Q: What do you do in your work?
A: I’m interested in the molecular basis of biological function. Particularly, we rely heavily on the atomic structures of proteins as a basis for determining how they work and as a basis for how to alter the way they work. Such alterations might be by drug designs designed to fit into certain cavities in the protein structure and alter or prevent its function. We use molecular structures also to understand the mechanism of phenomena in biology. I’m especially interested in things called transporters that transport nutrients across the membranes of biological cells to incorporate essential nutrients, and transporters that are co-opted to eliminate drugs and thus provide for drug resistance.
We’re also very interested in voltage activated channels in the nervous system. Voltage changes across the membranes serve to conduct electrical signals. We have worked out some of the basic science behind how voltage serves to control protein conformation and function.
Q: What’s your favorite part about being a scientist?
A: Just the ability to see how life works at the level of individual protein molecules as the machines of life. These amazing structures really show us in a very quantitative way how things are actually brought about.
Q: What have you created or discovered that you are most proud of or excited about?
A: The thing I am best known for is the mechanism and structure of the so called water channels, which are otherwise called aquaporins. They conduct water. For example, in humans there are fourteen different water channels. One of them is important in the kidney in saving water from urine as it is excreted. Another one is important in the eye lens to allow it to change shape, and it does so by relieving the water stress. Another one is involved in the brain quite heavily and by altering its function we can have a positive, better effect on stroke. It’s called Aquaporin 4 (AQP4). There are human lethal autoimmune diseases associated with humans making antibodies against this particular brain water channel. We’re trying to find ways of preventing that autoimmune condition from happening.
Q: At the end of the day, why does your work matter?
A: Many of the specific things we work on are guided by medicine or guided by disease condition. As the great tutor of biology, disease conditions identify the function of components and we have used that to guide our investigations in many cases. For example, we study the proteins specifically involved in HIV viral infection: how that virus, with only thirteen small proteins, gets into human cells and replicates itself and then can reproduce and leave the cell and go infect other immune cells of the immune system. We ask “how does it shut down the immune process.?” We look at molecular structures, which is the closest thing to realizing how we can improve drugs. We’ve had a big hand in that over the years. Among the first structures of the so-called protease drugs were being developed in our hands with our structures and likewise, the drug is now being introduced for integrase. We also had a hand in elucidating how that integration enzyme works. That is the enzyme that takes a copy of the HIV genome and inserts it into the human genome, so it immortalizes the virus into the human genome and then allows it to continue to live there.
Tuberculosis is a disease that kills millions of people over a year, and there we are focused on the one essential transport protein that is required for the tuberculosis bacterium to build a cell wall around itself. If it can’t build that cell wall, then it would not survive in humans. We want to understand its molecular structure and design drugs which will prevent it from working. This will be the basis of the cure for TB.
Q: Outside of work, what do you do to relax?
A: I certainly relax, I think it’s very important. I play a guitar and I have my own band. We play rock music and maybe some folk rock, some blues, and some jazz. I sometimes play at home in the evenings, or if I’m traveling I always travel with my traveling guitar. It’s a full size electric guitar, it’s just constructed differently. So I get a lot of vicarious playing in. I play with my band several hours a week. We rent a studio.
I’m a windsurfer, so I love windsurfing as a hobby out in the ocean. I travel the world with windsurfing.
Q: What situation do you think you’d feel the most out-of-place in? What is something that makes you uncomfortable?
A: Donald Trump’s White House.
Q: In 100 years, what do you want to be remembered for?
A: I want to enable the cure of human disease. That will come not necessarily as home runs or drugs, because drugs are often not built in universities. But the fundamental principles of where to develop drugs... that is what comes out of the kind of research I do and the kinds of processes that we could intervene with.
We worked for many, as we still do a little bit, on one of the most important targets for cancer therapeutics. It’s an enzyme called thymidylate synthase, and there we developed a lot of new principles for drug discovery, introduced some of the early proof of concept ideas behind drug discovery. I have a number of patents concerned with discovering principles for drug discovery, all based on molecular structures of important therapeutic targets.
With HIV, it is easy to say that molecular structure shows you the geographic map in 3-dimensions of protein and that is the code by which you can design drugs to prevent things working. But in HIV, for example, we worked in the area of HIV for a long time and as you know there is no cure yet because HIV, unlike many other viruses, finds ways of hiding out. We really want to face these most difficult projects. HIV is one of the most difficult areas and for me to sit here and be able to say that structure helps us, we ultimately want to see the end of HIV on the planet, the end of tuberculosis and the end of malaria. We worked on all of these diseases from the point of view of identifying essential components, and then looking at their molecular structure and finding a way to stop them working with drugs.
Journalism credit: Alexa Rocourt