Every Sunday afternoon, molecular biologist Steve Dowdy grabs his surfboard and tries to catch a wave. It's a ritual that clears his mind and sparks his creativity.
"The waves are constantly changing," Dowdy says. "And when you are on the face of a 10- or 12-foot wave you are constantly adapting what you are doing. I find it freshens the mind and allows me to think in different ways."
That ability to find new approaches to problems has resulted in a career that has included deciphering critical aspects of the cell cycle, exploring tumor suppressors, and developing unique drug delivery systems.
Dowdy's path to studying cancer and drug delivery wasn't straightforward. He considered pursuing either biology or high-energy physics in college. "The tools for genetic engineering were just being discovered," Dowdy says. "It really seemed like biology was where you could make some big advances."
Working in an immunology lab as an undergraduate convinced Dowdy he would become an immunologist. However, his first lab rotation in graduate school at the University of California, Irvine, School of Medicine disabused him of that notion.
"I absolutely hated that immunology rotation," Dowdy laughs. "I became interested in cancer because of the implications to society and the fact that it touches so many aspects of cell biology."
As a postdoc, he studied tumor suppressors in the Whitehead Institute laboratory of Robert Weinberg, who had first cloned the gene for a tumor suppressor—the retinoblastoma (Rb) suppressor. At the time, Dowdy says, the tumor suppressor research world was essentially concentrated in Boston. "While I was there it became crystal clear that Rb suppressed transcription and that it was regulated by the cell cycle machinery. It was a merger of the cell cycle world with the tumor suppressor world."
That realization set Dowdy on a quest to study the many cellular pathways that are active in cancer when he started his own lab at the Washington University School of Medicine. Even though the link between Rb and the cell cycle—the growth and division of cells—was established in cultured tumor cells, understanding its role in the cell cycle of normal cells had been hampered because it was impossible to deliver the tumor suppressor into all the normal cells.
"For two years, we couldn't really ask the questions we wanted to ask," remembers Dowdy, who is currently at the University of California, San Diego, School of Medicine. "We had our backs up against the wall. It was very frustrating."
Then he remembered a paper about a small section of protein from the human immunodeficiency virus that he had read about as a graduate student. That small section of protein—called the protein transduction domain (PTD)—could slip across cell membranes. Curiously, that ability plays no role in HIV pathology. Dowdy and his lab hooked the PTD to tumor-suppressor proteins to see if these fusion proteins could enter cells and stop them from dividing.
"When we added the fusion proteins to synchronized normal cells it stopped their growth. I guess desperation drives you to creativity," Dowdy says. His lab ultimately detailed how the cell cycle machinery regulates Rb in normal cells. The team has generated more than 50 fusion proteins with the PTD system.
That success led to work on PTD–tumor-suppressor fusion proteins that could be developed as potential cancer therapeutics. "With large molecules like enzymes, delivery into the cell is the problem," Dowdy says. "Several biotech companies now have ongoing clinical trials with PTD-based therapeutics."
In 2003, Dowdy focused his efforts on RNA inhibition (RNAi)—a mechanism that silences genes through short double-stranded RNA fragments. Introducing these small bits of RNA into a cell is a very potent way to shut down a gene. Dowdy saw the potential for developing specific and highly active cancer therapies. Because cancer causes so many genetic changes in the cell, he figured he could target specific changes, shut them down, and keep the cancer at bay.
First, however, he had to figure out how to deliver these small inhibitory RNAs (siRNAs) into cancer cells. Simply adding siRNAs to a PTD peptide failed. The siRNAs are highly negatively charged and PTDs are positively charged—"they stick together like glue." Dowdy decided to try to solve the problem by attaching a PTD to a chunk of protein that swaddles the siRNA and masks its negative charge.
Using this approach in mouse models of glioblastoma, Dowdy's team was able to see a complete RNAi response in less than 6 hours. He is now working to create RNAi methods that can be continually tweaked to combat new mutations. His goal is to eventually turn cancer into a disease that, even if it cannot be cured, can be managed.
"When you see something like PTDs, you have to hope that you don't just discard the information as an oddity and that your training has prepared you to dig down," he says. "I think the next 5 to 10 years are going to be very exciting."
