Luke Wiseman Sets Out to Understand How Cells Deal with Stress

By Mika Ono

R. Luke Wiseman, who earned his Ph.D. from The Scripps Research Institute in 2005, finds himself back on the California campus these days, this time as the Arlene and Arnold Goldstein Assistant Professor. He's thrilled at the opportunity to start a lab at his alma mater.

"Scripps is just such a great place," he said. "It's so telling that a lot of the faculty did graduate or post-doctoral work here and came back. For me, it's the level of collaborations you can have here with faculty in different fields."

Wiseman is now taking full advantage of those opportunities for collaborations with several joint projects ongoing with Scripps Research labs of Jeffery Kelly and Bill Balch.

Thanks to the support from the Arlene and Arnold Goldstein Family Foundation, Wiseman is now applying his talents to investigating how human cells deal with levels of stress encountered during normal, day-to-day activity.

A Lifelong Interest in Science

Luke Wiseman's interest in science goes way back.

"I can't remember a time when I wasn't interested in science," said Wiseman. "I remember telling my mom I wanted to work in a lab for the FBI."

From a childhood in West Virginia, it wasn't too far to attend the University of Virginia in Charlottesville, where he studied chemistry. For graduate studies, he chose The Kellogg School of Science and Technology at The Scripps Research Institute – in part because he wanted to travel and experience the West Coast – and to the laboratory of Professor Jeff Kelly, who is now chair of the Department of Molecular and Experimental Medicine. There, Wiseman got his first taste of research on protein misfolding diseases.

Protein misfolding diseases include a number of inherited and acquired conditions, including Alzheimer's disease and cystic fibrosis. These disorders involve disruptions in the folding and/or trafficking of specific proteins, resulting in either a loss of function or gain of toxicity that interferes with normal cellular function.

Wiseman's Ph.D. project involved research on the protein transthyretin, a normally stable molecule secreted by the liver into the bloodstream that carries both thyroid hormone and the retinol binding protein. Mutations of transthyretin, however, destabilize the protein fold, and lead to the accumulation of microscropic fibrils called amyloid. These fibrils deposit on tissues such as the heart, leading to organ malfunction. For his thesis work, Wiseman both characterized the activity of small drug-like molecules that prevented transthyretin aggregation and explored how specific mutations of transthyretin lead to diverse phenotypes (individual characteristics).

When it came time for postdoctoral studies, Wiseman chose to go to New York University School of Medicine to work with Professor David Ron, who is well known for his research on stress signaling pathways – the body's mechanism to remodel intracellular biochemical pathways in response to environmental, developmental, or genetic insult.

In his initial project, Wiseman focused on the mechanisms by which the activity of large protein complexes called proteasomes changes in response to the environmental toxin arsenite. Through a comparative proteomics approach, Wiseman discovered the intriguing arsenite-dependent disappearance of a protein called "thioredoxin related protein of 32 kDa" (TRP32). Wiseman biochemically characterized the previously unknown chemical association between TRP32 and the proteasome, revealing a potential role for TRP32 in cellular response to stress. Further studies of TRP32 provided Wiseman with a tour of different techniques and model organisms.

"It was the best experience I could possibly have had," said Wiseman. "I worked in genetics in yeast, genetics in [the roundworm] C. elegans. I worked in mouse models. I worked in proteomics. The experience laid a lot of groundwork for different directions I could later take my research."

In a second project in the Ron lab, Wiseman sought to identify small molecule strategies to selectively activate the stress signaling protein IRE1 – one of three arms of the unfolded protein response (UPR) involved in maintaining intracellular protein folding efficiency. Using screening technology, the team identified a highly potent activator of IRE1, which the scientists demonstrated to provide a new "druggable" binding site on IRE1. This may one day yield a therapeutic strategy to manipulate proteins for the treatment of diseases including cancer and protein misfolding disorders.

Breaking New Ground

Since his arrival as an independent investigator at Scripps Research last year, Wiseman has been bringing together different aspects of his previous research to explore how protein folding pathways are remodeled by stress.

One of his projects examines how protein folding and trafficking in the early secretory pathway is influenced by UPR signaling generated by physiological levels of stress—the kind of stress your body encounters every day. Using a chemical biology approach to separate signaling within the three arms of the UPR, the Wiseman lab is evaluating how this signaling influences protein folding efficiency in the endoplasmic reticulum – a subcellular compartment where the synthesis and folding of many proteins takes place – and how that relates to human disease.

In other avenues of research, Wiseman and his team are examining the biophysical requirements for protein folding in the mitochondria – an organelle involved in a variety of essential cellular functions such as energy production and whose disruption is associated with numerous disorders, including Parkinson and Huntington's disease.

"The mitochondrial protein folding pathway is really kind of crazy, with proteins being made in the cytosol and imported into the matrix," said Wiseman. "We're trying to develop some sensitive reporters of mitochondrial protein biogenesis to evaluate the sensitivity of this pathway to exogenous stress. I think we are making really nice progress."

To realize some of his many ideas for research, over the past year Wiseman has had to learn the art of running a lab – and learn quickly. Fortunately, he has found a variety of mentors and colleagues happy to offer help.

"Even faculty who I didn't know before have been really supportive," said Wiseman. "I can't thank them enough. I was also quite lucky with the two postdoctoral fellows I hired. Not only are they hard workers, but they both are really friendly and set the tone of the lab and facilitate interactions with other groups. I'm also really grateful for my administrative assistant Kristy, who has been invaluable in getting my lab going."

Will Wiseman continue to build personnel in his lab?

"I'd like to get a graduate student this summer," he said. "The graduate program here is fantastic, and I want to be involved in it."

For their part, Wiseman's Scripps Research colleagues are delighted to have him back in a new role.

"As a graduate student, it was a privilege to have Luke in my laboratory – owing to his intellectual curiosity, his creativity, and his relentless persistence and drive to make discoveries," said Kelly. "Now that he's a Scripps Research colleague and a scientific collaborator, I am even more impressed with the sophistication by which he conducts his science and mentors students and post-doctoral fellows."

Send comments to: mikaono[at]scripps.edu

Assistant Professor Luke Wiseman is building a team to look at the effects of stress on protein folding. Shown here are (left to right): Kristy Nguyen, Estella Gustilo, Luke Wiseman, and Neli Atanassova.