David M. Sabatini

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David M. Sabatini
WALS David M. Sabatini 3m04s (cropped).jpg
Born (1968-01-27) January 27, 1968 (age 55)
New York, United States
Nationality American
Citizenship United States
Alma mater Brown University
Johns Hopkins School of Medicine
Known forCo-discovery and study of mTOR
Scientific career
Fields Biochemistry
Cell Biology
Institutions Whitehead Institute
Massachusetts Institute of Technology
Broad Institute
Doctoral advisor Solomon H. Snyder

David M. Sabatini (born January 27, 1968) is an American scientist and a former professor of biology at the Massachusetts Institute of Technology. From 2002 to 2021, he was a member of the Whitehead Institute for Biomedical Research. He was also an investigator of the Howard Hughes Medical Institute from 2008 to 2021 and was elected to the National Academy of Sciences in 2016. He is known for his contributions in the areas of cell signaling and cancer metabolism, most notably the co-discovery of mTOR. [1]

Contents

In 2021 and 2022, Sabatini was fired from the Howard Hughes Medical Institute and resigned his positions at the Whitehead Institute and the Massachusetts Institute of Technology, following allegations of sexual harassment. [2] [3] [4] Sabatini denies the allegations.

Biography

David M. Sabatini was born and raised in New York to David D. Sabatini and Zulema Sabatini, both Argentine immigrants from Buenos Aires. He obtained his B.S. from Brown University followed by both his MD and his Ph.D. at Johns Hopkins School of Medicine, where he worked in the lab of Solomon H. Snyder. He joined the Whitehead Institute as a Whitehead Fellow in 1997, the same year he graduated from Johns Hopkins. [5] In 2002 he became an assistant professor at MIT and a Member of the Whitehead Institute. He was promoted to tenured professor in 2006.

Sabatini's father, David D. Sabatini, is a cell biologist and professor at New York University. His younger brother, Bernardo L. Sabatini, is a neuroscientist and professor at Harvard Medical School. [5] [6]

Sabatini is the scientific founder of Navitor, [7] Raze Therapeutics, [8] and KSQ Therapeutics. [9]

Allegations of sexual misconduct

In late 2021, following an investigation by an outside law firm of concerns surrounding sexual harassment, the Howard Hughes Medical Institute fired Sabatini, and he resigned from the Whitehead Institute. [2] [10] Following this, MIT placed Sabatini on administrative leave while it conducted its own investigation. [11] MIT's investigation concluded that Sabatini had violated its policies on sexual relationships in the workplace. The investigation gave a recommendation to revoke tenure, at which time Sabatini resigned from his position at MIT. [3] [11] Sabatini denies that the alleged behavior was sexual harassment, and he has filed a defamation lawsuit against the Whitehead Institute and two of its scientists. [3] [12] [4]

In 2022, Sabatini was under consideration for a position at the NYU Grossman School of Medicine. [13] After significant protests from students and some faculty over the sexual harassment allegations, he withdrew his name from consideration. [4] [14] [15]

Independent funding and IOCB Prague

In February 2023, Bill Ackman and an unnamed partner announced $25 million to fund Sabatini's research, though it is unclear if he could successfully find an institution willing to host his lab or if one could be built independently. [16] [17] By November 2023, Sabatini had accepted a position at the Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences in Prague. [18] [19]

Scientific contributions

As a graduate student in Solomon Snyder's Lab at Johns Hopkins, Sabatini began working on understanding the molecular mechanism of rapamycin; a macrolide antibiotic discovered in the soil of Easter Island that has potent antifungal, immunosuppressive, and anti-tumorigenic properties. [5] Although the TOR/DRR genes had been identified in 1993 as conferring rapamycin resistance in budding yeast, the direct target of rapamycin and its mechanism of action in mammals was unknown. [20] [21] In 1994, Sabatini used rapamycin and its binding partner FKBP12 to purify the mechanistic Target of Rapamycin (mTOR) protein from rat brain, showing it to be the direct target of rapamycin in mammals and the homolog of the yeast TOR/DRR genes. [5]

Since starting his own lab at the Whitehead Institute in 1997, Sabatini has made numerous key contributions to the understanding of mTOR function, regulation, and importance in diseases such as cancer. [22] For example, his lab discovered the mTORC1 [23] and mTORC2 [24] multi-protein complexes, the nutrient sensing Rag GTPase pathway upstream of mTORC1, [25] as well as the direct amino acid sensors Sestrin [26] [27] and CASTOR. [28] [29]

mTOR signaling pathway. MTOR-pathway-v1.7.svg
mTOR signaling pathway.

Sabatini's research interests have expanded in recent years to include cancer metabolism as well as technology development surrounding the use of high-throughput genetic screens in human cells, most notably through the use of RNA interference [30] and the CRISPR-Cas9 system. [31]

Selected awards and honors

Selected publications

Related Research Articles

<span class="mw-page-title-main">Leucine</span> Chemical compound

Leucine (symbol Leu or L) is an essential amino acid that is used in the biosynthesis of proteins. Leucine is an α-amino acid, meaning it contains an α-amino group (which is in the protonated −NH3+ form under biological conditions), an α-carboxylic acid group (which is in the deprotonated −COO− form under biological conditions), and a side chain isobutyl group, making it a non-polar aliphatic amino acid. It is essential in humans, meaning the body cannot synthesize it: it must be obtained from the diet. Human dietary sources are foods that contain protein, such as meats, dairy products, soy products, and beans and other legumes. It is encoded by the codons UUA, UUG, CUU, CUC, CUA, and CUG.

<span class="mw-page-title-main">Sirolimus</span> Pharmaceutical drug

Sirolimus, also known as rapamycin and sold under the brand name Rapamune among others, is a macrolide compound that is used to coat coronary stents, prevent organ transplant rejection, treat a rare lung disease called lymphangioleiomyomatosis, and treat perivascular epithelioid cell tumor (PEComa). It has immunosuppressant functions in humans and is especially useful in preventing the rejection of kidney transplants. It is a mechanistic target of rapamycin kinase (mTOR) inhibitor that inhibits activation of T cells and B cells by reducing their sensitivity to interleukin-2 (IL-2).

mTOR Mammalian protein found in humans

The mammalian target of rapamycin (mTOR), also referred to as the mechanistic target of rapamycin, and sometimes called FK506-binding protein 12-rapamycin-associated protein 1 (FRAP1), is a kinase that in humans is encoded by the MTOR gene. mTOR is a member of the phosphatidylinositol 3-kinase-related kinase family of protein kinases.

<span class="mw-page-title-main">Folliculin</span> Protein-coding gene

The tumor suppressor gene FLCN encodes the protein folliculin, also known as Birt–Hogg–Dubé syndrome protein, which functions as an inhibitor of Lactate Dehydrogenase-A and a regulator of the Warburg effect. Folliculin (FLCN) is also associated with Birt–Hogg–Dubé syndrome, which is an autosomal dominant inherited cancer syndrome in which affected individuals are at risk for the development of benign cutaneous tumors (folliculomas), pulmonary cysts, and kidney tumors.

<span class="mw-page-title-main">EIF4EBP1</span> Protein-coding gene in the species Homo sapiens

Eukaryotic translation initiation factor 4E-binding protein 1 is a protein that in humans is encoded by the EIF4EBP1 gene. inhibits cap-dependent translation by binding to translation initiation factor eIF4E. Phosphorylation of 4E-BP1 results in its release from eIF4E, thereby allows cap-dependent translation to continue thereby increasing the rate of protein synthesis.

<span class="mw-page-title-main">RHEB</span> Protein-coding gene in the species Homo sapiens

RHEB also known as Ras homolog enriched in brain (RHEB) is a GTP-binding protein that is ubiquitously expressed in humans and other mammals. The protein is largely involved in the mTOR pathway and the regulation of the cell cycle.

<span class="mw-page-title-main">P70-S6 Kinase 1</span> Protein-coding gene in the species Homo sapiens

Ribosomal protein S6 kinase beta-1 (S6K1), also known as p70S6 kinase, is an enzyme that in humans is encoded by the RPS6KB1 gene. It is a serine/threonine kinase that acts downstream of PIP3 and phosphoinositide-dependent kinase-1 in the PI3 kinase pathway. As the name suggests, its target substrate is the S6 ribosomal protein. Phosphorylation of S6 induces protein synthesis at the ribosome.

<span class="mw-page-title-main">RPTOR</span> Protein-coding gene in humans

Regulatory-associated protein of mTOR also known as raptor or KIAA1303 is an adapter protein that is encoded in humans by the RPTOR gene. Two mRNAs from the gene have been identified that encode proteins of 1335 and 1177 amino acids long.

<span class="mw-page-title-main">LPIN1</span> Protein-coding gene in the species Homo sapiens

Lipin-1 is a protein that in humans is encoded by the LPIN1 gene.

<span class="mw-page-title-main">RICTOR</span> Protein-coding gene in the species Homo sapiens

Rapamycin-insensitive companion of mammalian target of rapamycin (RICTOR) is a protein that in humans is encoded by the RICTOR gene.

<span class="mw-page-title-main">DEPTOR</span> Protein-coding gene in the species Homo sapiens

DEP domain-containing mTOR-interacting protein (DEPTOR) also known as DEP domain-containing protein 6 (DEPDC6) is a protein that in humans is encoded by the DEPTOR gene.

<span class="mw-page-title-main">MLST8</span> Protein-coding gene in humans

Target of rapamycin complex subunit LST8, also known as mammalian lethal with SEC13 protein 8 (mLST8) or TORC subunit LST8 or G protein beta subunit-like, is a protein that in humans is encoded by the MLST8 gene. It is a subunit of both mTORC1 and mTORC2, complexes that regulate cell growth and survival in response to nutrient, energy, redox, and hormonal signals. It is upregulated in several human colon and prostate cancer cell lines and tissues. Knockdown of mLST8 prevented mTORC formation and inhibited tumor growth and invasiveness.

mTOR inhibitors Class of pharmaceutical drugs

mTOR inhibitors are a class of drugs that inhibit the mammalian target of rapamycin (mTOR), which is a serine/threonine-specific protein kinase that belongs to the family of phosphatidylinositol-3 kinase (PI3K) related kinases (PIKKs). mTOR regulates cellular metabolism, growth, and proliferation by forming and signaling through two protein complexes, mTORC1 and mTORC2. The most established mTOR inhibitors are so-called rapalogs, which have shown tumor responses in clinical trials against various tumor types.

mTORC1 Protein complex

mTORC1, also known as mammalian target of rapamycin complex 1 or mechanistic target of rapamycin complex 1, is a protein complex that functions as a nutrient/energy/redox sensor and controls protein synthesis.

mTOR Complex 2 (mTORC2) is an acutely rapamycin-insensitive protein complex formed by serine/threonine kinase mTOR that regulates cell proliferation and survival, cell migration and cytoskeletal remodeling. The complex itself is rather large, consisting of seven protein subunits. The catalytic mTOR subunit, DEP domain containing mTOR-interacting protein (DEPTOR), mammalian lethal with sec-13 protein 8, and TTI1/TEL2 complex are shared by both mTORC2 and mTORC1. Rapamycin-insensitive companion of mTOR (RICTOR), mammalian stress-activated protein kinase interacting protein 1 (mSIN1), and protein observed with rictor 1 and 2 (Protor1/2) can only be found in mTORC2. Rictor has been shown to be the scaffold protein for substrate binding to mTORC2.

<span class="mw-page-title-main">Michael N. Hall</span> American-Swiss molecular biologist

Michael Nip Hall is an American-Swiss molecular biologist and professor at the Biozentrum of the University of Basel, Switzerland. He discovered TOR, a protein central for regulating cell growth.

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<span class="mw-page-title-main">Ragulator-Rag complex</span> Aspect of cell metabolism

The Ragulator-Rag complex is a regulator of lysosomal signalling and trafficking in eukaryotic cells, which plays an important role in regulating cell metabolism and growth in response to nutrient availability in the cell. The Ragulator-Rag Complex is composed of five LAMTOR subunits, which work to regulate MAPK and mTOR complex 1. The LAMTOR subunits form a complex with Rag GTPase and v-ATPase, which sits on the cell’s lysosomes and detects the availability of amino acids. If the Ragulator complex receives signals for low amino acid count, it will start the process of catabolizing the cell. If there is an abundance of amino acids available to the cell, the Ragulator complex will signal that the cell can continue to grow. Ragulator proteins come in two different forms: Rag A/Rag B and Rag C/Rag D. These interact to form heterodimers with one another.

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Phosphatidylinositol 3-phosphate-binding protein 2 (Pib2) is a yeast protein involved in the regulation of TORC1 signaling and lysosomal membrane permeabilization. It is essential for the reactivation of TORC1 following exposure to rapamycin or nutrient starvation.

References

  1. ↑ Sabatini DM, Erdjument-Bromage H, Lui M, Tempst P, Snyder SH (July 1994). "RAFT1: a mammalian protein that binds to FKBP12 in a rapamycin-dependent fashion and is homologous to yeast TORs". Cell. 78 (1): 35–43. doi:10.1016/0092-8674(94)90570-3. PMID   7518356. S2CID   33647539.
  2. 1 2 Wadman, Meredith (August 21, 2021). "HHMI fires prominent biologist for sexual harassment". Science. American Association for the Advancement of Science.
  3. 1 2 3 Wadman, Meredith (April 1, 2022). "Prominent biologist David Sabatini out at MIT after breaching sexual relationship policy". Science. American Association for the Advancement of Science. Retrieved April 2, 2022.
  4. 1 2 3 Wong, Ashley (May 3, 2022). "N.Y.U. Will Not Hire Scientist Accused of Harassment After Backlash". The New York Times. Retrieved May 25, 2022.
  5. 1 2 3 4 Viegas, Jennifer (December 26, 2017). "Profile of David M. Sabatini". Proceedings of the National Academy of Sciences of the United States of America. 115 (3): 438–440. doi: 10.1073/pnas.1721196115 . PMC   5777013 . PMID   29279397.
  6. ↑ Ware, Lauren (2013). "Science in their Blood". HHMI Bulletin. Howard Hughes Medical Institute. Retrieved April 5, 2017.
  7. ↑ "Navitor Pharmaceuticals". Archived from the original on November 14, 2017. Retrieved September 12, 2015.
  8. ↑ "Founders". Raze Therapeutics. Archived from the original on December 1, 2016. Retrieved May 4, 2022.
  9. ↑ Kendall Square Therapeutics
  10. ↑ Stocio, Nick (August 21, 2021). "MIT professor, biotech founder placed on leave following investigation into sexual harassment". Boston Globe. Retrieved August 21, 2021.
  11. 1 2 Fox, Jeremy C. (April 2, 2022). "MIT professor accused of sexually harassing grad student resigns". Boston Globe. Retrieved April 29, 2022.
  12. ↑ Fox, Jeremy C. (December 7, 2021). "Lawsuit alleges MIT professor 'groomed' young women, ran 'sexually charged' lab". The Boston Globe. Retrieved June 4, 2022.
  13. ↑ Wadman, Meredith (April 25, 2022). "NYU may hire biologist pushed out of MIT, Whitehead for sexual misconduct". Science. American Association for the Advancement of Science. Retrieved May 25, 2022.
  14. ↑ Merlan, Anna (May 3, 2022). "Biologist Accused of Sexual Misconduct Withdraws from Consideration at NYU". Vice. Retrieved May 25, 2022.
  15. ↑ El-bawab, Nadine (May 3, 2022). "Former MIT professor accused of sexual harassment withdraws from NYU hiring consideration". ABC News. Retrieved May 25, 2022.
  16. ↑ Arsenault, Mark (February 7, 2023). "New funding for controversial MIT and Whitehead Institute scientist David Sabatini draws divided reactions". The Boston Globe. Retrieved February 19, 2023.
  17. ↑ Wadman, Meredith (February 3, 2023). "David Sabatini, biologist fired for sexual misconduct, lands millions from private donors to start new lab". Science. American Association for the Advancement of Science. Retrieved February 19, 2023.
  18. ↑ Arsenault, Mark (November 13, 2023). "Former MIT biologist, who lost positions after engaging in a prohibited sexual relationship, accepts new science position in Prague". The Boston Globe. Retrieved November 13, 2023.
  19. ↑ Wadman, Meredith (November 13, 2023). "Despite sexual harassment shadow, biologist David Sabatini lands job at top Czech institute". Science. American Association for the Advancement of Science. Retrieved November 18, 2023.
  20. ↑ Kunz J, Henriquez R, Schneider U, Deuter-Reinhard M, Movva NR, Hall MN (1993). "Target of rapamycin in yeast, TOR2, is an essential phosphatidylinositol kinase homolog required for G1 progression". Cell. 73 (3): 585–96. doi:10.1016/0092-8674(93)90144-f. PMID   8387896. S2CID   42926249.
  21. ↑ Cafferkey R, Young PR, McLaughlin MM, Bergsma DJ, Koltin Y, Sathe GM, Faucette L, Eng WK, Johnson RK, Livi GP (1993). "Dominant missense mutations in a novel yeast protein related to mammalian phosphatidylinositol 3-kinase and VPS34 abrogate rapamycin cytotoxicity". Mol. Cell. Biol. 13 (10): 6012–23. doi:10.1128/mcb.13.10.6012. PMC   364661 . PMID   8413204.
  22. ↑ Saxton RA, Sabatini, DM (2017). "mTOR Signaling in Growth, Metabolism, and Disease". Cell. 169 (2): 361–371. doi: 10.1016/j.cell.2017.03.035 . PMID   28388417.
  23. ↑ Kim DH, Sarbassov DD, Ali SM, et al. (2002). "mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery". Cell. 110 (2): 163–75. doi: 10.1016/s0092-8674(02)00808-5 . PMID   12150925. S2CID   4656930.
  24. ↑ Sarbassov DD, Ali SM, Kim DH, et al. (2004). "Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton". Curr. Biol. 14 (14): 1296–302. doi: 10.1016/j.cub.2004.06.054 . PMID   15268862. S2CID   4658268.
  25. ↑ Sancak Y, Peterson TR, Shaul YD, et al. (2008). "The Rag GTPases bind raptor and mediate amino acid signaling to mTORC1". Science. 320 (5882): 1496–501. Bibcode:2008Sci...320.1496S. doi:10.1126/science.1157535. PMC   2475333 . PMID   18497260.
  26. ↑ Wolfson RL, Chantranupong L, Saxton RA, et al. (2016). "Sestrin2 is a leucine sensor for the mTORC1 pathway". Science. 351 (6268): 43–8. Bibcode:2016Sci...351...43W. doi:10.1126/science.aab2674. PMC   4698017 . PMID   26449471.
  27. ↑ Saxton RA, Knockenhauer KE, Wolfson RL, et al. (2016). "Structural basis for leucine sensing by the Sestrin2-mTORC1 pathway". Science. 351 (6268): 53–8. Bibcode:2016Sci...351...53S. doi:10.1126/science.aad2087. PMC   4698039 . PMID   26586190.
  28. ↑ Chantranupong L, Scaria SM, Saxton RA, et al. (2016). "The CASTOR Proteins Are Arginine Sensors for the mTORC1 Pathway". Cell. 165 (1): 153–64. doi:10.1016/j.cell.2016.02.035. PMC   4808398 . PMID   26972053.
  29. ↑ Saxton RA, Chantranupong L, Knockenhauer KE, Schwartz TU, Sabatini DM (2016). "Mechanism of arginine sensing by CASTOR1 upstream of mTORC1". Nature. 536 (7615): 229–33. Bibcode:2016Natur.536..229S. doi:10.1038/nature19079. PMC   4988899 . PMID   27487210.
  30. ↑ Moffat J, Grueneberg DA, Yang X, et al. (2006). "A lentiviral RNAi library for human and mouse genes applied to an arrayed viral high-content screen". Cell. 124 (6): 1283–98. doi: 10.1016/j.cell.2006.01.040 . PMID   16564017. S2CID   630641.
  31. ↑ Wang T, Wei JJ, Sabatini DM, Lander ES (2014). "Genetic screens in human cells using the CRISPR-Cas9 system" (PDF). Science. 343 (6166): 80–4. Bibcode:2014Sci...343...80W. doi:10.1126/science.1246981. PMC   3972032 . PMID   24336569.
  32. ↑ "Columbia Presents Horwitz Prize to Three Scientists for Cancer Discoveries". Columbia University Irving Medical Center. January 10, 2020. Retrieved January 29, 2023.
  33. ↑ "The Louisa Gross Horwitz Prize". Columbia University Irving Medical Center. June 14, 2018.
  34. ↑ "Whitehead Institute Member David Sabatini Receives the 2020 Sjöberg Prize from the Royal Swedish Academy of Sciences". Whitehead Institute. February 4, 2020.

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