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is father, Ernest Beutler, M.D., currently chairman of The Scripps Research Institute Department of Molecular and Experimental Medicine, and his mother, Bonnie Beutler, a technical writer and avid pianist, raised their children in an atmosphere saturated with science, computers, music, and medicine. "My parents' interests were transmitted to us in a fragmentary way," Bruce Beutler says. "Perhaps it was environment, or perhaps Mendelian genetics at work." Two of Beutler's three siblings are now physicians, while the third made his career writing software. Beutler and his eldest brother are passionate about classical music (in Bruce Beutler's case, Bach). Of the four children, Beutler alone decided upon a career in basic science.

As a teenager, Beutler worked in his father's lab during the summer, and while he liked hiking and birding, his infatuation with research was consuming. From the beginning, he saw solving problems in the laboratory as similar to the adventures of early explorers. Gamblers all, they left the familiar behind and headed out into the unknown, some to triumph, others to obscurity and defeat. But all went just the same, their lives driven by an undefined force.

"In the natural sciences, as in exploration of any kind, discovery is inevitable," Beutler says. "If Admundsen hadn't lived, someone would have gotten to the South Pole. And if Newton hadn't lived, we would still understand the laws of motion and gravitation. Nonetheless, there is a thrill to knowing you are the first person to do something. And in science, more than other forms of exploration, there's room for pure invention. It's possible to be the first to create something that never existed before."

Like so many of those early explorers, anxious to discover something first, Bruce Beutler became a young man in a hurry.

FROM SAN DIEGO TO CHICAGO TO TEXAS

He completed his undergraduate work at the University of California, San Diego (UCSD) in two years, graduating when he was just eighteen years old: "I was in a rush in those days to get into research." He immediately headed for Chicago to study medicine, graduating in 1981, and then to the University of Texas (UT), Southwestern Medical Center in Dallas for his internship and residency.

One reason for the rush was Beutler's sense that great changes were taking place in biology, and he wanted to be part of it. "The molecular cloning revolution was just then starting," he remembers. "It began while I was an undergraduate at UCSD, and I wanted to become involved quickly."

He had chosen medical school on the advice of his father who said it would give him a broad scientific education. It did. It also deepened his hunger for the lab, particularly during his internship and residency. "I felt a real need to work on fundamental scientific problems, rather than to follow a routine of treating patients according to pre-established protocols. I missed doing laboratory research, and being in the midst of it." Although he no longer treats patients, his medical background has become useful: "Learning to diagnose diseases in humans makes it easier to understand what may have gone wrong in a mouse [with] a novel mutation."

In the middle of his medical training, Beutler managed to marry and start a family. Of his three teenage children, Beutler says -- with a slight wistfulness that other parents can especially appreciate -- that none have shown any inclination toward a career in science, although the youngest has an interest in computers. "All of them are still young," he adds with a smile.

In 1983, Beutler moved to New York's Rockefeller University. His research flourished, and he quickly gained prominence as the first investigator to isolate mouse tumor necrosis factor, or TNF, a protein hormone originally known for its ability to kill tumor cells, but now understood to be critical to the body's response to infections. It was Beutler who initially recognized the breadth of TNF's actions.

TNF is made in large amounts in response to endotoxin, a molecule that makes up most of the outer membrane of deadly Gram-negative bacterial cells. It was Beutler's discovery that TNF is one of the main causes of the shock syndrome seen during severe infections, a notion once hotly debated, but now universally accepted. Recognizing from the start that TNF is an important cause of inflammation in general, Beutler began to develop TNF inhibitors. One that he developed and patented is now used clinically as the drug Enbrel, among the most effective treatments for rheumatoid arthritis.

After three years in New York, Beutler returned to Dallas, where at UT Southwestern Medical Center, he became an investigator with the prestigious Howard Hughes Medical Institute. He remained in Dallas for fourteen years. It was there that he embarked on the biggest gamble of his career -- an expedition into the genome in search of a mutation that was tiny in size but large in its importance to immunology.

WINNER-TAKE-ALL GAME

In 1998, Beutler and his colleague, Scripps Research Institute Assistant Professor Alexander Poltorak, Ph.D., described the cloning of the Lps gene (a.k.a. the Toll-like receptor 4 gene or Tlr4) in a paper in Science. Two years later, Beutler published a more popular and historical account of the quest for the elusive gene in the Journal of Endotoxin Research. In it, he wrote: "Positional cloning is a winner-take-all game. Once the target gene is discovered, most of the work that has been done by unsuccessful competitors is for naught. If we were to expend the effort needed to clone Lps, we wanted to be the first to find it, and we were aware that many others in this field were challenged by the same scientific problem."

Beutler's account of the cloning of Lps is a scientific adventure story, the laboratory version of the race to the South Pole, complete with triumphs, false leads and moments of personal doubt. For example, when Beutler learned early on that his competitors might be far ahead of him, a competing researcher curtly suggested "with an implicit sigh of resignation that there would be other genes [for Beutler] to clone."

After five years of extraordinary effort, Beutler and his colleagues finally found their mutation.

Ultimately, the discovery of Tlr4 accomplished what good exploration always does: It opened the door for still more discovery. As Beutler wrote of their accomplishment, "The new-found identity of Lps has enlightened understanding of how we, as vertebrates, sense infection. It has revealed the principal receptors of innate immunity. It has allowed us to search for new approaches to the blockade of inflammation, and also, to search for defects in microbial sensing that might explain immunodeficiency disorders."

THE NEXT EXPEDITION

Finding Tlr4 was a triumph of "positional" or "forward" genetics. Forward genetics begins with a particular trait, or phenotype, that is caused by a discrete genetic difference between two individuals, and relies upon traditional methods of genetic mapping to place the gene in a particular area in the genome. It makes use of the exceptionally powerful sequencing methods and computational tools that now exist, first to identify candidate genes that are present in the region, and then to locate the mutation itself.

A professor in The Scripps Research Institute Department of Immunology since 2000, Beutler focuses his laboratory's efforts on discovering abnormalities in the immune system caused by mutations, with the ultimate goal of finding genes that are important for the immune system to function correctly: "You start with a phenotype -- for example, a [system] that doesn't respond to the presence of endotoxin -- and work backwards from there to find out what mutation caused the innate immune system not to respond."

Innate immunity is a form of immune defense all of us are born with, he says: "It doesn't depend upon antibodies, or prior contact with germs. We all have an innate immune response to bacterial, fungal, and protozoal infections whether we have been exposed to these agents or not. We are hard-wired to defend ourselves."

Beutler is searching for mutations that disrupt innate immunity.

"The Tlr4 gene encodes a protein that is the gateway for endotoxin detection and endotoxic shock," he points out, "while other Tlr genes encode proteins that detect other microbial molecules. Collectively these receptors tell us when we're infected. So each mutation is the beginning of a new quest. And we've found some really beautiful mutations."

But most of the time, they find nothing at all. Their method creates thousands of mutations utterly at random. In that sense, it is exactly like gambling, playing the odds and hoping that they get lucky. From time to time -- like beating the house in Las Vegas -- they hit the jackpot. Recently, Beutler and his team discovered a new mutation that causes endotoxin resistance, a mutation in a gene that is clearly different from Tlr4, or any other known gene required for endotoxin responses.

"I do think that mutations are the key to the understanding of immunity," he says. "The immune system is so complex that there are probably thousands of ways to disrupt it. The result might be autoimmunity, or an immunodeficiency that could wipe out a whole class of cells. In the long run, once we understand the proteins that are involved in a particular immune function, it should be possible to design drugs that target those proteins, either enhancing or blocking their function. Take a mouse with a severe allergy, for example. Once we understand why the allergy is there, we might be able to design a drug that would prevent it."

Beutler enjoys the haphazard turns of mutagenesis, largely because "it presents a new puzzle at least once a month." Prodded by unexpected phenotypes, Beutler and his group delve into areas of biology that they might not otherwise consider.

Mutagenesis also compels the researchers to be inventive, for they must design tests that will reveal the presence of a mutation that might otherwise be passed over. They must also ask questions that are difficult to answer because evolution has created biological systems of vast complexity.

ANOTHER EVOLUTIONARY MYSTERY

In a roundabout way, Bruce Beutler began thinking about precisely such a system: the placenta, a tissue that nourishes the growing embryo and fetus of all advanced mammals, including humans. The riddle of the placenta presents the same sort of exploratory opportunity that Lps did -- a new chance to leap into the unknown.

"The immunological mystery that the placenta poses was first raised in the 1950s," he says. "I remember talking about it with my father when I was a teenager, as we discussed many scientific questions. Grafts of foreign tissue are rejected by the immune system, but the placenta is not. Why? It is a fundamental exception in immunology, and an evolutionary puzzle. When the placenta first evolved some 170 million years ago, the immune system was already well entrenched in vertebrates. It should have rejected the placenta. But somehow, in this one special case, something happened to defeat adaptive immunity. The development of tolerance to the placenta occurred only once. It did not occur in different species at different times. It may have involved a single, crucial mutation. And it is very likely that we will be able to dissect the phenomenon using mutations, perhaps getting a glimpse into our human past."

The mutagenesis project is carried out, he says, by a remarkable assembly of postdoctoral associates, students, and technicians: Alison Affleck, Xin Du, Jason Goode, Kasper Hoebe, Navjiwan Mann, Koichi Tabeta, Pia Viviani, and Zuping Zhou.

"All in all, the best group of people with whom I have ever worked," Beutler says. "Without patient and devoted people this type of approach couldn't succeed. With such people, it can't fail."

Spoken like a true explorer.