Cancer Pioneer

A biotech company reported earlier this year that one of its products helps patients with metastatic breast cancer live longer.

The announcement could turn out to be a milestone. Genetic engineering has led to helpful therapies for a handful of uncommon cancers. But prior to the new drug, Herceptin, it had never helped slow the major tumors–breast, lung, colon, prostate–that make cancer such a broadly lethal disease.

The drug acts by blocking an oncogene, an abnormal gene linked to cancer. And the announcement related to it had special resonance for MIT’s Robert Weinberg, professor of biology. “We studied that oncogene,” he notes, “but that was in the early ’80s. Another group has carried the work forward since then.”

Had he felt like it, he could have elaborated further. Weinberg, a member of the Whitehead Institute for Biomedical Research as well as the MIT faculty, last fall won the National Medal of Science for his pioneering oncogene work. “He’s made so many pivotal contributions,” says David Livingston, Harvard professor of medicine in genetics, “that it would take a long time just to list them all.”

Today, when oncogenes like BRCA1 and BRCA2–both culprits in breast cancer–are staples of newspaper stories on the disease, it’s hard to imagine a time when cancer-causing genes represented a small outpost of cancer research. But that’s how it was in the ’70s, when Weinberg first started probing the deadly genes.

Eighteen explanations

Though scientists suspected genes had a role in cancer, other factors, like viruses, were seen by some as the real villains. What’s more, scientists who focused on the gene-cancer link faced a huge challenge.

“The whole area appeared to be infinitely complicated,” says Weinberg. “It seemed as if any phenomenon involving this system could be explained in eighteen different ways.”

There weren’t many daring–or foolhardy–enough to try making sense of the subject. “You’d have a conference in the 1970s, and everyone doing interesting work in cancer genetics could fit into one meeting room,” says the scientist, who joined the MIT faculty in 1973.

Though Weinberg himself had doubts about plunging into the field, he was amply motivated to try. “I’ve always been obsessed by how cancer works at the molecular level,” he says.

He also had a maverick streak. “He’s quite willing to pursue hypotheses that aren’t fashionable if he thinks they’re right,” notes Livingston.

Still, Weinberg and his associates made fitful progress in their efforts to pinpoint a specific gene that triggers human cancer. The quest, described in his book, “Racing to the Beginning of the Road,” took years. There were detours down what turned out to be dead ends. There was also a scare when Weinberg heard a colleague declare–incorrectly, it later turned out–that he’d worked out the gene-cancer connection.

“It seemed at that point as if the whole game was over–that the problem had been solved,” recalls Weinberg.

Finding the oncogene

Eventually, a graduate student in Weinberg’s lab reported finding a gene that turned out to play a pivotal role in triggering human cancer. Dubbed “ras,” it came from a bladder cancer patient. Work since has shown ras plays a role in as many as a quarter of human malignancies.

This discovery and others spurred more scientists to join the hunt. Researchers also created more sophisticated tools for probing oncogenes and their counterparts. Soon, findings about gene-cancer links were popping up regularly in scientific journals.

With the identification of specific oncogenes came an ever-clearer picture of how they work. “When we discovered a mutant ras in a human tumor,” notes Weinberg, “we hadn’t the vaguest idea of its role in the normal cell.” Now it’s known that ras, like many oncogenes, is involved in signaling normal cells whether to grow–a role that gives the gene a pernicious power when it turns bad.

Such knowledge is vital in creating drugs. “A normal cell and its cancerous counterpart are more than 99 percent identical,” says Weinberg, “so you need precise knowledge of the defects to accurately target cancer cells without damaging normal ones.”

The scientist says drug designers are starting to accomplish that. “Today I can say something I wouldn’t have said five years ago,” he notes, “which is that over the next several years, there will be dramatic advances in cancer treatment.”

Ending immortality?

Recent work by Weinberg’s group may help. The researchers report they’ve found the explanation for one of the most lethal traits exhibited by cancer cells–their ability to grow without limit.

The basis of this trait, often called cellular immortality, seems to be an enzyme, telomerase, that’s found in most types of cancers but not in normal tissues. Weinberg’s group has pinpointed a stretch of the enzyme that may be its weak point. “If you could create a drug that crippled telomerase,” he notes, “it would represent a highly useful adjunct to other types of therapies.”

But Weinberg won’t be standing by, waiting to see if the concept works in practice. “The thing that’s the most fun for me,” he says, “is thinking about a problem, putting the pieces together, and finally getting to say, ‘This is what’s really going on.’”

But the scientist, who recently had just such a revelation about the origin of certain types of breast cancer, emphasizes that the “Eureka!” moment isn’t the end of the story. “Once you’ve got the idea,” he notes dryly, “you get to spend three, four or five years figuring out if it’s right.”

by Richard Anthony

On Topic: cancer research, genetics