Professor Stephen Curry
Stephen Curry is a Professor of Structural Biology at Imperial College London. After starting his career in physics his research now deals with applying physics to biological problems. He is also a regular writer and blogger on science for the Guardian.
It actually took until the 1950’s before the very first protein structure was solved.
On becoming interested in science
So I did a physics degree to begin with and I can’t quite remember why I chose physics, but as a boy I was always interested in planes and rockets and space and I think that was probably part of the motivation. And I very much enjoyed doing physics, but it struck me while learning my degree that all the interesting stuff had been done in the early part of the 20th century, you know, like special relativity or Rutherford splitting the atom or Bohr working out the structure of the atom or developing quantum mechanics, all the stuff that was left to do in physics seemed to me extraordinarily difficult. I know there’s been some excitement over the Higgs boson but I actually don’t really have a good feel for, you know…I know the Higgs is important but even though I’ve got a degree in physics, I still struggle with it as such. So when I was sort of getting to the end of it, the course that really excited me was a course in molecular biophysics which is all about applying physics to illogical problems, and that was where I first encountered using X-ray crystallography and first really started to understand protein structure. Protein molecules are enormously complex: they’re simple in conception in a way because a protein is simply a chain made up of a selection of 20 different amino acids, but the diversity of structures and functions you can get with that simple toolkit is really amazing. And the molecule that early, sort of, lit a fire for me was haemoglobin, which is the molecule that’s stuffed into our red blood cells and it transports oxygen from our lungs all the way around the body. But it’s not just a molecule that can pick up molecules of oxygen, it’s regulated to a very fine degree, it’s sensitive to the local ph, it’s sensitive to the local carbon dioxide concentration, it binds chemical regulators which allow us to adjust our habits if we live at low or high altitudes and so all that exquisite regulation was encapsulated in one molecule and so it was a real genuine piece of nanotechnology. I know that human beings talk about getting into nanotechnology, but the stuff we make at the minute is really just microtechnology, its hundreds or thousands of nanometers so people are exaggerating a bit but, you know, nature has really cracked it as far as I’m concerned. And so when I then thought, and actually it was very late on in my degree that I thought I would be the type that might go on and do a PhD and make a career of science, but when I did, I very much wanted to move in that direction.
That was the area of science that really excited me but it was also something I felt I would be able to talk to other people about, and I was sort of thinking I could’ve got, you know, a PhD in spectroscopy or something and talked about, you know, the fine structure of the hydrogen atom or something but I kind of felt if I was going to go to parties, I wanted to be able to explain what it was I was working on, and I guess it was also a sense of maybe wanting to work on something biological, being that it might one day be of utilitarian value to mankind, to humankind.
On the crossover between physics and biology
Certainly the techniques that we use involve X-ray diffraction, which is an optical phenomenon essentially because X-rays are a form of light and diffraction is the phenomenon of particular ways of scattering light by small objects or sharp edges. And it would’ve been shortly after the discovery of X-rays towards the end of the 19th century that people then started applying it, looking at crystalline samples, and it started out as a way of trying to find out what X-rays actually were – they were famously called X-rays because they didn’t know what they were – and there was a lot of talk about whether they were waves or particles at the time, and one of the ways of trying to determine which it was was to feed it through a crystal, because there was a German scientist called Max von Laue who thought that the spacings between atoms within a crystal would be about the same size as the wavelength of X-rays, and it was known from optical experiments that if you shined light through a narrow slit about the same width as the wavelength of light, then it spreads out and you get these patterns of fringes. And so Laue convinced a couple of colleagues to do the experiment and they got a diffraction pattern when they fired X-rays at a crystal and so that showed that X-rays were likely to be a wave and that sort of settled that particular debate.
But there were was also a father/son team in England, the Braggs, William and Lawrence, his son, who sort of picked up the baton from Laue immediately, because Laue couldn’t quite interpret the pattern of scattering that he got; he had a go and got most of the way there but he sort of…he realised, and other people realised, that he hadn’t quite solved it. He’d figured out the way that the way that the X-rays scattered was actually telling you something about the internal structure, of the way that the atoms were arranged inside the crystal, and he started off with a crystal of copper sulphate so it was a pretty simple type of matter.
And it was Lawrence Bragg, the son, he’d actually just graduated from his physics degree at Cambridge and he had been talking about X-rays with his dad and he’d been studying crystals as part of his physics degree and he just, sort of, the things came together and he just realised how the X-rays were interacting with the crystals and so he was able then to figure out what was the structure inside the crystal. So they very quickly started solving lots of crystal structures, of very simple things; the first one they did was table salt, so sodium chloride, which is a structure that just has two atoms in it but has a regular repeating structure in the crystal, then over the years, through the sort of decades, this was about 1912, 1913, that they started off, but people realised that if you can have any sample that forms a crystal, you can analyse the internal structure, the atomic arrangement within the molecules, so if you can get it to crystallise, then you can apply this technique to it and work out the structure.
So they went on from simple salts, they started looking at minerals, gemstones, and then, chemists had been crystallising chemical compounds for years as a final purification step, so they had lots of samples that were crystalline and people started working out the structures of chemicals, steroid molecules for example; Dorothy Hodgkin , who is so far Britain’s only female Nobel laureate, won the Nobel prize for chemistry, largely for her early work in chemical crystallography. So she solved penicillin just during the Second World War and then vitamin B12, which was a large organic compound, about a thousand atoms, so already they’d gone far more complicated, and that was in the 50s. But even overlapping with her work, and she was also quite involved in it, was work on biological molecules and, again, since about the late nineteenth century, people had realised that you could grow crystals from protein molecules and in the 30s and 40s they started to work on these and mathematically it’s a much more complicated problem to solve because the complexity of the structure is much greater than with sodium chloride, so the mathematical techniques that you have to apply are more sophisticated.
So it actually took until the 1950s before the very first protein structure was solved and that was myoglobin, which is an oxygen storage protein in muscle, but since then there have been hundreds of thousands of structures solved and now it’s an absolutely standard tool in a modern biological and even in a modern pharmaceutical company, because we’re all interested in what protein molecules look like; drug companies are interested in it because most drugs these days will be a chemical compound that interacts with a protein and interferes with its normal function; often diseases are caused when proteins run amok in the cell, shall we say, and so one designs chemical inhibitors of these proteins in order to generate new therapies.
On current research
OK, so most of my work is focused on looking at proteins that are involved in the protease viruses, and the viruses I’m interested in are foot and mouth disease virus and something called norovirus, or more commonly known as the “winter vomiting bug”, which is a very unpleasant thing to get. Not very deadly if you’re in reasonable health otherwise, but a very nasty experience.
So viruses are a terribly simple form of life, I guess its debatable whether or not they are even a form of life, but they’re basically an assembly of molecules and these two types of virus, they’re actually distantly related to one another, although you wouldn’t know that from the diseases that they cause, but they’re both similar in the sense that they contain a shell of protein which contains a single molecule of RNA, which is of course a variant of DNA, and all the virus is seeking to do is to make copies of itself, and so it gets inside and infects the cell and converts the cell to a factory for making new virus particles; pretty much all viruses do that. They have no intention of causing disease, although sometimes the symptoms that are associated with the diseases are in the virus’ interest, so the fact that the cold virus makes you sneeze, that’s it controlling the host and making it easier for the virus to be transmitted.
So we’re interested in the proteins that the virus makes, inside infected cells, in order really to understand at the molecular level how a virus goes about making copies of itself, because what it has to do…and, you know, they’re very simple creatures, as it were; so foot and mouth, for example, it has just one gene in its genome and that one gene causes the havoc that, well it’s well known in this country from the outbreaks in 2001, but foot and mouth is still a worldwide problem. But that one gene codes for a long protein which is made inside the infected cell and that long protein has the ability to cut itself up into twelve different pieces and those twelve pieces, twelve different proteins, then cooperate together. Some of them basically go to construct the shell over new virus particles and the rest of them make copies of the RNA molecule which will be packaged inside new particles which will then burst out of the cell and go on and infect others.
So we’re interested just in seeing what the bits look like and most of our work is really just trying to understand the fundamental biology of what makes the virus tick. Some of it should have offshoots which may help us to think about ways that we could go about developing therapies, either improving vaccines or developing drugs against the virus to stop it in its tracks.