'Worthy of investment'

Among the scores of graduate students and fellows who toil in the research labs of the Hutchinson Center each year, many will parlay their superb training experiences into jobs at prestigious universities or make breakthroughs in their fields. And as recent news headlines show, some may even go on to win a Nobel Prize.

Such is the case for Dr. Craig Mello, co-recipient of this year's Nobel Prize in medicine or physiology, who with Dr. Andrew Fire was recognized for the discovery of a fundamental mechanism for controlling the flow of genetic information. Mello was a postdoctoral fellow in Dr. Jim Priess' Basic Sciences Division laboratory from 1990 to 1994. There he made key contributions to the understanding of the earliest steps of embryo development in Caenorhabditis elegans, the microscopic soil worm that is hailed by biologists as a model system for studying the process.

Priess described Mello as "extremely creative and one of the hardest-working postdocs I've known," and credits philanthropic gifts to the Center for supporting the first two years of Mello's research. Donations from individuals and foundations, which last year totaled more than $32 million, provide critical funding for fellowships, early stage research studies, faculty recruitment and other essential activities that may not be eligible for federal grant support.

Mello and Fire discovered the mechanism for a process known as RNA interference, or RNAi, through which normally active genes are silenced when RNA is injected into cells. RNA is a typically single-stranded molecule related to DNA, the double-stranded molecule that holds the cell's genetic blueprint. Though RNAi was first observed as a laboratory phenomenon, this form of gene silencing is now known to be a naturally occurring process in a wide range of organisms that probably evolved to protect cells from viruses. RNAi has enormous implications for human health, since it affords the possibility of engineering the shut-off of specific genes, such as those that are abnormally activated in cancer cells. Several large pharmaceutical companies, including Merck & Co., have already invested in drug development based on this technology, with a number of therapies entering human clinical trials.

Mello's prize-winning work was conducted entirely in his own laboratory at the University of Massachusetts Medical Center, where he has been a faculty member since 1994. But his initial intrigue in how RNA can shut off genes was sparked by observations made in the lab of the late Dr. Hal Weintraub, a founding member of the Basic Sciences Division.

In the 1980s, Weintraub and his postdoctoral fellow Dr. Jon Izant developed a technology known as antisense RNA to reduce the activity of genes in mammalian cells. Scientists often wish to "knock out" or reduce the output of a gene to determine its function.

The antisense technique is based on the injection into cells of strands of RNA that are complementary to the blueprint-containing DNA strand of a gene. Such strands of RNA are known as antisense because they are the exact complement of the "sense" DNA strand. Weintraub and Izant's method was later used by Calgene Inc. to develop the Flavr Savr tomato, which uses antisense technology to inhibit production of a ripening enzyme, allowing the fruit to stay firm longer. The product is no longer on the market due to difficulties in harvesting.

When Dr. Ken Kemphues of Cornell University applied the antisense RNA technique to worms, he found that it was highly effective in inhibiting gene function. However, he discovered that the sense RNA (complementary to the "nonsense" DNA strand) worked equally well on worms. Mello and others in the Priess Lab found similar results for several of the genes they were studying. Priess said that at the time, it was unclear whether these surprising results had general biological significance or were simply an aberration of the worm system.

Prize-winning discovery

"To Craig's credit, when he started his own lab, he decided to start studying it as a phenomenon, which led to the Nobel-winning discovery," Priess said. Working with Fire, then at the Carnegie Institute of Washington, Mello deduced that double-stranded RNA (sense and antisense paired together) could silence genes; that this RNA interference is specific for the gene whose code matches that of the injected RNA molecule; and that RNA interference can spread between cells and even be inherited. Mello and Fire have patented this technology.

Dr. Helmut Zarbl, an investigator in the Human Biology and Public Health Sciences divisions, also contributed early observations that suggested a role for RNA in gene regulation. He and Dr. Bahman Bhramian made their observations in 1994 using mammalian cells; they hold a patent on technology that is based on that work.

Priess noted that Mello's experience at the Center illustrates the important role that philanthropy plays in launching the careers of promising junior scientists. "Craig was an extremely talented and creative scientist but had trouble obtaining a postdoctoral fellowship from the National Institutes of Health or other traditional sources to support his training in my lab," he said. "Funds raised from donations to the Center supported him until he had enough results to eventually get his own grant — and it's clear today that he was worthy of investment."