The Intersection of Chemistry and Biology with Jason Gestwicki

Running cross country at Dunkirk High School in New York also meant training on a rigorous course—advanced chemistry. The cross county coach was the chemistry teacher, and the kind who inspired his team to follow his passions in the lab and in the field.

On day one, when LSI research assistant professor Jason Gestwicki enrolled at SUNY Fredonia, he declared his field—chemistry—and it doubled soon after when he added biology.

The oldest of seven children, Gestwicki, 30, also played electric bass with his father, a professional musician.

"I wasn't very good," smiled Gestwicki. "My dad has been a choir director at a church in Dunkirk, NY for 35 years, so as children, we all played."

But entering the science field always made sense to Gestwicki, who hung up his track shoes and his guitar when he began college.

"A lot of people wonder why I went into science. It always made perfect sense to me. My dad played music, and to me, music and science were never that different," said Gestwicki. "I always considered art, music, science to be sort of the same thing—all creativity-based disciplines where you don't do things that people have done before."

Michael Marletta, a SUNY Fredonia alum, a former U-M faculty member, was Gestwicki's first U-M contact. When Gestwicki was awarded an Outstanding Researcher award from SUNY Fredonia's Chemistry Department it was Marletta, who presented it.

"Marletta was visiting Fredonia and gave it to me," said Gestwicki. "He had just won a MacArthur award around that time. So that was kind of cool."

Although he did consider Michigan for grad school, Gestwicki chose Wisconsin, where he was awarded the NIH Biotechnology Training Program Fellowship in 1998, and worked with Professor Laura Kiessling.

"Laura was a fantastic person to work with," said Gestwicki. "She's the one that really got me interested in doing chemical biology as it's now called."

That sent Gestwicki along the path of the type of science he's now doing—solving biological problems with chemistry.

Wanting to marry his chemistry and biology, Gestwicki did his post-doc with Jerry Crabtree at Stanford where he won a Helen Hay Whitney Postdoctoral Fellowship. There, he conducted groundbreaking research on small molecules and protein interactions. One study published in 2004 used small molecules to block the formation of plaques characteristic of Alzheimer's Disease and was named one of the Chemistry Highlights of 2004 by Chemical and Engineering News.

"We can think of science as a series of Venn diagrams. Biologists live in one, chemists in another. When we think like someone in the biology sphere, we ask how nature normally inhibits protein/protein interactions?" said Gestwicki. "How does nature do it? What's the observation from nature? And we discover that nature uses these types of molecules. But then we need to fit in the chemistry part and ask what molecule will work."

Gestwicki, now in his own chemical biology lab at the Life Sciences Institute, actively inhabits the space in the Venn diagram where chemistry and biology overlap.

"I make nature-inspired molecules—inhibitors of protein/protein interactions," he said. "I synthesize molecules with the intent to find out how those molecules influence a biological process. Not to learn new ways of making that molecule, but to make the molecule that gets me to the biological questions."

Many human diseases, such as Alzheimer's, Parkinson's, and Huntington's are caused by protein/protein interactions. The body has natural mechanisms for dealing with these interactions, but sometimes these systems fail and disease follows.

Gestwicki takes the contributions of biology and the information provided about the natural protective mechanisms and uses innovative chemical approaches to help the body do what it was programmed to do.

"It's like getting a vaccine. That is very different than popping an aspirin," said Gestwicki. "That aspirin inhibits an enzyme. Very classic. Your headache goes away. That's not how vaccines work. In a vaccine, you put in an attenuated virus and your body does the rest of the work. This type of approach takes into account the whole system, the whole organism, and it isn't classically leveraged by small molecules. That's got to change."

LSI was attractive to Gestwicki, who arrived last summer, because of the interdisciplinary collaborations and resources such as the Center for Chemical Genomics.

"One of the things that CCG is trying to do now is inhibit protein/protein interactions. I think the best way to do this is to bring together biologists who understand the natural systems, chemists who can build new molecules and new devices, and engineers who can put the pieces together." said Gestwicki. "My big interest in the CCG is being involved in something that in some ways is very traditional, but new to academics, and in some ways, totally innovative because of the new environs. In academics, we don't have the same priorities."

"It's an exciting time to be in science."