Recorded: 08 Mar 2006
Well, the biggest accomplishments that we have done have been in finding some new repair systems, probably my biggest single one with students in my group and I cherish it most because it was working with undergraduates that we first started this. We discovered in e. coli a repair system for oxidative damage. Then cloned the human gene and did knockout mice studies to show that that’s involved in preventing cancer, and then were able to help because of having cloned those genes indirectly at least another group that just very recently showed that there are a number of human families that when they lack this gene have a greatly increased susceptibility to colon cancer. That’s probably our best and most piercing finding.
The very initial discovery, the mute y-gene as its called, was published in the proceedings of the National Academy of Science in 1988. And then there were a series of papers showing the mechanism of that. One of which is a short review in the Journal of Bacteriology that covers that work. Then we published the knockout mice study just more recently in Cancer Research, just a couple years ago. The way that we came to this initially was that we wanted to find new repair genes and wanted to find them by looking for things that increased the mutation rate, but we wanted to find things that hadn’t been found before, so we developed new ways of looking.
As Sydney Brenner once said, he seeks to make a better telescope so that you can see better things. And speaking allegorically, of course. What we found was that when we increased the resolution of detection by the two methods we used, then we found new things. One of the things we found turned out to be a gene that when we mapped both in bacteria and humans, turned out to be instrumental in preventing colon cancer that occurs spontaneously.
And it’s particularly pleasing also because we did the initial work with undergraduates who were at UCLA, and this was their first exposure to research. And it was very pleasing. In fact the first name on the first paper is an undergraduate’s name. The gene mutY was named after her, because her first name begins with Y.
At the time the early mutators, mutators are cells that have higher mutation rates than normal very often but not always because they lack a repair gene. So the first mutator in bacteria ever found was by Tom Treffords so it was called MutT and this tradition extended to many others. Her name was Ylon, beginning with a Y, it’s a Japanese name. She was one of several people working on, but we decided to put her name first on it. That’s how it became mutY, which many people know, because now it’s a widely studied gene. That’s really one of the most important discoveries, and it also underscores the fact that you can work with bacteria yet still find things that will be very relevant to human health.
Jeffrey H. Miller, Ph.D., is the Distinguished Professor of the Department of Microbiology, Immunology, and Molecular Genetics at the University of California, Los Angeles. After receiving his undergraduate degree in biology from the University of Rochester, he did graduate work in biochemistry and molecular biology at Harvard in the department that included Jim Watson and Walter Gilbert, doing his thesis work under Jonathan Beckwith at Harvard Medical School. His postdoctoral work was pursued under Benno Müller-Hill at the Institute for Genetics of the University of Cologne in Germany, followed by 11 years on the faculty at the University of Geneva's Department of Molecular Biology, which was then headed by Alfred Tissières. In 1983 he joined the faculty at UCLA, where his scientific focus has been large-scale DNA sequencing and genomic analysis, the enzymology of DNA repair, protein structure, and the role of DNA repair enzymes in human cancer. He received the 2007 Career Award for Research from the Environmental Mutagen Society.
Miller has been a frequent participant at Cold Spring Harbor Symposia, a course lecturer at Cold Spring Harbor Laboratory, and a co-organizer of two meetings at the Cold Spring Harbor Laboratory's Banbury Center. He has been a consultant and principal in various biotechnology companies since the 1980s. In 1994 he co-founded Diversa Corporation, which has merged to become Verenium, a publicly owned biofuel company. He is the author of several books and laboratory manuals published by Cold Spring Harbor Laboratory Press, including "Experiments in Molecular Genetics" (1972), "A Short Course in Bacterial Genetics" (1992), and "Discovering Molecular Genetics" (1996).