Cancer Biology, Cell Biology
Dr. Beachy is also Ernest and Amelia Gallo Professor at Stanford University School of Medicine and an associate at the Institute of Stem Cell Biology and Regenerative Medicine at Stanford University School of Medicine.
Hedgehog Signaling in Development and Disease
Although he enjoyed working in an operating room during his first summer after starting college, Philip Beachy eventually decided against medical school and instead pursued a career in biological research. This decision was inspired in part by Horace Freeland Judsons book, The Eighth Day of Creation, an account of the birth of molecular biology, which Beachy first encountered in serialized form in the pages of The New Yorker magazine. "Reading those articles got me excited about molecular biology," says Beachy, who then spent the year following his graduation from Goshen College doing research and taking additional chemistry courses at Indiana University. In 1980, he went to graduate school at Stanford, where he studied the molecular genetics of fruit fly (Drosophila) development with David Hogness. Today, he is a leader in the study of developmental signaling pathways and has pioneered the understanding of their normal and pathological roles in embryonic growth and cancer.
After earning his Ph.D. degree at Stanford University in 1986, Beachy worked at the Carnegie Institutions Department of Embryology in Baltimore, and two years later accepted a faculty position at the Johns Hopkins University School of Medicine. By 1990, he was focused on the Drosophila hedgehog gene, which acquired its name because fly embryos look spiky if this gene is faulty. Conserved from flies to humans, the hedgehog genes produce protein signals in specific cells, and these signals establish the patterns of embryonic tissues by instructing neighboring cells to divide or to become a particular type of differentiated cell. The hedgehog gene thus orchestrates the development of body segments and appendages in Drosophila. In vertebrates, hedgehog genes pattern the digits on the limbs and organize the spinal cord and brain. Not surprisingly, faulty hedgehog genes can cause birth defects, and inappropriate activation later in life can trigger certain cancers.
By 1992, Beachy's group had cloned the Drosophila hedgehog gene, and a landmark paper was published in Cell that year. His group discovered that the Hedgehog protein undergoes an unusual autoprocessing reaction. In this reaction one portion of the precursor causes the protein to split in two and the other portion, which becomes the fragment active in signaling, is linked to cholesterol. This was a surprising new role for this lipid and an unprecedented form of protein modification.
Many groups then began to isolate hedgehog genes. After cloning a dozen or so from various vertebrates, Beachy's group began to study the functions of the corresponding proteins, especially one that came to be called Sonic hedgehog. In collaboration with Thomas Jessell (HHMI, Columbia University), Beachy's group exposed dissected pieces of a chick's embryonic nervous system to Sonic hedgehog protein. They observed that the cell types that normally arise near the midline of the body, where Sonic hedgehog is expressed, differentiated in response to high protein concentrations. Cell types that typically lie farther away differentiated in response to lower protein concentrations. The collaborators concluded that a cell's response to Hedgehog depends on its distance from the source and the length of exposure. Beachys group and others also found that the Sonic hedgehog protein influences the pattern of the digits in the developing limb, and concluded that hedgehog proteins elicit concentration-dependent responses in a range of developing organs.
To investigate how faulty hedgehog genes waylay vertebrate development, Beachy and collaborators mutated the mouse Sonic hedgehog gene. The resulting embryo had several bizarre features, including cyclopia—a single eye in the center of the face. In this respect, it resembled the most severe form of a human developmental disorder called holoprosencephaly, which affects perhaps 1 in 250 pregnancies, causing early miscarriages in most cases.
The occurrence of cyclopia also suggested a connection to previous epidemics of cyclopia in lambs born to pregnant ewes that had been taken to high mountain meadows for grazing during a drought. In the 1960s, scientists discovered that these effects were due to cyclopamine, a compound present in the corn lily, commonly found at these higher altitudes. When Beachy's group administered cyclopamine to chick embryos, they found that it blocked the normal responses to Sonic hedgehog. This observation led to the finding that cyclopamine binds to a membrane protein called Smoothened on cells that Hedgehog targets. When bound by cyclopamine, Smoothened could no longer activate the Hedgehog signaling pathway.
The Smoothened protein normally is kept in check by the Patched protein. The Hedgehog protein, when present, binds to Patched and blocks its inhibition of Smoothened, thus allowing Smoothened to activate the pathway. Matthew Scott (HHMI, Stanford University School of Medicine) and others had shown that people with basal cell nevus syndrome, who are at high risk for certain cancers, such as basal cell carcinoma and the childhood brain tumor medulloblastoma, have mutations in the Patched gene. When Beachy and his colleagues exposed mouse medulloblastoma cells to cyclopamine, tumor growth regressed. They, along with other research groups, further showed that Hedgehog signaling promotes the growth and metastasis of various tumors, including some of those arising in organs that develop from the endodermal layer of the embryo. Moreover, cyclopamine in some cases could block or reverse the growth of these tumors. Several drug companies are now developing cyclopamine derivatives and other compounds that act in a similar way as potential therapies for tumors involving Hedgehog pathway activity.
In 2006, Beachy moved from Johns Hopkins to Stanford University's Department of Developmental Biology and its Institute for Stem Cell Biology and Regenerative Medicine. He is interested in the function of Hedgehog proteins and other extracellular signals in morphogenesis (pattern formation) and in injury repair and regeneration (pattern maintenance), in particular the normal roles of such signals in stem cell physiology and their abnormal roles in the formation and expansion of cancer stem cells. He is also interested in how the distribution of such signals is regulated in tissues, how cells perceive and respond to distinct concentrations of signals, and how such signaling pathways arose in evolution.