‘Free-Radical’ Scientist Recalls Research Journey

Almost 50 years ago, Denham Harman’s theory of aging as a biochemical process started a chain reaction in theoretical medicine.

Published October 1, 2002

By Fred Moreno, Dan Van Atta, and Jennifer Tang
Academy Contributors

Louis Pasteur once noted: “Chance favors the prepared mind.” Denham Harman’s mind was unusually prepared to develop a notion that took well over a decade to attract any serious attention, but is now a driving force in biomedical research: the free-radical theory of aging, a phrase Harman coined in 1960.

Now professor emeritus at the University of Nebraska Medical Center and still spry at 86, Harman recently edited Annals of the New York Academy of Sciences volume 959, Increasing Life Span: Conventional Measures and Slowing the Innate Aging Process. The volume also includes a recent paper by Harman on Alzheimer’s Disease: Role of Aging in Pathogenesis.

Free radicals are molecules or atoms that feature an unpaired electron. Because electrons prefer to travel in pairs, free radicals can set off chain reactions – their loner electrons cut in on the dance of another molecule’s two electrons in an attempt to grab one. This move satisfies the original unpaired electron, but merely creates a new free radical bent on pairing up.

Thus, like bulls in the china shop of living cells, free radicals, especially the hydroxyl radical, damage delicate cell membranes and muck up proteins whose functions depend on their structure. And the cellular damage wrought by free radicals is the mechanism, according to Harman, of the natural process we take for granted as aging.

A Circuitous Route

Harman took a circuitous, but in retrospect necessary, route to this conclusion. He was born in 1916 in San Francisco, but did live briefly as a boy in New York City, where his father worked for a jewelry company located just blocks from the site of The New York Academy of Sciences (the Academy) on 63rd Street near Fifth Avenue. The family returned to the Bay area in 1932, and Harman graduated from Berkeley High School two years later. Jobs were scarce, but Harman’s father happened to meet the director of the Shell Development Company, the chemical research division of the Shell Oil Company, at a local tennis club. Harman began working for Shell as a lab assistant.

The position sparked a true interest in chemistry. Harman went on to receive his undergraduate degree and, in 1943, his doctoral degree from the University of California, Berkeley, in chemistry. He continued with Shell the entire time, at first working with lubricating oils. But he was fortunately transferred – to the reaction kinetics department, where much of the work concerned free-radical reactions. During seven years there, Harman was instrumental in gaining 35 patents for Shell, including work on the active ingredient of something designed to shorten, not extend, life: the famous “Shell No-Pest Strip.”

Time to Think

In December 1945, Harman’s wife Helen put a bee in his bonnet. “She showed me a magazine article she thought might be of interest. It was a well-written piece by William Lawrence of the New York Times about aging research in Russia,” he recalls. Harman knew a lot of chemistry, but not much biochemistry or physiology. And the idea of aging as a biochemical process so fascinated him that in 1949 he decided to attend medical school. Berkeley turned him down because of his advanced age – he was 33 – but Stanford accepted him.

After his internship, Harman became a research associate at the Donner Laboratory back at Berkeley. “Donner was great,” he remembers, “because I didn’t really have to do anything, other than a hematology clinic on Wednesday mornings. I could just think.” And what he thought about was aging. “One thing you learn in biology,” he notes, “is that Mother Nature has a tendency to use the same processes over and over. My impression was that since everything ages, there was probably a single, basic cause.”

Pondering the issue at first left him frustrated. “I thought perhaps there wasn’t even enough knowledge available at the time to solve the problem,” he says. “And then in November of 1954 I was sitting at my desk when all of a sudden the thought came to me: free radicals. In a flash, I knew it could explain things.”

He quickly discussed the idea with medical colleagues – most thought it was interesting but too simple to explain such a complex phenomenon. “I got encouragement from only two people, both of whom were organic chemists, not medical doctors,” he recalls.

The Ubiquitous Enzyme Superoxide Dismutase

Harman spent the next decade on virtually a lone research effort that produced circumstantial evidence for his idea. The limits of the instrumentation of that time made it difficult to even show that free radical species existed in living cells. Electron spin resonance studies found free radicals in yeast in 1954, but it was not until 1965 that free radicals were detected in human blood serum.

Then in 1967 biochemists discovered the ubiquitous enzyme superoxide dismutase, whose job it is to protect cells by sopping up free radicals formed during aerobic respiration in cells. The presence of a defense implies that free radicals are indeed a clear and very present danger to cells.

Ensuing research has implicated free radicals in cancer, heart disease, Alzheimer’s disease and other conditions. And observations of the animal kingdom are especially suggestive of the general aging theory. Harman points out that rats and pigeons, for example, have about the same body weights and metabolic rates. But pigeons produce far less hydrogen peroxide (formed from the superoxide radical) during cellular processes than do rats – and the birds live some 15 times longer than the rodents.

Judging by the sales of antioxidant supplements that scavenge free radicals, the American public has clearly subscribed to Harman’s ideas. Many physicians and scientists also have signed on to his view of aging, with the free-radical theory underlying much of current aging research.

“I think we’re now getting to a point where we may be able to actually intervene in the aging process,” Harman says. If his prediction proves true, our extra years will be owed to his many well-spent ones.

Also read: A New Approach to Studying Aging and Improving Health