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Fast-Tracking Lifesaving Discoveries

USC College alumnus Ray Stevens energizes structural biology research.

Fast-Tracking Lifesaving Discoveries

Impatience can be a virtue.

Just ask USC College alumnus Raymond Stevens (Ph.D., chemistry, ’88).

As a young professor at UC Berkeley, Stevens’ frustration with the slow pace of research in his field drove him to develop an automated, speedier process to study the three-dimensional molecular structures of proteins.

“Everyone was doing protein investigations one protein at a time, each one taking three to five years to get the complete structure or understanding,” said Stevens, 44, now a professor of biology and chemistry at the Scripps Research Institute in La Jolla, Calif. “Fairly early on, I realized that going at that pace I would never achieve all that I wanted to do in my lifetime.”

Stevens’ sense of urgency, combined with persistence and what seems a ceaseless supply of energy, has enabled him to achieve a startling amount since graduating from USC. He also credits the mentoring and opportunities he received at USC College for helping to establish that career. Now, he hopes to find a way to give back to the university that nurtured him.

An internationally known structural biologist, Stevens studies the biochemistry underlying cell-to-cell communication in the brain and nervous system and develops treatments for neurologically related disorders. At Scripps, he runs a 40-person lab supported by tens of millions of dollars from competitive federal research grants. He has published hundreds of peer-reviewed scientific articles and holds a significant number of patents. And although he began his career eschewing industry ties, Stevens has helped found three biotech companies (dtek, Syrrx and MemRx), all since sold to larger companies at impressive profits. Most satisfying to Stevens, his research has produced promising new therapies for cerebral palsy, phenylketonuria (PKU), type 2 diabetes and certain forms of cancer.

Married with three children under 9, he also makes sure he carves out substantial family time. That has meant sometimes taking his kids along on business trips, which they love. Somehow, he also manages to find time to train for and compete in 100-mile ultramarathons.

Growing up in Auburn, Maine, Stevens recalls being fascinated by science and nature. His father, a military man, died when Stevens was only six. His mother worked many jobs to support the family. A computer wiz, he arrived as a freshman at the University of Southern Maine in 1982 planning to study computer science. But a professor’s enthusiasm — and extremely entertaining lectures — drew him to chemistry.

“He really loved molecules, and I absorbed some of that enthusiasm,” Stevens said. “Plus, I couldn’t imagine sitting still in front of a computer all day — I’m much too hyperactive.”

To this day, Stevens remains motivated by his own love of molecules and the sense of play he finds in scientific research. “If I didn’t love it, I wouldn’t be here — life is too short,” he said. “I really enjoy playing with molecules, making molecules. With the tools of chemistry, you can create something that no one else has ever made before.”

What hooked him for good was not the time spent in chemistry classes — he actually failed organic chemistry three times before passing it — but the two summers he spent with his undergraduate mentor at the Brookhaven National Lab on Long Island, N.Y. It was there he first used x-rays to determine the molecular structure of chemicals. It was also where he first met a research team from USC led by Robert Bau, a professor of chemistry in the College.

Stevens came to USC College to study for his Ph.D. with Bau in 1986, and considers Bau one of his most important influences, scientifically and professionally.

“I was incredibly fortunate to have an advisor who let me make my own mistakes,” Stevens said. “Bob always gave me the space I needed. He was there if I had a question or got stuck, but he encouraged all of us to become independent. The experience was priceless. In science, you fail all of the time, so you need to be ready for that.

“I’ve modeled my lab on Bob’s, where students learn independence and to fail as much as they do to succeed. It’s more like the real world of scientific collaboration.”

Stevens flourished in Bau’s lab. He split his time between New York and Los Angeles, collecting data at Brookhaven and analyzing them back at USC. By regularly putting in 20-hour days and, he admits mischievously, monopolizing the computers whenever and however he could (including writing software programs that made the computers appear “busy” to other users), he completed his dissertation in just two years and two months.

“I was lucky,” he said. “Everything worked.”

It wasn’t just luck, Bau said. “Ray is street-smart — he knew how to work it. He also worked really hard. And he was very good with computers.”

Bau considers Stevens, who received the chemistry department’s Distinguished Alumni Award in 2005, one of his three most successful students. They all were also his most efficient students.

“They didn’t waste time. They’d do the experiment, do the write-up immediately. I’d have the report on my desk the next morning. They were not necessarily perfectionists — they got a lot done and they weren’t afraid of taking risks and making mistakes. Ray was always impatient to go on to the next step. His attitude was like ‘Bam! Bam! Bam! Let’s get going! Let’s go on to the next project!’ ”

As a graduate student, Stevens remembers talking with his peers about pursuing only “pure” chemical research — driven by intellectual curiosity, they would create new knowledge for knowledge’s sake, not for some “tainted” commercial end.

It wasn’t until he got an unexpected request to help the Bay Area company Gilead Biosciences develop what is now called Tamiflu — an FDA-approved treatment for the influenza virus — that he began to question his earlier perspective on fundamental versus applied research.

Since then, he’s had a true change of heart. “Now, I think that it doesn’t have to be one or the other. If one chooses their projects wisely, they can do both. I found out that it’s very rewarding to convert basic science information into applications and to become involved with the companies that complete drug development and the families affected by diseases.”

For example, in his work with the inherited metabolic disease PKU, he said, “the basic science involved satisfies the intellectual side of things, but the clinical work, and even the outreach and fundraising activities I do for the PKU community, is rewarding personally.”

As he did while an undergraduate and graduate student, Stevens still uses x-rays to reveal the precise shapes, twists and turns of molecules, only now the crystals he studies are made up of large, extremely complex proteins.

Stevens’ crystallography work revealed the 3-D structure of the enzyme that malfunctions in those born with PKU. Normally the enzyme helps the body break down phenylalanine, one of the 20 essential amino acids in the human diet. For the 50,000 Americans with PKU, eating phenylalanine leads to a buildup of the amino acid that, at toxic levels, causes permanent mental retardation, organ damage and other problems. Restrictive, low-protein diets help control the disease’s effects, but can be hard to follow. There is no cure.

With the enzyme structure in hand, however, Stevens and his collaborators identified another enzyme that can metabolize phenylalanine. The enzyme was developed into an injectable therapy with BioMarin Pharmaceutical Inc. and is in pre-clinical testing as a treatment for severe PKU. Stevens and his team’s related work has led to the development of a separate potential therapy for patients with moderate or mild PKU, now in stage III clinical trials.

In the last year, Stevens’ team published the 3-D structure of botulinum toxin, also known as Botox, and the human cell receptor with which the toxin interacts. With further development, the same potent toxin that most associate with cosmetic surgery can be used to relax muscles that are abnormally contracted in diseases like cerebral palsy and muscle dystonias, Stevens said.

Most exciting is what’s next: His team has determined the structure of a protein that he’s pursued for 15 years. A member of the G-protein receptor family, the protein sits inside the cell membrane and, it turns out, is a bit of a shape-shifter, both factors that made solving the structure a formidable technical challenge. To be published this fall, their new finding is huge — some 50 percent of all therapeutic drugs bind to a G-protein receptor — and will form the intellectual basis of Stevens’ next start-up company.

Getting more involved with his alma mater is another project Stevens plans to pursue with his usual zeal. “Now that I’ve got to this stage in my career, I’d like to help USC in any way possible,” he said. “USC is a great university.”

Specifically, he wants to help USC College life scientists find ways to commercialize their research. Boosting connections between venture capitalists, industry and scientists at the College would provide many benefits to the university, Stevens said, “from increased research funding to better recruitment and building up the school’s reputation as a life sciences powerhouse. By partnering with industry, you can transform basic research into medical advances faster. And the creation of new biotech and science industries in L.A. would benefit the whole region.”

He’s also gotten involved in a more direct way. Last spring, Stevens began a new collaboration with USC College professors Myron Goodman and Xiaojiang Chen. Their teams will work together to study the structures of the APOBEC enzyme family, which Goodman, a biochemist, and Chen, a structural biologist, have been studying for a number of years. Already, Stevens has brought his characteristic need-for-speed to the problem. “I said to them, ‘If you really want to understand the biology, why not solve the molecular structures of all 12 APOBEC enzymes at once?’ ”

It’s ambitious, yes. But the payoff, Stevens noted, could make it all worth it.