BOSTON (Boston Globe) - MIT cancer biologist Robert Weinberg's favorite diagram these days looks as if it were designed by one of his colleagues across the way in the engineering department. It shows a cancer cell masquerading as an electronic circuit, covered with an array of lines and arrows.

Twenty-six years of research, Weinberg said, has revealed cells to be much like circuits. Both are logical networks of switches and signals. His analogy tantalizes: Circuits are manipulated with ease. So, too, the cancer cell?

That far-off scenario became markedly more imaginable last month after the spectacular debut of the cancer-fighting drug, Gleevec. Though it works only on two rare forms of cancer, Gleevec prompted sunny optimism among usually cautious cancer researchers, including Weinberg, one of the giants of the field.

"Gleevec is a dramatic validation of the idea of rational drug design," said Weinberg, whose lab made some of the fundamental discoveries that made Gleevec possible.

Gleevec grew from a deep, hard-earned understanding of the cancer cell, scientists say. For perhaps the first time, they can manipulate the inner workings of a tumor. The drug's more practical lesson, scientists say, is that the surest course to lifesaving drugs is through the methodical unraveling of nature, an approach embodied by Weinberg. Frantic, monied quests for silver bullets should be treated skeptically, the scientists say.

Gleevec, in other words, marks a new phase in the three-decade war on cancer, where medicine proceeds with an intimate knowledge of the enemy.

Chemotherapy simply wipes out all the cells in its path, cancerous or otherwise. In the past, most drugs were derived from rote testing of hundreds of chemicals. Whatever produced results, however meager, was accepted until something better was found. But Gleevec targets a single protein, jamming cancer-prompting signals without hurting patients. More than a dozen "smart" drugs like it are in the works, many in the latter stages of clinical trials.

"In the past, we didn't understand cancer to the same degree," said Dr. Bruce Chabner, cancer clinic director at Massachusetts General Hospital. "Gleevec is much more sophisticated, like a rifle rather than a shotgun."

Ninety percent of early-stage chronic myelogenous leukemia, or CML, patients who took Gleevec in clinical trials went into remission. Later, it was found to cause quick remissions in 60 percent of those with a lethal stomach cancer called gastrointestinal stromal tumor, or GIST.

And Dr. Richard Stone, who led trials of Gleevec on CML patients at the Dana-Farber Cancer Institute, said the new drug is much easier on patients than a staple of current treatment, interferon, an immune-system booster that often gives patients chronic flu-like symptoms.

"Every time you put someone on interferon, they hate you," he said, calling Gleevec "one of the three or four most important developments in cancer treatment" in 15 years.

Perhaps not surprisingly, the striking results led the U.S. Food and Drug Administration to rush it to market in record time.

But Gleevec comes with significant caveats. It has yet to show it can increase the life span of patients, the gold standard of cancer drugs. It works, so far, only on CML and GIST, two cancers caused by a single genetic defect. Most cancers are caused by a far more complex series of DNA mutations.

Understanding this complexity has been the life's work of Weinberg and hundreds of others. The roots of Gleevec can be traced back to the 1970s, when Weinberg was a freshly minted Ph.D. and cancer still an enigma.

The watershed moment occurred in 1976, in the San Francisco lab of Harold Varmus and J. Micheal Bishop. They managed to isolate the guilty gene in a cancer-causing chicken virus. Then came a startling, Nobel prize-winning finding: A dormant version of that same gene was already present in healthy chicken cells. The virus had stolen the gene, made it cancer-causing, and went on to start tumors in other chickens.

The larger meaning was sobering: Every healthy living cell could conceivably mutate into a cancerous one. The enemy is within, became the refrain. Weinberg's lab was the first to turn healthy cells cancerous by injecting them with genes from a tumor, proving one errant cell could transmit its deadly message to others via DNA.

Hundreds joined the hunt. Over two decades, dozens of genes that contributed to cancer, called oncogenes, were found. They fell into two categories, those that allowed cells to multiply without end, and those that disabled cells' internal mechanisms for preventing such proliferation. The combination - a floored accelerator and no brakes - allowed a cancer cell to fulfill its deadly Darwinian quest - to reproduce endlessly.

It became evident that numerous genetic mutations were needed to reach this stage. They took years to accumulate, explaining why cancer risk increased with age.

And Weinberg was to make another discovery that would further underscore human frailty. Genes are made up of thousands of As, Cs, Ts and Gs, the amino acids that make up the genetic alphabet. As they are copied from cell to cell, or bombarded by carcinogens, these letters are often switched. Most such "errors" don't produce major effects on the gene.

Weinberg found that one prominent oncogene in bladder cancer was created by a single mutation, rather than the multiple mutations that were expected. A simple change of one G into a T rendered the entire gene cancerous.

Weinberg found satisfaction in the simplicity of it. In fact, he peppers his talks with terms like "elegant" and "beautiful," associated more with physicists describing the simplicity of physical laws rather than biologists dealing with messy and mysterious life. But achieving the physicists' commanding understanding of nature is Weinberg's hope for his field.

"It's clear that we're talking about molecular circuitry," he said of the cancer cell.

In 1999, Weinberg was able to create a cancerous cell in a test tube simply by pulling the right genetic switches.

"We're now in a situation where we've accumulated an enormous amount of information about the molecular defects involved in cancer," Weinberg said.

All the oncogenes identified by researchers presented obvious targets for drug companies. Unfortunately, positive results proved elusive. But, in the mid-1980s, Weinberg's former boss at the Whitehead Institute, who once ran a lab on the same floor, was laying the seeds for Gleevec.

Nobel laureate David Baltimore, now president of the California Institute of Technology, and his colleague, Owen Witte of UCLA, were using oncology breakthroughs to study chronic myelogenous leukemia. All CML victims have a slight abnormality in their 22nd chromosome: One of the two copies is missing a small DNA segment.

Baltimore and Witte realized the missing piece created an oncogene that, on its own, disrupted the internal communications system of white blood cells, causing cells that normally help the body fight disease to multiply without end. The result was a cancer that annually afflicts about 4,500 people in the United States. Bone-marrow transplants or drugs with severe side effects were the main treatment, but CML was usually a death sentence.

Dr. Brian Drucker of the Oregon Health Sciences University in Portland, Ore., was one researcher struggling to create medicines from the basic research then streaming out of labs. He found that a particular chemical, called STI-571, stopped the CML oncogene from spurring production of excess white blood cells.

Working with the Swiss drug company, Novartis, Drucker conducted clinical trials on a pill form of STI-571, dubbed Gleevec. The electrifying results, a decade in the making, were released last month.

"It's one of those proof-of-principle events. It proves that, if you can find a target, then you can design a drug to hit that target," said Dr. Edward Benz, president of the Dana-Farber Cancer Institute.

"Patients are aware of this drug, and they're very interested in it," he said. "They don't always understand that it is effective against a small amount of cancers."

Gleevec is part of a class of drugs that target PDGF receptors on cells, which receive the errant cancer-causing messages that result in cancer. In addition, another batch of drugs target the similarly-functioning EGF receptors. Herceptin, a drug used in some cases of breast cancer, is one of the few in use. It has proven helpful but not as effective as Gleevec, researchers said.

Companies like Millenium Pharmaceuticals in Cambridge, Mass., Amgen, AstraZeneca, Pharmacia Upjohn, Pfizer and others are furiously testing PDGF- and EGF-targeting drugs. But Benz said it was premature to compare any to Gleevec.

Chabner, at Massachusetts General Hospital's cancer clinic, said these drugs may not work alone but could augment a familiar, albeit unwieldy, weapon.

"We can use these drugs to enhance chemotherapy. They increase the sensitivity of tumor cells to cell death," he said.

Another class of much-anticipated drugs are angiogenesis inhibitors. Dr. Judah Folkman at Children's Hospital discovered two decades ago that cancer tumors require nourishment to live and thrive. To get it, they hijack blood vessels from the body, a process called angiogenesis. Drugs that seek to stop this, and starve tumors, have proven safe and are now being tested for effectiveness at several sites around the country.

Across the Charles River from Folkman, Weinberg's mode of operation over the years has been to stick to basic questions about cell life rather than seek to turn his discoveries into therapies as Folkman has. His lab has made a string of major discoveries in a field where even single breakthroughs are rare.

At the moment, Weinberg is struggling with metastasis, where local tumor cells spread throughout the body, typically a death blow. He calls it "the last big frontier" in his field, the least understood aspect of cancer.

"We're very confused," he said, quickly adding, "but it, too, will yield."

Copyright 2001 The Boston Globe. All rights reserved.