Richard Henderson, CH, FRS, FMedSci, HonFRSC

I am Richard Henderson. I'm a physicist and now doing structural biology. I work at the Medical Research Council Laboratory of Molecular Biology at Cambridge. I've been doing structural biology, protein structures, membrane proteins for about 50 years. Last December, I shared the Chemistry Nobel Prize with Jacques Dubochet and Joachim Frank for helping to develop the Cryo-EM methodology that's now been so successful in determining the structures and things that were inaccessible by other methods.
We're already in the state, largely from X-ray crystallography, we know about the structure about half of the things in biology but there's a lot of terribly important structures that are not yet determined. So that would be a principal impact of the Cryo-EM, you know. It's a revolution really, not just a resolution revolution. But alongside that, starting in 1990 with the x-ray crystallography, many pharmaceutical companies whose businesses designed drugs to either block or activate particularly biological activities to cure you of some disease or physiological dysfunction or virus infection, they've used structural biology to determine the structures of their drug targets and then to develop better drugs.
And in the last, I would say, since probably 2000, in the last three or four years, the companies have realized that this methodology, the Cryo-EM is equally powerful and can be used to target previous inaccessible targets. And so now in the world, four big companies, pharma companies have bought into this.
So there's Merck, Novartis, Genentech, and Pfizer. They have invested, you know, 5 to 10 million each and buy one or two of these high-end electron cryo-microscopes. The littler companies haven't been able... They haven't felt able to put so much money in.
So there are a few companies working together. For example, in Cambridge, for two years now, we've had a consortium consisting of AstraZeneca, GSK, UCB Pharma, and then two little companies Astex and Heptares. They bought one day a week each, and FEI run this. And now at Diamond, today it's announced that alongside the four or five microscopes that are funded by charities and Medical Research Council and so on, there will be a couple that are actually focused on the pharmaceutical industry, and that's being run by Thermo Fisher.
The great advantage is they've finessed it into a pre-existing structure involving a hall of residence. This is Ridgeway House, they have 100 rooms. People come here all the time and stay for a day or two or a week to use the synchrotron beamlines. They can now do the same and do the Cryo-EM. And they have eBIC and ePSIC, E-P, so Physical Sciences, electron microscopy investment, they're all co-located in the same building.
There is a, sort of, feeling of all-for-one, one-for-all mostly, which means there's a lot of support for this and it's obviously cost-effective too. So I think it's a very good step forward. The advantages that you don't need crystals. It works from not very small things, which still has some minor advantage for NMR from medium-sized things up to any size that you want and putting enormous viruses, hundreds of megadaltons.
You don't need it to be completely pure because you can see in the image and you can ignore the impurities. The proteins don't need to be so stable because you're not making a crystal. You don't have to set up crystallizations that take days to do. You plunge freeze it in a few seconds and then you've trapped it in a sort of metastable state so that you can find the structure of it.
So not so pure, not so stable and the amount you need is tiny, and then it's also quick. So as a result, many projects that were taking people 10 or 20 years, you can now do them in a day or 2. It's going to work for basic knowledge, basic biology, basic science, and it's also going to work for practical things like a better drug design and understanding where you're going in commerce and technology developed so we use greater health and greater wealth for the UK.
So thinking about the future of Cryo-EM, most scientists are optimists. And for example, what has already happened we thought would happen. We thought it might take about a year in 1997.
Actually, it took a bit longer than that. So probably, even though we think it's all going to be...everything is going to be solved in the next two years, it'll be a perfect method, everyone will want to use it. However good it is, you can always make the detectors bigger and faster, and the microscopes have a faster throughput.
So exactly how fast that will go, it's hard to say, but I think all the problems are going to be solved, all the [inaudible] into force, you can determine the structure of anything that you want quite quickly. So I think we're all optimists. Pessimists should go and do something else.