Spotlight on Barry Stoddard

Targeting Disease with Biochemical Guided Missiles

Barry Stoddard, Structural Biologist

In his laboratory at Fred Hutchinson Cancer Research Center, Dr. Barry Stoddard uses some of the most advanced technology in the world to probe the structure and function of biological molecules atom by atom. Yet one of the most important moments in his career came when he was using a shovel.

While he and a friend dug up a broken water main at his home, they engaged in some shop talk. The friend, a University of Washington biologist, was researching a unique group of proteins: homing endonucleases.

Those proteins act as biochemical guided missiles, seeking out and attaching themselves to specific DNA sequences in living cells — quite a feat considering they must distinguish their target from several billion others. "Gee," thought Stoddard as his friend continued describing the proteins, "I’d like to know what those look like."

Dr. Barry Stoddard
Dr. Stoddard believes it’s only a matter of time before targeted gene correction becomes a reality in the clinic. Robert Hood / Fred Hutch

Stoddard, a structural biologist, soon began studying the proteins and over the last decade has advanced the world’s understanding of the form and function of homing endonucleases. As one of the first scientists to reveal the atomic structures of homing endonucleases and, later, to demonstrate they could be engineered to home in on human genes, Stoddard is poised to exploit their capabilities to treat life-threatening disease through a technique known as targeted gene correction.

Collaborating with the Center’s physician-scientists, Stoddard is starting with chronic blood-borne viral infections, including HIV and hepatitis B, because the blood stem cells are easily accessible in the bloodstream. That could be just the beginning, though. "There’s no end to the potential application of homing endonucleases to treat human disease," Stoddard said.

"Whether it’s my particular approach or not, there’s no question that [targeted gene correction] is going to happen before my career is over," he said.

Although still in the developmental stage, targeted gene correction represents a giant step forward from existing gene therapy. The current approach involves introducing a corrected version of a defective — and disease-causing — gene with the hope it assumes the role normally performed by the defective gene. The problem is that the corrected gene doesn’t always find its way into a safe or useful location in a patient’s DNA — a drawback that limits the therapeutic benefit and often causes harmful side effects.

Targeted gene correction involves directly repairing the disease-causing gene — an approach that promises more predictable results without harmful side effects. The key is to deliver the therapy to precisely the right gene. Homing endonucleases can do just that.

Fred Hutch’s Dr. Barry Stoddard works to understand the form, motion and mechanism of molecules and then puts them to use for biotech and medical applications against cancer.

Occurring naturally only in microbes such as algae, fungi and bacteria, homing endonucleases perform no particular function on their own. "They just hitch a ride in the DNA of their host organism," Stoddard said.

The magic is that they can be redesigned to recognize specific human genes and carry out helpful chemical processes. To prove the concept is viable, Stoddard used a redesigned homing endonuclease to modify a gene thought to be associated with Parkinson’s disease.

Stoddard said it’s only a matter of time before targeted gene correction becomes a reality in the clinic. "Whether it’s my particular approach or not, there’s no question that it’s going to happen before my career is over," he said. "And that makes this a very exciting field."


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