Washington, D.C. — Andrew Z. Fire, a scientist who discovered RNAi, or RNA interference while at the Carnegie Institution’s Department of Embryology, along with Craig C. Mello of the University of Massachusetts Medical School, was awarded a Nobel Prize for the discovery today.
The Fire-Mello discovery that double-stranded RNA can quash the activity of specific genes is an important breakthrough in modern molecular biology. RNAi is now being widely used both as a research tool and for the development of products that could combat diseases such as cancer and HIV.
“I am very honored that our work has received such positive attention,” said Fire. “Science is a group effort. Please recognize that the recent progress in the field of RNA-based gene silencing has involved original scientific inquiry from research groups around the world. Any prize recognition should go to the many scientists who have made individual contributions, and to the spirit of scientific community that has allowed information and ideas to flow freely. Our lab's work in this field has also been a group effort. I have been fortunate to work on this project with many talented colleagues at the Carnegie Institution, with Dr. Craig Mello and his talented colleagues at the University of Massachusetts, and with the insightful support of the National Institutes of Health,” he stated.
“Every one of us at Carnegie is thrilled for Andy, for the institution, and for the promise this discovery has for advancing our understanding of basic molecular processes and helping cure disease,” said Carnegie president Richard A. Meserve. “Andy’s work is a vivid example of how Carnegie’s commitment to freedom of research can yield extraordinary results for humanity.” Two other Nobel geneticists have come from Carnegie—Alfred Hershey, who won the prize in 1969 for his discovery that genes were made of DNA, and Barbara McClintock, who won in 1983 for her work on jumping genes, also known as transposable elements. Fire was employed by the Carnegie Institution for 17 years. He joined the faculty of Stanford University in November 2003 in order to be closer to family.
The Tale behind the Discovery
In 1997 the Fire-Mello team found that by specially designing RNA with two strands they could silence targeted genes. The singled-stranded RNA molecule of messenger RNA, also known as “sense” RNA, conveys information from a DNA template to the machinery that “turns on,” or expresses, a specific gene. The Fire-Mello RNA molecule has two strands similar to the famous double-helix structure of the related molecule DNA. One strand of the double-stranded RNA molecule is sense RNA, with a structural sequence that is the same as the nucleotide sequence in the target gene. The other strand, known as “antisense” RNA, has a complementary sequence to that in the target gene. When the double-stranded molecule is introduced into an organism, it interferes with the message-carrying process and shuts down the gene.
RNAi also exists naturally as a defensive mechanism in cells. Since its discovery it has become a powerful tool to understand developmental processes, and it is now commonly used to investigate gene function. Using RNAi, scientists now routinely “knock out” specific genes to prevent their expression, observe the disruptions to normal processes, and thereby help determine what the gene does. The method also opens up the possibility of treating various types of diseases by either shutting down the disease-causing gene or by directing researchers to appropriate pathways for developing new drugs. The Fire-Mello discovery was recently patented and has been widely licensed in the U.S., Europe, and Japan to address a broad range of research questions. Science magazine identified RNAi as a “Breakthrough of the Year” in its December 2002 issue.
As with many scientific discoveries, the research that led to the discovery of RNAi started out with a very different purpose. More than 15 years ago, Fire became interested in understanding the genes involved in the earliest steps of cellular development. He wanted to know how, in just 12 hours, a fertilized egg of the tiny soil-dwelling worm Caenorhabditis elegans changes from one cell to over 500, neatly arranged into body structures. To understand this complexity, Fire and technician Susan White-Harrison designed an experiment to increase gene expression—that is, to turn on a specific gene—to see if they could plot the steps involved in cellular development from the beginning. They injected the worm with a piece of DNA called a promoter, which initiates the synthesis of messenger RNA (mRNA). But the mRNA didn’t do what they expected. Instead of turning the gene on, it inactivated it.
These results sat on the shelf for some time, bolstered along the way by observations by other animal and plant biologists that small amounts of sense RNA could apparently turn genes off. Then the puzzle deepened: graduate student Sam Driver in Mello’s lab discovered that just one injection of RNA into a worm’s body cavity could inactivate genes throughout the entire animal. It appeared that something both potent and stable was turning genes off.
A key experiment in Fire’s lab later provided the explanation for what was happening—the researchers mixed sense RNA with a small amount of antisense RNA, and the two strands together generated the silencing effect. It was found that the earlier experiments had included trace amounts of antisense RNA, thus causing the RNA interference.
The Man behind the Prize
Fire, a California native, received an A.B. in mathematics from the University of California, Berkeley, in 1978. He went to the Massachusetts Institute of Technology (MIT) for graduate work, studying RNA polymerase type 2 transcription under Phillip Sharp, a Nobel laureate in gene research. Fire received his Ph.D. from MIT in 1983 and won a Helen Hay Whitney Fellowship to conduct research on the nematode Caenorhabditis elegans at the Medical Research Council Laboratory of Molecular Biology in Cambridge, England, under the guidance of Sydney Brenner.
In 1986 Fire was appointed a staff associate at Carnegie’s Department of Embryology, ordinarily a nonrenewable junior faculty position. However, Fire’s research progress was so significant in three years that he was promoted to the position of staff member. Staff members at the department automatically receive an unpaid part-time position in the Department of Biology at the Johns Hopkins University. Fire joined the faculty of Stanford University in November 2003, but maintains strong ties with Carnegie as a Carnegie Investigator.
In 1989 Fire was awarded the Rita Allen Foundation Scholar Award, a grant to young investigators. Since the discovery of RNAi, Fire has received numerous awards including the 1997 Maryland Distinguished Young Scientist Award, the 2002 Meyenburg Prize from the German Cancer Research Center, the 2002 Genetics Society of America Medal, the 2003 Passano Award, the 2003 Wiley Prize, the 2003 National Academy of Sciences Award in Molecular Biology, and now the Nobel Prize.
The Carnegie Institution of Washington (www.CarnegieInstitution.org), a private nonprofit organization, has been a pioneering force in basic scientific research since 1902. It has six research departments: the Geophysical Laboratory and the Department of Terrestrial Magnetism, both located in Washington, D.C.; The Observatories, in Pasadena, California, and Chile; the Department of Plant Biology and the Department of Global Ecology. in Stanford, California; and the Department of Embryology, in Baltimore, Maryland.