Ben Cravatt: A Passion for Chemical Biology

This year, The Scripps Research Institute is celebrating its 100-year anniversary! Their motto? Turning scientific inquiry into innovative treatments that benefit the world. In this series of articles, we aim to shine a spotlight on some of the leading analytical scientists at Scripps – and the crucial role their work plays in delivering on Scripp’s raison d’etre. Here, Ben Cravatt, Professor and Norton B. Gilula Chair in the Department of Chemistry at Scripps, shares his passion for chemical biology – and for Scripps.

With Ben Cravatt

What makes Scripps unique?  
 

Scripps is one of the largest nonprofit biomedical research institutes in the world – but people are often confused about its culture and structure, which I think is what makes us unique.

Our main difference from universities is that everyone here is interested in biomedical research – there are no English, Philosophy or Arts departments. We also do not facilitate undergraduate programs like other universities. Instead, we have an independent accredited graduate program in the biological and chemical sciences with an emphasis on research. That definitely shifts our focus on a more science-centered and practical mission. 

It is an incredible place to work on interdisciplinary scientific collaborations – the departmental boundaries are almost nonexistent. Take our lab, for example; we are interested in understanding the chemistry of life. Some of the lab members have a synthetic chemistry background, but we also have incredible cell and molecular biologists, meaning we can work at the interface of chemistry and biology through collaboration. 

If you distill down the labs at Scripps, many are interested in understanding how proteins function and the biology of disease, using a chemistry-first approach. John Yates, myself, and others have been committed to that field for quite some time, but we are just a small part of this much larger biomedical Institute. 

Scripps is certainly much larger and more diverse than just protein science. We have always had a strong footprint in technological advancements. I feel like Scripps has always had a firm commitment – whether it be in proteomics or in other fields like structural biology and synthetic chemistry – to push the boundaries of technologies and methodologies. And we value innovation tremendously here – we are “science changing life” after all!

Where does your Scripps story start? 
 

While I was working as an undergraduate in a laboratory that was operating at the interface of chemistry and biology, I started becoming more interested in that type of multidisciplinary science. I eventually came to Scripps as a graduate student in the early 1990s – it was one of the only programs at that time (perhaps the only program) that had a dedicated commitment to training at the interface of chemistry and biology. 

I stayed here as a faculty member, working on the characterization of an enzyme involved in endogenous cannabinoid signaling, which revealed this lipid signaling pathway in the brain – somewhat of a breakthrough in that field. That success helped me launch my own independent lab and, over the ensuing years, I have always tried to integrate synthetic and analytical chemistry approaches to solve problems in biology to benefit human health. 

In my graduate career, I could already see the potential impact of mass spec in large scale protein science, and it was pretty clear genome sequences were going to be completed in the near term in the early 2000s. Today, with genome-wide DNA sequencing advances, we now basically know the genetic basis for an incredible number of diseases – but we do not really know the biochemical mechanisms, in many cases, that cause the diseases. Our goal is to fully understand what proteins do in disease and guide the development of chemical probes and, ultimately, drugs. Put another way, our primary goal is not to blindly develop drugs, we know that we need to understand the functions of the proteins in physiology and disease first.

What are some of the main focus areas for your lab? 
 

As our lab started evolving, we began to think about ways to parse out the proteome, based on shared principles of small molecule reactivity and recognition. There was initially this misconception that there are limits to what small molecules could do in their interactions with proteins, but we felt  this wasn’t true; natural products and other small molecules that have been serendipitously discovered can have very atypical mechanisms; for example, allosteric regulation of proteins through cryptic sites. Our lab approached the problem of systematically identifying first-in-class chemical probes to study protein functions. Sometimes those probes reveal functions of biology that were missed by genetics…

We eventually designed the activity-based protein profiling method – which allowed us to go into biological systems and capture proteins based on their differential reactivities. We demonstrated that there is an incredible array of small molecule binding pockets across the proteome that can regulate proteins in fascinating ways.

The concept of ligandability – how small molecules bind proteins – has become a fundamental underpinning of chemical biology. We have become quite fascinated with the breadth of ligandable sites throughout the proteome, and we are currently trying to understand how they affect protein function. That is quite a challenging objective when you have hundreds of ligandable sites  across proteins that all have different types of functions. To tackle the challenge, we have been trying to come up with new approaches – using mass spectrometry to better understand how proteins participate in binding other biomolecules, such as other proteins, DNA, or RNA. 

In the future, protein structure predictions and deep human genetic maps of phenotyptic mutations might allow us to predict how ligands will affect protein function – but we’re pretty far away from that right now. The faster the mass spectrometry-based proteomics experiments can be performed, the more data can be acquired. Here, computational approaches could be integrated, so we know exactly what residue is reacting to a small molecule. Such approaches may be too sophisticated from a computational point of view for us, but that’s why we advocate for collaborations – within and beyond Scripps.

Why is analytical chemistry crucial at Scripps?  
 

If genome sequences and mass spectrometers existed 20–30 years ago at the level they exist today, someone would have developed activity-based protein profiling and designed chemical proteomic type methods. As is often the case, new technologies drive new biological discovery, and the confluence of those two advances made it a reality – protein science really exploded with mass spectrometry-based approaches and genome sequences provided a near-complete “parts list” of the proteins produced by biological systems. Those two analytical methods have enabled labs like ours to ask and answer questions that wouldn’t have been possible decades prior.  

Analytical chemistry has been key to our research – and to Scripps’ stated aim of turning scientific inquiry into innovative treatments that benefit the world. It enables us to gain more in-depth access to shallow cryptic pockets in the proteome. It has been hard to systematically study those types of principles, but with some of the platforms we have developed, we can now look at thousands of sites in the proteome for interactions with small molecules. 

As our platforms have matured, they have been adopted by the biotech and pharmaceutical industry and turned towards more translationally focused research. In fact, there are multiple drugs in clinical development now that have leveraged our lab’s activity profiling and chemical proteomic platforms as a way to discover ligands, optimize them, and develop target engagement assays. 

I’m excited to see what we can achieve in the coming years at Scripps – and what that might mean for human health.

_{Headshot - Credit: Supplied by Interviewees | Hero Credit - Images supplied by The Scripps Research Institute}