Navigating the Human Body

by Alanna Berman | June 2012 | 1 Comment »

By Alanna Berman

Some really exciting, cutting-edge science is happening at La Jolla’s Salk Institute for Biological Studies. Of course, that’s what Salk is known for: hiring the best scientists in the world to study some of the most complex biological processes in existence. It has been home to 11 Nobel laureates since its 1960 founding, and now, Ronald Evans, its current March of Dimes chair in developmental and molecular biology, as well as head of Salk’s Gene Expression Laboratory, has been awarded Israel’s Wolf Prize in medicine (thought by many to be an early predictor of future Nobel Prize winners).

Considered one of the highest honors in medicine, Israel’s Wolf Prize is awarded annually in six areas — chemistry, mathematics, medicine, physics, agriculture and the arts — to recipients who have made great achievements in their respective fields, in the interest of all mankind. Along with the prestigious honor, Evans will receive a $100,000 prize for his research. He was in Israel May 13 to be honored at Israel’s House of Representatives in Jeusalem. (President Shimon Peres, who was scheduled to present the awards, was recovering from surgery, so Knesset Speaker Reuven Rivlin and Education Minister Gideon Sa’ar, who is chairman of the Wolf Foundation, did the honors.) On June 5, Consul General of Israel David Siegel will hold a second ceremony for Evans at Salk.

“It’s very unusual,” Evans says of the prize’s distinction among other honors. “There are only a small number of awards given by countries, and then by the head of state. It’s a very wonderful, special kind of award.”

Science Behind the Prize

So what does it take to receive such a prestigious honor? For Evans, it’s taken years and years of research that has led to groundbreaking discoveries in the area of genes, hormones and nuclear receptors, which has led to new drugs and treatments for cancer, diabetes, obesity, heart disease and other ailments. He’s also uncovered new roles hormones play in asthma and osteoporosis.

Most specifically, though, the Wolf Prize recognizes his work on and discovery of the gene super-family-encoding nuclear receptors (or proteins within cells that sense hormones and other molecules and control the expression of genes) and how those receptors work. In basic terms, he’s discovered how genes, hormones and their receptors work toegther to control physiological functions in the body.

“While we knew what those molecules did in our body, we didn’t know how they actually worked,” he says. “For example, you can measure the action of giving someone a thyroid hormone or taking it away, but [that doesn’t explain] what becoming [energized] is, what becoming lethargic really means. You can feel it, but what are you actually feeling and why?”

To reach this point has taken lots of work and a foundation of other discoveries that have preceded these most recent ones. Essentially, he explains, one breakthrough has led to more concrete understanding of a physiological process, which, in turn, has led to the next discovery.

 

Emerging Interest

Evans, a Southern California native and “modest student,” has come a long way since his days leading up to high school graduation, when his father completed and submitted his undergraduate application to UCLA for him.

“My father was a physician, and my brother was an electronics engineer,” he says, “[so] when I went to college, my dad filled out all the forms for me and enrolled me as a business major. I had no idea, and honestly… I was very immature, I was young, and we knew by the numbers that I would get in, so I went to UCLA.”

As an undergrad, Evans began working in a research laboratory, and his interest in science grew. Realizing he wasn’t so much a business guy, he changed his major to bacteriology and received his Bachelor of Science degree in 1970. He would then become a graduate student at UCLA, working under a professor who studied leukemia viruses in chickens and who theorized that a genetic component to certain types of cancer exists. Evans launched his career in virology after graduating with a Ph.D. in microbiology and immunology in 1974.

 

The Science Guy

When Evans began his career, “there was an emerging theory of the genetic basis of cancer and that cancer was a problem of genes,” he remembers. “Here we had a virus that was able to promote cancer, at least the way we studied it.”

That time marked a major transition point in the medical world’s understanding of cancer, from the standpoint of viruses to one of recominant DNA (or rDNA), Evans explains.

As a postdoctoral fellow at New York’s Rockefeller University, Evans continued to study the nature of different viruses and their relation to certain types of cancers. But following both his father and older brother’s deaths from lung cancer and leukemia, respectively, Evans decided to return to California and change the way he looked at disease, from the perspective of viral genes to one of cellular genes.

A connection he had made at UCLA led Evans to the Salk in the early ‘80s, where he began to study the ways hormones regulate gene functions in the body.

In 1985, six years of research culminated in the first major breakthrough for Evans and his lab. The glucocorticoid receptor, which controls a class of steroid hormones like stress hormone cortisone, seemed to have the same signature for a cancer gene Evans had studied in graduate school.

“I was probably the only one who could have made that link,” he says. “There were no computer databases at the time, so if you didn’t know that virology of it, it was like a world that didn’t exist.

“It was a little bit like [Howard] Carter wandering around looking for King Tut’s tomb, and though he eventually discovered the tomb, the hard thing was how to get in. In science, the secret to solving a big problem is being able to ask the right kinds of questions to open the door, and if you don’t know how to do it, just being there doesn’t mean you’re going to get in.”

But Evens did open the door time and again, and each time, another discovery about the human body’s physiological processes awaited him. His background in virology ultimately led to “a reevaluation of the entire view of how hormones, physiology and disease works,” he says. Evans and his team quickly realized they were on the path to discovering how even common molecules, or receptors, function in relation to genes and hormones. That brings us back to his most recent work, which won him the coveted Wolf Prize.

 

Current Work

“[One of the things] we found was the receptor for the thyroid hormone, which is the accelerator controlling your body’s metabolism,” he says. “That was key to another discovery. The thrill was based on the recognition that we had stumbled upon the secret universe of hormone physiology.”

Important to this research was realizing how extensive this new universe is. After five years, Evans and his lab were on a path to determining the mechanism of action behind common molecules; in other words, what makes them do what they do.

Once Evans and his team understood these complex functions, they set out to develop new technologies to manipulate them, which is what the Wolf Prize celebrated last month.

“If you understand the normal process of how physiology goes bad, how your glucose loses control, then you can figure out a way to correct it, like with diabetes and insulin resistance,” he says. “You can be a diebetician, but you do not really have a way to correct diabetes without knowing how it’s controlled. We are the ones who are revealing the coding mechanism for physiology, and once you know the coding mechanism, then you can jigger the code.”

To date, medicines and therapies resulting from research in Evans’ Salk lab have included new steroids, synthetic thyroid hormone, contraceptives, hormone replacement therapy with new estrogen compounds, and cholesterol treatment. Almost all drug companies developing treatments for hormone physiology-related diseases are using technology developed in Evans’ lab, he says. More drugs are being developed all the time.

The most promising of these are new treatments and models for prevention of certain types of cancer.

“There are a lot of people who believe, for example, that vitamins A and D are thought to lower your risk for cancer, because if you are deficient in either, your risk for cancer goes up,” he says. “If you are overweight, your risk for cancer goes up. If you are diabetic, your risk for cancer goes up. There are drugs [that can correct these problems], and some of the ones we develop are those involved in controlling weight and controlling sugar. They improve health and therefore reduce the risk of cancer.”

One of the lab’s findings, a derivative of vitamin A, later became an FDA-approved drug to treat leukemia. Recent focus on a new exercise mimetic drug nicknamed “exercise in a pill,” which triggers the muscle function that occurs during normal exercise, could lead to another treatment for weight-related diseases.

“Muscle burns nutrients like sugar and fats,” he explains. “We’re experts in that, so we know that through this process we can control muscle function and trigger that process, the same process that gets triggered by exercise.”

Evans’ studies of molecular triggers related to even the most basic physiological processes could hugely affect the nature of life — and disease — as we know it, but he remains humble, even with the Wolf Prize still fresh in his mind.

“There are still things we don’t know,” he says. “We are still interested in understanding the mechanics of the physiologic process itself, and [there may still be] some very important ways to control body physiology and disease [left for us to find].”

To learn more about the ongoing research at the Salk Institute, visit www.salk.edu.

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