I am a structural person; that’s what I do. I am interested in the structure of viruses, particularly. I have developed technology for doing that, for many years. I’m also very interested in the results. In the case of rhinovirus, my lab was the first to ever publish a paper examining the interaction of the virus with its receptor in the structural sense. That paper also received a considerable number of citations.

“...it’s the pure curiosity about how nature works that drives us.”

I started learning crystallography when I studied for my Ph.D. in chemistry at the University of Glasgow. Then I was a postdoc at the University of Minnesota, working on chemical crystallography, organic compounds, and natural products. Then I returned to England, for six years in Cambridge, where I was involved in working on the first protein structures ever solved. I was Max Perutz’s postdoc, and we worked on the structure of hemoglobin. Myoglobin and hemoglobin were the first protein structures ever to be determined. That was 1959-1960.

I then came to Purdue, where I worked on enzymes, particularly dehydrogenases, for the first decade. That was quite adventurous, but I always wanted to work on viruses. In 1970, I made a determined effort to switch the direction of my laboratory. It took me a decade to switch completely over to viruses.

Gradually, over time, we came to look at more and more complicated, sophisticated viruses. We initially looked at plant viruses, which are easy to harvest. After Steve Harrison’s lab at Harvard and our lab at Purdue determined the first 3D structure of two plant viruses in atomic detail in 1979, we decided it was time to look at animal viruses. These are much more complicated. Initially we worked with rhinoviruses (common cold viruses) in collaboration with Roland Rueckert at the University of Wisconsin.

A lot of my emphasis now is on more complex viruses still. Rhinoviruses are what we call naked viruses. There are other viruses with lipid envelopes, which function as membranes that surround the so-called nuclear capsid. These are more complicated, and to understand them we’ve had to move away from crystallography to some extent and into electron microscopy, because crystallography can no longer deal with these issues. So over the years, we’ve moved to more and more interesting biological problems, mostly in collaboration with Richard Kuhn at Purdue, and in the process we’ve had to also modify or adapt or develop the technology to tackle them.

There is more than one single problem. For instance, we’re now starting to look at polymorphisms in viruses. "Polymorphic" means many different shapes. Viruses, such as influenza and SARS, are not strictly icosahedral like other viruses—rhinovirus, polio virus, and plant viruses. These all have very regular geometric structures. We’ve also been working on things like the Dengue virus, yellow fever, and West Nile viruses. They have an envelope. They’re the next stage in complexity, but they’re still very geometrical in structure. Not so for the flu virus or SARS or the coronaviruses and many others. In these cases, each virus particle has a slightly different shape. This is not like the common cold virus, where each virus is nearly identical to the next one, and this is the challenge in terms of structure.

Well, there’s a technique known as tomography, an electron microscopy technique, whereby you take many different pictures of the same virus. Although the problem there is you’re bombarding the biological specimen with electrons and it can deteriorate with this radiation damage, so people have been working on ways of getting around this problem.

It depends on what you mean by the field. I’ve spent much of my life doing crystallographic studies. That is a field that’s become highly automated where it used to be highly un-automated. The techniques have largely been worked out. They can now be put into computer programs and most anybody can use these techniques without really understanding what they’re doing. Thus in terms of crystallography, which is still used extensively, this is a major change. It comes faster and easier and it doesn’t require highly skilled expert technicians. Electron microscopy has been very rapidly developing. It’s where crystallography was 30 or 40 years ago. It has a future, too, that’s very powerful, but it’s not yet automated.

At the same time, we now have much more knowledge of viruses themselves. When I first stated working on viruses in the late 1970s, I took a sabbatical in Sweden and worked with Bror Strandberg. Nothing was known about the structure of viruses. "Nothing" may be slightly too strong, but in the context of what we now know today, "nothing" is very appropriate. We now know so much more. I think that is how the field is changing. The virology, crystallography and electron microscopy and also the molecular biology; the ability to manipulate compounds, as we did, for instance, in our 200 PNAS paper (He YN, et al., "Interaction of the poliovirus receptor with poliovirus," PNAS 97: 79-84, 2000), to manipulate the receptor in an in vitro fashion.

As I said, we’re trying to deal with these polymorphic viruses. I don’t feel we’ve made a very good start yet, but that’s one place I’m going. I’m anxious to pursue that. In another study, we are working on an unexpected situation concerning parvovirus that are initially icosahedral but become asymmetric on infecting cells. Hopefully, this work will result in a major publication and could open up all kinds of interesting questions about how the virus interacts with its receptor in the initial stages of infection. Half my lab deals with prokaryotic viruses—viruses which infect bacteria—and those are extremely interesting viruses too.

This just speaks to the question of what is originality. Where do ideas come from? As I told you, I worked with Max Perutz in the late 1950s and early 1960s, and we were working on the structure of hemoglobin. That had two alpha chains and two beta chains arranged with a certain kind of symmetry, and I got to asking, could we have determined that the alpha chain and beta chain actually have very similar structure? Could we have determined that more easily without the use of a method called isomorphic replacement? This question gave rise to the technique that is now known as molecular replacement, which is one of the major methods for solving structures these days? That really came to my mind because of work I was doing with Max on hemoglobin. In my own experience, there’s always something that sparks an original idea, and some people call it serendipity, but could also just be called originality.

I suppose most people are interested in the world around them, one way or the other. It’s curiosity that drives us. It’s curiosity and the joy of discovery which keeps scientists going over a long period of time. The point is that the actual benefit to society is not necessarily immediately apparent. But usually, there are both benefits and banes to any work, and they become apparent sooner or later. Still, it’s the pure curiosity about how nature works that drives us.