Joe Thornton is a molecular archaeologist. He resurrects ancient genes and follows their changes over hundreds of millions of years.
Combining computer power with statistical evolutionary analysis, Thornton’s research team at the University of Oregon infers the sequences of ancient genes, compares them with modern forms, and works out the timeline of which mutations took place when. They then use molecular biology and biophysics to synthesize those ancient genes, characterize the atomic structure and function of the proteins they coded for, and determine how historical mutations changed their shape and function through time.
Thornton’s aim is to discover the origins of the human endocrine system—the set of hormones and receptor proteins that regulate growth, metabolism, mood, and more. In less than a decade, Thornton has made giant leaps in our understanding of how this complex system evolved and, more generally, how proteins evolve new functions—this from an English literature major whose environmental activism steered him toward science.
Thornton’s interest in hormones was sparked by his work in the environmental health movement in the 1980s and 1990s. He left his Yale University degree temporarily unfinished to join Greenpeace: “I was hungry for reality, and political work is what reality meant for me at the time,” he says.
His advocacy focused on chemical pollution of the environment, specifically endocrine-disrupting pollutants—pesticides and industrial chemicals that interfere with hormones in humans and other animals. He started as a community organizer but ended up helping the public understand the science of endocrine disrupters; writing briefing papers for community groups, regulators, and legislators; and even testifying before Congress. “I learned the most from the communities I worked with who were facing major sources of toxic chemicals,” he remembers. “They weren’t looking for a cause, but their health and communities were threatened, so they became engaged in some very intense activism.”
And science began to attract him. “I saw the impact of science on politics. And the more I learned about how chemicals disrupt our hormones, the more fascinated I became with the molecular biology of the endocrine system,” he says. “The relationship between each hormone and its receptor is incredibly sensitive and specific. I wanted to know how that system evolved.” After nine years with Greenpeace, Thornton went back to school, finishing his undergraduate studies and then earning a Ph.D. in molecular and evolutionary biology.
Today, his lab studies the evolution of steroid hormone receptors—the same proteins that mediate the effects of most environmental endocrine disrupters. Thornton is reconstructing the precise molecular mechanisms by which each of our receptors evolved to be specific for its favorite hormone. Recently, for example, his group has been studying the receptor for cortisol (a stress hormone) and the receptor for aldosterone (which regulates salt and water balance). Using a database of hundreds of hormone receptor DNA sequences from present-day species, he deduced that the two types of receptors represent copies of a single, ancient gene that existed about 440 million years ago. “That’s before the common ancestor of humans and sharks,” he says.
Over time, one copy became the cortisol receptor; the other became the aldosterone receptor. Thornton’s group discovered exactly how that occurred. Using computers to work backward along the evolutionary tree from existing receptor genes, they deduced the ancient gene sequence, chemically synthesized it, and inserted it into cells in the lab. The receptor functioned beautifully and was activated by both cortisol and aldosterone.
Thornton’s group then introduced into the receptor the same historical mutations that occurred in the lineage leading to the modern-day cortisol receptor. They identified seven changes that caused the receptor to evolve its specificity for that hormone and showed that they had to occur in a specific order. Thornton’s group went on to determine the atomic structure of the ancient receptor by using x-ray crystallography, which shows precisely how those seven mutations sculpted the protein long ago to produce a function critical to our health today.
Thornton’s discoveries provide the first high-resolution, experimentally tested answers to questions about ancient evolutionary processes. Thornton is now applying his methods to other steroid hormone–receptor pairs, such as testosterone and estrogen. He continues to see a connection between science, politics, and culture.
“Studying history gives us perspective on why our society is the way it is, and how it could be different,” he says. “In the same way, evolution explains why our bodies work the way they do. Our findings suggest that our biology and those of other animals could be very different if a few chance events had turned out differently. That’s a pretty startling idea.”