October 9, 2003 - Today's Other News Items

Biologist Resurrects 600 million-year-old Gene

By successfully resurrecting a gene that existed 600 million years ago, evolutionary biologist Joe Thornton, Ph.D. has brought a bit of Jurassic Park to the University of Oregon. Thornton's research demonstrates that estrogen was the first of all steroid hormones to evolve, dating back to the early eons of animal evolution, far earlier than previously thought.

Thornton's findings, published in the Sept. 19 issue of Science, has important implications for evolutionary theory and environmental health. The strategy of resurrecting ancient genes promises major advances for evolutionary biology, because it allows the function of long-extinct molecules to be studied experimentally.

Steroid receptors were previously known only in vertebrates, but Thornton's research establishes that estrogen and its receptor had already evolved when primitive jellyfish, sponges, and small worm-like creatures were the only animals on Earth. Other hormones like testosterone, progesterone, and cortisol evolved much later through a process of gene duplication and divergence. "Hormones have no function without a receptor to interact with, and vice versa," Thornton said. "So how can a new hormone or a new receptor evolve unless its partner already exists? We wanted to understand the origin of steroid hormones and their receptors, so we resurrected the very first receptor, and we've found that its partner was estrogen."

The paper's coauthors are UO research assistant Elle Need and Professor David Crews, a collaborator at the University of Texas.

To conduct the study, the team first isolated the gene for a steroid hormone receptor from a modern mollusk, the sea slug Aplysia californica. Steroid hormones control reproduction, behavior, and many other processes in humans and other vertebrates. Each hormone interacts with a specific protein called a receptor in the cells of hormonally responsive tissues.

Thornton's finding that steroid hormone receptors exist in distantly related invertebrates indicates that the majority of animal species inherited these molecules from their ancient common ancestor, broadening the scope of damage that hormone-disrupting chemicals in the environment may cause. Most chemical testing and regulatory programs are focused on vertebrates and take little account of impacts on other kinds of animals.

They then turned to the ancestral gene from which all of today's steroid receptors evolved. Applying cutting-edge statistical techniques to a large number of modern-day receptors, Thornton's group inferred the DNA sequence of the ancestral gene. They used biochemical methods to synthesize the gene and transferred it into cells they culture in the lab, which were made to produce large quantities of the ancient receptor protein. A series of experiments on the ancestral receptor showed that it responds only to estrogens and that other hormones evolved more recently. "Testosterone and progesterone are chemical building blocks the body uses to make estrogen," Thornton explained. "The ancient animal that used estrogen as a hormone produced these other steroids as intermediates, but they weren't hormones yet. The ancestral estrogen receptor gene duplicated in the genome, and the new copy gradually mutated, evolving greater affinity for testosterone and progesterone. By co-opting these steroids as binding partners, evolving receptors turned biochemical steppingstones into new hormones."

Thornton's evolutionary research program is a natural outgrowth of his passion to protect the environment and reduce the effect of chemicals on human health. His book on global chemical pollution, Pandora's Poison: Chlorine, Health, and a New Environmental Strategy (MIT Press), was called "a masterpiece" and "a landmark book" by the scientific journal Nature.

"There are tens of thousands of man-made chemicals in the environment today, and many of them can interfere with our hormones, leading to severe health effects, especially on reproduction and development," he explained. "As I learned more about hormones and receptors through my environmental work, I became increasingly fascinated with how our endocrine systems have evolved."

Thornton came to the University of Oregon last fall from Columbia University's Earth Institute. UO graduate and post-graduate biology students are working with Thornton on the project's next steps.

"Now that we've recreated the ancestor and know its functions, we'd like to trace the specific changes in the gene that allowed it to evolve affinity for new hormones," he said. "We'll also reconstruct other ancient members of this gene family to determine the exact sequence of events by which our modern hormones and receptors evolved." The study was funded in part by the National Institutes of Health.