| The Magazine of the CALIFORNIA ACADEMY OF SCIENCES |
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| Counterpoints in science California's Wild Research Frontiers
California Wild is our new name. A lot of what was once wild in California is resting in the La Brea tar pits and a lot of what we think of as wild today is going extinct because of human interference. But the frontiers of scientific research are perhaps more wide open here in California than anywhere else in the world. The state boasts a glittering array of institutions that cover the investigative spectrum from atoms to universes, and these treasure-houses of knowledge are amazingly available to individuals trying to answer science's intriguing questions. Research is defined as diligent inquiry into a subject in order to discover facts, theories, or applications. Another definition, which I prefer, is to "re-search"--to search and search again. Somehow the search here seems freer, more unfettered and less tied to past assumptions than on the East Coast, where I grew up and went to school. Perhaps it is the newness of California, the lack of long-standing traditions, that makes anything seem possible. When I first came here as an intern at Stanford in 1953, I was eager to do research in the new field of nuclear medicine. Radioactive tracers were just beginning to find medical applications, and Stanford had one of the first nuclear medicine labs. Iodine-131, for example, a by- product of nuclear fission, was being used for the diagnosis and treatment of thyroid diseases. Iodine is an essential component of the thyroid hormone thyroxine that controls the body's metabolism. Before we had I-131, measures of thyroid function had been indirect and not very reliable. With I- 131, we could directly measure the uptake of iodine by the thyroid gland, which may be high or low in various thyroid diseases, and get pictures of the thyroid, which help to distinguish between benign lumps and thyroid cancer. I-131 has become the standard treatment for overactive thyroids and for some kinds of thyroid cancer. Professor Robert Newell, who directed the lab at Stanford, and who had given the field of nuclear medicine its name, was an imposing figure: tall, bald, with two stereo-sized hearing aids. He was a pioneer in developing the lead lenses called collimators that focus gamma rays. He kept a big pot of lead bubbling over a Bunsen burner and would pour the hot lead into honeycomb-like wooden molds that he had turned out on the lathe in his garage. One thing about research that discourages some people and lures others is not knowing what will happen next or where a line of investigation will lead. It was thyroid research which drew me into the mysteries of evolution. When Stanford moved its medical school from San Francisco to the Palo Alto campus in 1959, I joined the thyroid research group at the University of California, San Francisco (UCSF). This move led serendipitously to, of all places, the Gal~pagos Islands, where Charles Darwin had crystallized his ideas about evolution. In 1964 the University of California and the California Academy of Sciences organized an international expedition to the Gal~pagos. The expedition's leader was Robert Bowman, of San Francisco State University, an expert on Darwin's finches and currently a science trustee of the Academy. In the Galapagos, I worked with Robert Stebbins, a renowned herpetologist at the University of California, Berkeley, studying the thyroid hormones of marine iguanas and lava lizards. Stebbins was intrigued by the reptilian third eye, an organ that doesn't actually see, but senses light and heat and is connected to the pineal gland in the brain. By doing I-131 uptakes on marine iguanas and lava lizards, we investigated how the third eye influences the lizards' thyroid function and their daily activity cycle. Unexpectedly, we found much higher I-131 uptakes in males than in females, a distinction which is not evident in humans or other mammals. The lizards were in the midst of their mating season, and we deduced that there was a link between male sexual and thyroid gland activity. The Galapagos expedition was a tremendous adventure and education. Among the 60 or so scientists were experts on climate, volcanoes, insects, birds, fish, lichens, and barnacles. Allan Cox of Stanford, a pioneer in the embyonic science of plate tectonics, was busy drilling lava cores for paleomagnetic measurements, to prove that these islands, like the continents, drifted with time. Working relationships among this group of scientists led to many long-term collaborations, lifelong friendships, and a general committment by all of us to help preserve the Galapagos ecosystem. A shared interest in evolution led to one very close collaboration, my marriage to Adrienne Zihlman, professor of anthropology at the University of California, Santa Cruz. Adrienne teaches and does research on human evolution. In 1976 she gave a talk in Nice, France, at a conference on The Most Ancient Hominids. While attending some of the sessions and listening to anthropologists arguing about whether certain fragmentary fossils were or were not ancient humans, I was struck by the idea for my next research project: using a nuclear medicine technique to detect molecules in ancient fossils. Radioimmunoassay, a technique used to measure thyroid hormones in the blood, involves antibodies tagged with radioactive iodine. These antibodies zoom in on their target molecules like heat-seaking missiles. I made a new set of antibodies and instead of aiming them at thyroid hormones, targetted the proteins at collagen and albumin, the most abundant molecules in the bones. Some human fossils reacted positively with these antibodies. The idea seemed to be panning out! I applied for support from the National Science Foundation, but was turned down three times. The experts who reviewed the proposal already knew there were no protein molecules in fossils, so there was no point wasting money re-searching them again. One of the hazards of doing research is encountering this kind of "peer review," which perhaps from necessity, is centered in established opinion. Fortunately for my future as a molecular evolutionist, some support did come from the Research Committee at UCSF and the Leakey Foundation, then in Pasadena--two California institutions. The pursuit of this project led to a collaboration with Vince Sarich and Allan Wilson at the University of California in Berkeley. Sarich and Wilson had stirred up a hornet's nest in the world of anthropology in the mid 1960s when they did molecular comparisons between humans and apes and concluded that humans, chimpanzees and gorillas had a common ancestor five million years ago. Most anthropologists at that time believed that the common ancestor lived 20 to 30 million years ago. Furious debates ensued between the molecular and the classical schools of thought (sometimes characterized as Berkeley versus Yale) that went on for more than twenty years. New fossil finds and more molecular data have confirmed the five million year divergence between humans and apes, which is now widely accepted by anthropologists. In 1980, I joined forces with Wilson, Sarich, and their colleague Ellen Prager in trying to detect albumin molecules in the tissues of a 40,000-year-old Siberian mammoth. We were able to identify fossil molecules for the first time and show that these ancient molecules were almost identical to those of living elephants. The results were published in Science, the nation's leading scientific journal, and became front page news in the New York Times. Subsequently it happened that Russell Higuchi, in Allan Wilson's lab, and I were simultaneously but independently working on fossil molecules from the recently extinct quagga, a South African zebra. This obscure species also hit front pages all over the world when Higuchi was able to extract and sequence a fragment of DNA, the first time this genetic material had been successfully obtained from a fossil. Since then fossil molecules, which twenty years ago didn't officially exist, have become a scientific growth industry, the subject of dozens of conferences and innumerable publications, to say nothing of the biggest cash dinosaur of all time, "Jurassic Park." Though the book and film dramatically depict dinosaurs recreated from dinosaur DNA in amber-preserved mosquitoes, no scientist has yet been able to extract DNA or protein molecules from dinosaur bones and teeth, though many have tried, let alone from a mosquito's stomach. Nevertheless, the search for such very ancient molecules has inspired research on ways of detecting ever smaller amounts of biological material. Developing such supersensitive techniques requires special equipment and collaborations with those who have it, which is half the fun of doing research. Science is a cooperative venture involving many individuals and institutions. Our present pursuit of the genetic essence of T. rex benefit from the brilliant Bay Area bonanza of scientific institutions and enterprises. The Conservation Genetics Laboratory at San Francisco State University was established so that students and faculty could apply the new PCR (polymerase chain reaction) method to studying the DNA of plants, animals, and disease-bearing parasites in South America. This laboratory also serves as an ideal venue for collaborative research on fossil molecules. The most advanced PCR devices in the world, capable of measuring the smallest amounts of DNA and proteins, are being developed at Roche Molecular Systems in Alameda, California. On my first visit there, I found that one of the leading investigators is Higuchi, the man who first sequenced quagga DNA in the 1980's. The woolly mammoth went extinct in these parts about 10,000 years ago, but for those of us addicted to the need to search and search again, California frontiers remain as wild and woolly as they were when the first human explorers walked across the Bering straits to a New World.
Jerold M. Lowenstein is a professor of medicine at the University of California at San Francisco and chairman of the Department of Nuclear Medicine at California Pacific Medical Center in San Francisco. |
Fall 1997
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