Gerald Crabtree

Last updated
Gerald R. Crabtree
Born (1946-12-18) December 18, 1946 (age 77)
Wheeling, West Virginia
Nationality American
Alma mater West Liberty State College, Temple University
Scientific career
Fields Developmental Biology
Institutions Stanford University

Gerald R. Crabtree is the David Korn Professor at Stanford University and an Investigator in the Howard Hughes Medical Institute. He is known for defining the Ca2+-calcineurin-NFAT signaling pathway, pioneering the development of synthetic ligands for regulation of biologic processes and discovering chromatin regulatory mechanisms involved in cancer and brain development. He is a founder of Ariad Pharmaceuticals, Amplyx Pharmaceuticals, and Foghorn Therapeutics.

Contents

Education and training

Crabtree grew up near Wellsburg, West Virginia, earned his B.S. in Chemistry and Mathematics from West Liberty State College and his M.D. from Temple University. While at medical school, he became interested in laboratory research and started to work at Dartmouth College with Allan Munck on the biochemistry of steroid hormones.

Key discoveries 1980s, 1990s and 2010s

In the early 1980s Crabtree worked with Albert J. Fornace Jr. to use early bioinformatics approaches to identify remnants of transposition events (rearrangements) in the human genome [1] and to discover the HNF1 transcription factor. [2] In 1982 Crabtree discovered that one gene could produce more than one protein [3] thereby demonstrating that the coding capability of the genome is larger than expected and breaking the long-held dictum: “one gene; one protein."

In the late 80’s and early 90’s Crabtree mapped the pathways initiated by the antigen receptor on T cells by beginning in the nucleus with the early T cell activation genes like IL-2 and working biochemically toward the cell membrane. These studies led to the discovery of NFAT and the conclusion that membrane signaling by the antigen receptor led to the rapid nuclear entry of this transcription factor and the activation of group of genes like Il-2, gamma interferon and others essential for the immune response. In the late 1980s and early 1990s Crabtree, along with Stuart Schreiber further defined the Ca2+/calcineurin/ NFAT signaling pathway, [4] [5] [6] [7] [8] which carries signals from the cell surface to the nucleus to activate immune response genes. These discoveries resulted in the first understanding of the mechanism of action of the two most commonly used immunosuppressant drugs: cyclosporine and FK506. [9] Crabtree and Schreiber found that these drugs prevent signals originating at the cell membrane from entering the nucleus by blocking the actions of the phosphatase, calcineurin preventing the entry of the NFATc proteins into the nucleus. NFAT proteins activate a large group of genes necessary for the immune response. When these genes are not activated, as occurs with Cyclosporine or FK506 administration, transplant rejection is prevented. The elucidation of the Ca2+ - Calcineurin-NFAT signaling pathway and the discovery that it is the target of Cyclosporine and FK506 was covered in the New York Times. [10] Later his laboratory used genetic approaches in mice to show that calcineurin-NFAT signaling plays essential roles in the development of many vertebrate organ systems [11] and its dysregulation is likely to be responsible for many of the phenotypes of Down Syndrome. [12] The understanding of this signaling pathway provided one of the first biochemical bridges from the cell membrane to the nucleus. (see also: Stuart Schreiber).

In 1992, working with Calvin Kuo, then a graduate student in his laboratory, he discovered that the immunosuppressive drug, rapamycin blocked a biochemical pathway leading to protein synthesis in response to membrane cell proliferation signals. [13] This work contributed to the development of rapamycin as a therapeutic for certain human cancers and also played a role in the founding of Ariad Pharmaceuticals in Cambridge, Massachusetts.

In 1993 Crabtree and Stuart Schreiber designed and synthesized the first synthetic ligands to induce proximity of proteins within cells . [14] Crabtree then used these molecules to understand the role of proximity in biologic regulation.  His studies revealed that chemically induced proximity was a fundamental mechanism underlying many aspects of cellular signaling, including receptor activation , [15] [16] kinase function , [17] protein localization , [18] transcription [19] and epigenetic regulation . [20]   He generalized this approach to other types of chemical inducers of proximity (CIPs) including natural molecules involved in plant signaling that have expanded the usefulness of this approach. [21] At present CIPs are being used to probe the function of many signaling pathways and biologic events within cells . [22] This approach has proved useful in rapidly activating and inactivating molecules to allow one to study their function. Crabtree and colleagues Nathan Hathaway and Oli Bell have used induced proximity to make measurements of the dynamics of chromatin regulation in living cells leading to an understanding of the stability of epigenetic changes involved in cellular memory. [17] [18] The development of chemical inducers of proximity by Crabtree and Schreiber was covered in the New York Times [19] and also in Discovery Magazine in 1996. [20] Later, Ariad Pharmaceuticals developed this technology for gene therapy . [23] These discoveries led Steve Crews at Yale to develop PROTACS for the selective degradation of therapeutic targets. [24]

More recently, Crabtree and colleague Nathanael Gray at Stanford have made use of induced proximity to rewire the cancer cell to kill itself using its own mutated driver [25] thereby specifically killing the mutated cancer cell and not normal cells lacking the mutation. This gain-of-function strategy shows promise for avoiding cancer relapse due to secondary cancer drivers and compensation. The development of these molecules (TCIPs for Transcription/epigenetic Chemical Inducers of Proximity) was covered in the New York Times by Gina Kolata.

In the early 1990s Crabtree worked with Paul Khavari, now the Carl J. Herzog Professor of Medicine at Stanford University, to define the mammalian SWI/SNF or BAF complex by purifying and cloning the genes that encode its subunits. [26] [27] Using biochemical and genetic approaches he discovered that the genes that encode its subunits are put together like letters in a word to give a wide variety of different biological meanings. [28] In 2009 he worked with postdoctoral fellow, Andrew Yoo to discover a genetic circuitry controlling the assembly of specialized, brain-specific chromatin regulatory complexes necessary for the development of the mammalian nervous system and demonstrated that recapitulating this circuitry in mammalian cells converts human skin cells to neurons. [29] [30]

Crabtree's laboratory completed the characterization of the subunits of BAF (mSWI/SNF) chromatin remodeling complexes, and found that these complexes contribute to the cause of over 20% of human cancers and can act as either oncogenes or tumor suppressors, potentially opening a new avenue for treatment. [31] [32] [33]

In 2013, Crabtree published "Our Fragile Intellect" in Trends in Genetics, The prediction that our intellectual abilities are genetically fragile was based on the determined rate of human de novo mutations (those mutations that appear in each generation). This rate has been determined in several human populations to be about 1.20 x10-8 per nucleotide per generation with an average father’s age of 29.7 years. [34] This rate doubles every 16.5 years with the father’s age and ascribes most of the new mutations to the father during the production of reproductive cells.  Thus about 45 to 60 new mutations occur per generation per human genome with each new generation.  The conclusion that the accumulation of these new mutations over the generations would lead to intellectual fragility was based on the estimate of the fraction of genes necessary for normal development of the nervous system, which is thought to be several thousand. The nervous system is unique in that an extraordinarily large number of genes are required for the development and function of the brain representing perhaps 10- to 20% of all human genes. [35] The simple combination of the number of genes required for normal brain development (>1000) and the fact that each human generation has 45-60 new mutations per genome led Crabtree to suggest that our intellectual abilities are particularly genetically fragile over many generations.

Selected awards

Notable students and their current affiliation

Related Research Articles

<span class="mw-page-title-main">Calcineurin</span> Class of enzymes

Calcineurin (CaN) is a calcium and calmodulin dependent serine/threonine protein phosphatase. It activates the T cells of the immune system and can be blocked by drugs. Calcineurin activates nuclear factor of activated T cell cytoplasmic (NFATc), a transcription factor, by dephosphorylating it. The activated NFATc is then translocated into the nucleus, where it upregulates the expression of interleukin 2 (IL-2), which, in turn, stimulates the growth and differentiation of the T cell response. Calcineurin is the target of a class of drugs called calcineurin inhibitors, which include ciclosporin, voclosporin, pimecrolimus and tacrolimus.

<span class="mw-page-title-main">SWI/SNF</span> Subfamily of ATP-dependent chromatin remodeling complexes

In molecular biology, SWI/SNF, is a subfamily of ATP-dependent chromatin remodeling complexes, which is found in eukaryotes. In other words, it is a group of proteins that associate to remodel the way DNA is packaged. This complex is composed of several proteins – products of the SWI and SNF genes, as well as other polypeptides. It possesses a DNA-stimulated ATPase activity that can destabilize histone-DNA interactions in reconstituted nucleosomes in an ATP-dependent manner, though the exact nature of this structural change is unknown. The SWI/SNF subfamily provides crucial nucleosome rearrangement, which is seen as ejection and/or sliding. The movement of nucleosomes provides easier access to the chromatin, enabling binding of specific transcription factors, and allowing genes to be activated or repressed.

<span class="mw-page-title-main">Stuart Schreiber</span> American chemist

Stuart Schreiber is an American chemist who is the Morris Loeb Research Professor at Harvard University, a co-Founder of the Broad Institute, Howard Hughes Medical Institute Investigator, Emeritus, and a member of the National Academy of Sciences and National Academy of Medicine. He currently leads Arena BioWorks.

<span class="mw-page-title-main">FKBP</span>

The FKBPs, or FK506 binding proteins, constitute a family of proteins that have prolyl isomerase activity and are related to the cyclophilins in function, though not in amino acid sequence. FKBPs have been identified in many eukaryotes, ranging from yeast to humans, and function as protein folding chaperones for proteins containing proline residues. Along with cyclophilin, FKBPs belong to the immunophilin family.

Nuclear factor of activated T-cells (NFAT) is a family of transcription factors shown to be important in immune response. One or more members of the NFAT family is expressed in most cells of the immune system. NFAT is also involved in the development of cardiac, skeletal muscle, and nervous systems. NFAT was first discovered as an activator for the transcription of IL-2 in T cells but has since been found to play an important role in regulating many more body systems. NFAT transcription factors are involved in many normal body processes as well as in development of several diseases, such as inflammatory bowel diseases and several types of cancer. NFAT is also being investigated as a drug target for several different disorders.

<span class="mw-page-title-main">SMARCA4</span> Protein-coding gene in the species Homo sapiens

Transcription activator BRG1 also known as ATP-dependent chromatin remodeler SMARCA4 is a protein that in humans is encoded by the SMARCA4 gene.

<span class="mw-page-title-main">NFATC2</span> Protein-coding gene in the species Homo sapiens

Nuclear factor of activated T-cells, cytoplasmic 2 is a protein that in humans is encoded by the NFATC2 gene.

<span class="mw-page-title-main">NFATC1</span> Protein-coding gene in the species Homo sapiens

Nuclear factor of activated T-cells, cytoplasmic 1 is a protein that in humans is encoded by the NFATC1 gene.

<span class="mw-page-title-main">SMARCB1</span> Protein-coding gene in the species Homo sapiens

SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily B member 1 is a protein that in humans is encoded by the SMARCB1 gene.

<span class="mw-page-title-main">ARID1A</span> Protein-coding gene in humans

AT-rich interactive domain-containing protein 1A is a protein that in humans is encoded by the ARID1A gene.

<span class="mw-page-title-main">SMARCC1</span> Protein-coding gene in the species Homo sapiens

SWI/SNF complex subunit SMARCC1 is a protein that in humans is encoded by the SMARCC1 gene.

<span class="mw-page-title-main">NFATC3</span> Protein-coding gene in the species Homo sapiens

Nuclear factor of activated T-cells, cytoplasmic 3 is a protein that in humans is encoded by the NFATC3 gene.

<span class="mw-page-title-main">SMARCE1</span> Protein-coding gene in the species Homo sapiens

SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily E member 1 is a protein that in humans is encoded by the SMARCE1 gene.

<span class="mw-page-title-main">NFATC4</span> Protein-coding gene in the species Homo sapiens

Nuclear factor of activated T-cells, cytoplasmic 4 is a protein that in humans is encoded by the NFATC4 gene.

<span class="mw-page-title-main">PPP3R1</span> Protein-coding gene in the species Homo sapiens

Calcineurin subunit B type 1 also known as protein phosphatase 2B regulatory subunit 1 is a protein that in humans is encoded by the PPP3R1 gene.

<span class="mw-page-title-main">PBRM1</span> Protein-coding gene in the species Homo sapiens

Protein polybromo-1 (PB1) also known as BRG1-associated factor 180 (BAF180) is a protein that in humans is encoded by the PBRM1 gene.

<span class="mw-page-title-main">SMARCD3</span> Human protein and coding gene

SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily D member 3 is a protein that in humans is encoded by the SMARCD3 gene.

<span class="mw-page-title-main">SMARCD2</span> Protein-coding gene in the species Homo sapiens

SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily D member 2 is a protein that in humans is encoded by the SMARCD2 gene.

<span class="mw-page-title-main">Chemically induced dimerization</span>

Chemically induced dimerization (CID) is a biological mechanism in which two proteins bind only in the presence of a certain small molecule, enzyme or other dimerizing agent. Genetically engineered CID systems are used in biological research to control protein localization, to manipulate signalling pathways and to induce protein activation.

<span class="mw-page-title-main">Diana Hargreaves</span> American biologist

Diana Hargreaves is an American biologist and assistant professor at The Salk Institute for Biological Studies and member of The Salk Cancer Center. Her laboratory focuses on epigenetic regulation by the BAF (SWI/SNF) chromatin remodeling complexes in diverse physiological processes including development, immunity, and diseases such as cancer.

References

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  2. ↑ Courtois G, Morgan JG, Campbell LA, Fourel G, Crabtree, GR. Interaction of a liver-specific nuclear factor with the fibrinogen and alpha1- antitrypsin promoters. Science. 238(4827): 688-692, 1987. PMID   3499668.
  3. ↑ Kant JA, Crabtree GR. Alternative mRNA splicing patterns produce the gamma A and gamma B chains of fibrinogen. Cell. 31(1): 159-166, 1982. PMID   6896326.
  4. ↑ Shaw JP, Utz PJ, Durand DB, Toole JJ, Emmel EA, Crabtree GR. Identification of a putative regulator of early T cell activation genes. Science. 241(4862): 202-205, 1988. PMID   3260404.
  5. ↑ Emmel EA, Verweij CL, Durand DB, Higgins KM, Lacy E, Crabtree GR. Cyclosporin A specifically inhibits function of nuclear proteins involved in T cell activation. Science. 246(4937): 1617-1620, 1989. PMID   2595372.
  6. ↑ Flanagan WM, Corthésy B, Bram RJ, Crabtree GR. Nuclear association of a T-cell transcription factor blocked by FK-506 and cyclosporin A. Nature. 352(3668): 803-807, 1991. PMID   1715516
  7. ↑ Clipstone NA, Crabtree GR. Identification of calcineurin as a key signalling enzyme in T-lymphocyte activation. Nature. 357(6380): 695-697, 1992. PMID   1377362.
  8. ↑ Graef IA, Mermelstein PG, Stankunas K, Neilson JR, Deisseroth K, Tsien RW, Crabtree GR. L-type calcium channels and GSK-3 regulate the activity of NF-ATc4 in hippocampal neurons. Nature. 401(6754): 703-708, 1999. PMID   10537109.
  9. ↑ Schreiber SL, Crabtree, GR. The mechanism of action of cyclosporin A and FK506. Immunology Today. 4: 136-142, 1992. PMID   1374612.
  10. ↑ Kolata, G. Scientists decipher mysterious process of signaling in cells. New York Times. June 1993.
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  13. ↑ Kuo CJ, Chung J, Fiorentino DF, Flanagan WM, Blenis J, Crabtree GR. Rapamycin selectively inhibits interleukin-2 activation of p70 S6 kinase. Nature. 358(6381): 70-73, 1992. PMID   1614535.
  14. ↑ Spencer, David M.; Wandless, Thomas J.; Schreiber, Stuart L.; Crabtree, Gerald R. (1993-11-12). "Controlling Signal Transduction with Synthetic Ligands". Science. 262 (5136): 1019–1024. Bibcode:1993Sci...262.1019S. doi:10.1126/science.7694365. ISSN   0036-8075. PMID   7694365.
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  17. 1 2 Spencer, D M; Graef, I; Austin, D J; Schreiber, S L; Crabtree, G R (1995-10-10). "A general strategy for producing conditional alleles of Src-like tyrosine kinases". Proceedings of the National Academy of Sciences. 92 (21): 9805–9809. Bibcode:1995PNAS...92.9805S. doi: 10.1073/pnas.92.21.9805 . ISSN   0027-8424. PMC   40891 . PMID   7568222.
  18. 1 2 Klemm, Juli D; Beals, Chan R; Crabtree, Gerald R (September 1997). "Rapid targeting of nuclear proteins to the cytoplasm". Current Biology. 7 (9): 638–644. Bibcode:1997CBio....7..638K. doi: 10.1016/S0960-9822(06)00290-9 . PMID   9285717.
  19. 1 2 Ho, Steffan N.; Biggar, Stephen R.; Spencer, David M.; Schreiber, Stuart L.; Crabtree, Gerald R. (August 1996). "Dimeric ligands define a role for transcriptional activation domains in reinitiation". Nature. 382 (6594): 822–826. Bibcode:1996Natur.382..822H. doi:10.1038/382822a0. ISSN   0028-0836. PMID   8752278.
  20. 1 2 Hathaway, Nathaniel A.; Bell, Oliver; Hodges, Courtney; Miller, Erik L.; Neel, Dana S.; Crabtree, Gerald R. (June 2012). "Dynamics and Memory of Heterochromatin in Living Cells". Cell. 149 (7): 1447–1460. doi:10.1016/j.cell.2012.03.052. PMC   3422694 . PMID   22704655.
  21. ↑ Liang, Fu-Sen; Ho, Wen Qi; Crabtree, Gerald R. (2011-03-15). "Engineering the ABA Plant Stress Pathway for Regulation of Induced Proximity". Science Signaling. 4 (164). doi:10.1126/scisignal.2001449. ISSN   1945-0877. PMC   3110149 . PMID   21406691.
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  25. ↑ Gourisankar, Sai; Krokhotin, Andrey; Ji, Wenzhi; Liu, Xiaofan; Chang, Chiung-Ying; Kim, Samuel H.; Li, Zhengnian; Wenderski, Wendy; Simanauskaite, Juste M.; Yang, Haopeng; Vogel, Hannes; Zhang, Tinghu; Green, Michael R.; Gray, Nathanael S.; Crabtree, Gerald R. (2023-08-10). "Rewiring cancer drivers to activate apoptosis". Nature. 620 (7973): 417–425. Bibcode:2023Natur.620..417G. doi:10.1038/s41586-023-06348-2. ISSN   0028-0836. PMC   10749586 . PMID   37495688.
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  33. ↑ Dykhuizen EC, Hargreaves DC, Miller EL, Cui K, Korshunov A, Kool M, Pfister S, Cho YJ, Zhao K, Crabtree GR. BAF complexes facilitate decatenation of DNA by topoisomerase IIalpha. Nature. 497(7451): 624-627, 2013. PMID   23698369.
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