The Nuclear Man

By Eric Sauter

Tom Burris, a new professor in the molecular therapeutics department at Scripps Florida, was born in 1968 in the heart of the country, a small Illinois town called Cahokia just across the Mississippi River from St. Louis. His father was an engineer with IBM, his mother was a housewife, and Burris never considered science as a career until late in high school. Even then, he thought first of engineering and computing, not biology.

Then he hit high school chemistry and discovered he really liked it.

In the process, he took physiology and became interested in medicine. In fact, his was a rather large interest in medicine—he planned to become a doctor. Accordingly, as an undergraduate at Southern Illinois University, Burris worked as a patient care technician at Washington University Hospital, part of the St. Louis universities medical school. And he changed his mind about medicine.

"I worked on the neurology floor and the vast majority of patients, those with Parkinson's and Alzheimer's disease, didn't ever get better," he said. "That was my first real exposure to medicine. If I had gone to work in another part of the hospital, I might have gone another way."

Instead, the experience led him to research. "When I went on rounds with physicians, I got to see the clinical correlation between science and medicine," he said, "or at least I saw the implications of the science because a lot of the doctors were researchers, too."

After graduating with an undergraduate degree in chemistry in three years, magna cum laude, Burris decided to go to Florida State University in Tallahassee for a Ph.D. in molecular biophysics, which was as close as you could come to a degree in chemical biology in those days. From there, he did a postdoctoral fellowship in molecular endocrinology at Baylor College of Medicine, followed with a fellowship in molecular genetics at the University of California, Los Angeles (UCLA) School of Medicine. Next, he went to work for Johnson & Johnson's research division in Raritan, New Jersey.

A Life in Industry

What Burris focused on in industry was consistent with that inkling he'd first gotten following around the doctors at Washington University—the connection between science, research, and patients.

"I was interested in industry because of its ability to develop chemical tools for pharmacology and applying science to medicine," he said. "I worked at the R.W. Johnson Pharmaceutical Research Institute, which is about as close to basic research as you could get at a big pharmaceutical company."

Burris spent four years there and learned a number of things, both in and out of the laboratory. "It was my first exposure to the type of resources that a pharmaceutical company can put toward a problem," he noted. The company was also in the process of developing high throughput screening and Burris was exposed to that as well. He came away with a clearer understanding of the technology and, more importantly, the potential of various technologies for solving problems in biology.

His work was focused on endocrine therapeutics—hormone therapy—and nuclear receptors, protein molecules that mediate hormone activity inside the cell, an interest he had called his own even before his postdoctoral work at Baylor.

Burris recalls the impact on him of a book he read as an undergraduate, called The Nobel Duel, a non-fiction account by Nicholas Wade about the rivalry (at times, outright hostility) between Roger Guillemin, a French physician, and Andrew Schally, a Polish refugee who began as a laboratory technician. Their competition revolved around identifying the hormones in the hypothalamus that control reproduction, growth, and other functions. As it turned out, the two made their discoveries almost simultaneously and eventually shared the 1977 Nobel Prize in medicine with a third researcher.

"The book sent me in that direction [of endocrine therapeutics]," he said. "As a grad student, I was interested in gene regulation, too, endocrine and gene regulation interface at nuclear receptors."

Nuclear receptors make tempting drug targets because they can bind directly to DNA and can activate genes through specific ligands—molecules that affect receptor behavior—such as the sex hormones, vitamins A and D, and glucocorticoids, which modulate the body's response to stress. Nuclear receptors have been implicated in a number of cancers, including prostate, breast, and colon cancers, and other diseases as well, including type 2 diabetes, atherosclerosis, and metabolic syndrome.

The other great thing about nuclear receptors is that you can design small molecule therapeutics to force them to change their ways.

"As a nuclear receptor pharmacologist, you go wherever the receptor leads you, so you have to learn about many disease states, such as diabetes, cancer, and autoimmune disorders," he said. "My knowledge is mostly from the literature and then just jumping in with both feet."

Burris' definition of a successful experiment is one that offers a significant contribution to the field. This usually means the work is published in a widely recognized journal, something he has a good record of doing. "I think I've published papers on over half of the 48 receptors in at least a dozen different disease states," he said.

Significant Studies

Some of those discoveries may have significant clinical ramifications.

For example, in 2007, Burris was part of a team of scientists who showed that a single ligand, heme, the iron-carrying component of many proteins, including hemoglobin, and a co-factor needed for energy metabolism, worked with two orphan nuclear receptors REV-ERBa and REV-ERBb. Heme binding to REV-ERB caused the repression of target genes including BMAL1, an essential component of the circadian oscillator, the body's central time keeper. The discovery of the heme ligand extends the known types of ligands used by the human nuclear receptor family beyond the endocrine hormones and dietary lipids uncovered previously. The team further found that heme regulation of REV-ERBs may link the control of metabolism and the mammalian clock.

A 2008 study published in the journal Proceedings of the National Academy of Sciences and conducted with Patrick Griffin, who heads Scripps Florida's molecular therapeutics department, produced a novel method to help determine the probable effectiveness of drug candidates for the treatment of estrogen-dependent disorders such as breast cancer, findings that could lead to the development of a new generation of optimized estrogen receptor modulators (SERMs) with improved selectivity profiles, a key to more effective treatment.

With new drug candidates, it's necessary to have the right interaction with the target and to accurately predict the full range of activity of that potential candidate. The single biochemical test compares new drug candidates against currently available SERMs, so that it can be determined, in rapid fashion, if the new compound is worth pursuing.

Traditional drug discovery programs involve multiple assays to identify high affinity modulators or ligands for estrogen receptors. Unfortunately, success translating these extensive laboratory tests into live tissue results has been limited.

The new technology devised by Griffin and Burris has enormous potential in the development of new treatments for breast cancer—and for diseases beyond cancer, including cardiovascular disease and osteoporosis. As a single biochemical assay, this new platform can replace the current load of expensive, multiple cell-based procedures that often take weeks to produce useful results.

Moving On

It is these kinds of discoveries—ones that, as Burris says, can make a difference—that led him to leave industry in the first place.

"There are restrictions in industry," Burris said. "For one, it's sometimes hard to publish studies. Here at Scripps Florida doing science and publishing the results is probably the most important thing we do. I can collaborate with people who want to design drugs and want to look for answers to questions about how receptors function. All this is in pursuit of potential treatments, which in some way feels a lot like industry but without the bureaucracy."

Burris feels most comfortable working in metabolic diseases partially for practical reasons—the National Institutes of Health looks to fund those areas with the greatest opportunity to affect the health of Americans.

"Of course you want to do work that is important and has an impact on health," Burris said. "Nuclear receptors are targets for drugs used to treat a number of diseases and our work can help make improvements to these drugs. We're trying to both work with receptors where there are issues with the ligands and to figure out how to optimize them for clinical use, as well as finding ligands for orphan receptors."

With only 48 known receptors, including those orphans without known ligands, the field might appear limited, but Burris isn't particularly worried.

"The estrogen receptor, which has been worked on for many decades, is enough for my lifetime and probably a couple other researchers' lifetimes as well," he said. "We've been studying estrogen since the early 1900s and the idea of a receptor only came about in the late 1950s. But it wasn't that long ago that we discovered a second estrogen receptor, so there are still surprises out there. Some of these orphans without known ligands will keep us busy for awhile."

Send comments to: mikaono[at]scripps.edu

"As a nuclear receptor pharmacologist, you go wherever the receptor leads you, so you have to learn about many disease states, such as diabetes, cancer, and autoimmune disorders," says Scripps Florida Professor Tom Burris. Photo by James McEntee.