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Philip A. Beachy

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Philip Beachy
Beachy at Stanford
Born
Philip Arden Beachy

(1958-10-25) October 25, 1958 (age 66)
Red Lake, Ontario, Canada
CitizenshipAmerican
Alma mater
Known forHedgehog signaling pathway[2]
AwardsNAS Award in Molecular Biology (1998)
March of Dimes Prize in Developmental Biology (2008)
Keio Medical Science Prize (2011)
Scientific career
FieldsBiochemistry, Developmental & Stem Cell Biology
Institutions
ThesisThe UBX Domain in the Bithorax Complex of Drosophila (1986)
Doctoral advisorDavid Hogness[1]
Notable studentsMichelle Monje
Website

Philip Arden Beachy (born October 25, 1958)[3] is Ernest and Amelia Gallo Professor at Stanford University School of Medicine.[1][4] Beachy isolated the Hedgehog gene in flies, discovered how it is processed and released from cells, and identified its signaling mechanism in target cells[5][6][7][8][9][10].

He also studied the roles of Hedgehog signaling in development, regeneration and cancer[11][12][13], discovered small molecules that could block the Hedgehog pathway, and advanced them toward patient treatments.[14]

Awards and honors

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Beachy has received numerous awards and prizes for his work, including the

Beachy was elected a member of the United States National Academy of Sciences in 2002, and a Fellow of the American Academy of Arts and Sciences (2003).[16]

Research

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Philip Beachy made several contributions to the understanding of the Hedgehog signaling pathway; he discovered the Hedgehog signaling protein, how it is processed and released from cells, and identified its mechanism of signaling in target cells[6][7][8][9][10][17]. Additionally, Beachy revealed critical roles of Hedgehog signaling in embryonic development[18], uncovering the basis of human birth defects, including holoprosencephaly, the most common human birth defect in early gestation, affecting ~1 in 200 fetuses. He established the concept that morphogens, such as the Hedgehog protein, form extracellular signaling gradients to pattern embryonic tissues[11], and demonstrated the continued importance of Hedgehog signaling in the maintenance and regeneration of adult organs[12][13]. Beachy also pioneered small molecule Hedgehog pathway inhibitors, leading to FDA approval of three such inhibitors (vismodegib, sonidegib, and glasdegib) for the treatment of basal cell carcinoma and chronic myelogenous leukemia.

Hedgehog signaling was unknown when Beachy began his work in the early 1990s. Nüsslein-Volhard's and Wieschaus's seminal 1980 study showed that hedgehog mutations cause unusual bristle patterns in Drosophila embryos. Beachy isolated the Drosophila hedgehog gene and revealed that it encodes a secreted signaling protein, thus launching the field of Hedgehog signaling.[5]

Beachy also identified Hedgehog genes critical for the embryonic development of vertebrates, including mammals. He found, surprisingly, that during its production and release the Hedgehog protein autocatalytically cleaves itself and acquires two lipid modifications, cholesterol and palmitate.[8][19] These lipids render the Hedgehog signal hydrophobic and shape its cellular distribution throughout tissues. These discoveries established covalent lipid modification as a novel mechanism for regulating signaling protein activity; such lipid modification was later extended to Wnt signaling proteins which, like Hedgehog, play important roles in development, regeneration, and cancer.

Beachy also discovered how Hedgehog is released from the cell. The Dispatched protein, powered by Na+ flux through its transmembrane ion channel, extracts the lipid-modified Hedgehog protein from the membrane and releases it as a complex with its carrier Scube, enabling its long-range action as a developmental signal.[20]

Career

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After receiving his Ph.D, he worked as an independent fellow (Staff Associate) at the Carnegie Institution's Department of Embryology in Baltimore for two years. He then accepted a faculty position at the Johns Hopkins University School of Medicine and in the Howard Hughes Medical Institute. In 2006, Beachy moved from Johns Hopkins to  Stanford University School of Medicine, where he has been affiliated with the Institute for Stem Cell Biology and Regenerative Medicine and has held appointments in the Departments of Developmental Biology, Biochemistry, and Urology.

Early life

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Beachy was born in Red Lake, Ontario, Canada, on October 25, 1958.[21] Beachy spent eight of his early years of life in the hills of central Puerto Rico. His father was a pastor of a rural church. He attended a school taught in Spanish during the day and then learned to read and write English once he came home from school. At nine, Beachy and his family returned to their home base of Goshen, Indiana where he began attending public school. At the early age of 16, Beachy headed off to Goshen College which was very close to home. At this time, Beachy still did not know of his love for science. “Unlike many people who knew they were going to be scientists from a very early age, I didn't decide that I would try to become a scientist until fairly late on in college,” he says.[1]

Education

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Beachy received his bachelor's degree in natural sciences at Goshen College. Beachy first envisioned himself as a doctor, but eventually decided to pursue biological research. He became interested in this field after reading a serialized form of Horace Freeland Judson's book, The Eighth Day of Creation in The New Yorker. "Reading those articles got me excited about molecular biology," says Beachy. After graduating, he continued to do more research and took chemistry courses at the nearby South Bend campus of Indiana University. He then decided to attend graduate school at Stanford University and studied the molecular genetics of fruit fly development with David Hogness.[1][4] Beachy earned his Ph.D in biochemistry in 1986 at Stanford for research into the Ultrabithorax homeotic gene and its products.

Personal life

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Beachy is married to Katrin Andreasson[22] and is the brother of historian Robert M. Beachy, and a cousin of biologist Roger N. Beachy and author Stephen Beachy.[citation needed]

References

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  1. ^ a b c d Marino, M (2004). "Biography of Philip A. Beachy". Proceedings of the National Academy of Sciences. 101 (52): 17897–9. doi:10.1073/pnas.0408740102. PMC 539818. PMID 15611474.
  2. ^ Porter, J. A.; Young, K. E.; Beachy, P. A. (1996). "Cholesterol Modification of Hedgehog Signaling Proteins in Animal Development". Science. 274 (5285): 255–9. Bibcode:1996Sci...274..255P. doi:10.1126/science.274.5285.255. PMID 8824192. S2CID 11125394.
  3. ^ Marquis Who's Who TM. Marquis Who's Who, 2008.
  4. ^ a b "Philip A. Beachy, PhD". HHMI.org. Retrieved 2014-06-17.
  5. ^ a b Lee, J. J.; von Kessler, D. P.; Parks, S.; Beachy, P. A. (1992-10-02). "Secretion and localized transcription suggest a role in positional signaling for products of the segmentation gene hedgehog". Cell. 71 (1): 33–50. doi:10.1016/0092-8674(92)90264-d. ISSN 0092-8674. PMID 1394430.
  6. ^ a b Lee, J. J.; Ekker, S. C.; von Kessler, D. P.; Porter, J. A.; Sun, B. I.; Beachy, P. A. (1994-12-02). "Autoproteolysis in hedgehog protein biogenesis". Science (New York, N.Y.). 266 (5190): 1528–1537. Bibcode:1994Sci...266.1528L. doi:10.1126/science.7985023. ISSN 0036-8075. PMID 7985023.
  7. ^ a b Chamoun, Z.; Mann, R. K.; Nellen, D.; von Kessler, D. P.; Bellotto, M.; Beachy, P. A.; Basler, K. (2001-09-14). "Skinny hedgehog, an acyltransferase required for palmitoylation and activity of the hedgehog signal". Science (New York, N.Y.). 293 (5537): 2080–2084. Bibcode:2001Sci...293.2080C. doi:10.1126/science.1064437. ISSN 0036-8075. PMID 11486055.
  8. ^ a b c Porter, J. A.; Young, K. E.; Beachy, P. A. (1996-10-11). "Cholesterol modification of hedgehog signaling proteins in animal development". Science (New York, N.Y.). 274 (5285): 255–259. Bibcode:1996Sci...274..255P. doi:10.1126/science.274.5285.255. ISSN 0036-8075. PMID 8824192.
  9. ^ a b Porter, J. A.; von Kessler, D. P.; Ekker, S. C.; Young, K. E.; Lee, J. J.; Moses, K.; Beachy, P. A. (1995-03-23). "The product of hedgehog autoproteolytic cleavage active in local and long-range signalling". Nature. 374 (6520): 363–366. Bibcode:1995Natur.374..363P. doi:10.1038/374363a0. ISSN 0028-0836. PMID 7885476.
  10. ^ a b Lee, J. J.; Ekker, S. C.; von Kessler, D. P.; Porter, J. A.; Sun, B. I.; Beachy, P. A. (1994-12-02). "Autoproteolysis in hedgehog protein biogenesis". Science (New York, N.Y.). 266 (5190): 1528–1537. Bibcode:1994Sci...266.1528L. doi:10.1126/science.7985023. ISSN 0036-8075. PMID 7985023.
  11. ^ a b López-Martínez, A.; Chang, D. T.; Chiang, C.; Porter, J. A.; Ros, M. A.; Simandl, B. K.; Beachy, P. A.; Fallon, J. F. (1995-07-01). "Limb-patterning activity and restricted posterior localization of the amino-terminal product of Sonic hedgehog cleavage". Current Biology: CB. 5 (7): 791–796. Bibcode:1995CBio....5..791L. doi:10.1016/s0960-9822(95)00156-4. ISSN 0960-9822. PMID 7583126.
  12. ^ a b Beachy, Philip A.; Karhadkar, Sunil S.; Berman, David M. (2004-09-23). "Mending and malignancy". Nature. 431 (7007): 402. Bibcode:2004Natur.431..402B. doi:10.1038/431402a. ISSN 1476-4687. PMID 15385990.
  13. ^ a b Beachy, Philip A.; Karhadkar, Sunil S.; Berman, David M. (2004-11-18). "Tissue repair and stem cell renewal in carcinogenesis". Nature. 432 (7015): 324–331. Bibcode:2004Natur.432..324B. doi:10.1038/nature03100. ISSN 1476-4687. PMID 15549094.
  14. ^ "Leading Hedgehog inhibitor submitted for approval as skin cancer drug". Nature Reviews Drug Discovery. 10 (11): 803. 2011-11-01. doi:10.1038/nrd3594. ISSN 1474-1784. PMID 21997751.
  15. ^ Anon (2008). "An Interview With... Cliff Tabin". Nature Reviews Genetics. 9 (6): 420. doi:10.1038/nrg2863. PMID 18504824. S2CID 45619315.
  16. ^ "Book of Members, 1780-2010: Chapter B" (PDF). American Academy of Arts and Sciences. Retrieved May 28, 2011.
  17. ^ Lee, J. J.; von Kessler, D. P.; Parks, S.; Beachy, P. A. (1992-10-02). "Secretion and localized transcription suggest a role in positional signaling for products of the segmentation gene hedgehog". Cell. 71 (1): 33–50. doi:10.1016/0092-8674(92)90264-d. ISSN 0092-8674. PMID 1394430.
  18. ^ Chiang, C.; Litingtung, Y.; Lee, E.; Young, K. E.; Corden, J. L.; Westphal, H.; Beachy, P. A. (1996-10-03). "Cyclopia and defective axial patterning in mice lacking Sonic hedgehog gene function". Nature. 383 (6599): 407–413. Bibcode:1996Natur.383..407C. doi:10.1038/383407a0. ISSN 0028-0836. PMID 8837770.
  19. ^ Porter, J. A.; Ekker, S. C.; Park, W. J.; von Kessler, D. P.; Young, K. E.; Chen, C. H.; Ma, Y.; Woods, A. S.; Cotter, R. J.; Koonin, E. V.; Beachy, P. A. (1996-07-12). "Hedgehog patterning activity: role of a lipophilic modification mediated by the carboxy-terminal autoprocessing domain". Cell. 86 (1): 21–34. doi:10.1016/s0092-8674(00)80074-4. ISSN 0092-8674. PMID 8689684.
  20. ^ Wang, Qianqian; Asarnow, Daniel E.; Ding, Ke; Mann, Randall K.; Hatakeyama, Jason; Zhang, Yunxiao; Ma, Yong; Cheng, Yifan; Beachy, Philip A. (November 2021). "Dispatched uses Na+ flux to power release of lipid-modified Hedgehog". Nature. 599 (7884): 320–324. doi:10.1038/s41586-021-03996-0. ISSN 1476-4687. PMC 8785653. PMID 34707294.
  21. ^ "Philip A. Beachy - Stanford University". Yatedo.com. 1958-10-25. Retrieved 2014-06-17.
  22. ^ "Beachy, Ada B. Miller (1925-2005) - MLA Biograph Wiki". mla.bethelks.edu. Retrieved 2025-01-01.
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