Cutting-edge Curiosity

by Danielle LaVaque-Manty

As an undergraduate at The Ohio State University, Stephen Weiss worked in a chemistry lab. He was so excited by the opportunity that he insisted on doing it for free.

"I still remember when the head of the lab said he could only pay me the minimum wage," he says. "I couldn't believe (and I still can't) that someone was going to pay me to learn to work in a laboratory. I thought, no, I should be paying you."

Despite this early enthusiasm, the experience made him wonder if he would ever be interested in pursuing a basic science career. "I was enamored with the hardware they brandished, so I thought it would be neat." But he soon realized he had no idea why he was doing what was doing. "It was like trying to learn how to be a chef, and someone puts you in the kitchen and has you cutting carrots and celery. Eventually, you might start to understand, I sure didn't at the time."

Nevertheless, he majored in biological sciences and biochemistry and then enrolled in medical school at Ohio State, thinking he might pursue a career in clinically-oriented, academic medicine. When he was about half way through his medical degree, he felt a tinge of regret about giving up the laboratory and another opportunity caught his eye. Through a chance meeting, he began working with Albert Lobuglio in hematology and oncology.

It wasn't until he decided to take what he was learning and apply it to a problem different from the one Lobuglio had assigned that he became sure that research was for him. "I thought, I'll do what my mentor wants me to do, but in addition, I'll take on this little side project. And that was actually the beginning of my career. I discovered the joy you get from identifying an important, but unanswered question, plotting a course, and solving the problem."

After medical school, Weiss was a resident in pathology at Washington University. While in St. Louis, Lobuglio moved to the University of Michigan to be Chief of Hematology/Oncology and invited him to follow. He's been here ever since. "Thirty years next summer."

In addition to being educated at Ohio State, Weiss was born and raised in Columbus. So which team does he root for come football season? "I'm almost embarrassed (I emphasize almost) to suggest that I don't know anything about sports," he says. "I went to one football game at Ohio State when I was twelve years old, and one at the UM the first year I came here. And that's it."

Today, he is Chief of the Division of Molecular Medicine & Genetics and the Upjohn Professor of Medicine and Oncology, in addition to holding an appointment at the Life Sciences Institute. Having one foot inside the medical center and one inside the LSI, he says, provides him with unique opportunities to work with many talented investigators.

When Weiss stumbled onto his current path of research, studying the mechanisms of a group of enzymes he calls "molecular scissors," his lab had been examining the ways in which white blood cells protect the body from invading microorganisms. In particular, they were working on oxygen radicals, highly reactive small molecules "that nobody would think would ever be purposely generated in a biological system."

One of the downstream products of oxygen radicals is hypochlorous acid—"the same stuff that's in Clorox bleach."

While trying to figure out how the cells generated this molecule, he found that in addition to killing microorganisms, hypochlorous acid activates a latent enzyme secreted by white blood cells that can cut through connective tissues. "It's as if the acid removes a sheath that covers the blade of the scissors so that they can begin to cut," he says.

Tumor cells and blood vessel cells also make molecular scissors—the human genome codes for more than five hundred varieties. Though these scissors are activated by mechanisms distinct from those used by white blood cells, Weiss is currently working on several interrelated projects exploring how cells mobilize these scissors "and use them to cut their way through surrounding tissues in order to invade and metastasize as well as build new blood vessels."

It's possible that turning some of these scissors "off" could offer therapeutic benefits for diseases such as cancer and other diseases where connective tissues are remodeled, such as rheumatoid arthritis.

Because he loves his work, it can be hard for Weiss to believe that his three daughters have no interest in science. When one asked to learn physics at home as an independent study project, he thought it would be a great bonding opportunity. "But of course, it was because she didn't really like physics and thought this was the path of least resistance. It was a rude—and challenging—experience for both of us!"

Weiss enjoys nothing more than solving new puzzles. "I always tell people this is no different from being an artist, a novelist, or a musician, in that every year you're trying to enhance your intellectual portfolio so you can imaginatively tackle bigger, more difficult projects and bring them to fruition," he says. "It's all about being curious."