Though Art Horwich has a full schedule—he’s on the editorial boards of three scientific journals—he still makes time to keep his hands in the work at the lab bench.

“In science, it’s not what did you do for me 20 years ago, it’s what have you done for me today,” says a cheerful Horwich, who has been an HHMI investigator since 1990. Today his full attention is on a mystery of biology gone wrong that has eluded scientists for decades and a disease that takes thousands of human lives every year. His goal, pursued with relentless open-mindedness, is nothing short of a cure.

The View from the Bench

On a chilly Sunday afternoon in April 1939, New York Yankees’ first baseman Lou Gehrig went to bat in the Bronx for the last time. Having played a record-setting 2,130 consecutive games, Gehrig’s power and once uncanny aim were fading visibly. He struck out. Inside his body, clumps of misfolded proteins wrecked the nerve cells that for 35 years had faithfully sent messages from his brain to the muscles operating his arms, legs, and lungs. Just a couple of months after that game, Gehrig was diagnosed with the neurodegenerative disease that would thereafter be linked with his name; he lived just over two more years.

These days, the prognosis for a patient diagnosed with amyotrophic lateral sclerosis (ALS) remains grim. For Horwich, a sad reminder of that fact came in 2003 when his children’s beloved tennis coach began limping on the court and struggled to communicate. Like Gehrig at the time of his diagnosis, this man was in his 30s and otherwise healthy; he died a year after his ALS diagnosis.

“It really affected me,” says Horwich, whose career has straddled clinical medicine and basic science. Having spent decades studying cellular machines called chaperones that help proteins fold properly into their useful forms, Horwich turned his attention to a scientific problem with a human face: “Why, in ALS and other neurodegenerative diseases, are chaperones failing to do their jobs?” he asked.

And so five years ago, Horwich transformed a laboratory dedicated to the biology and kinetics of protein folding—a field in which he is widely recognized as a pioneer—to a multidisciplinary combat zone against a brutal human disease. “I felt a deep obligation to go in this direction,” he says.

Revisiting a Classic

Although that decision required Horwich to become expert in disciplines in which he had little experience—mouse genetics, stem cell biology, neuroscience—it was also a natural extension of his past work.

Proteins are made from chains of amino acids that fold in intricate, specific ways into three-dimensional structures. The physical shape of a protein, once folded, governs its behavior. The process sometimes goes awry, however, and misfolded proteins are associated with a number of neurodegenerative and other diseases. In the 1950s, American biochemist Christian Anfinsen unfolded a protein—a common mammalian enzyme—in a test tube and found that it spontaneously refolded into its useful conformation. His conclusion, and that of most scientists who conducted protein research in the following three decades, was that proteins don’t need help from the cell to get into shape.

Photos: Mark Mahaney

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