The long war

On March 26, 1945, in the village of Topusko in the mountains near Zagreb in German-occupied Yugoslavia, Rifka Schlessinger went into labor. Gunfire crackled and artillery exploded outside the battered house where she delivered a baby boy who was given the name Joseph. His parents, Jewish partisans fighting the invaders and local fascists, swaddled the newborn in silk cut from a British soldier’s parachute and grabbed their rifles. With Topusko about to fall to German forces, the family boarded a cart and retreated into the mountains. The parents of Yossi, as he was called, fought on for two more months until the end of the war in Europe.

Their struggles, though, were not over. After Schlessinger’s father was jailed for several months for making a joke at work about Marshal Josip Tito, the Communist leader who had taken control of Yugoslavia, the Schlessingers fled to Israel, where Yossi’s parents had family. But as soon as the Schlessingers disembarked from their ship, they stepped into the war between the new Jewish nation and its Arab neighbors—battles that continue to this day. For their son, a lifetime of war had just begun.

Just surviving such inauspicious and violent beginnings would seem an achievement: Yossi Schlessinger, however, would go on to discern some of the most important mechanisms in the life cycle of the cell and make discoveries about the causes of cancer that have led to some of the most effective new treatments for the disease. Now the William H. Prusoff Professor of Pharmacology, and chair of the department, Schlessinger made one of his frequent trips back to Israel last May, where he maintains close scientific ties. This visit was an occasion for joy. Schlessinger took the stage in a Tel Aviv University auditorium alongside cellist Yo-Yo Ma and the Polish journalist and leader in the fight against Communist repression, Adam Michnik. The three were among the recipients who shared three $1 million Dan David Prizes, established in 2001 by David, an inventor of photographic technologies, to honor cultural, scientific, social or technological achievements. Schlessinger’s citation praised him “for his critical role in deciphering a new code for the flow of information from the cell surface into the cell. Dr. Schlessinger epitomizes the scientist that has paved the road from basic research in the laboratory, all the way to the patient.”

Today Schlessinger, who has published almost 500 papers, is regarded as one of the world’s leading cellular biologists and cancer investigators. His studies have helped to open a new understanding of the ways in which signals from growth factor proteins circulating in the blood reach the interior of cells and stimulate them to divide and grow. He has also shown how aberrant cellular signals can lead to cancer and has suggested ways to block them. His discoveries have led to a new field of cancer therapy research that has already produced a new generation of targeted anticancer drugs.

Along the way, Schlessinger also cofounded two biotechnology companies and serves as an advisor to several others—work that has led to one drug that is extending cancer patients’ lives and other agents that are at the testing stage.

Living at the forefront of the scientific world and financially secure beyond the dreams of most academic scientists, Schlessinger seems far removed from the wars that dogged his life from the very first moment. But although he may no longer fear bombs and bullets striking home, the impact of war never goes away.

A scientist-soldier

A few months before Schlessinger left for Israel to accept the Dan David prize, he sat in his sunlight-filled corner office in the new extension of the B-wing of Sterling Hall of Medicine. Behind him the window offered a view of downtown New Haven. He faced out toward the department he leads and whose laboratories and offices fill the new building. He personally hired many of its junior members—including six new professors—as part of a wholesale effort to revamp one of Yale’s flagship programs. In the five years since he arrived at Yale from New York University, he has built new facilities for his own laboratory and brought in 13 new graduate students and postdoctoral fellows.

Life, it seems, had prepared him for such disruptions and new starts. “Our life,” he recalls of his childhood, “had a lot of dramatic events.” The most tragic occurred even before he was born. Before the war his parents had been married to others and his father had had a daughter. Their spouses and children, however, as well as nearly all of their parents, grandparents, aunts, uncles, sisters, brothers and cousins—80 percent of Schlessinger’s extended family—were shot by Germans and local fascists or herded into gas chambers.

The family’s past with its unredeemable losses could never be pushed far away from the Schlessinger household. The war also left them impoverished. “We were in pretty bad shape,” he says, recalling his family’s arrival in Israel. Although his parents doted on him and his younger brother, their sadness about the past and fears for the future made home, he recalls, “not a very happy environment. It took me many years to figure out how their mood influenced me.”

Schlessinger, who is heavyset and speaks with a thick Israeli accent, can look doleful at times. He talks freely about his difficult childhood, but when discussing the destruction of his parents’ families, a deep sadness comes into his eyes. Perhaps that is why John Mendelsohn, M.D., president of The University of Texas M.D. Anderson Cancer Center in Houston and co-recipient of the David Prize with Schlessinger, says, “He’s not one to make small talk. He’s interested in serious issues.” Schlessinger, who knows the history of World War II intimately, has visited the towns in the former Yugoslavia where his family and many other Jews once lived, as well as the places where his parents battled the Nazis. He admits to a hair-trigger temper in response to what he perceives as statements that may harbor antisemitism. “I’m very sensitive about these things,” he says.

Growing up in Israel, he never lived far from a battlefield. Like most young Israelis in the new nation’s early years, he was raised to be “a macho fighter.” He entered the military, becoming a captain in the elite Golani Brigade. As part of that force, he preceded the regular infantry to lay or remove landmines, setting or demolishing thousands of explosives in the course of fighting in the 1967 Six-Day War, the 1973 Yom Kippur War and the 1982 invasion of Lebanon. He claims not to have been scared clearing minefields. “A mine is a task,” he says. “It plays into the scientific mind.” He feels differently about enemy fire. “A sniper shooting at you is not science.”

From these early experiences, Schlessinger learned that survival in a dangerous world depended upon intuition, study and hard work. During World War II his father, captured by the Gestapo, jumped from a moving train to escape certain death in a prison camp. “My father,” Schlessinger recalls, “said the only reason he survived was because he fought. I knew I would also have to make it on my own. I didn’t have safety nets and had to depend on myself.”

Despite the disruptions of serving in Israel’s military reserve and call-ups for wars, he completed a doctorate in biophysics at Israel’s Weizmann Institute of Science in 1974. He had been fascinated with science since childhood. “I was always interested in addressing fundamental questions,” he said. At the institute he studied the dynamic nature of proteins by measuring the circular polarization of their fluorescence, a preparation seemingly far removed from his later work in cellular biology. After postdoctoral study in the United States, at Cornell and the National Institutes of Health, he focused on how signals were communicated into the interior of the cell.

In the late 1980s, Schlessinger took a sabbatical from his lab in Israel and, after directing a drug research team at a pharmaceutical company, returned to academic life at the medical school at New York University (NYU). He continued to elucidate signaling pathways while directing the Department of Pharmacology, and, for a time, the Skirball Institute of Biomolecular Medicine. His laboratory analyzed the mode of action of growth factor receptors on the cell surface and the intracellular signaling pathways that are activated in response to growth factor stimulation. He recognized the critical role played by the components in the signaling pathways in the control of many fundamental cellular processes, including cell proliferation, differentiation and metabolism, as well as cell survival and cell migration—and their role in many diseases caused by dysfunctions in signaling pathways.

At the time, Mendelsohn was on the faculty at Memorial Sloan-Kettering Cancer Center. He and Schlessinger would regularly drop in on each other. “He’s fun to talk to,” Mendelsohn says. “He’s a very creative and rigorous scientist who’s willing to try out new ideas. He’s more likely to look at something in a new way.” Mendelsohn also points out that Schlessinger is “a driven person. He’s driven to use science productively. He brings a collaborative spirit and sustained intellectual power to a question and works at it until it’s solved.”

Unlocking the signaling pathway

Irit Lax, Ph.D., a faculty member in pharmacology, has been working for Schlessinger since she was a graduate student in Israel in the early 1980s. They are a couple now. Each has two children from a previous marriage. They spend, says Schlessinger, “99.8 percent” of their time together, which, he adds, “is amazing.” Although he goes to his office seven days a week, he rarely steps into the laboratory any longer. “He reads,” Lax says. “He has a unique capacity to integrate things that at first sight seem not connected. He has an instinct for which direction to go.”

While they were at NYU, Lax recalls Schlessinger saying that once all the signaling pathways have been elucidated, “finding the abnormal, disease-causing pathways will be a trivial matter.” In the early 1980s, Schlessinger and his colleagues showed how epidermal growth factor (EGF) protein binds and activates a receptor tyrosine kinase (RTK), an enzyme located on the cell surface. Schlessinger’s laboratory revealed how this coupling launches a cascade of signals that eventually reach the cell nucleus and tell the cell either to divide and grow, or to ignore checkpoints that would normally cause it to die. He then demonstrated that genetically aberrant forms of EGF-receptors and other RTKs can set off the rampant cell growth seen in cancer, including malignant brain tumors and other human cancers.

He recognized that drugs that could inhibit EGF-receptors or other RTKs could also control cancers. And these discoveries did in fact lead to a new class of targeted anticancer drugs—tyrosine kinase inhibitors. The approval in 2001 of the first such inhibitor, Gleevec, a treatment for chronic myelogenous leukemia, was celebrated as the beginning of a new era in cancer treatment. Mendelsohn concurrently produced an antibody that could block the action of EGF-receptors in cancer cells. That antibody was eventually developed into Erbitux (cetuximab), a monoclonal antibody used for treating colorectal cancer. Other related treatments include Herceptin (trastuzumab), a monoclonal antibody previously approved for the treatment of breast cancers for its action against overexpression of the protein ErbB2; and the tyrosine kinase inhibitors Iressa (gefitinib) and Tarceva (erlotinib). Pharmaceutical companies are now discovering and developing scores of kinase inhibitors. Schlessinger also decided to pursue the possibilities for cancer therapy that his findings indicated. “I don’t know any basic scientist who, if he had the opportunity to develop drugs, would ignore it,” he says. “We all want to be Louis Pasteur.”

In 1991 Schlessinger formed the pharmaceutical company Sugen with Axel Ullrich, Ph.D., his longtime collaborator at the Max Planck Institute of Biochemistry in Germany. (The “S” and “U” in the company’s name stood for the two founders’ last names.) The company was acquired by Pharmacia in 1999 in a deal valued at $750 million. Pharmacia was subsequently acquired by Pfizer. The head of Pharmacia at the time of the Sugen acquisition, Fred Hassan, is now chief executive officer and chair of the pharmaceutical giant Schering-Plough. He recalls Schlessinger as “the ‘big science’ presence at Sugen. ... He is one of the more insightful science innovators I have encountered.”

That characterization was borne out in January, when the U.S. Food and Drug Administration (FDA) approved SU11248, sold by Pfizer as Sutent, the first drug derived from work begun at Sugen. Clinical trials of the drug were moved quickly through the FDA approval process because of its obvious effectiveness in treating advanced kidney cancer as well as a stomach cancer known as gastrointestinal stromal tumor, or GIST. Pfizer is also testing Sutent and other drugs based on Sugen’s discoveries as treatments for more common renal cancers, as well as breast and other cancers.

When Schlessinger learned in January that the FDA had approved Sutent, Lax recalls that he shared a bottle of champagne with his lab members and then returned to work. He will receive royalties from a drug projected to bring Pfizer more than $1 billion in annual revenues. “Money doesn’t speak to him,” says Lax, noting that life went on unchanged after Sutent was approved “He didn’t buy three more houses or a sports car. He didn’t slow down his working schedule.” According to Lax, the couple plans to give Yale and other organizations most of the money one day. Schlessinger also intends to give his department part of his half share of the $1 million prize he received in Tel Aviv.

Exploring the darkness

With many biotechnology companies pursuing kinase inhibitors, Schlessinger realized by the end of the 1990s that the same assays were leading to the same drugs with the same limitations. He took a counterintuitive approach and began to study chemical compounds that weakly inhibited RTK and other cell surface receptors. Those potential drugs would not work as cancer therapies themselves. By using structural biology methods, however, investigators could find the targets to which they linked and then “reverse engineer” the target to design drugs that would bind tightly enough to them to inhibit their signals. Schlessinger co-founded Plexxikon, a Berkeley, Calif., biotechnology company in late 2000 together with Peter Hirth, Ph.D., the former president of Sugen, and Sung-Ho Kim, Ph.D., a professor from Berkeley. Unusually for an academic scientist, he serves not only as a member of its scientific advisory board but also as chair of the board of directors. The company already has one drug in clinical testing. Its most advanced compound and its first to be tested in humans is a treatment for adult-onset diabetes and other metabolic disorders. Plexxikon also developed a new drug for the treatment of melanomas and colon cancer.

Most successful drugs require 12 to 15 years for discovery, testing and FDA approval at a cost that can reach hundreds of millions of dollars. Sugen required 15 years for its first drug to gain approval. Schlessinger thinks his new company may bring its first drug to market by 2009. “Chances are not high we succeed,” he says, “but if we do, it’s a world record.”

While pursuing industrial ties, Schlessinger is also creating a drug discovery program at Yale. The Center for Drug Discovery, a pilot program with one scientist and two more soon to be hired, will develop agents based on departmental research for so-called “orphan” diseases—those with fewer than 200,000 patients in the United States and which are of little interest to drug companies. He hopes the center will grow to a staff of 20 specialists who will function as “an engineering arm of department scientists.” Their products will be licensed to industry or serve as the basis for new companies to be established by Yale’s Office of Cooperative Research.

Schlessinger has been offered numerous presidencies of drug companies but has rejected them all. “I need the freedom of academia,” he says. “It’s the freedom that makes me work. A true scientist will work harder that way than if you tell him how many hours he has to work.” He worries that the increasing pressure from various funding agencies to move academic research more directly into finding treatments for diseases will undermine the basic scientific research culture that led him to his own breakthrough discoveries. “You’ll never be creative if you know the answer ahead of time. That’s not science,” he says. “The key thing is to let creative people have intellectual fun. I sincerely believe you need to let good people think and do what they want if you want science to succeed. We are always in the darkness exploring a hypothesis. What you think is of no value may prove to be of great value. But science takes time. You need to be patient.”

The tide in support of academic science is moving the other way these days. But fighting for what he believes has never been a question for Schlessinger. “I have tremendous anxiety because of what happened to my parents,” he says. That anxiety has been transferred from the battlefield to the laboratory. “You’re only as good as your last work,” he says. “You have to prove yourself again.” That need drives him to return to work every day. “The anxiety I did not cure myself of is a good thing.” YM