Philip A. Beachy
Philip Arden Beachy is Ernest and Amelia Gallo Professor at Stanford University School of Medicine. Beachy isolated the Hedgehog gene in flies, discovered how it is processed and released from cells, and identified its signaling mechanism in target cells.
He also studied the roles of Hedgehog signaling in development, regeneration and cancer, discovered small molecules that could block the Hedgehog pathway, and advanced them toward patient treatments.
Awards and honors
Beachy has received numerous awards and prizes for his work, including the- 1997 Outstanding Young Scientist Award from the Maryland Academy of Sciences
- 1998 National Academy of Sciences Award in Molecular Biology
- 2008 March of Dimes Prize in Developmental Biology jointly with Cliff Tabin.
- 2011 Keio Medical Science Prize.
Research
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. Additionally, Beachy revealed critical roles of Hedgehog signaling in embryonic development, 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, and demonstrated the continued importance of Hedgehog signaling in the maintenance and regeneration of adult organs. Beachy also pioneered small molecule Hedgehog pathway inhibitors, leading to FDA approval of three such inhibitors for the treatment of basal cell carcinoma and chronic myelogenous leukemia.1. Hedgehog protein identification
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.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. 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.
2. Hedgehog signal transduction mechanisms
How is the extracellular Hedgehog signal transmitted to the interior of target cells? Beachy purified active Hedgehog protein and showed that it binds a transmembrane receptor, Patched. Genetically, Patched was known to inhibit the downstream Hedgehog pathway activator, Smoothened. Hedgehog binding to Patched activates the pathway by alleviating Patched-mediated suppression of Smoothened. This theme of signaling through relief of inhibition recurs in other signaling pathways.In resolving the longstanding mystery of how Patched represses Smoothened Beachy found that cholesterol binding activates Smoothened, and that Patched constitutively represses Smoothened by removing accessible cholesterol from the inner leaflet of the plasma membrane. Hedgehog binding to Patched blocks the cholesterol conduit within Patched, thereby restoring inner-leaflet cholesterol and permitting Smoothened activation. As outlined in his recent review, this solution to the longstanding puzzle of how Patched regulates Smoothened revealed a unique and completely novel mode of developmental signaling whereby a common lipid directly activates a cell-signaling protein.
3. Hedgehog signaling in development, birth defects, and adult tissues
Beachy demonstrated the central importance of Hedgehog signaling in vertebrate development, showing that mouse embryos lacking Sonic hedgehog or other Hedgehog pathway genes have profound defects in development of the brain, spinal cord, axial skeleton, limbs, and other organs. Beachy found that Hedgehog signals emanating from small groups of cells in signaling centers or organizers form gradients that pattern adjacent fields of cells. With collaborators, Beachy demonstrated that addition of biochemically purified, functionally active Hedgehog protein to explanted embryonic tissues induced different cell-types in a concentration-dependent fashion. This is beautifully exemplified in the developing spinal cord, where a Hedgehog signaling gradient specifies the locations of motor neurons, interneurons, and other neuronal types. Beachy’s foundational demonstration of morphogen action in vertebrate development has become a central tenet of developmental biology.Beachy found that Hedgehog pathway mutations produce cyclopia and other midline face and brain malformations, thus uncovering a mechanism for human holoprosencephaly, the most common first-trimester human birth defect, often associated with SHH mutations. Human birth defects involving the limbs, skeleton, and other organs are also attributable to mutations affecting Hedgehog signaling. The current literature on human birth defects thus is full of references to Beachy’s work. His seminal 1996 Nature article describing developmental defects in Shh-/- mouse embryos is one of the most highly-cited developmental genetics papers, with over 3600 citations.
Beachy also demonstrated a continuing requirement for Hedgehog signaling in maintenance and regeneration of multiple adult tissues, entailing reciprocal signaling between epithelial and mesenchymal cells. Beachy showed that this Hedgehog-driven epithelial-mesenchymal feedback loop operates in many organs, including bladder, prostate, pancreas, and colon, thus suggesting new treatments for certain degenerative diseases and cancers.
4. Human therapies
When Beachy initiated his work on Hedgehog in the 1990s, there were few—if any—pharmacologic tools to modulate developmental signaling pathways. In a fascinating story, Beachy discovered such tools for Hedgehog. In the 1950s, one-eyed cyclopic lambs were born in Idaho, attributable to a plant-derived compound, cyclopamine. Beachy noted the similarity to cyclopic Shh-/- mice and in a brilliant leap demonstrated that cyclopamine inhibits Hedgehog signaling. Beachy’s lab pioneered small molecule Hedgehog pathway inhibitors and showed such inhibitors can treat cancers caused by dysregulated Hedgehog pathway activity, including a mouse model of the childhood brain cancer, medulloblastoma. Collectively, cyclopamine and other synthetic Hedgehog pathway modulators discovered by Beachy have provided a powerful and widely used pharmacological toolkit.Publications and patents from Beachy’s laboratory have now led to the FDA approval of three Hedgehog pathway inhibitors that have been approved by the FDA as therapeutics for advanced basal cell carcinoma and acute myelogenous leukemia, with therapeutic use for additional Hedgehog-linked cancers and other indications such as fibrosis likely to receive FDA approval in the future.