Brandeis celebrated the 70th anniversary for the Graduate School of Arts and Sciences (GSAS) this week, bringing together current graduate students, alumni, faculty and administrators. This year’s speaker was Dorothee Kern, who is a Professor of Biochemistry and a Howard Hughes Medical Institute Investigator. Beyond her responsibilities leading her research group at Brandeis, Kern also serves executive roles at the two biotechnology companies she co-founded: Relay Therapeutics and MOMA Therapeutics. Her work on leveraging protein dynamics for therapeutics and drug design has been recognized by numerous awards and she was recently elected to the American Academy of Arts and Sciences.
Proteins are microscopic molecules that act as the units of cellular machinery. Protein structure is known to be essential to protein function. However, proteins are not static molecules; they dance and wiggle, Kern described. Therefore, the specific functionality of proteins is not only dependent on their three-dimensional shape, but also the unique movements that result from their structure. For example, protein channels can transport various compounds into and out of cells by tilting outwards to open and inwards to close.
Given the prominent role of protein movements in their functions, Kern’s group sought to characterize protein dynamics and explore the implications of these findings for highly specific drug binding. One early discovery the lab had was the evolutionary pressures that underlie protein function in biology today. Kern explained that over Earth’s history of life, ocean temperatures grew cooler on average and therefore proteins had to find the appropriate balance between stability and activity performance rates.
Furthermore, using techniques such as nuclear magnetic resonance (NMR), x-ray crystallography, enzyme kinetics experiments and computational modeling, the group illustrated that protein movement is often the rate-limiting step in chemical reactions and happens in non-random patterns. The group is also working on further characterizing how proteins can switch between different conformations, or three-dimensional shapes, without having to completely unfold. Elucidating the dynamics of protein movement during reactions provides insight into how scientists can design artificial enzymes with high rates of performance.
Furthermore, the group’s findings on protein dynamics are now helping develop ways to selectively target proteins involved in cellular processes that go awry in diseases such as cancer. In fact, previous research done by the lab has shown that while protein binding to the drug may be unchanged, the protein exhibits aberrant motions, rendering the drug ineffective. In some cases, the drug cannot even bind to the protein because the access point for binding is enclosed within the core of the protein and requires the protein conformation to change in order to enable binding.
“The most devastating part of drug discovery in cancer is that they work and then after one year, the patient makes mutations in the protein, so the drug doesn’t work anymore,” Kern explained. To combat this, Kern sought to understand how proteins bind other molecules at locations that are not directly involved in the chemical reaction, called allosteric sites, that may be subject to less change. The group is now deploying novel techniques in their companies where they are using smaller scale proteins as drugs targeted towards allosteric sites on malfunctioning proteins of interest. This effect can dial up or dial down protein function by changing protein dynamics. “Proteins have built in these dynamics for their functions … All we have to do is take advantage of that to build drugs,” Kern noted.
During the GSAS celebration, Kern shared not only her scientific research but also her career journey and background. Kern’s youth was spent in what was then East Germany. Her interest in protein dynamics started from an early age, but her interests were not contained to biochemistry: Kern was a former player of the East German basketball team, holding positions as a point guard and later as the captain. Sports continue to be an important part of her life, as she and her family participate in cross-country skiing.
Kern reflected on her journey and imparted her thoughts about navigating life with the audience. She emphasized the importance of surrounding oneself with supportive and motivated people, following one’s passion and above all, dreaming big.
