Matthew Scott has loved the beauty found in the shapes of animals ever since he started his insect collection as young boy. He remembers wondering what caused the insects' different forms and distinct behaviors that made them suited for their ecological niches.
For the past 25 years, Scott has satisfied his curiosity by deciphering the molecular underpinnings of the developmental processes that lead eventually to the adult appearance of many organisms, including the fruit fly, mouse, and humans.
Among his many accomplishments is the identification of the homeodomain, a 60–amino acid region found in proteins that regulate development. The homeodomain section of the protein binds DNA to control the activities of genes that form the body's emerging structures.
His seminal finding, in 1984, showed that developmental proteins share a control mechanism—the homeodomain—and have features related to ancient proteins bacteria use to bind DNA.
"It was the most interesting discovery of my life," Scott says. "Not only did we find something in common among a handful of seemingly different types of regulators, but we could trace the protein's shape back through about a billion years of evolution. That similar hardware would be used by all animals to build their bodies and to regulate how they build their bodies was not even imagined."
Scott became interested in the molecular genetics of development in fruit flies as a postdoctoral fellow at Indiana University in the early 1980s. At the time, the then new tools of recombinant DNA technology allowed scientists to begin to purify or clone genes.
For decades before, classical genetics researchers had characterized developmental anomalies in fruit flies, such as altered numbers of body segments or body parts in the wrong places. Scientists had found that these abnormalities were due to mutations either in homeotic genes, which cause transformation of one body part into a copy of another body part, or in segmentation genes, which alter the subdivision of the body into sections.
Scott hoped to isolate and analyze the genes responsible for certain homeotic mutations. In the laboratories of Thomas Kaufman and Barry Polisky, he focused on a homeotic gene cluster called the Antennapedia complex. Mutations in the Antennapedia gene, part of the cluster, put legs on the fly where antennae should be.
When analyzing the cluster's homeotic and segmentation gene sequences, Scott found the homeobox, the DNA sequence encoding the homeodomain. Soon after, Scott showed that the homeodomain is related to bacterial and yeast DNA-binding domains. His finding sparked isolation of hundreds of genes with a homeobox, including genes in mammals.
Scott started his own laboratory in 1983 at the University of Colorado at Boulder, and throughout the 1980s continued to study the Antennapedia and other homeotic and body segmentation genes: how the genes are turned on and off; where the proteins they encode are made in development; and how a mutation in one gene affects other genes, because genes expressed earlier in development affect genes used later.
Although most of the fruit fly genes he isolated encode transcription factors, which bind DNA and control activity of other genes, he also cloned a gene called patched, which encodes a membrane-bound protein. Eventually, work from several laboratories revealed that the Patched protein is a receptor for the protein encoded by the hedgehog gene, so-called because flies with mutations in it have bristly embryos.
"Binding of the Hedgehog protein to the Patched receptor leads to genes being turned on and off in the receiving cell," Scott explains. "The mechanism is used in nearly every tissue and organ in most growing animals, as part of the basic developmental tool kit, and in stem cells in the adult body as they differentiate."
In 1990, Scott moved to Stanford and began to also study mammalian versions of developmental genes. He made this move to an academic medical center, because he thought "developmental biology was going to be increasingly important for medicine and that medicine would be informative for developmental biology."
By the mid 1990s, Scott found that a mutation in the human PATCHED gene is linked with Gorlin's syndrome, a rare, inherited condition characterized by skin cancers and birth defects. He then showed PATCHED mutations also occur in basal cell carcinoma, the most common skin cancer, and in medulloblastoma, the most common malignant childhood brain cancer.
He also found that the signaling protein Sonic Hedgehog (Shh), which controls the Patched protein, stimulates growth of the cerebellum. The cerebellum cancer, medulloblastoma, could then be understood as excessive Shh signaling. Development biology and cancer research were, as he had hoped, were mutually informative.
His interest in PATCHED led him to a related protein, NPC, which, if mutant, causes Niemman-Pick disease type C1, an often fatal childhood disease characterized by neuronal death and failures of cholesterol trafficking inside cells. He believes the PATCHED protein evolved from the NPC1 protein, which also is found in yeast and plants.
Scott continues to study developmental genes, intrigued by how genes go awry in cancer, control organ and tissue formation, and influence the wiring of the nervous system. "Prospects are really great for applying fundamental knowledge about these pathways to understanding birth defects, neurodegeneration, and cancer," Scott says.
Reflecting on his career, Scott says he always has followed where the genes have led him and his students and postdoctoral fellows. "As an academic scientist, my joy is to support young scientists who pursue new and exciting research," says Scott. And with each new discovery his laboratory makes about genetic processes of development, Scott remains awed by their ability to create the beauty of forms he first observed as a child.