UC Berkeley biochemist developed 'Ames test' to identify substances likely to cause cancer
Bruce N. Ames, a University of California, Berkeley, biochemist who developed a low-cost test for carcinogens that became an initial screen for drug toxicity and ultimately kept many cancer-causing chemicals out of food and consumer products, died on Saturday, Oct. 5, at the age of 95. He passed away at Alta Bates Summit Medical Center in Berkeley surrounded by friends and family.
Ames, a UC Berkeley professor emeritus of molecular and cell biology, developed what became known as the "Ames test" during the 1960s and '70s, purportedly after wondering whether the ingredients listed on a bag of potato chips could potentially cause cancer.
While at the National Institutes of Health, he noticed that some mutant Salmonella bacteria that lacked the ability to make the essential amino acid histidine occasionally developed mutations that allowed them to begin synthesizing histidine again. It occurred to him that, if carcinogens are basically mutagens, carcinogenic chemicals might stimulate reversion mutations at a rate proportional to their toxicity. The bacteria could make a simple, quick and inexpensive assay for mutagens and potential carcinogens.
After arriving at UC Berkeley, he turned these bacteria into an assay and set his undergraduate students to testing common chemicals found in food and consumer products. Students eagerly brought in substances to test.
"The simple test was to look for colonies that form on a histidine-free medium in a ring around a source of mutagen placed on a piece of filter paper on a Petri plate that had been layered with mutant bacteria unable to grow," said Randy Schekman, a close friend who is a UC Berkeley professor emeritus of molecular and cell biology and a Nobel laureate. "Nothing surprising here, but with Bruce's imagination, the experiment turned into an undergraduate laboratory exercise to look for common foods and household products that produced this effect. The range of mutagens (they found) was astonishing and frightening and led to the worldwide application of the Ames test in the early stages of product development."
Among the products that were removed from the market after being flagged by the test was Tris, a chemical used as a flame retardant in children's sleepwear. Ames originally reported that about 5% of all chemicals showed mutagenicity indicative of carcinogenicity.
Controversy
Not surprisingly, the test kicked off a fierce debate about how concerned people should be about cancer-causing chemicals in everyday products, especially after Ames' students flagged hair dyes and some food additives as potentially carcinogenic or as causing birth defects, which are also due to genetic mutations. Ultimately, more than half of the chemicals that tested positive were shown to cause cancer in animals, and chemical companies adopted the Ames test to screen out potentially dangerous chemicals before they were incorporated into products. At the time, each test, which cost several hundred dollars, took about three days. This was much cheaper and quicker than alternatives like animal tests, which took about three years and cost approximately $100,000 per animal. The Ames test is still required today in Phase 1 clinical tests of potential drugs.
"Bruce was unique in making his test protocol and bacterial mutant strains available to anyone, commercial or academic, with no expectation of profit -- frankly unheard of these days," Schekman said.
The test also flagged as potentially carcinogenic a few natural ingredients in foods, some of them possibly more toxic than the residual pesticides on foods that people often worry about. Displaying what Schekman referred to as his "libertarian" streak, Ames criticized overzealous regulation of pesticides and some other pollutants, observing that "eating vegetables and lowering fat intake will do more to reduce cancer than eliminating pollutants."
"I think his lasting legacy is in confirming the relationship between mutation and cancer," said Ames' colleague Edward Penhoet, a UC Berkeley professor emeritus of molecular and cell biology. "He wasn't the first person to think about that issue, but I think Bruce's work really was pioneering in showing the extent of that and the role of mutating DNA in diseases, generally, but especially in cancer."
In 1978, Ames teamed up with Lois Gold to create a publicly accessible database of all studies conducted around the world on how animals, primarily rats and mice, respond to chemicals. Among their key findings, contrary to previous understanding, were that naturally occurring compounds test positive as often as human-made ones, challenging the assumption that synthetic chemicals are inherently more dangerous and highlighting that carcinogens vary considerably in potency. To Ames and Gold, that meant that the public should understand that a synthetic carcinogen is not always worth worrying about, compared to ones present in natural products. Ames' Italian wife and research colleague, Giovanna Ferro-Luzzi Ames, said she forbade him to subject espresso to the test.
Ames and Gold operated the database together for 30 years, and it continues to be used.
"Bruce became cautious about ascribing all cancers to things in the environment. I think, in a way, he thought that it almost got overdone and that society, in general, started to fear all chemicals," Penhoet said. "Bruce urged caution that not all chemicals are mutagens, and therefore not all chemicals are likely to cause cancer. He was more measured about that in the long run."
Establishing a new lab
When Barker Hall, the UC Berkeley building where Ames conducted his research, closed for seismic retrofitting in the late 1990s, Ames retired from Berkeley and moved his lab to the Children's Hospital Oakland Research Institute (CHORI) in 2000 . He used his own money to help outfit his lab and the new institute, to contribute to the Barker Hall renovation, and to fund his ongoing research. At CHORI, he helped establish a vibrant and diverse research group, which focused primarily on the role played by oxygen free radicals on DNA damage, a significant cause of aging, cancer and other diseases, and on the importance of micronutrients and vitamins, such as vitamin D, in protecting the body from this DNA damage. He continued to conduct his research there until several years ago.
What most impressed Michael Botchan, professor emeritus of molecular and cell biology and former dean of the biological sciences in UC Berkeley's College of Letters and Science, was Ames' great enthusiasm for science.
"He was full of life and so obsessed by his science," Botchan said, noting that Ames, even into his 80s, always referred to his current research as "the best work of my life."
"He was inspirational in his love of science," Botchan said.
This enthusiasm spilled over into the classroom. Ames always had undergraduate students working in his lab, according to Penhoet.
"Bruce was a really great mentor of young people in science and a person who stimulated interest in science on the part of young people," he said.
"Bruce's unique persona created an electric atmosphere in the lab that was at once intellectually stimulating and entertaining," wrote Gerald Fink, one of Ames' former students, in a forward for Ames' oral history. "His broad-ranging interests and fearless pursuit of unpopular ideas cultivated my own instinct to find a scientific problem that stimulated my curiosity and gave me the courage to forge ahead when the odds seemed stacked against me."
Fink currently is the Inaugural Margaret and Herman Sokol Professor at the Whitehead Institute in Massachusetts.
Growing up in New York City
Bruce Nathan Ames was born Dec. 16, 1928, in New York City, the son of Maurice Ames, a law school graduate and high school chemistry teacher, and Dorothy Andres, who worked at the time as a secretary at a high school. Ames' father was a descendant of German-speaking Jews who had immigrated from what is now Ukraine, while his mother came to the U.S. from Eastern Europe in 1910 with her Russian-speaking Jewish parents.
Bruce Ames attended the Bronx High School of Science, where he first encountered science research. He attended Cornell University to study chemistry, graduating in 1950 with a B.A. in chemistry and a minor in biology. He obtained his biochemistry Ph.D. from the California Institute of Technology in 1953, then served a year as a postdoctoral fellow and another year as a biochemist at the NIH. After a year-long sabbatical, he returned to the NIH as chief of microbial genetics for five years (1962-67) before joining the UC Berkeley faculty in 1968.
Ames's initial research, begun as a graduate student at Caltech, was on how the body synthesizes the essential amino acid histidine. In his first year of Ph.D. work, he mapped out the synthetic pathway of histidine, both genetically and biochemically, and continued to study the detailed regulation of this pathway through his time at the NIH. According to Penhoet, combining genetics and biochemistry was the underlying theme of Ames' career.
"His iconoclastic views led him to speculate that a simple genetic mutant reversion test, using his huge collection of histidine biosynthetic mutants, could be used to quantify the mutagenic potency of chemicals that he then showed to correlate to their potential as carcinogens," Schekman wrote in an introduction to Ames' oral history, published in 2021.
"It was such an amazing proof of concept that cancer is caused by mutations," Botchan said.
Ames was honored for his work with a National Medal of Science in 1998, membership in the National Academy of Sciences and the American Academy of Arts and Sciences, and a fellowship in the American Association for the Advancement of Science. He received more than 30 international honors and awards, including the Japan Prize in 1997 and the Gairdner Foundation Award in 1983.
Ames is survived by his wife, Giovanna Ferro-Luzzi Ames, a UC Berkeley professor emerita of molecular and cell biology; daughter Sofia Ames of Los Angeles; son Matteo Ames of Brooklyn, New York; and two grandchildren, Dorotea and Giovanni. Ames' colleagues are planning a symposium in his memory.