Form and Function

Scientists Study the 3D Structures of Proteins to Discover New Drugs

Dr. Brian Volkman discusses experiment results with Andrew Kleist
Structural biologist Dr. Brian Volkman (standing) discusses nuclear magnetic resonance spectroscopy results with Andrew Kleist, an MCW medical student and doctoral candidate.

Brian Volkman, PhD, MCW professor of biochemistry, sees the world at a unique scale. He looks far beyond the proverbial forest and its trees in order to view the structure of proteins, atom-by-atom, with an understanding that the smallest of details about how proteins are ordered may lead to sizable benefits in the form of new drugs to treat disease.

"The three-dimensional structures of proteins are central to their function and the role they play in complex biological systems," says Dr. Volkman.

Dr. Volkman's interest in science began to grow during a fifth-grade science project. "My mom was an organic chemist, so she helped me study the effects of salt on melting and freezing points," he recalls. Using plastic tubs of water and thermometers, the young scientist conducted his first experiment by comparing the effects of salt to other solutions made from household products.

"There were other family influences as well, including my aunt serving as a faculty member in California and both of my grandfathers with careers in science and engineering. I grew up with the notion that science was a worthwhile topic of study," he adds.

Dr. Volkman was recruited to Butler University in Indianapolis on a chemistry fellowship. Mentors on the faculty there trained him to begin helping with research early in his undergraduate career, including inviting him to work in the laboratories over the summers after his freshman and sophomore years. After his junior year, however, he spent the summer in a science program at the University of Iowa.

"I had the opportunity to work with structural biologists, which helped cement my interest in protein structure and also crystallized my plans to go to graduate school," shares Dr. Volkman. During one of his graduate school visits, he was introduced to the emerging field of nuclear magnetic resonance spectroscopy. This technique, typically used by chemists and biochemists to study the characteristics of organic molecules, involves sending signals from a radio-frequency emitter at a sample positioned at the center of a very strong magnetic field. By gathering data on the frequency and intensity at which the sample absorbs and releases electromagnetic radiation, scientists can measure the interactions of atoms within the sample molecule and use those details to infer the molecule's chemical architecture. Obtaining the three-dimensional structure of a protein molecule in this manner is especially useful for understanding its biological function.

After earning his PhD in biochemistry at the University of California-Berkeley and serving as postdoctoral fellow, assistant scientist and associate scientist at the University of Wisconsin's National Magnetic Resonance Facility, Dr. Volkman joined MCW's faculty in 2000. It was in Madison that he began research on the chemokine family of proteins, writing his first successful National Institutes of Health grant proposal on the topic of chemokines and their potential involvement in the spread of HIV infection from cell-to-cell throughout the body. His laboratory's research on chemokines continues today at MCW with an additional emphasis on the protein family's role in cancer.

For nearly 15 years, Dr. Volkman has studied the chemokine protein CXCL12 – known to be a key biological player in the metastasis of breast cancer cells (moving beyond the original tumor).

His team had uncovered that the protein naturally existed in two forms. "In 2008, we learned that the two forms had very different properties. While one promoted the migration of cells, the second form inhibited cell migration," says Dr. Volkman.

This finding came with an opportunity to potentially reduce or delay metastasis, buying more time for surgery and other therapies to eliminate the original tumor before it spread and became more difficult to treat.

Chemokine protein CXCL12

In 2011, Dr. Volkman's lab and the group led by Michael Dwinell, PhD, MCW professor of microbiology and immunology, published a paper which built upon the earlier structural studies by testing the effects of a small molecule designed to block CXCL12's activity. The investigators demonstrated that this molecule was effective at reducing metastasis in a rodent model of cancer. MCW has patented this molecule, and Drs. Volkman and Dwinell continue to work closely with MCW's Office of Technology Development to advance this line of research and translate their laboratory findings into a product that may one day pass clinical trials and benefit patients.

Drs. Volkman and Dwinell's relationship with the Office of Technology Development helped them seize on a related opportunity to create a company, Protein Foundry, which produces custom chemokine proteins purchased by researchers throughout the world for use in their respective experiments. Co-founders include Francis Peterson, PhD, associate professor of biochemistry, and Chad Koplinski, laboratory coordinator. "The founding of Protein Foundry was awesome and I'm happy to say that it is profitable. Working with MCW's director of research commercialization, Dr. Bill Clarke, has been invaluable – as he's been a great supporter and a constructive critic," comments Dr. Volkman.

For Dr. Volkman and his colleagues, developing a company from the ground up was a significant learning experience – and it helped having experienced mentors available within MCW. Beginning with his undergraduate years and moving through scientific training to his current work with the Protein Foundry, Dr. Volkman has understood the value of mentorship. He strives to share his expertise with postdoctoral fellows and graduate students in his lab, such as Andrew Kleist, a medical student and doctoral candidate in MCW's Medical Scientist Training Program.

Brian Volkman lab at MCW

"MCW attracts talented and highly motivated students who teach me something new every day, and Andy is one of the brightest young investigators I've encountered here or anywhere," adds Dr. Volkman.

"Dr. Volkman gives us a lot of freedom in our experiments, and he expects us to lead the conversation in our project meetings before he makes his own suggestions," says Kleist. "He's also been really supportive in sending us to workshops and conferences. All of this is paying off now, as I feel confident in making decisions about my research – which I will have to do in the future as an independent scientist."

Kleist notes that his dissertation project is gaining momentum, and he remains enthusiastic about his work in the Volkman lab and a future career that includes biomedical research. "I love structural biology, and I think I want to keep doing research in this field throughout my career."

– Greg Calhoun
 

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