Black Cats on the Black Sea

One summer in the late 1980s, Yuri Lazebnik needed to sort some cells.

By Karen Hopkin(khopkin@the-scientist.com) | January 17, 2005

<p>Yuri Lazebnik</p>

Courtesy of Bill Geddes

One summer in the late 1980s, Yuri Lazebnik needed to sort some cells. A graduate student at St. Petersburg State University in the Soviet Union, Lazebnik was studying proteins involved in regulating the cell cycle. The project required labeling and separating cells in various stages of division. So Lazebnik built a cell sorter, and when he realized he didn't have the necessary marker proteins, he headed to the Black Sea, fished out some red algae, and purified the fluorescent moieties himself. "It was warm and sunny and really fun," says Lazebnik, now a biochemist studying how cell death contributes to cancer at the Cold Spring Harbor Laboratory on Long Island.

"That's Yuri!" laughs Michael Hengartner, a fellow cell-death researcher at the University of Zurich and Lazebnik's former officemate. "It just shows how determined and resourceful the guy is." And how he does things a bit differently. "Yuri is known for being unconventional, for not traveling down the standard path," says David Vaux, who works on cell death at the Walter and Eliza Hall Institute (WEHI) in Melbourne.

CHROMATIN AND CAKE

He may be a renegade, but Lazebnik was essentially going with the flow when he decided to leave Russia and strike out for America. "By 1990, most of the bright people had already left," he says. "There was nobody left to talk to." Then he met Bill Earnshaw at a Russian conference on chromatin structure. "He was evading me by all means possible," recalls Lazebnik. "But I cornered him while he was eating a piece of cake." The cake talk was a success, and Lazebnik joined Earnshaw's lab at Johns Hopkins University to study mitosis.

It was there, oddly enough, that Lazebnik stumbled onto cell death. When he arrived in the lab, he began work on a cell-free system for studying mitosis, which had been set up by another post-doc. He could reproduce his colleague's results, but something wasn't right. "The chromosomes looked weird," says Lazebnik. And the cells didn't look like cells in the throes of division. "It made me very unhappy and made my boss very unhappy, too. Common sense was: I was going to get kicked out of the lab."

With nothing to lose, Lazebnik felt free to fool around with his cultures, testing far-fetched notions such as contamination with mycoplasma. He soon realized that his cells weren't dividing – they were dead. His lab mates were dubious. "They thought I was going crazy." But Lazebnik went to the literature and started reading about apoptosis. "Some of it was complete garbage," he says. Still, the pictures of apoptotic cells looked exactly like what he saw in his culture dishes. And those weird chromosomes, when separated on a gel, displayed the ladder-like signature pattern of programmed cell death.

Earnshaw was convinced, and Lazebnik's curiosity essentially transformed a nonfunctional assay for mitosis into an in vitro assay for apoptosis that is used widely today. The discovery was just another example of Lazebnik's "eye for detail and an unwillingness to ignore anything that doesn't quite fit," says Vaux. "He keeps hammering away until he knows what's going on."

SEDUCED BY CELL FUSION

Currently under Lazebnik's hammer is the question of whether cancer cells can fuse with one another or with normal cells. Again, his interest was piqued by an unusual observation. Lazebnik and his postdoc Dominik Duelli were exploring how cancer-causing oncogenes can enhance a cell's sensitivity to drugs that induce apoptosis. The experiments involved coaxing transformed cells and normal cells to fuse by bathing them in polyethylene glycol (PEG). The hybrid cells, like their normal parent, were resistant to apoptosis, suggesting that normal cells produce a factor that protects them from cell death. Oncogenes, Lazebnik reasoned, somehow defeat this safety feature. He eventually hopes to exploit this situation to develop treatments that encourage cancer cells to turn themselves off.

Then came the odd observation: Duelli discovered that the cells fused even without the PEG. "I've spent the last three years trying to figure out why," Duelli says. The answer could shed light on how cancers evolve, and why they spread. If, for example, a tumor cell in the body fused with a macrophage, a cell that lives to travel, the resulting hybrid would be a recipe for metastasis.

The possibility seemed well worth exploring. "I spent a month reading in my basement," says Lazebnik, who likens his love of old books and papers to a literary and scientific form of necrophilia. He discovered that the notion that cancer progression is fueled by fusion dates back to 1911. He also found that other biologists have made observations consistent with the idea that tumor cells and normal cells can unite.

"Intellectually, it's a very interesting possibility," says Lazebnik, who received a small, high-risk/high-impact grant to investigate fusion further. "We'll see what happens," he says. "We're looking for a black cat in a dark room, and maybe there's no cat."

PASS THE SHOVEL

<p>SEE NO CELL DEATH:</p>

Courtesy of David Vaux

Lazebnik, Michael Hengartner, and Scott Kaufmann share a light moment during the Gulbenkian PhD program in Portugal, November 2004.

Fellow cat searcher Duelli was attracted to the lab by a review paper Lazebnik had written. He was captured by Lazebnik's style. "He didn't even show up to my job seminar," laughs Duelli. "When I asked him about it later, he said, 'Well, it wasn't really relevant to cancer.' I still give him a hard time about that."

Joking aside, Lazebnik is a big fan of looking for inspiration, and information, far from the well-trodden paths. "It's important to dig in areas where no one else is digging," he says. "First, you could find something others have overlooked." Second, who wants to engage in a war of shovels? "I just don't find I'm interested in seeing who digs faster," he says.

But most importantly, Lazebnik muses, "What if everyone is digging in the wrong place?" Consider ulcers, for example. For decades, physicians and researchers assumed that stomach ulcers were caused by a dysregulation of acid secretion. "They studied beta agonists and cyclic AMP and the like." Then it was discovered that most ulcers are caused by Helicobacter pylori. "The field was focused on one thing, and getting results, being productive. Everything fit," says Lazebnik. "But it turns out to be something totally different."

Perhaps something similar is happening with cancer research. "It makes me less enthusiastic about doing what other people are doing en masse," says Lazebnik, "and more enthusiastic about following weird observations." Which could lead to something unexpected. Or to disaster. "If you don't focus, you can get into trouble. This is where I now find myself," says Lazebnik. "I enjoy all these ideas. But the day will come: 'Where are the publications? Where are the papers?"' he asks, banging his hand on the desk. He and Duelli are currently writing up their recent findings on cell fusion. But in the meantime, Lazebnik notes, it's just as Einstein said: "Science is a wonderful thing if one does not have to earn one's living at it."

Lazebnik will continue to work at it. "Yuri is an outstanding scientist in the classical definition," says Hengartner. "He's out there trying to make sense of the world. And he's not afraid to question things." Or people. "Yuri sits in the last row in seminars, but you fear his questions," says Hengartner. "He doesn't tolerate [worthless banter] and likes to expose it."

"You'd better have all the proper controls and not overinterpret your data," notes Duelli. Occasionally, one of Lazebnik's questions will leave "the whole audience going, 'Huh?"' says Hengartner. "But it just shows how he's thinking laterally, making connections that nobody else makes."

TUNED IN

Lazebnik is also making unusual connections in totally new fields, thanks to an essay he published entitled "Can a biologist fix a radio?" (Cancer Cell, 2:179-82, 2002) In it, he entreats biologists to think and talk about living systems more like engineers do. The paper garnered him an invitation to give the keynote address at the 5th International Systems Biology Conference in Heidelberg. "At first I thought someone was making a prank," says Lazebnik. "So I replied in a polite way, like 'wink wink.' But it turned out to be true." The talk was well received and Lazebnik – who now refers to himself as "the used radio salesman," a title bestowed on him by Vaux's WEHI colleague Jerry Adams – hopes to collaborate with systems biologists on various projects.

"He's been bothering us for years about that," says Hengartner, who, along with Vaux and Lazebnik, teaches a weeklong class on cell death and critical thinking to PhD students in Portugal. "Now the systems biologists love him." As do the Portuguese students, who are rewarded with candy for asking good questions, a practice started by Lazebnik.

The lecturers, too, find the course rewarding. "The students are great and we get to catch up with each other, hang out, and eat Portuguese food," says Vaux. And the food is key. Two years ago, Lazebnik had what Hengartner refers to as a "religious experience" with the perfect baccalau, a salted codfish dish. "The guy was floating a couple feet off the ground," he says. "It was flowing through my veins like a concentrated rejuvenation solution," says Lazebnik. "I feel it like it was just yesterday."

As for tomorrow, Lazebnik plans to keep following his instincts. "I will do logical experiments in a tractable way, but look for discrepancies, look for something weird."

"I always envy people who seem to have a well-defined plan," he says. "I don't. It just doesn't work for me." Plan or no, Lazebnik's friends and colleagues hope that he catches his black cat. "If there's a God in heaven," says Vaux, "he'll make sure that Yuri finds something big." Maybe this one won't involve another dip in the Black Sea.

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