Hunting for killer genes is a blast Cancer: Bert Vogelstein and his team of researchers put in long hours studying it -- and seem to be having a great time.

THE BALTIMORE SUN

In a renovated supermarket on Orleans Street, to the blare of alternative rock music, Bert Vogelstein and a score of the world's smartest young scientists are searching for the genes that can program us for death.

They put in grueling days and nights studying human colon cancer cells. They've published more than a thousand scientific papers. They've made signal discoveries -- including the identification, announced Monday, of an inherited genetic defect carried by some American Jews that doubles their risk of developing a common form of colon cancer.

And they seem to be having a heck of a good time.

"Other scientists look at what this laboratory has done and think, 'I should have done that, I could have done that'," said Steve Laken, 26, a cell biologist and doctoral student working in the lab. "People think Bert must possess a slave driver's mentality to get his people to perform like this. But it's not like that at all."

In the warren of research space, there's the usual laboratory clutter of workbenches, incubators and centrifuges, of course. But a sign on a lab microwave: "No, no, no!!! FOOD, DRINK, CATS." A faucet bears the label "Farrah Fawcett." A sticker above the room where radioactive materials are used warns: "Chateau Glow."

Vogelstein himself has a dark, cluttered office with green bamboo curtains across the doors. He fixes his own scientific thermometer, and plays keyboard in Wild Type, thelab's rock band.

He and the lab's co-director, Dr. Kenneth W. Kinzler, who holds a doctorate in pharmacology (and plays drums in the band) "are very caring and compassionate," Laken said. "They're also very driven to find a cure."

This week, Vogelstein, Kinzler and Laken announced their latest finding, which included the development of a test to detect the mutant gene. But yesterday, both senior scientists gave all the ,, credit to their team.

"The work is virtually all done by trainees -- postdoctoral and predoctoral fellows," said Vogelstein, casually dressed and sprawled in a chair in his office. "They get paid nothing, or close to nothing. They were the smartest students in college. The most intelligent people, from all over the world.

"Ken and I, we supervise," he said. "We watch."

Kinzler, who wears button-down shirts and cultivates a discreet pony tail, cheerfully agrees, sounding in awe of his subordinates. "People here are not just scientists," he said. "They're kind of like artists."

Vogelstein and Kinzler have worked together for 14 years. It's been a remarkable time.

Since deciding to tackle colon cancer in 1981, Vogelstein and his colleagues have shown not only that the disease is genetic in origin, but that it is caused by the accumulation of five or six mutations in a single cell. Without all the mutations, a cell is safe from the destructive spiral that leads to pre-cancerous polyps and, finally, to malignant tumors.

"Vogelstein was really the first to subject a given type of human cancer to systematic study, and in a fashion that remains unparalleled to this day," said Dr. Robert Weinberg of the Massachusetts Institute of Technology, who in 1979 identified the first cancer-causing gene in humans. "He plotted out a biography of a colon cancer from conception to its malignant progression in terms of genes that are mutated in a cancer cell."

Most of the mutations are acquired during a person's lifetime, said Vogelstein. But in in this decade, the Hopkins group has described two inherited mutations that greatly increase a person's risk of acquiring the full complement of mutations that spell cancer. The first, reported in 1993, accounts for a small portion of colorectal cancers -- perhaps 3 percent of the 130,000 cases reported each year in the United States.

Now, the group has found a subtler mutation that tends to run through Jewish families of Eastern European descent. Vogelstein believes that similar mutations running through other ethnic groups may, together, explain 15 percent to half of all cases.

Vogelstein grew up in affluent Pikesville, the son of a lawyer and the descendant of a long line of Orthodox rabbis.

He bleeds Hopkins blue. He was born at Hopkins Hospital, in a room 50 feet from the current office of the medical school's dean.

While he majored in mathematics at the University of Pennsylvania, he graduated from Hopkins medical school, and served as an intern and resident there. Today, at 48, he's one of the Hopkins elite, a university professor.

"You could describe my whole life as a two-block sojourn from the dean's office to the grocery store," he said.

He decided cancer research "was a reasonable way to spend your life" soon after graduating from medical school. His first patient turned out to be a 5-year-old girl, the daughter of a mathematics instructor at the U.S. Naval Academy, who suffered from leukemia.

Watching her die, he felt helpless and frustrated. Not just that he couldn't help. But that he didn't understand what was happening. "Here I was, a physician, and I couldn't tell her father anything about why his daughter had cancer."

Compassionate and caring? Sure. But Vogelstein is driven to get results.

"We have to work as quickly and as hard and as intelligently as we can," he said. "That's the way we make progress."

He's made a lot of progress.

"He is the most productive cancer researcher alive today, and that is not a small compliment," said MIT's Weinberg.

Kinzler, 35, spent his childhood in a rowhouse neighborhood in ++ Northeast Philadelphia, liked "Star Trek" and science fiction in general and thought it would be "neat" to work in a laboratory.

Affluent? He gave up the drums in high school because he couldn't afford a car to haul them around.

He studied toxicology at the Philadelphia College of Pharmacy and Science, and was a bit awed when he first came to Hopkins as a doctoral student in 1983. That same year, he started working as a short-timer in Vogelstein's lab.

Today, he's not only co-director, he's described as the team's guiding spirit, its inventive genius -- encouraging everybody to make do, but get it done.

In the late 1980s, the laboratory needed a piece of equipment to isolate genes. Machines on the market were expensive and hard get. Kinzler built one himself, partly out of a device that rotates television antennas.

The gizmo played a role in one of the laboratory's important discoveries -- that the so-called P53 gene, a gene linked to numerous human cancers, acts like a kind of brake on the growth of tumors. Kinzler donated the machine to the Smithsonian for an exhibit.

In the Vogelstein-Kinzler lab, huge refrigerators contain about 400 specimens of human colorectal cancer cells, stored at about minus 200 degrees Farenheit.

Once thawed, they're cultivated, like orchids, in incubators. Under the microscope, these malignant little life-forms, with their grotesquely swollen nuclei, crowd in on each other -- refusing to stop growing, even in vitro.

Graduates of Vogelstein's laboratory have gone on to found their own labs at Hopkins, Columbia and other academic centers. They are editors of research journals. They are trying to crack the genetic codes that may lie behind cancers of the head and neck, pancreas, cervix and kidney.

"That's our legacy," Vogelstein said.

Pub Date: 8/27/97

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