A scientist soldiers on

When Joseph Schlessinger, Ph.D., was born in Nazi-occupied Yugoslavia in 1945, gunfire crackled and shells exploded outside. His parents were Jewish partisans fighting the German invaders and local fascists. Three years later, with nearly all their relatives shot by the Germans or murdered in concentration camps, his family immigrated to Israel, only to land in the midst of the first of what would be many wars between the new Jewish nation and its Arab neighbors.

Sitting in his office in the Sterling Hall of Medicine recently, Schlessinger says, with some understatement, “Our life had a lot of dramatic events.”

Just surviving such inauspicious, violent beginnings would seem an achievement. However, Schlessinger—known to friends as “Yossi”—not only lived, he went on to discern some of the most important mechanisms in the life cycle of the cell, discoveries that have led to effective new treatments for cancer.

Along the way, Schlessinger cofounded two biotechnology companies and has served as an advisor to several others—work that led to Sutent, a drug approved by the U.S. Food and Drug Administration in January 2006 for advanced kidney cancer and for a stomach cancer known as gastrointestinal stromal tumor, or GIST. Sutent, now marketed by Pfizer, and other drugs based on Schlessinger’s discoveries are being tested as treatments for more common renal cancers, as well as breast and other cancers.

Growing up in Israel, Schlessinger never lived far from a battlefield. He joined the Israeli army, becoming a captain, and fought in two wars and served in a third. But despite the disruptions of military reserve duty and call-up for wars, Schlessinger never lost his childhood fascination with science.

“I was always interested in addressing fundamental questions,” he says, and he had a productive career studying intracellular signaling and the role of growth factors circulating in the blood in the life cycle of the cell.

After moving to New York University in the early 1980s, Schlessinger and colleagues showed how epidermal growth factor (EGF) protein binds and activates cell-surface enzymes known as receptor tyrosine kinases (RTKs).This crucial 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.

Schlessinger’s lab then demonstrated that genetically aberrant EGF receptors and other RTKs can set off the rampant cell growth seen in cancer, including malignant brain tumors and other human cancers.

Schlessinger recognized that drugs that could inhibit RTKs might also control cancers, and the development of tyrosine kinase inhibitors like Sutent heralded the beginning of a new era of highly targeted cancer treatments.

Although he works closely with industry and has been offered presidencies of drug companies numerous times, Schlessinger, now the William H. Prusoff Professor and chair of the Department of Phamacology, has chosen instead to continue his seven-day workweek at Yale. “I need the freedom of academia,” he explains. “It’s the freedom that makes me work.”

He ascribes his drive to his tumultuous origins. “I have tremendous anxiety because of what happened to my parents,” Schlessinger says. That anxiety, forged in war, has been an advantage at the lab bench. “You’re only as good as your last work,” he says. “You have to prove yourself again.”