Plenary lecturer

‘Choose a problem that you’re passionately interested in’

Ian A. Wilson will give a plenary lecture at the American Society for Biochemistry and Molecular Biology annual meeting in Boston. He will present his lecture, titled “Structural basis of broad neutralization of viral pathogens,” at 8 a.m. Wednesday, April 1, in Room 253 A/B/C of the Boston Convention & Exhibition Center.

Ian A. Wilson is a structural biologist at The Scripps Research Institute. His laboratory focuses on how the immune system recognizes and neutralizes foreign antigens, such as the ones found on pathogens. The laboratory uses high-resolution X-ray crystallography to study various components of the immune system, such as antibodies and T-cell receptors, and their complexes with antigenic proteins.

Rajendrani Mukhopadhyay, the science writer for the American Society for Biochemistry and Molecular Biology, spoke with Wilson to learn more about his laboratory’s work and to find out what Wilson views as the big challenges in structural biology. The interview has been edited for length and clarity.

What does your lab work on?

We’re working on the structural biology of influenza virus, HIV and hepatitis C virus. We are trying to understand how these viruses are recognized by the immune system and, in particular, how broadly neutralizing antibodies recognize the viruses they target. We are thinking about how we can use that information for structure-based vaccine design.

What are your favorite structures?

Oh, that’s difficult. Most recently, one of the major successes that we’ve had is something we’ve worked on for many, many years. It was the HIV trimer, the structure of which appeared in (the journal) Science last year. We started working on that in the early 2000s through a collaboration with John Moore and Rogier Sanders at Cornell (University) in New York City. People had been waiting for that particular structure for a long time. My colleague Andrew Ward solved a similar structure with a different antibody by electron microscopy. We solved it by X-ray crystallography. That is my most recent favorite structure.

From the past, one of my favorite structures was the T-cell receptor structure. That was also something that was very, very challenging. We solved that in 1996. That was also quite a significant breakthrough at the time.

My all-time favorite structure, stemming from my postdoctoral work, is influenza virus hemagglutinin, and we continue to work on that to this day! It doesn’t go away. We solved a structure of hemagglutinin from the H3 subtype when I was at Harvard (University) in 1981. Since then, we’ve continued to solve lots of different subtypes — H1, H2, H5, H6, H7, H10 — for all of the emerging influenza viruses, complexed with neutralizing antibodies.

(Author’s note: The influenza type A virus is a class, which causes seasonal flu epidemics, can be categorized into subtypes based on two proteins on its surface: hemagglutinin, designated by “H,” and neuraminidase. There are 18 different hemagglutinin subtypes.) 

You understand it’s a hard question to answer with one favorite structure. Several structures have been quite revealing once they were solved.

What have been the major advances in X-ray crystallography in the past 10 to 15 years?

We’ve been developing higher throughput methods for X-ray crystallography. The technological breakthroughs in X-ray took place a number of years ago with synchrotrons and with better detectors. The question became “Can you actually solve structures a lot faster?” By developing tools like crystallization robots and better expression systems — basically better ways of screening constructs to be able to actually get them to crystallize and to get crystals that diffract — the field has been able to accelerate the progress on X-ray crystallography. Larger and larger structures are being done. We’ve seen that with the ribosome. The technology just continues to improve, so the bottleneck goes back to the expression of proteins you are interested in.

What are the big challenges in structural biology?

Clearly one would like to look at the entire cell. Can we reconstruct the whole cell from a structural point of view? It can be done by integrative approaches, by using all of the biophysical technologies, such as X-ray crystallography, electron microscopy, and (nuclear magnetic resonance), and combining the results using computation. We want to be able to reconstruct large organelles and eventually reconstruct a whole cell. I think that’s where the field is going — toward more challenging systems, such as multiprotein complexes. You want to reconstruct how a cell operates at a structural level and obviously relate that to function.

What made you decide to become a scientist?

I was interested in chemistry. We’re going back a long ways now, back to the ’60s. I really hadn’t done much biology, and biochemistry was an emerging field then. I thought that seemed like a very interesting thing to do. I grew up in Scotland. There was a lot of pressure to become a medical doctor. But I became really interested in biochemistry. I became more fascinated as structures started to appear when I was in high school and as an undergraduate. I wanted to understand how proteins evolved. That took off, and I’ve been doing that ever since.

Who have been your scientific mentors and inspirations?

When I was in Oxford (for my Ph.D.), the professor I worked with was David Philips, who had solved the lysozyme structure. He inspired me to work on enzyme structures and try to use the structural information to understand function. I think that’s important — it’s not just doing structure for structure’s sake but to understand what that structure is telling you.

Then I went to Harvard, where I worked with Don Wiley. It was a fantastic project that I heard about when I was at Oxford. Don was working with John Skehel on influenza virus hemagglutinin. It was a very exciting challenge to understand what the structure of a viral antigen was and how that structure informed how influenza worked — how receptor binding and fusion worked and how the immune response was generated against influenza virus. It was very inspirational to work in Don’s lab.

Outside of your expertise, what area of research do you find fascinating?

What’s really driving a lot of the excitement at the moment … is the ability to sequence very quickly. To be able to sequence whole organisms has driven the field and opened up all sorts of exciting new possibilities. For example, microbiomes. We can now sequence the collection of organisms that are present in our guts and in other parts of our bodies.

The same thing is true in virology now. You’ve got the ability to pull out single B cells, sequence the antibodies and look at the evolution of an immune response upon infection. Not only can you look at the antibodies that are produced, but you can see how the virus is mutating to escape the recognition. Again, that’s opened up huge possibilities for understanding how the virus evolves to escape when the immune system starts to mount a response.

Do you have any hobbies or interests outside of science?

I like to play golf. As I said, I grew up in Scotland, so golf is the game. I like to do things I can still get better at, and I can still get better at golf. In Southern California, you can play year-round, which is also nice and not true for Scotland. I like skiing. Again, it’s something I can improve at. I also like to go to the opera. I have season tickets at the L.A. Opera and the San Diego Opera. I also like cooking.

For young scientists, what advice or motto would you give them?

Choose a problem that you’re passionately interested in but that is also challenging. If you find a good problem, you can pursue it for the rest of your life. I’ve been working on influenza hemagglutinin since 1977, and it’s still very exciting and topical!

Rajendrani Mukhopadhyay Rajendrani Mukhopadhyay is the senior science writer and blogger for ASBMB. Follow her on Twitter, and read her ASBMB Today blog, Wild Types.