PSU Magazine Summer 1987

herpesvirus was discovered just last year, said Millette, but not much is known about it. Considering the broad swath that herpesvirus cuts through human medicine and society, it is easy to understand Millette's long-term interest in HSV-1 as well as the $112 million commitment made to him by the National Institutes of Health during the last eight years. "It's of medical importance," says Millette modestly of his research. But the biologist gets more visibly excited when he discusses the herpesvirus phenomenon at the ~?lec~lar .level, where he is most familiar with 1t. Millette and his assistants rarely deal even with a whole herpesvirus. "We're working with isolated viral genes and fragments of genes," s~id Millette, "taking them out of the virus, cloning them, and studying their regulation in test-tube experiments." Mill.ette's lab has contributed to the research technology with development of an in vitro "assay system" for studying the first stages ofgene expression. As the PSU researcher explains it, during a viral infection the genetic material of the virus goes into the nucleus of a cell and uses the cellular "machinery" to replicate itself. The cell's protein and nucleic acid synthesis is interrupted and the cell is converted to an "assembly plant" for making viral proteins and viral nucleic acids. "The whole goal of a virus infecting a cell is to make more virus," said Millette. With no metabolism of its own, a virus is a kind of intracellular parasite that requires the host cell to reproduce itself. All it takes is one invading virus to create about 200 virus progeny, a process that occurs at the expense of the cell, which is usually destroyed. This electron micrograph shows a herpes simplex virus, consisting of 100 or so genes in a nucleocapsid surrounded by a lipid envelope (275, 000x magnification). S pecifically, Millette is interested in the ordered sequence by which viral genes are turned on and the cell's metabolism is turned off. "Of the 100 or so genes in the virus, only five are initially expressed when the virus first goes into the cell," said Millette. "These are regulatory genes and they help control the cell and turn on the next class of genes. There's an ordered sequence of expression which sets up the cell for making more virus progeny." This "programming of events" is not unlike the programming of gene expression in the development of an organism, says Millette. Thus, his research may be of interest to de– velopmental biologists. "One of the big questions facing biologists is how one cell, the zygote, can develop and differentiate into all the marvelous tissues found in an organism," says Millette. "It must mean that genes get selectively turned on and off during development to create nerve cells, bone cells and all the other spe– cialized cells." Pinpointing the "immediate early" genes that begin the regulated process in an infected cell and learning how they function can open doors to treat– ment, too. "Mutating one gene can block the whole process," said Millette, PSU MAGAZINE PAGE 6 > who called these immediate early pro– ~ teins "good targets for chemotherapy." ~ For this reason, pharmaceutical com– ~ panies have a keen interest in work O such as his. ~ Millette, now in his fourth year at ~ Portland State, began his investigation ~ of the herpesvirus at the University of z Colorado- Medical Center in 1974, con- 8 tinuing at Wayne State University's ~ Department of Microbiology and "- Immunology for nine years. As an 0 > American Cancer Society Scholar, ~ - Millette spent a year-long sabbatical at ~ the Fred Hutchinson Cancer Center in 8 Seattle. Nearly a native Oregonian, Millette went to Lincoln High School in Port– land and earned an undergraduate de– gree in biochemistry from Oregon State. After receiving his doctorate from the California Institute of Tech– nology, Millette served as an NIH research fellow at the Max-Planck– Institut fur Biochemie in Munich. "The field of virology has increased exponentially" during the course of his career, said Millette. Developing technology has made it easier to work with animal viruses. And with the great scientific and cultural interest in can– cer, more funding has been available for animal virus study. Millette's lab has contributed to the research technology with development of an in vitro "assay system" for studying the first stages of gene expression. This test-tube system lets researchers inject viral DNA into extracts of infected or uninfected cells and watch it being copied into RNA and then into proteins. It is not the first cell-free system, explained Millette, but for his work it has some advantages over other techniques. Another technique refined in Millette's lab uses polyacrylamide gel and an electric field to do a "foot– printing analysis" of DNA sequences and the proteins that bind to them. "We recently identified a protein factor apparently responsible for con– trolling a class of late viral genes," noted Millette proudly. Such sub-microscopic discoveries characterize the meticulous herpes– virus research that Millette hopes will increase the world's understanding of disease. ' • •