Ben Davis talks to James Mitchell Crow about 'nature's fuzzy logic.'

Ben Davis is a professor of organic chemistry at the University of Oxford, UK. His research interests include carbohydrate and protein chemical biology, in particular redesigning and manipulating carbohydrate-containing structures to probe biochemical mechanisms.

Who or what inspired you to become a scientist?

My Mum and Dad are both scientists and the way they approach life, in terms of the way they look at things, is scientific in the truest sense of the word. Science is about opening your eyes to what's going on in nature, at all levels - molecular, biological, the engineering level - and appreciating and having fun with that; and that was something that was always there as a kid. 

How would you define chemical biology?

For me, chemical biology means using chemistry to understand or solve biological questions and problems; using the molecular, using principles of thermodynamics,  using the arsenal of precision that is available in chemistry, and bringing that to bear in biology. You could argue that the genomic revolution is almost entirely chemically-driven in terms of the chemical technology that's enabled it, but also the chemical science that it's created. 

What motivated you to specialise in chemical biology?

I'm a chemist, but the problems I'm most interested in are biological ones, so I think about them from a molecular point of view. Molecular can mean big things; even protein complexes behave like they're macromolecules. Some of the most amazing mechanisms I know take place inside enzyme active sites. 

In particular, sugars (I'm completely biased) are mind-blowing. We haven't even begun to understand the complexity. Chemical biology and chemical glycobiology have just been the place, for me, where the most incredible stories happen, the most incredible mechanisms emerge.

You have described carbohydrate chemistry as beautiful. Which aspects appeal to you and why?

Where do I begin? What gets me most of all is the complexity and why? The most abundant organic molecule on the planet, glucose, has 5 contiguous stereogenic centres. Not only is that an amazing resource chemically, biologically, energetically, but it's where nature has invested so much of its biosynthetic effort. 

Yet, that complexity has led to two essential problems: one, carbohydrate chemistry is perceived as being complicated, and that scares a lot of people off. Also, the biology associated with it has been daunting, partly because we've not had the tools to unpick it, but partly because people haven't been able to see a clear system that nature's using. 

Instinctively, we're much happier with simple codes - taking DNA, and reading it out, to give you an exact protein structure. The concept of the genome is like a recipe. Sugars are almost the opposite, mediating subtle and specific events. The way that sugars do things is not lock and key, it's dynamic, it's flexible, it fluctuates - it's complexity, both in a molecular sense and in a systems sense, a mathematical sense. Sugars are nature's fuzzy logic, and that's what's fascinating.

Do you feel like you're starting to understand what's going on?

I do feel like we are starting to glimpse it. We work in a lot of areas of glycoscience but you see repeating mechanisms, repeated ways of recognising sugars that have evolved separately. 

Elements of the kinetics and thermodynamics of the interactions of carbohydrates with proteins are very different from some of the classic protein-protein interactions, and you can start to see that as the probable evolutionary driving force behind it. Nature doesn't make so many sugars because of a lack of selectivity, it does it because it needs that many building blocks to code in some form of complexity that we don't quite understand yet. 

What projects are you working on at the moment?

Something we're really excited by is wrapped up in this whole business of biological complexity. The genome was just the starting point, but the post-genomic era is full of fantastic chemical challenges. We can annotate the primary sequence of a protein and say it probably does such and such, but what really happens only chemical approaches can address. We have to really go in and work out what the functions of these proteins are. That's what I'd call functional genomics.

We've a lot of programs developing methods to correlate gene sequences with actual function in carbohydrate-active proteins. Some of that's screening methodology, some is trying to understand the interactions of sugars with proteins. 

The other aspect of that is post-translational modification [chemically modifying a protein after it has been decoded from mRNA]. Putting sugars onto proteins is just one of many modifications: you can put phosphates on serines, put lipids on. We recently made a mimic of a human protein associated with inflammation, from a fairly standard protein scaffold, simply by understanding the importance of the post-translational modifications. From basic strategies like that, we can start to pick apart the way that nature does things, even in some of the most complicated schemes. 

We've quite a few projects looking at how you can use the complexity of protein-sugar interactions to make better vaccines, better protein drugs, better small molecule drugs. We do that from quite a fundamental point of view, but in the back of our minds we always want to do stuff that's relevant to therapeutic applications, to disease, to making lives better.

What do you think is hot at the moment, or going to be the next big thing in your field?

You can identify areas that are going to be full of interesting questions. Everyone's talking about systems biology, but that hasn't really focused on the molecular in explicit detail, and I think the element of molecular complexity, how that plays a role in biology and how that's essential, is going to be really exciting. 

We're involved in a consortium that's looking at trying to create artificial cells, trying to understand the principles of complexity and put them in. And that ties into how we think about the mechanisms of life. How can we make something that looks like life? We'll never be able to prove an hypothesis about how life molecules evolved, but we can create a system that might have been the way. 

What's the trickiest problem you've had to overcome in your research, and how did you solve it?

If you're trying to make a target molecule, sometimes a strategy won't work but in that case you try and come at it from another way. Often, when people talk about problems, they're talking about chemistry as though it's a technology. Whereas chemistry is a science and that means creating new knowledge, by definition. None of the things we come up against ever seem like problems, they're just the unexpected and that's often as valuable as something you thought might happen; sometimes it may be more valuable.

If you could solve any scientific problem in any field, what would it be?

Some of the things that we're just starting to touch on, because we feel that we should contribute even though we're novices, are those associated with the challenges that are going to face humanity; resistance to antibiotics, re-emergence of diseases that we failed to tackle 30 years ago. Those are vitally important. 

But also the problems that we're making for ourselves in terms of the resources we have on the planet. It doesn't matter if you're there in your hybrid car; there's going to be someone else rolling along at 3 miles per gallon in a gas-guzzler. We have to change the way the world does things, to find a way of fuelling the planet, not only in terms of energy, but in terms of resource. Chemistry has a lot to offer; sugars are a great resource but the only source of energy that's limitless is the sun. We need to be thinking about how we harvest energy from the sun, whether that's through existing biosynthetic mechanisms and plants, and taking the materials they create, or through trying to mimic things that look like photosystems. 

Scientists have a responsibility to try and make life better for humanity, they have a role in society and should be responsible for that. The great scientists have always thought like that. 

If you weren't a scientist, what would you do?

What I really love, and it ties in with part of the reason I love seeing what nature does, because I love the aesthetic of chemistry, is modern art. And if I could be - it's not really a job you can apply for - I'd be a dealer or a curator in modern art.