Ben Cravatt talks to Michael Smith about his research into the function of the proteome and success in cloning the cDNA of a hotly pursued enzyme

              

Benjamin Cravatt is a professor and chair of the Department of Chemical Physiology at The Scripps Research Institute in California, US. His research combines synthetic organic chemistry, proteomics and metabolomics. He is a member of the Molecular BioSystems editorial board.

 

What inspired you to be a scientist? 

There wasn't a plan from birth, but my Dad, a dentist, and my Mom, a dental hygienist, inspired me to think about biology. I went to Stanford University in the US with a view to going to medical school. My major subject was biology and I got the chance to work in John Griffin's bio-organic chemistry lab. That inspired me not only to do research, but also to work at the interface of the chemical and biological disciplines.

How did you decide what to do at graduate school? 

Most graduate programmes in the early nineties were very restrictive. You were expected to see yourself as a chemist or a biologist and encouraged to pursue a sub-discipline in one of these subjects. However, the Scripps Institute in California aimed to keep their students as dedifferentiated as possible. Students were allowed to use whatever technologies they wanted to address problems at the interface of medicine and molecular sciences. I started at Scripps and never looked back!

Would you describe yourself as a chemical biologist?

Yes: to be a chemical biologist, you have to appreciate how chemistry and biology are performed to address difficult problems. From a synthetic chemistry viewpoint, this means knowing how to make a molecule that requires more than one step to synthesise. From a biology perspective, it might mean trying to enrich and purify a protein sufficiently to get sequence information to determine its primary structure. Both were aspects of my education at Scripps. Despite not considering myself a card-carrying synthetic chemist or pure biologist, I had sufficient experience in both fields to tackle problems that others couldn't.

What did you do after your PhD?

I'd been fortunate in graduate school to succeed in purifying the enzyme fatty acid amide hydrolase (FAAH) and cloning its cDNA. FAAH degrades endogenous lipids in our nervous system involved in interacting with the cannabinoid receptor. It was a hotly pursued enzyme by several labs and we just happened to use chemical approaches to enrich it using synthetic inhibitor columns. This gave us the opportunity to dive into that field with a unique set of tools. At that time, the Skaggs Institute for Chemical Biology started at Scripps was keen to bring in young people and I got the opportunity to join the faculty.

What kind of research do you do?

We range from using synthetic organic chemistry, proteomics and metabolomics to mouse genetics and animal pharmacology. We use chemical and systems biology techniques to shine a light on the 50 per cent or so of the proteome that is still uncharacterised to discover and understand its function. That means going from the biochemical characterisation of an enzyme to identifying its endogenous substrates and products, the pathways those exist in and the ramifications of perturbing those pathways in higher organisms. This usually gets us into mouse genetics and pharmacology at some point.

What aspects of mammalian biology are you interested in?

We're interested in enzymes that regulate small molecule metabolism and signalling pathways. Such enzymes are a rich source of interesting new biology and potential therapeutics. If you look at the number of enzymes for which there are drugs on the market today, more than 70 per cent perform chemistry on small molecules. There was a great review a few years ago by Robertson that discussed this.¹ Metabolic pathways that regulate similar molecules in mammals tend to be in pathways controlling higher-order behavioural/physiological functions and their perturbation can produce effects on processes ranging from inflammation to cognition and depression. Monoamine oxidase and COX inhibitors are excellent examples of drugs that perturb enzymes that regulate small molecule signals. I think that's a great area for chemical biologists to exploit because you have enzymes that are druggable and the pathways they regulate are essentially organic chemistry.

How do you think this field is going to develop?
 

We've gotten to this stage thanks to the successes in genome sequencing. The challenge from now on is to understand how all these identified proteins function in the cell and to identify promising therapeutic targets. With the example of FAAH, it's taken six to seven years to build a knowledge base sufficient to convince the pharmaceutical industry that it's worth investing in as a possible drug target. The job of academics, as I see it, is to characterise proteins and provide sufficient information to gauge their suitability as drug targets for the pharma industry. For this reason it's important that 'systems biology' academics follow up on their own large data sets: you have to test out the hypothesis yourself. You have to be committed to downstream follow-up on targets. Of course something could still be interesting whether or not it's going to be a good drug target, but you have to come to a decision in translational research and pharma need academics to help with this. It's hard to say that the proteome will ever be fully understood. In 20 years we'll have a much better appreciation of primary binding partners - substrates of enzymes - but how it all fits together in the cell is a lot to work on. Large-scale mass spectrometry is still slow. The high spatial distribution and temporal resolution needed is still in development and how it translates into what is going on in the cell is a big challenge.

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

I don't think any other job would inspire me as much. There's freshness and a drive when working with talented colleagues in an environment that is always changing. However, I was a competitive athlete at college, which I miss, so if I wasn't a scientist, maybe I'd dream of being a professional athlete.