Oscar Miller (1925–2012)

Oscar Lee Miller Jr. died on 28 January 2012 in Charlottesville, Virginia, at the age of 86. He was a “magician” of molecular cytology, whose stunning views of active genes provided new insights into gene expression. His important glimpses opened the doors for exploring numerous fundamental questions about chromosomes. Oscar was born in 1925 in Gastonia, North Carolina. His path to scientific research was unusual. After serving 3 years in the U.S. Navy during World War II, he earned a bachelor's and master's degree in agronomy at North Carolina State University. He then became a tobacco farmer in North Carolina for 6 years. Unsatisfied with this life, he enrolled at the University of Minnesota, where he earned a doctoral degree in plant genetics (focusing on corn). His postdoctoral work included research with one of us (J.G.) in the Zoology Department at Minnesota where he was interested in chromosome structure. Because we were nearly the same age, we were not so much mentor and student as enthusiastic collaborators. In 1961, at the age of 36, Oscar took his first independent position at Oak Ridge National Laboratory. In the ensuing decade, he wove his magic, perfecting a technique that allowed visualization of active genes with the electron microscope. His most famous paper was coauthored with his technician, Barbara Beatty, in 1969. The phrase “a picture is worth a thousand words” aptly describes the electron micrograph of ribosomal RNA (rRNA) genes that graced the cover of Science 43 years ago. In the 1960s, it was known that DNA was the genetic material, and the central dogma had become, “DNA makes RNA makes protein.” What was not known, particularly for eukaryotes, was the size of the genes, whether they had distinct beginning and end points, and how they engaged RNA polymerase molecules. Oscar's technique clarified all these issues. Simple inspection of active rRNA genes immediately revealed that they had discrete starting and stopping points—the tips and bases of the serially repeated “Christmas trees.” The existence of nontranscribed spacers between genes was evident, and a ruler could be put to the micrograph to measure the size of genes. One could count the number of genes along the chromosome. One could see that the rRNA genes were all in the same orientation and that each gene was simultaneously transcribed by hundreds of RNA polymerases. Remarkably, these watershed observations were made four decades before the dawn of genomics. In one fell swoop, Oscar Miller revealed the anatomy of a gene. ![Figure][1] CREDIT (TOP TO BOTTOM): DAVID SKINNER/UNIVERSITY OF VIRGINIA; OSCAR MILLER AND BARBARA BEATTY/OAK RIDGE NATIONAL LABORATORY What else was learned from this technique— the “Miller Chromatin Spread”—in which a cell's DNA is spread out for viewing by an electron microscope? Oscar's laboratory soon discovered that transcription and translation are coupled in bacterial operons, regions of DNA containing a cluster of genes controlled by a single regulatory apparatus. Ada and Donald Olins described “Nu bodies,” beads on a string that turned out to be the fundamental structural units of chromatin, now called nucleosomes. Yvonne Osheim visualized amplified chorion genes in the oocytes of the fruit fly Drosophila melanogaster , supporting the “onion skin” model of gene amplification predicted by Allan Spradling (the rereplication of a gene occurs in a single cell cycle). The list of discoveries coming from Oscar's technique goes on and on, providing a lasting legacy—our shared mental image of active genes. Textbooks need not include schematics of these beautiful micrographs because the real thing is so crystal clear. How did Miller invent the technique? First, he held the passionate belief that it should be possible to see genes up close and personal, an idea that was wildly unconventional a half-century ago. Although he employed technically sophisticated methods of electron microscopy (EM), it was his treatment of the cell nucleus that was the magic of his success; he simply dissolved it in distilled water. The nuclear contents were then centrifuged directly onto the EM grid, dried, stained, and visualized. Simple, yes, but the trial and error required to accomplish the feat took skill, fortitude, and creative thinking. Had Miller not made this discovery, how much longer would it have taken for another scientist to do so—or would we never have had these remarkable images? Oscar Miller was recognized in many ways, including election to the U.S. National Academy of Sciences. Fittingly, this scientific adventurer held the Lewis and Clark chair at the University of Virginia (UVA), an endowment named for the two most celebrated adventurers in U.S. history. Miller chaired the Department of Biology at UVA and mentored many graduate students, postdoctoral fellows, and young faculty members. Those of us so fortunate as to have worked under his guidance learned how to think freely, yet rigorously, and how to dream big and gamble on new adventures. We learned from Oscar how to free ourselves from convention, yet abide by the principles of science as crafted by its most honorable pillars. We remember two pieces of advice given by Oscar: “Don't believe everything you read in the scientific literature” and “There are a thousand Ph.D. thesis projects in a mound of dung.” The latter brings to mind the famous phrase of Vannevar Bush that science is an “endless frontier.” Oscar Miller was comfortable on the frontier of the unknown; he taught us that it is only on the frontier that discoveries of significance can be made. Our community of science will miss Oscar, as will all his dear friends and family. A good man has passed. [1]: pending:yes