Chemicals in Environment Deserve Study for Possible Role in Fat Gain, Says Byers Award Recipient

Unintended exposures to chemicals in our food and the surrounding environment might be contributing to obesity, according to the 2009 UCSF recipient of the Byers Award in Basic Sciences. Kaveh Ashrafi, MD, PhD, speaking at a 15-year anniversary celebration of the award on Dec. 7, described how high-risk, potentially high-reward research on tiny worms is shedding light on metabolism and behavior – and on obesity, an issue at the forefront among the nation’s public health challenges. The award is sponsored by Brook Byers and his family. Byers is a partner in the prominent venture capital firm Kleiner Perkins Caufield and Byers. The award recognizes the value of high-risk, high-reward research. Many government-research funders use decision-making procedures that result in the conservative awarding of research funds to projects that are almost certain to succeed, even if only by advancing knowledge by small increments. Potentially game-changing research proposals that might be less likely to succeed often are passed over by government agencies. The Byers Award won by Ashrafi is an important source of research support that is available to innovative scientists through the UCSF Program in Breakthrough Biomedical Research. The program, supported by philanthropy, focuses on projects that are substantially more creative or risky than projects supported by National Institutes of Health (NIH) and through other traditional funding mechanisms.

C. Elegans: Key to Understanding Fat

To learn about fundamental mechanisms controlling energy balance, Ashrafi works with the microscopic, soil-dwelling, bacteria-eating nematode, C. elegans. It’s only one-millimeter long and has only 959 cells. However, it also has about 20,000 genes, making it nearly as genetically complex as humans. That means worms can make use of similarly complex biofeedback in regulating feeding behaviors and metabolism, for example. Ashrafi labels fat in the worms with dyes that emit bright red light. The fat can then be easily tracked under the microscope because the worm is translucent. By inactivating one gene at a time Ashrafi has discovered that 400 genes are involved in making worms more or less fat. “Among the very few obesity genes known in humans and rodents … it turns out the same genes act the same way in the worm, demonstrating that the body’s natural weight-regulating mechanisms are truly ancient,” Ashrafi said.
Working with worms, Ashrafi discovered that the neurotransmitter serotonin acts to help control feeding and fat storage independently, through different cascades of biochemical events, starting with attachment to two distinct types of serotonin-receptor molecules.

Obesity Epidemic – Worms Shine a Light

Studies of C. elegans are yielding clues in the battle of the bulge. “There was an incredible rise in obesity in the US in the 1980s and 1990s,” Ashrafi said. “Our genes didn’t change in those decades, and our brain regulation didn’t change in those decades.” Ashrafi does not attribute it all to eating too much and exercising too little. Physical activity accounts for only a small amount of the energy we expend. Most energy is spent via normal cellular metabolism, according to Ashrafi. Ashrafi’s lab team identified another fat-storage-regulating molecule operating in the nematode – not in its nervous system, but in its peripheral regions. Coincidently, the mammalian form of the molecule, called SF-1, already was under study by UCSF scientists Holly Ingraham, PhD and Robert Fletterick, PhD. Ingraham led research which showed that the common herbicide atrazine acts on SF-1 to cause sex changes in fish. In addition, Ashrafi said, scientists from South Korea had discovered that atrazine makes rats fat, independent of feeding behavior. “It’s possible that the sorts of genes that play a role in reading signals on the way from the brain to the periphery to regulate fat are being acted upon by pesticides and all these things that are in the environment,” Ashrafi said. Ashrafi mentioned another study in which mice exposed for five day in utero to DES – an estrogen-like drug once used to prevent miscarriage -- were born at a normal weight and grew at a normal rate, but ended up much fatter over time. This was true even though the mice continued to eat normally and were as physically active as mice that were not exposed to DES.
“Maybe environmental toxins are essentially drugs that we are taking in without knowing it – and they’re acting in this process to promote fat regulation,” Ashrafi said. Ashrafi’s lab team is exposing worms to various compounds to check for effects on fat. The researchers will investigate chemicals that affect worms in other organisms as well.

Program in Breakthrough Biomedical Research

The UCSF Program in Breakthrough Biomedical Research (PBBR) is funded by philanthropy, including matching awards by an anonymous donor, and provides about $6 million yearly to UCSF scientists. That’s less than one percent of the basic science research budget at UCSF, but the research has great impact, according to UCSF Chancellor Susan Desmond-Hellmann, MD, MPH. “This funding is unlike any other resource, and has a disproportionate effect on our community and how it thinks about problems,” she said. “It fuels our culture of creative discovery by challenging our faculty to think bigger, bolder, and riskier. And we have the results to prove it. “Since its inception, hundreds of our faculty have used PBBR grants to turn intriguing ideas into exciting projects that have gone on to successfully compete for conventional funding. At the time of its 10-year anniversary we did an analysis. PBBR-funded projects had generated more than $300 million in subsequent grant funding, including some 200 NIH awards, 900 peer-reviewed publications and 50 patents awarded or pending. “These are remarkable statistics given the average PBBR grant is $50 thousand to $150 thousand. It also demonstrates how a relatively modest amount of funding can have an outsized effect when directed to the right place.” “When we start things we never know how they are going to end up,” Byers said. That’s the way it is in science. All of you scientists – who are my heroes – when you’re working in the lab you learn as much from failure as from success.” As for the high-risk basic research award program he launched 15 years ago and that he and his family support to this day, Byers said. “It’s been great. I certainly get more out of it than I could have imagined.” Photos by Susan Merrell

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Program in Breakthrough Biomedical Research