThesisAbelson virus-transformed cells as models of early B lymphocyte differentiation (1990)
InfluencesStanley Falkow Naomi Rosenberg
Websitewww.med.cam.ac.uk/ramakrishnan/

Early life and education

Ramakrishnan was born in 1959 in Baroda (now Vadodara)[12] and grew up there.[13] Her parents were both scientists as is her brother, Nobel laureate Venki Ramakrishnan.[14] When Ramakrishnan was a child, her mother had three bouts of spinal tuberculosis.[3]

As a high school student, Ramakrishnan excelled at math and physics.[3] Ramakrishnan began attending medical school at age 17, which is "not atypical in India, where specialized training begins shortly after high school."[4] In 1983, she graduated with a Bachelor of Medicine degree in Vadodara[15] from Baroda Medical College.[16]

After taking an elective course in advanced immunology, Ramakrishnan decided to study immunology. In 1990, she graduated from Tufts University with a PhD in Immunology.[15] She then became the first foreign graduate of the medical residency program at Tufts-New England Medical Center.[4] After completing a fellowship in Infectious Diseases at the University of California at San Francisco hospitals, including San Francisco General Hospital (now Zuckerberg San Francisco General Hospital and Trauma Center),[17] Ramakrishnan completed postdoctoral work in Stanley Falkow's lab at Stanford University, where she developed the strategy of using Mycobacterium marinum infection in zebrafish as a model for tuberculosis.[6]

Career and research

In 2001, Ramakrishnan joined the faculty of the University of Washington,[6] where she worked both as a basic scientist and infectious diseases physician. While at the University of Washington, she pioneered the study of tuberculosis in zebrafish as a close approximation to tuberculosis in humans. This strategy led to a fundamental new biological understanding of how disease develops. Zebrafish larvae are optically transparent and lend themselves to genetic manipulation; by infecting them with their natural pathogen, Mycobacterium marinum, a bacterium that causes tuberculosis in fish and is a close genetic relative of the bacteria that cause tuberculosis in humans, she could carefully track the infection while manipulating the genes of both the larvae and the bacteria. This approach "enabled a detailed dissection of granuloma formation"[6] (a granuloma is a structure of the immune system made up principally of cells, called macrophages, that ingest bacteria and other foreign particles). In 2010, Ramakrishnan was the senior author of a study which was published as the cover story of Cell.[18]

In 2014, Ramakrishnan joined the faculty of the University of Cambridge as a Principal Research Fellow for the Wellcome Trust and Professor of Immunology and Infectious Diseases. Work in Seattle, and subsequently in Cambridge, led to the discovery of the molecular and cellular details of mycobacterial and host interactions at each step of infection. This yielded fundamental insights that suggest entirely new approaches to treat tuberculosis. Ramakrishnan and her research group showed that two lipids (a type of fatty molecule) on the surface of the mycobacteria work together to enable the bacteria to initially avoid the macrophages that would kill them and instead enter macrophages that provide them a niche for growth.[19] She found that the bacteria then stimulate the formation of granulomas that provide them a safe harbour, in contrast to the normal role of granulomas in protecting the host from the bacteria.[20] Later the infected macrophages in the granulomas die, and this accelerates bacterial growth and promotes the development of the disease.[21][22][23][24] These findings led to host-targeting therapies that show promise in tuberculosis patients. Ramakrishnan and her group tackled the problem of drug tolerance in tuberculosis, and found a drug that inhibits the development of resistance to the standard drugs used to treat the disease.[25]

Ramakrishnan later exploited the zebrafish to study leprosy, another devastating disease with morbid neurological consequences. She showed that a Mycobacterium leprae lipid causes nerve damage by inciting abnormal responses in the macrophages.[26]

In addition to basic science investigations, Ramakrishnan, along with Marcel Behr and Paul Edelstein, reviewed studies concerning the concept of latent tuberculosis in order to determine whether tuberculosis-infected persons have life-long infection capable of causing disease at any future time. These studies, both published in the British Medical Journal (BMJ), show that the incubation period of tuberculosis is short, usually within months after infection, and very rarely more than 2 years after infection.[27] They also show that more than 90% of people infected with M. tuberculosis for more than two years never develop tuberculosis even if their immune system is severely suppressed.[28] Immunologic tests for tuberculosis infection such as the tuberculin skin test and interferon gamma release assays (IGRA) only indicate past infection, with the majority of previously infected persons no longer capable of developing tuberculosis. Ramakrishnan told the New York Times that researchers "have spent hundreds of millions of dollars chasing after latency, but the whole idea that a quarter of the world is infected with TB is based on a fundamental misunderstanding."[9]

The first BMJ article about latency was accompanied by an editorial written by Dr. Soumya Swaminathan, Deputy Director-General of the World Health Organization, who endorsed the findings and called for more funding of TB research directed at the most heavily afflicted parts of the world, rather than disproportionate attention to a relatively minor problem that affects just the wealthy countries.[9] Earlier researchers had warned of a "ticking time bomb" of TB cases in the US and other wealthy countries that should be a focus of attention.[29] The work of Ramakrishnan and her coauthors cast doubt on this warning.

Awards and honours

Ramakrishnan was elected in 2015 to the National Academy of Sciences[16] of the United States.[30] She has received a number of other awards, including a National Institutes of Health (NIH) Director's Pioneer Award and a Burroughs Wellcome Fund Investigators in the Pathogenesis of Infectious Disease Award.[4] In 2018 she was elected a Fellow of the Royal Society (FRS)[31] and Fellow of the Academy of Medical Sciences (FMedSci).[32][33] She was made a member of the European Molecular Biology Organization (EMBO) in 2019.[34]

References
  1. Lalita Ramakrishnan publications indexed by Google Scholar
  2. Ramakrishnan, Lalita. Curriculum vitae. 2019
  3. Anon (2013). "An interview with Lalita Ramakrishnan". Trends in Pharmacological Sciences. 34 (4): 197. doi:10.1016/j.tips.2013.02.005. PMID 23566316.
  4. "Awardee Profile - Lalita Ramakrishnan | Burroughs Wellcome Fund". bwfund.org. Retrieved 24 April 2016.
  5. "Principal Research Fellows | Wellcome Trust". wellcome.ac.uk. Retrieved 24 April 2016.
  6. Sheffield, University of. "Professor Lalita Ramakrishnan - Faculty Events - Faculty of Medicine, Dentistry and Health - Faculties - The University of Sheffield". sheffield.ac.uk. Retrieved 24 April 2016.
  7. "Stanley Falkow", Wikipedia, 26 September 2019, retrieved 25 October 2019
  8. Lalita Ramakrishnan publications indexed by the Scopus bibliographic database. (subscription required)
  9. McNeil, Donald G. Jr. (20 September 2018). "'Latent' tuberculosis? It's not that common, experts find". The New York Times.
  10. Behr, Marcel A.; Edelstein, Paul H.; Ramakrishnan, Lalita (23 August 2018). "Revisiting the timetable of tuberculosis". BMJ. 362: k2738. doi:10.1136/bmj.k2738. ISSN 0959-8138. PMC 6105930. PMID 30139910.
  11. Behr, Marcel A.; Edelstein, Paul H.; Ramakrishnan, Lalita (24 October 2019). "Is Mycobacterium tuberculosis infection life long?". BMJ. 367: l5770. doi:10.1136/bmj.l5770. ISSN 0959-8138. PMC 6812595. PMID 31649096.
  12. "Venkatraman Ramakrishnan - Biographical". www.nobelprize.org. Retrieved 24 April 2016.
  13. "Northwest Association for Biomedical Research" (PDF).
  14. "Venkatraman Ramakrishnan", Wikipedia, 23 October 2019, retrieved 25 October 2019
  15. "About | Lalita Ramakrishnan Lab". depts.washington.edu. Retrieved 24 April 2016.
  16. "- BSI Inflammation Affinity Group Speakers Bio - Lalita Ramakrishnan - British Society for Immunology". immunology.org. Retrieved 24 April 2016.
  17. "Zuckerberg San Francisco General Hospital and Trauma Center (ZSFG) | San Francisco Level 1 Trauma Center". Zuckerberg San Francisco General. Retrieved 25 October 2019.
  18. "Researchers discover gene that affects susceptibility to TB and clues to how it works | (e) Science News". esciencenews.com. Retrieved 24 April 2016.
  19. Cambier, C. J.; O'Leary, Seónadh M.; O'Sullivan, Mary P.; Keane, Joseph; Ramakrishnan, Lalita (19 September 2017). "Phenolic Glycolipid Facilitates Mycobacterial Escape from Microbicidal Tissue-Resident Macrophages". Immunity. 47 (3): 552–565.e4. doi:10.1016/j.immuni.2017.08.003. ISSN 1097-4180. PMC 5610147. PMID 28844797.
  20. Conrad, William H.; Osman, Morwan M.; Shanahan, Jonathan K.; Chu, Frances; Takaki, Kevin K.; Cameron, James; Hopkinson-Woolley, Digby; Brosch, Roland; Ramakrishnan, Lalita (7 February 2017). "Mycobacterial ESX-1 secretion system mediates host cell lysis through bacterium contact-dependent gross membrane disruptions". Proceedings of the National Academy of Sciences of the United States of America. 114 (6): 1371–1376. doi:10.1073/pnas.1620133114. ISSN 1091-6490. PMC 5307465. PMID 28119503.
  21. Tobin, David M.; Vary, Jay C.; Ray, John P.; Walsh, Gregory S.; Dunstan, Sarah J.; Bang, Nguyen D.; Hagge, Deanna A.; Khadge, Saraswoti; King, Mary-Claire; Hawn, Thomas R.; Moens, Cecilia B. (5 March 2010). "The lta4h locus modulates susceptibility to mycobacterial infection in zebrafish and humans". Cell. 140 (5): 717–730. doi:10.1016/j.cell.2010.02.013. ISSN 1097-4172. PMC 2907082. PMID 20211140.
  22. Tobin, David M.; Roca, Francisco J.; Oh, Sungwhan F.; McFarland, Ross; Vickery, Thad W.; Ray, John P.; Ko, Dennis C.; Zou, Yuxia; Bang, Nguyen D.; Chau, Tran T. H.; Vary, Jay C. (3 February 2012). "Host genotype-specific therapies can optimize the inflammatory response to mycobacterial infections". Cell. 148 (3): 434–446. doi:10.1016/j.cell.2011.12.023. ISSN 1097-4172. PMC 3433720. PMID 22304914.
  23. Tobin, David M.; Roca, Francisco J.; Ray, John P.; Ko, Dennis C.; Ramakrishnan, Lalita (2013). "An enzyme that inactivates the inflammatory mediator leukotriene b4 restricts mycobacterial infection". PLOS ONE. 8 (7): e67828. Bibcode:2013PLoSO...867828T. doi:10.1371/journal.pone.0067828. ISSN 1932-6203. PMC 3708926. PMID 23874453.
  24. Thuong, Nguyen T. T.; Heemskerk, Dorothee; Tram, Trinh T. B.; Thao, Le T. P.; Ramakrishnan, Lalita; Ha, Vu T. N.; Bang, Nguyen D.; Chau, Tran T. H.; Lan, Nguyen H.; Caws, Maxine; Dunstan, Sarah J. (1 April 2017). "Leukotriene A4 Hydrolase Genotype and HIV Infection Influence Intracerebral Inflammation and Survival From Tuberculous Meningitis". The Journal of Infectious Diseases. 215 (7): 1020–1028. doi:10.1093/infdis/jix050. ISSN 1537-6613. PMC 5426373. PMID 28419368.
  25. Adams, Kristin N.; Takaki, Kevin; Connolly, Lynn E.; Wiedenhoft, Heather; Winglee, Kathryn; Humbert, Olivier; Edelstein, Paul H.; Cosma, Christine L.; Ramakrishnan, Lalita (1 April 2011). "Drug tolerance in replicating mycobacteria mediated by a macrophage-induced efflux mechanism". Cell. 145 (1): 39–53. doi:10.1016/j.cell.2011.02.022. ISSN 1097-4172. PMC 3117281. PMID 21376383.
  26. Madigan, Cressida A.; Cambier, C. J.; Kelly-Scumpia, Kindra M.; Scumpia, Philip O.; Cheng, Tan-Yun; Zailaa, Joseph; Bloom, Barry R.; Moody, D. Branch; Smale, Stephen T.; Sagasti, Alvaro; Modlin, Robert L. (24 August 2017). "A Macrophage Response to Mycobacterium leprae Phenolic Glycolipid Initiates Nerve Damage in Leprosy". Cell. 170 (5): 973–985.e10. doi:10.1016/j.cell.2017.07.030. ISSN 1097-4172. PMC 5848073. PMID 28841420.
  27. Behr, Marcel A.; Edelstein, Paul H.; Ramakrishnan, Lalita (23 August 2018). "Revisiting the timetable of tuberculosis". BMJ (Clinical Research Ed.). 362: k2738. doi:10.1136/bmj.k2738. ISSN 1756-1833. PMC 6105930. PMID 30139910.
  28. Behr, Marcel A.; Edelstein, Paul H.; Ramakrishnan, Lalita (24 October 2019). "Is Mycobacterium tuberculosis infection life long?". BMJ. 367: l5770. doi:10.1136/bmj.l5770. ISSN 0959-8138. PMC 6812595. PMID 31649096.
  29. Maugh II, Thomas H. (17 May 2011). "Shorter treatment found for latent tuberculosis". Los Angeles Times. Although TB control measures in the United States have brought the incidence of the disease to an all-time low of 11,181 cases in 2010, it is estimated that at least 11 million Americans have latent TB. 'The 11 million Americans with latent TB represent a ticking time bomb,' Dr. Kenneth Castro, director of the Centers for Disease Control and Prevention’s division of tuberculosis elimination, said at a news conference Monday. 'They're the source of future TB cases.'
  30. "National Academy of Sciences Elects New Members for 2015". India West. Retrieved 24 April 2016.
  31. "Lalita Ramakrishnan". royalsociety.org.
  32. "New Fellows for 2018 announced - The Academy of Medical Sciences". acmedsci.ac.uk.
  33. "Distinguished scientists elected as Fellows and Foreign Members of the Royal Society". The Royal Society. 9 May 2018. Retrieved 10 May 2018.
  34. EMBO. "EMBO elects 56 new Members". EMBO. Retrieved 25 October 2019.

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