Paul Thompson: Uncovering the Mechanisms of Autoimmune Diseases

By Eric Sauter

Paul Thompson, an associate professor in The Scripps Research Institute's Department of Chemistry, likes to think of himself as a dabbler, a name that, at face value, doesn't do justice to the 40-year-old Toronto native and his efforts in drug discovery.

"In our lab we do a lot of things—chemistry, biochemistry, cell biology, you name it," Thompson said. "Our goal is to develop feedback between chemistry and biochemistry, and then use those tools to study what's going on in the cell."

In a nutshell, Thompson is focused primarily on the mechanisms of enzyme families involved in the modification of an amino acid (one of the protein building blocks of the body) called arginine. He is especially interested in a family of proteins called arginine deiminase (PAD), because some are overexpressed in various autoimmune diseases such as rheumatoid arthritis and multiple sclerosis.

Thompson and his group members are looking for inhibitors of these enzymes. They have already found at least one remarkable in its potential abilities. In a series of studies published earlier this year, Thompson and his colleagues described a single PAD inhibitor, known as Cl-amidine, that can, to varying degrees, suppress colitis, reduce spinal cord injury, kill certain types of cancer cells, and reduce the severity of rheumatoid arthritis. While all these studies were conducted in animal models, the research not only validates PAD proteins as therapeutic targets, but also strongly suggests Cl-amidine may be a good candidate to fight disease.

Although Thompson's main focus is the PAD proteins, he is also trying to develop synthetic versions of lectins, natural proteins often overexpressed on virus and cancer cells.

A New Home

After earning his undergraduate and graduate degrees in biochemistry from McMaster University in Canada, Thompson received a Canadian Institutes for Health Research postdoctoral fellowship for work in pharmacology at Johns Hopkins University.

He expected to return to Canada, but no jobs were open. Instead, he went further south, joining the University of South Carolina in 2004. In 2010, he arrived on the Florida campus of The Scripps Research Institute.

"I had a great career in South Carolina, but it was the opportunity to interact with people who thought like me that brought me to Scripps Florida," Thompson said. "Here, people know how to use chemistry and cell biology and cell signaling. They think about more than just what a protein does in the cell; they also want to use this information to drive drug discovery."

Basically, he said, he just felt more at home at Scripps Florida.

Target Rich

Thompson's primary field of study is an old one that has taken a long time returning to prominence.

In the 1950s, a Nature paper described the interplay of arginine and another amino acid, citrulline, in proteins. "For the next 20 years, there wasn't much work done in the area," Thompson said, "except for dermatology studies, because when your skin replenishes itself, arginine gets converted to citrulline."

Then, in 1998, rheumatologists found that patients with rheumatoid arthritis produced antibodies that recognized these citrullinated proteins. With that, the field pretty much took off. Research in the area further accelerated when one of the enzymes was shown to modify histones.

In the nucleus, DNA is wrapped tightly around histone proteins because if it wasn't, DNA would simply overwhelm the cell. (Each of our cells contains almost two meters worth of DNA.) Histones package the DNA into units called nucleosomes, and the whole package is known as chromatin.

Throughout the early 2000s, scientists discovered classes of enzymes—lysine and arginine residues—that could modify histones. In this case, PADs put citrulline residues in histones by altering arginine. This, in turn, modifies the transcription process, which can lead to autoimmune disease.

One PAD enzyme, for example, is highly expressed in neutrophils, a common form of white blood cell and part of the innate immune system. When confronted with a pathogen, neutrophils undergo netosis, a kind of cell death. Decondensing their chromatin, neutrophils throw out a net-like combination of histone proteins and DNA that, in turn, signals other immune molecules.

Thompson suspects autoimmune disease results from overactivation of these enzymes, so finding a way to inhibit them could make a difference in the course of a disease.

"This is a target-rich environment for drug development," Thompson said. "The one major issue is validating these nets as targets because not a lot is known about them. But something will come of it eventually."

Send comments to: mikaono[at]scripps.edu

"This is a target-rich environment for drug development," says Associate Professor Paul Thompson.