Infectious diseases kill millions of people every year, demanding greater translation of research into treatments. Namandjé Bumpus, Director and E.K. Marshall and Thomas H. Maren Professor of Pharmacology at Johns Hopkins University, explores molecular research through translational and clinical studies with a special interest in better understanding drug targets. Her work would be enhanced by cryogenic electron microscopy (cryo-EM), which reveals how proteins work.
Tell us about your research.
We’ve had a focus on the development of drugs for infectious diseases. We’ve done a lot of work trying to optimize and understand how we can improve drugs for HIV treatment, and even prevention. We have also worked on discovering new compounds that seem to, in pre-clinical models, have good efficacy for fatty liver disease. Serendipitously, we also identified compounds that seem to have anti-cancer activity. We work across disciplines, across diseases, but we’re always looking for new molecules that could be used for treatment and ways to optimize existing treatments.
What are the main challenges in your research?
We’ve looked at liver, lung and breast cancers. We have some compounds that we think work really well when we test them in cells. We think we understand how they’re working, but it would be nice to understand exactly what’s going on. What is the exact target? You’ll do assays and think that you know the target, but it’s often difficult to be completely sure. There are many drugs that we take where no-one fully understands their mechanism and exactly what the target or targets are. If we had a better understanding of the proteins that a drug interacts with, we could optimize the drug even better.
What drew you to cryo-EM in the first place?
That problem — understanding what a drug is really doing — made me interested in cryo-EM. With it, we can look directly at how a drug might be interacting with a protein and understand the dynamics of that. A drug may bind to a complex of proteins, and cryo-EM is really the only way that we can get a good sense of that. As we start to apply cryo-EM more to drug discovery and development, it will give us more of the specificity we’re looking for — really understanding the impact of drugs by being able to visualize the process.
How has cryo-EM impacted your research?
Although we have not had the opportunity to incorporate cryo-EM yet, we certainly are starting to think about how we can incorporate it, designing some of our studies to move toward that. To prepare for cryo-EM, we’re trying to do some molecular studies to pin down the proteins that we want to see if our drugs can bind. We know that cryo-EM, finally, gives us a way to really directly test some of the things we’re interested in. There is always an advantage when you can actually see something.
What are your thoughts on cryo-EM being used by non-structural scientists? Do you think it is possible?
Yes. For people like me, there’s a lot of untapped opportunities. In addition to working on drug targets and toxicities, we can apply cryo-EM to genetic variation. We often don’t understand why genetic differences have such an impact on reactions to drugs. I think cryo-EM gives us a chance to understand how a certain mutation is changing structure, how it’s changing the ability of the protein to interact with the drug, and how it’s changing the dynamics of interactions with other proteins. That could help us understand, mechanistically, why there might be this variability in response for that we see between people taking these drugs.
What is your outlook on cryo-EM in health and diseases, including its use in drug discovery and development?
Simplifying the technology and reducing the cost make cryo-EM accessible to more people. Once we have that accessibility, the sky is the limit. We’ll be more able to understand what some of these proteins look like that are altered in disease, which puts us in a much better position from the chemistry side of things to target those proteins, study toxicity and even how the body processes a drug. I think that we can’t even begin to fully imagine what we can do until we start getting cryo-EM into more hands.