Andrew Fire shares Nobel Prize for discovering how double-stranded RNA can switch off genes
BY KRISTA CONGER
Andrew Fire took his first look around at Stanford and started screaming. His response wasn't unusual—for a newborn, that is. The molecular biologist was born at Stanford Hospital, attended public schools in Sunnyvale and graduated from the University of California-Berkeley, after being turned down by his only other college choice: Stanford.
All pretty normal, he hastens to point out—not mentioning that he completed high school at age 15 and college at age 19. But as of 2:30 a.m. Monday, the quiet Stanford medical school professor with the self-deprecating air will have to work a little harder to convince the world that he's nothing special. He won this year's Nobel Prize in Physiology or Medicine, and it will be a long time before he sees "normal" again.
Fire shares the prize with Craig Mello of the University of Massachusetts Medical School. The announcement from the Nobel Assembly at Karolinska Institutet came a mere eight years after they published their breakthrough discovery of RNA interference. The relatively rapid recognition is unusual in the rarified Nobel world, which often rewards researchers decades after their initial findings.
"I was very surprised," said Fire, professor of pathology and of genetics, of the early morning phone call from the committee. "At first I thought that maybe they had a wrong number, or that I was dreaming. But I guess it's real." Such prompt accolades are one indication of how their finding has turned the field of molecular biology on its head—and how it hasn't yet stopped spinning.
"This is an extraordinary achievement for Andy Fire and Craig Mello, for science and for Stanford," said Philip Pizzo, MD, dean of the School of Medicine. "It affirms the importance of basic fundamental research, which often yields new insights into human biology. Their discovery is already unfolding in new directions that may translate into discoveries of new diagnostic and therapeutic approaches for a variety of human disorders."
Fire, PhD, 47, and Mello, PhD, 45, are part of a team of researchers credited with recognizing that certain RNA molecules can be used to turn off specific genes in animal cells. The discovery, made while Fire was at the Carnegie Institution's Department of Embryology in Baltimore, marked the first time that biologists were able to selectively "silence" the voice of one gene in the cacophony of the tens of thousands that give a cell its marching orders from development to death. Their description of the process, called RNA interference or RNAi, in Nature in 1998, jumpstarted a new biological field by opening up previously inaccessible areas of research.
"It was clear from the first week that I met Andy that he was destined to do something great," said a longtime friend and Carnegie Institution colleague David Schwartz, PhD, professor of genetics and of chemistry at the University of Wisconsin-Madison. "He was just such a natural about it. There are people who are excellent at sports, you just put a baseball bat in their hands and the ball flies. Andy is like that with science; without a fuss, it just happens."
Before the discovery, the only method of removing a gene's influence from a population of cells involved a laborious and time-consuming series of experiments with no guarantee of success. It was virtually impossible to "knock-out" even a small fraction of genetic suspects in a particular pathway. Now researchers around the world are using RNAi techniques to quickly and randomly silence one gene at a time in swaths of cells. By plucking out those that act abnormally with regard to the pathway in question, they are able to identify even previously unknown genes involved in the pathway.
The technique has also shown remarkable clinical promise. RNAi-based treatments are being tested in many animal models of disease—high cholesterol, HIV, cancer and hepatitis, among others—and clinical trials have been launched in humans with specific types of macular degeneration and pneumonia. The potential applications of the research are vast.
Despite some intriguing hints that RNA was more than just an assembly manual for proteins, much of this process remained a mystery until Fire and Mello published their findings in the nematode C. elegans, a tiny worm about the width of a No. 2 pencil lead. But Fire emphasizes that much of the preliminary legwork had already been done by other plant and animal researchers.
"We came into a field where a lot was already known," said Fire. "It was a complex jigsaw puzzle, and we were able to contribute one piece. Fortunately for us it was a very nice piece, but it would be really disingenuous to say we did the whole puzzle."
Such demurring is standard for Fire; colleagues often describe him as remarkably modest. Monday, Fire lived up to that reputation. After reluctantly agreeing to participate in numerous media interviews and press conferences, he made sure to credit "insightful and dedicated colleagues and students" with whom he has worked and "whose ideas and efforts are very much the subject of the prize." And he noted that scientists have a responsibility to society at large. "All of us in science look forward to sharing with the public both the responsibilities and opportunities that arise as we understand more about the human body," he said.
Fire added, "For me personally, the occasion of such an award is an opportunity to thank the many patient teachers and mentors who have opened doors to science and research, and especially my family, who have made everything possible.
"This day is a wonderful chance to acknowledge that science is a group effort," Fire continued. "The advances cited in the Nobel award grew from original scientific inquiry from numerous research groups throughout the world." He also thanked the National Institute of General Medical Sciences for providing the grants that made the research possible and continues to support both scientists.
Others were just a little more effervescent. "My wife and I have known him for 20 years, and we were jumping and hooting and hollering when we found out," said Schwartz, who is also the director of the Genomic Sciences Training Program at Madison's Laboratory for Molecular and Computational Genomics. "I spoke to him a couple of weeks ago and told him he was going to win the prize. With his typical understated personality, he said 'Let's talk about something else.'" In fact, Fire is so unassuming that he first suspected his early morning phone call was a prank by his old friend.
Fire will officially receive the award on Dec. 8 in Stockholm, and he and Mello will share the $1.4 million prize. He is the medical school's third Nobel laureate, joining emeritus professors Paul Berg, PhD, and Arthur Kornberg, MD.
"Professor Fire's contributions to his field have been of enormous importance and the recognition by the Nobel committee is a remarkable achievement at this early point in his career," said President John Hennessy. "The RNA research of professors Fire and Mello represents the very best of the collaborative nature of university scholarship. The fact that this basic discovery is already impacting the development of new therapies is a wonderful reminder of the importance of fundamental research."
As any graduate student can attest, fundamental research often means long hours of tedium. Although Fire is careful to credit others, he's no stranger to such drudgery. "I'd be working in the middle of the night," recalled Schwartz, "and Andy would be hunched over his microscope next door, feeding his worms. They had a mutation that made them so uncoordinated that he had to push food their way with a tiny brush." But the work paid off. "This is just gorgeous work that stands a chance to really change medicine, as well as being a remarkable tool for biology," said Schwartz. "Anyone who knows him will not be surprised that he won."
After Fire received his PhD from MIT, he was accepted as a Helen Hay Whitney Postdoctoral Fellow in Cambridge, England, in a laboratory headed by Nobel laureate Sydney Brenner, PhD. He conducted his initial work on gene silencing by double-stranded RNA between 1986 and 2003 while at the Carnegie Institution. He was an adjunct professor in the Department of Biology at Johns Hopkins University starting in 1989 and joined the Stanford faculty in 2003. Throughout his career, all of the major work in Fire's lab has been supported by research grants from the US National Institutes of Health.
Fire is a member of the National Academy of Sciences and of the American Academy of Arts & Sciences. He serves on the Board of Scientific Counselors and the NIH's National Center for Biotechnology. He has received and shared numerous awards, including the Maryland Distinguished Young Scientist Award, Meyenburg Prize, Genetics Society of America Medal, National Academy of Sciences Award in Molecular Biology, Passano Family Foundation Award, Wiley Prize, H.P. Heineken Prize in Biochemistry and Biophysics, Warren Triennial Prize, Rosenstiel Award, Gairdner Award, Massry Prize and Ehrlich/Darmstaedter Prize.
None of this has gone to Fire's head—and the Nobel Prize doesn't appear to be either. "I like what I do," he said when asked how the Nobel might affect his life. "I like teaching, I like research and I like talking to colleagues. This brings another dimension: an opportunity to have a voice beyond my own lab and field. That's a big responsibility, and I look forward to using that voice as needed. At the same time, I still want to do interesting and unusual experiments, while also making sure I don't get too much credit."
Now that's normal—at least for Fire.