Potential Solutions to Human Conditions Drive William Walden

William Walden. Credit: Joshua Clark, University of Illinois at Chicago 

AAAS Fellow William Walden recalls a handful of moments in his career as a basic scientist when he realized that he and his co-investigators knew something important that no one else knew. The best parts for him about those perfect moments, he says, was that they were the culmination of months or even years of teamwork, and that they always started with basic biology.

"It's so satisfying to see the process evolve," Walden says. "Those 'aha' moments come out of being able to say, 'Our data explain this phenomenon.'"

Walden, a researcher and professor of microbiology and immunology at the University of Illinois at Chicago, investigates the role of trace elements, especially iron, in molecular biology and genetics.

One of Walden's signal discoveries in 2003 involved the isolation of the first gene found to encode a protein of the cytosolic iron-sulphur cluster assembly system (CIA), an "essential system in eukaryotic life. We don't survive without it," he says.

But his most satisfying finding came a few years later, when Walden and his UIC colleague, crystallographer Karl Voltz, worked out the 3D crystal structure in which an iron-regulatory protein, IRP1, binds to ferritin (an iron-storage protein) mRNA (the "m" stands for "messenger"). Figuring out that structure, which was important to understanding iron regulation of translation of ferritin mRNA to protein, had been "the holy grail" in their field, he says.

The team had been working on the problem for a decade. Walden and Volz were ready to throw in the towel, but Anna Selezneva, a senior research specialist, "refused to give up, and one day got crystals that defracted, which means they deflected X-rays in ways we could interpret, and we were able to solve the structure," Walden says with quiet glee.

Most days in the lab don't end in that kind of breakthrough, of course, and even some successes can be disappointing, like Walden's very first "aha" moment, when he was a young scientist just starting his lab. His team actually discovered IRP1 in 1989, but on the same day they published their findings, after some frustrating delays, a competing lab announced similar results about the same protein.

Walden's work has often focused on how the body manages iron through gene regulation. Nearly every living thing needs iron. The element is essential in humans for the production of hemoglobin, which carries oxygen in our blood; most of the iron in our bodies can be found in red blood cells. But iron is also one of a number of trace elements, like copper and zinc, that make important contributions to enzymes.

Most healthy people easily get and keep all the iron they need, losing it mostly to cell death and occasional bleeding, but the body is constantly monitoring its iron resources with a hormone called hepcidin. While not enough iron can lead to serious problems and even death, so can too much iron.

Over the years, he has worked with animal tissues and cells, and especially yeast, which he prizes for its simplicity. "Yeast is a wonderful model organism for understanding the mechanisms in eukaryotic cells," he says.

However, in light of the growing emphasis on translational research—science that optimally will soon yield treatments for human conditions—Walden believes his work must employ model organisms closer to humans, such as genetically modified rodents. That work could eventually help address anemia and hemochromatosis, a genetic disease that causes disruption in normal hepcidin function and iron overload.

Walden's research also may increase our understanding of the mechanisms that control how certain enzymes function, he says. A number of DNA repair enzymes depend on CIA to mature, for example, and those enzymes play an important role in maintaining health. Uncorrected DNA damage can lead to the replication of pathological mutations and cancer, he says.

Walden grew up the middle child of five, outside Washington, D.C., where his father had a civilian job at the Pentagon and his mother was a housewife. He thinks spending much of his childhood outside in nature made a big difference in his choice of a career.

"From the moment I became aware of who I was, science and nature were the things that excited me," he says.

Walden might have gone into astronomy, which fascinated him, but Morgan State University, the historically black university in Baltimore, where he did his undergraduate work, was not strong in physics, he says, so he chose biology instead.

At first, Walden thought he would go to medical school. In the end, though, he decided he preferred the bench to the bedside. "I like to think about tough problems, and how nature works. I decided that if I could come up with potential solutions to human conditions, I could help people that way."

An undergraduate research stint at a National Institute of Science regional site in Baltimore gave Walden a taste of what it would be like to work in research, and he loved it. He did three rotations in graduate school at Washington University in St. Louis. The third one, on protein synthesis in eukaryotes, was the one that grabbed him.

Walden professes that all he really wants is to be a full-time academic, but he has also spent more than 20 years working in diversity efforts at UIC, beginning with the Summer Research Opportunities Program (SROP), in 1994. He eventually chaired the SROP Advisory Group. He has also worked to attract minority Ph.D. candidates to the university, such as through directing the Bridge to the Doctorate program funded by the National Science Foundation and administered by the Louis Stokes Alliance for Minority Participation. Most recently, Walden served as associate dean for diversity and inclusion in the university's college of medicine, through 2016. Now he's associate dean for faculty affairs.

"I've always been interested in diversity and I've contributed to the extent that I could," he says. "Diversity efforts build relationships with other schools, enhance our visibility, and help all students, because we're developing best practices as we go along."