Always Learning

From the start, I was drawn to techniques that allow you to ask very specific questions and cut through the ambiguity of biology. I get a real kick from obtaining clear results.

I was first exposed to the intricacies of molecular biology in the early 1980s as a high school student in the UK. My parents and teachers fed my interests. I quickly be came fascinated with the beauty of the structure of DNA and the clarity of its implications. So at age 17 I decided to study biochemistry at university. During my fourth year at Oxford, I took a course in protein engineering and read about the pioneering experiments using site-directed mutagenesis to understand protein function. I was hooked.

I became a Ph.D. student with Greg Winter at the Medical Research Council's Laboratory for Molecular Biology in Cambridge, UK. He had recently applied protein engineering to the “humanization” of antibodies. I began work on new approaches to site-directed mutagenesis, but in the middle of my Ph.D., two major new technologies arrived: PCR and phage display. The timing was perfect. We began to combine these new technologies to try to create anti-bodies in the test tube rather than in mice.

Two of the most intense and enjoyable years of my career followed. The pace was fast, and we were in an entertaining race with another group in the United States. I remember the thrill of having something so complicated finally work. My project culminated in a series of ELISAs; if the wells went green, we had succeeded in producing antibodies (and I had a thesis). They went green.

In Greg's group, I also got an early exposure to team-oriented work, to a degree unusual in an academic setting. Several students and postdocs worked on different aspects of the same project. That experience really shaped my concept of how science could be done.

For my postdoc, I went to San Francisco to work with another protein engineering pioneer, Jim Wells. The fact that he worked at a biotechnology company—Genentech—was incidental at the time, although in hindsight, a pivotal career decision. Genentech's postdoc program was (and remains) very strong and vibrant, and I had the time of my life, both scientifically and extracurricularly. Ironically, my stint there was perhaps the most academic experience I have had as a scientist. We used mutagenesis to ask basic questions about how proteins interact and identified “hotspots” of binding energy in protein binding sites.

As the time came to move on, I found myself gravitating towards biotech companies. Again timing was fortuitous. ARIAD had just committed to developing a new technology for controlling engineered proteins inside cells using chemical “dimerizers.” The opportunity was fascinating. I saw it as a way to apply my knowledge of protein engineering to drug development in an unusual way and to be involved right from the beginning. The only downside was moving from California to Massachusetts in the middle of winter.

We began developing the technologies and testing their use in gene and cell therapy settings, and had great success. Again collaboration was key, with chemists, biologists, and pharmacologists inside the company and academic groups outside. I enjoyed the team approach; we could be very productive, and I had the opportunity to learn beyond my core expertise.

From my initial focus on the proteins, I began thinking more and more about their small molecule ligands. It was a steep learning curve. But one day I woke up and realized I had become a chemical biologist. I remember writing a manuscript and noticing that it was unlike any thing I had written before. Yet the transition felt logical and natural; like protein engineering, chemical biology involves using technologies and tools to ask “clear” questions and break new ground.

Doing science in a company setting opens up many opportunities but also raises interesting challenges. After a few years, the complexity of developing gene therapy products forced us to think hard about where to take the technology. We were opportunistic. Our work had included using rapamycin analogs as dimerizing agents, and as a side project, we had explored their anticancer activities. We decided to refocus our efforts in this area. Now, several years on, we have just completed a phase II trial of our lead compound in patients with soft-tissue and bone sarcomas and are designing small molecule drugs to target other signaling pathways in cancer.

Although I have moved away from my scientific roots, and now juggle science and management, I like to think the lessons collected along the way have stuck. I still try to make sure we ask clear questions, and making a drug that works in patients would be the ultimate “clean result.” The most important thing is that I am continuing to learn.