Patrick Paddison, geneticist

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Patrick Paddison, geneticist

Manipulating genes to treat disease

When Dr. Patrick Paddison explains to his family what he does for a living, he favors a simple analogy: Imagine you've just been presented with a particularly exotic car and asked to figure out how it works-no blueprints included.

How would you go about pinpointing which parts, for instance, cause the engine to start? One good way would be to remove one component at a time and see what results.

At a basic level, that's what biologists like Paddison do—only in cells, of course, not cars—using a relatively new technology called RNA interference. RNAi, as it's known for short, allows scientists to switch off particular genes, creating the potential to determine which genes may be implicated in all sorts of diseases. Their hope is to spur more effective treatments for everything from cancer to HIV to degenerative brain conditions.

RNAi technology "has sort of been a revolution," Paddison said. "It has allowed us to address questions we wouldn't otherwise be able to address."

The idea of manipulating genes to uncover clues about human diseases isn't new, but it wasn't nearly as plausible in mammals before biologists essentially stumbled upon the RNAi phenomenon scarcely 10 years ago. Model organisms like yeast, fruit flies and worms have lent important insights and continue to serve important roles, but they're fundamentally different enough from humans that limitations inevitably arise.

In some ways, RNAi technology epitomizes how dramatically the scope of biomedical research has widened just since the turn of the 21st century, leaving a new generation of cancer researchers like Paddison uniquely situated to build upon past breakthroughs. 

"We've gone from racks of test tubes to robotically handled multichambered plates, from looking at how single genes function to probing almost all genes simultaneously," Paddison said.

The challenges, he said, are making sense of the mounds of new data that these powerful tools can generate and deciding which questions to ask.

Growing up in New Orleans, he always felt a certain curiosity about the way things work but never had a passion for science, per se. At one point, he thought that he wanted to be a psychologist. A college neurobiology class changed his tack. "I was immediately hooked," he recalled.

After graduation, he landed a job as a research technician working for Drs. Lee Hartwell and Steve Friend at the Hutchinson Center. The seasoned biologists were using budding yeast cells to identify genes that determine whether a cell is dividing normally, leading to key insights about cancer, which arises from abnormal, uncontrolled cell growth.

The post was a formative experience for Paddison. Hartwell and Friend "set me on the research path I find myself on today," he said.

Today, Paddison and his lab are using techniques based on RNAi to target one primary question: When we look at the some 200 types of cells in the human body, what genes allow them to maintain their particular functions, identities and survival? With the answers, he hopes to find new gene networks to target for therapies for various illnesses and to learn more about how RNAi itself may be used to treat diseases like cancer.

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