February 24, 2004
New DFCI center takes on lofty goal of mapping complete set of gene interactions within human cells
Left to right: William Hahn, MD PhD; Marc Vidal, PhD; and Todd Golub, MD
With a draft of the human genome map now in hand, a group of Dana-Farber researchers is moving to the next frontier in molecular research: a study of the interactions among the estimated 30,000 genes in human cells.
View the Center for Cancer Systems Biology's Web site
At DFCI's newly opened Center for Cancer Systems Biology, researchers will use sophisticated machinery and high-powered computers to find which genes act together in controlling the lives of cells. The hope is that by tracking these networks of gene activity, investigators will gain a deeper sense of how genes work in concert — and how they are disrupted in cancer cells.
"The sequencing of the genome has enabled us to ask, 'What is the universe of connections that exists among genes?'" says Marc Vidal, PhD, of Cancer Biology, one of the new center's leaders. "If we understand these networks better, we might have a clearer picture of how cancer happens and how it can be prevented or reversed."
The center has joined a worldwide effort to map the complete set of gene interactions — the so-called "interactome" — within human cells. This is a statistically gargantuan undertaking, considering the number of possible connections. Evidence that it can be accomplished, however, came in a recent study by Vidal and his colleagues. In a paper published earlier this year in Science, the team mapped a large portion of the interactome of the worm C. elegans, a tiny parasite with 17,800 genes. They identified more than 4,000 separate interactions, eavesdropping, in a sense, on the "molecular conversation" within the animal's cells.
"We may know, for example, that three genes are mutated in a particular cell," Vidal remarks. "But those mutations don't explain all the differences between this cell and a normal one. Thinking about one gene at a time isn't enough. Perhaps part of the answer is the networks they're involved in."
Systems biology can be thought of as the molecular version of social psychology, which views behavior through the lens of human relationships. The map of the interactome of C. elegans, for example, resembles nothing so much as an extremely complex telephone switchboard, with lines connecting all the genes doing business with one another.
It's clear from even a cursory glance at the worm's interactome map that whereas some genes are highly connected, others are more like molecular loners, with few links to other genes. Vidal and his colleagues will explore whether those highly connected genes are particularly important in cancer.
Tweaking genes
To learn what happens when gene networks are disrupted — and whether such disruptions have a bearing on cancer — another of the center's leaders, William Hahn, MD, PhD, of Medical Oncology, will be conducting experiments with reagents able to shut down individual or groups of genes. These reagents, known as RNAi, make it far easier to study gene loss than the traditional method, which uses "knockout" mice that lack key genes.
"With RNAi, we're able to tweak the activity of genes that occupy key 'junction' points in gene networks," says Hahn. "By doing this, we can see how these genes work together, and which connections are important to cancer and which are not." His work ties in closely with that of the center's third leader, Todd Golub, MD, of Pediatric Oncology, who is studying activity levels of genes in specific networks.
A key aspect of all this work — which together comprises the center's "flagship" project — is statistical analysis. Probing the interactions between genes produces an ocean of data that must be sifted for patterns and meaning. Robert Gentleman, PhD, and colleagues from the Biostatistical Science Department will lead the effort to develop analytical tools to accomplish this.
A 'go to' place
The cancer systems biology center is more than a laboratory with machinery for performing gene-interaction experiments. It is also a "think tank" for scientists interested in interactome research.
"We want to create a forum where people involved in this field can share ideas, ask questions, and learn from one another," Vidal remarks. "We also hope to invite scientists from outside Dana-Farber and Harvard to talk about their work."
The center's third component is what Vidal calls its "go to" function: making its equipment and expertise available to other Dana-Farber scientists interested in analyzing gene interactions.
"Our goal is to create a focus for these emerging research areas at Dana-Farber," Hahn remarks. "It promises to add a great deal to our understanding of cancer and, potentially, our ability to treat it."
