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Leaping into the fray

A young scientist exposes the perils of a common weedkiller. Published in California Monthly magazine.

Almost as soon as Tyrone Hayes was old enough to walk, he would venture outside to play with the many frogs he found in the back yard of his South Carolina home. Later, when other boys were out playing basketball, young Tyrone was busy raising tadpoles. Even as a teenager, he didn’t lose his fascination with these creatures. “While other people were out dating, I was looking at frogs,” chuckles Hayes. (When he did go on dates, he adds, he took them to the swamp.)

Now an associate professor of integrative biology at Berkeley, Hayes still spends his time around frogs, and his research on the effects of a widely used weedkiller on these animals has been causing quite a stir. Hayes has also been creating a stir in the classroom–he is one of Berkeley’s most popular and respected teachers.

For nearly ten years, Hayes has been spreading his enthusiasm about his work to students, colleagues, and just about anyone else who comes to any of his numerous talks on (and off) campus. Earlier this year, aged just 35, Hayes received a Distinguished Teaching Award, in part for his innovative course on human endocrinology and his dedication to his students, many of whom work with him in his lab. Hayes is known for taking on large numbers of undergraduate researchers–his lab has “graduated” 50 in the last five years, probably more than any other at Berkeley.

It was a long and sometimes difficult road from South Carolina to Berkeley. On his father’s side, Hayes was the first to graduate from high school. But his parents always encouraged him and his two brothers to pursue their interests, whatever they might be (although they weren’t always happy when Tyrone would bring frogs into the house). And they made schoolwork a priority. “In my home, the kids had no chores. Your ‘chore’ was to do well in school; that was your job,” he says.

Hayes did his job well, and his high SAT scores attracted the attention of top colleges. When a letter arrived from Harvard, he decided to apply. In fact, it was the only college he applied to. “Most people would say, ‘Wow! You were that confident.’ But I say, ‘No. I was that ignorant.’“ Harvard stood out to him, he says, because he remembered hearing about it on an episode of the 1960s TV show Green Acres.

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Harvard itself was a culture shock. “When I went from South Carolina to Harvard, it was my first time on an airplane, my first time in snow, and my first time being in a place where I truly was a minority, in the sense that there was a limited number of people who’d had my experience.” Hayes felt he didn’t fit in; even the squeaky floors made him feel alienated. His father was a carpet-fitter, and Hayes remembers thinking: Who cares if George Washington walked on this floor? They should fix the floors!

He may have been a fish out of water in those ivied halls but, in the summer of his freshman year, he found a home in the lab of amphibian expert Bruce Waldman. “I became immediately, directly involved in Bruce Waldman’s lab,” says Hayes. “I had a desk, and I was treated like a graduate student from that first summer.” It was also at Harvard that he met his future wife, Katherine Kim, MBA ‘96, MPH ‘96. They were married two days after graduation and, in 1989, they headed straight for Berkeley to pursue their graduate studies.

Wasting no time, Hayes finished his Ph.D. in just three and a half years, had his first child and, after a brief postdoc at the National Institutes of Health, was hired back at Berkeley as an assistant professor. At the age of 32 he was awarded tenure.

With his long, bushy beard and braided hair, Tyrone Hayes is hard to miss walking through the halls of the Valley Life Sciences Building–especially since fewer than one percent of Berkeley scientists are African American–but it was his skill as a teacher and his work on amphibian endocrinology that was starting to get him noticed. Because of his expertise in animal husbandry, Hayes is able to raise thousands of frogs, which means he can conduct huge, complex experiments that test many different parameters at once. “In part it’s the little boy who likes to play with frogs, remembering how to take care of animals and teaching my students how to take care of them,” explains Hayes.

Hayes uses his experience in Waldman’s lab as a model for how he treats his own undergraduate researchers. They each have their own research projects, and several students have co-authored papers that have appeared in such prestigious journals as the Proceedings of the National Academy of Sciences (PNAS) and Nature. Each has some desk space and, for many, it is as their “home” on campus. “He trusts us with a lot of responsibility,” says Melissa Lee ‘02, who has worked in the lab for nearly four years. Her name appeared on his recent PNAS paper. “It was exciting to be included. I think he does that because of his sense of fairness: You put in the work, you put in the time, so you should be recognized,” she says.

The lab is known for its diversity; but in at least one respect his students are all alike–Hayes chooses only those who will be able to keep up with the lab’s intense pace. It is not uncommon for students to work 40 hours a week in the lab on top of their studies, and they are often there with Hayes at 5 a.m. taking care of the frogs. “Part of the culture is that you have to put in the hours,” says Hayes. “The personality of the lab changes with each group of students, but underlying that there’s always been a work ethic and honesty and integrity.”

The competition to work in Hayes’s lab is intense, and he often has to turn students away. It helps to be tenacious. One student was so keen to join the lab, he’d turn up at 4 a.m., claiming he was just walking by. Another would come along when he knew they were having lab meetings and listen hopefully at the door. But inside, the atmosphere is anything but competitive. It’s young and informal–Hayes makes a point of getting to know his students personally, and his young children (Tyler, 9, and Kassina, 6) are frequent visitors. “He really cares,” says Lee. “I feel comfortable telling him about things that are happening in my life.” Last year, the College of Letters and Science gave Hayes its new award for Distinguished Research Mentoring of Undergraduates.

Hayes rejects the idea that one shouldn’t mix the professional and the personal–for him, work life, family life, and personal life are all seamlessly intertwined. (He gave his entire first lecture at Cal with his baby son in a sling around his chest. The baby slept right through it.) His course on human endocrinology–which follows the human life cycle from reproduction and fertilization through to puberty and adulthood–is peppered with examples from his own family. For his lecture on fetal development, he shows ultrasounds of his children, and his lecture on osmoregulation, titled “Why my daughter does not pee in the desert,” grew from a research trip with his family. The origin of that lecture epitomizes the way he tries to get the best of all possible worlds: “I’m there collecting frogs, doing field work and getting my research done, I’m getting good family time and, on top of it, I get a great lecture that people will remember,” he beams.

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Hayes knows firsthand the value of undergraduate research. For his thesis at Harvard, he looked at how water temperature determines whether a tadpole will grow into a male or female frog. That laid the groundwork for his current work studying the effects of atrazine–the world’s most widely used weedkiller–on frogs. “This is the same thing I did as a freshman–trying to understand frog development and how hormones are involved–except that now we’re throwing in a chemical, atrazine, and we’re asking: Does it act like a hormone?”

Evidence has been mounting that many of the thousands of synthetic chemicals that are part of modern life mimic natural hormones, with sometimes devastating results. Hormones steer the development of animals from eggs into adults, which makes these so-called endocrine disruptors particularly pernicious. Perhaps the best-known example of a human endocrine disruptor is diethylstilbestrol (DES), a synthetic hormone given to millions of pregnant women until the 1970s, which left many of their daughters sterile and much more likely to develop certain cancers. Even in the tiniest amounts–a few parts per billion or, in some cases, a few parts per trillion–endocrine disruptors can significantly alter the way an animal develops.

It was a visit to Africa just after his Ph.D. that got Hayes involved in the “endocrine-disruptor business,” as he calls it. At first, the National Geographic Society turned down his grant application to do field work in Africa because he didn’t have the necessary experience. Hayes went anyway, funding that first trip himself. (Since then, the National Geographic Society has funded all his trips to Africa, and whenever he goes he takes a student along: “Because now that student has the experience to get the next grant.”) On that first trip, Hayes was introduced to two frog species that would turn out to be important for him: Kassina, a small frog which he named his daughter after, and Hyperolius argus, the little-known African reed frog. The latter is very unusual among frogs in that the female is spotted but the male is plain. “When I collected them, I didn’t even know the male and the female were the same species,” recalls Hayes.

Because of his interest in the role of hormones in sexual differentiation–what makes males male and females female–Hayes exposed a male reed frog to estrogen. Sure enough, the frog developed the female spotted pattern. Hayes went on to show that all estrogens–natural and synthetic–that affect humans elicit this response in the African reed frog. Similarly, he found that chemicals that mimic testosterone masculinize the voice box of the female of the species, making it grow larger, and chemicals that mimic thyroid hormone speed up metamorphosis–the transition from a tadpole into a frog.

So here, with this one species, Hayes had a clear and simple way to test whether any chemical is an endocrine disruptor that mimics estrogens, androgens, or thyroid hormones–all of which are important in development. Hayes says that he did the work out of sheer curiosity. It was his wife Kathy, a businesswoman, who suggested patenting the test. “I would never think of something like that,” says Hayes. “Why would anybody patent a frog?” But he took his wife’s advice, registering the “Hyperolius Argus Endocrine Screen test”–the HAES test–at the U.S. Patent and Trademark Office. “I fought forever to try to come up with something that began with a Y!” says Hayes.

It was work like this that caught the attention of the scientific community, and in 1997 Hayes was approached by Syngenta, the agrochemical company that produces atrazine, which asked him to test the weedkiller on frogs. At first, he was uncertain about taking industry money. Though Syngenta didn’t know it, Hayes had already applied his HAES test to screen a large number of potential endocrine disruptors–including atrazine, which had come up negative. “My biggest worry was that I would do this work for the company and it would show nothing, and people would think I was on the payroll to produce data to show something negative,” says Hayes. Nevertheless, his lab voted to accept the money (they vote on everything) on the basis that this was important research and they should do it.

As it turned out, atrazine was not as harmless to frogs as Hayes first thought. When he exposed tadpoles of the African clawed frog to the chemical, he found that just 0.1 ppb was enough to cause sexual abnormalities in 20 percent of frogs. Some had multiple sex organs (as many as six in one animal); others were hermaphrodites, with both ovaries and testes. In all of the thousands of frogs that Hayes had seen in his life, this was the first time he had seen such abnormalities. This shocking result, especially at such a low dose–30 times lower than the level the EPA allows in drinking water–was widely reported when it was published in April of this year. The media attention caught him by surprise. “I hate talking on the phone, and my ringer had been broken for five years. [Professor] Dave Wake told me: ‘Go buy a new phone. You’ll need to answer it,’“ says Hayes. “That was the only warning I had.” For two days straight, Hayes was on his new phone talking to reporters.

Atrazine, it turns out, is no ordinary endocrine disruptor. It doesn’t directly mimic estrogen (which is why it tested negative on the HAES test); instead, the herbicide induces male frogs to convert testosterone into estrogen, in the process feminizing them. As long ago as 1993, emeritus professor of zoology Robert Stebbins first suggested that endocrine disruptors might be responsible for the recent worldwide decline in amphibian populations. Hayes thinks that Stebbins was on the right track. “I’m not going to say that atrazine’s causing amphibian declines,” says Hayes. “But might atrazine be a contributor? Absolutely. There’s no doubt in my mind.”

By the time the first atrazine study was published, Hayes had parted company with Syngenta. “It just wasn’t a comfortable environment for me. I no longer wanted to be on the payroll of the company that makes the compound, and I no longer wanted to feel like there was an influence of industry on our work,” says Hayes, who felt that Syngenta was dragging its feet in getting the work published. “If you are making money from the compound, then by definition there’s a conflict of interest,” he adds. The decision to leave took some soul searching. With the money from Syngenta, the lab had not had to apply for other grants but, says Hayes, “I thought about having come from South Carolina, being a first-generation high school graduate. It wasn’t easy for me to get here. I thought to myself, Is this really what I did it all for–to follow money?” It was not. So, even though the lab would be left with almost no other source of funding, Hayes ended his relationship with Syngenta.

Now operating on a shoestring, he set out to test his suspicion that there would be hermaphrodite frogs out in the farms of the Midwest, where atrazine is applied liberally to corn and other crops. (Levels as high as 40 ppb have been reported in ponds in agricultural areas.) And he needed to act quickly. His first study had come out just three months before atrazine was due for its periodic re-evaluation by the EPA. Because of his findings, the deadline was postponed, but only until January 2003. So Hayes picked a native species–Rana pipiens, the leopard frog–pulled out a map, and drew a straight line across the country, taking in sites that reported atrazine use and others that reported none. For three hectic weeks this summer, Hayes and his students gathered their data, collecting 100 frogs at each site and 18,000 pounds of water for analysis and further experiments.

The results of the study, published in Nature in October, are disturbing: While the leopard frogs they collected seem unremarkable on the outside, even to the trained eye, Hayes showed that they are far from normal. In one site, 92 percent of the males had eggs growing in their testes. Surprisingly, the site with the highest number of hermaphrodites was a wilderness area in Carbon County, Wyoming.

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Atrazine has been used for over 40 years in 80 countries and earns its manufacturer Syngenta $800 million a year. It is banned in some European countries–including Switzerland, where Syngenta is based–but atrazine finds its way into the atmosphere and has even been detected in the Swiss Alps. In the U.S. alone, 150 million pounds are sprayed on crops and golf courses and lawns each year. Two years ago, Syngenta successfully lobbied for atrazine to be taken off the EPA’s list of chemicals it considers likely to cause cancer in humans.

So Hayes says he was not surprised when a panel of Syngenta-funded scientists issued a critique of his newest study just days after it came out. “It’s not a matter of [the EPA] cutting atrazine use by half. You can’t use atrazine in a way that it’ll go below 0.1 ppb in the environment,” he warns. “If they accept my data, that means there’s no more atrazine. That’s $800 million a year. There’s a lot of people lobbying for that not to happen.”

The panel, which Hayes once sat on himself, said that his study showed “major inconsistencies.” How could an area in Wyoming, far from farmland and with no reported use of atrazine, be the worst affected? the panel asked. Hayes points out that the Wyoming site sits alongside the North Platte River, which is fed by atrazine-contaminated streams in Colorado, and that he detected significant levels of the herbicide in the water. Hayes says his studies show that where there’s atrazine, there are abnormalities; where there’s no atrazine, there are no abnormalities.

He was also challenged to explain why he was able to find an abundance of leopard frogs at some of the most contaminated sites. If atrazine was harming the sexual development of male frogs, one would expect there to be fewer of them. But Hayes believes constant exposure to the herbicide has caused these farm-dwelling frogs to adapt. A female leopard frog lays as many as 2,000 eggs and, Hayes points out, all it takes is for just one to mature and pass on her genes. If that frog is one of the lucky few that is less sensitive to atrazine, it might pass that characteristic on to future generations. Hayes is working on another set of experiments to see if such inherited “resistance” to the hormonal effects of atrazine is at play. “In my opinion, as a biologist, that’s not OK–that you have forced the adaptation and evolution of a species and have lost the original genetic diversity that was there.” He also worries about other species of amphibian–smaller frogs which lay fewer eggs might not have the capacity to adapt, he says. (Hayes had originally intended to collect the smaller cricket frog on his cross-country trip, as well as the leopard frogs, but he and his team couldn’t find any.)

If atrazine is causing male frogs to become hermaphrodites, what might it be doing to humans? That’s a questions Hayes says he can’t answer. Frogs are considered a “sentinel” species, one whose sensitivity can alert us to problems in the environment. Frogs, Hayes explains, are “completely naked.” They hatch from eggs that have no shell. As tadpoles, they absorb everything in their water–”It’s like their blood,” says Hayes. As adults they have thin permeable skin through which they breathe. And they go through a huge change–metamorphosis–in which “their entire genetic program gets turned off and an entirely new program gets turned on,” a process that is driven by hormones and is especially sensitive to disruption. By comparison, humans develop in a far more protected environment. But, as the case of DES shows, even in the womb we are not safe from chemicals that could disrupt development. Despite the obvious differences between frogs and humans, as vertebrates we share an almost identical developmental pathway controlled by the same hormones.

Apart from disturbing declines in amphibian populations, in the last decade there have been numerous examples of frogs turning up across North America with extra limbs, missing limbs, or other gross deformities, particularly in agricultural areas. “I’ve been looking at frogs my whole life and, up until I was 21, I’d seen only one frog with a limb deformity. I still have it–I thought it was so unusual,” says Hayes. “Now, I can drive across the country and see ponds where 20 percent of the frogs have limb deformities, in completely different places geographically. On any given day I can go out and find you a deformed frog.” Many scientists believe that pesticides are to blame. Wild frogs spend their lives bathing in a soup of agricultural chemicals, and Hayes is now also looking at the potential cumulative effect of such mixtures. Surprisingly, his preliminary results seem to indicate that the number of different chemicals in a mixture is more important than the amount of any one chemical.

“I would say that we have inadequate information to address the safety of most of the compounds we’re exposed to–in particular now with mixtures of chemicals, which the EPA has no plan to deal with. The threshold levels and the types of effects you’ll see are going to change dramatically when the chemicals are mixed,” he warns.

Hayes says he is interested in “connections and interactions.” “Whether it’s this gene that gets turned on or what happens to this population, I’m interested in the small connections and the big connections,” he says, and then brings things more down to earth, referring again to an old TV show. “On Gilligan’s Island, there was the Professor, and he was the professor of everything. Back in the day, there was ‘the scientist,’ who did everything from physics to chemistry to biology,” says Hayes. “Then we became more specialized–you were a biologist or a chemist. And then we became even more specialized–so you were a molecular biologist or a cell biologist or an endocrinologist. Now we’ve started joining things. You have to incorporate more things to understand this complexity. I think we’re almost back to Gilligan’s Island. I think that’s the future.”

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