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How Stanford Nobelists founded molecular biology on a red mold

STANFORD -- It was wartime, 1941. The United States was on the brink of joining the worldwide conflict and funds for science were scarce.

But in the "catacombs," the basement of Stanford's Jordan Hall, a revolution was being made. A small team of scientists and their students, led by George W. Beadle and Edward L. Tatum, undertook a series of experiments that gave birth to modern molecular genetics.

On Sept. 26, as part of Stanford's centennial celebration, scientists and students on the cutting edge of biology today acknowledged the pioneering work of Beadle and Tatum 50 years ago. They gathered to dedicate Stanford's new Gilbert Biological Sciences Building and attend a symposium titled "Frontiers in Biology for the 21st Century."

Beadle and Tatum's work welded genetics and biochemistry into the new science of biochemical genetics, which itself gave rise to molecular biology. Today, these sciences hold out the realistic hope of curing genetically based disease, of understanding the immune system and of mapping the human genome. Through their methodology and results, Beadle and Tatum opened hundreds of new doors, leading down still new corridors of inquiry.

Prior to their work, classical genetics was mainly concerned with studying physical characteristics like eye color and their inheritance in offspring. In work since the turn of the century, genes had been mapped and located on chromosomes. But the chemical composition of genes and the question of how they functioned had barely been addressed. Many scientists assumed that the key components of chromosomes were proteins, not DNA. Many also believed that genes were multifunctional. The fields of genetics and chemistry were worlds apart.

Tatum was a biochemist who graduated from the University of Wisconsin in 1930 and came to Stanford in 1937. Beadle, who grew up on a Nebraska farm, obtained his doctorate from Cornell in 1930, working on the genetics of corn. Prior to coming to Stanford in 1937, he worked at the California Institute of Technology on the genetics of the comon fruit fly, Drosophila.

At Stanford, Beadle and Tatum teamed up to confront a new question: What were the specific biochemical steps used by genes to determine the physical traits of offspring and regulate the life processes of organisms?

Initially, they worked on the genetic-biochemical relations of red and brown eye pigment in the fruit fly. The genetics of Drosophila was known, but the biochemistry was complex and little understood.

Norman Horowitz, now professor emeritus of biology at the California Institute of Technology, was a young research scientist in Beadle's lab at the time. Speaking at the symposium, he recalled how a lecture by Tatum gave Beadle the idea that changed the course of genetic science.

Tatum described how microbial species such as bacteria and fungi often have a common basic biochemistry, but that they differ in their nutritional requirements. Listening, Beadle hit on the idea of working with a simple organism, one whose nutritional needs and biochemical reactions were already known. If mutations could be produced that blocked specific known biosynthetic steps in the organism's manufacture of essential nutrients, these could be related to its genetic structure.

In 1941 Beadle revamped his lab. He and Tatum began work with Neurospora crassi. This leap from work with the well- known Drosophila to a red bread mold was a startling idea to most scientists at that time. It proved to be key.

Working under steam pipes in their basement lab, the team first established that Neurospora could be grown on a simple chemical medium. Then they began the mutant hunt, using X-rays to induce mutations.

According to Horowitz, Beadle and Tatum agreed to examine cultures of 5,000 Neurospora spores, searching for usable mutants. If none were found by the 5,000th try, they would give up. On their 299th try, they found what they needed: a mutant that required pyridoxine, a B-vitamin, to grow. The mutation of a single gene had changed the nutritional requirements of the fungus.

Experimentation over the next several years demonstrated that the synthesis of each required nutrient was orchestrated by a series of genes, in a number of discrete steps, and each gene controlled only one of those steps. By 1945 Beadle and his colleagues proposed the hypothesis of one gene, one enzyme. The one gene, one protein theory (as it became known) is today a basic principle in the study of the organization of living matter.

Beadle and Tatum's experiments also made a new, and in many ways ideal, microorganism available for biochemical and genetic study. Biochemical and genetic mutations could be generated at will, and in unlimited supply.

"It is rare in science that entire schools develop largely from the accomplishments of a few individuals," said Charles Yanofsky. A professor of biological sciences at Stanford, Yanofsky in 1964 offered further proof of Beadle and Tatum's hypothesis by showing the colinearity of genes and proteins.

Those who worked with Beadle and Tatum also remember the personal qualities that inspired them. Beadle, Horowitz recalled, was friendly and enthusiastic, and always did more than everyone else. One day, going into work early, Horowitz found Beadle painting his lab at two in the morning.

Stanford biology professor David Perkins worked in the lab with Tatum. He recalls him as shy, extremely honest and loyal to students and associates.

"Tatum was so honest," Perkins said, "that when serving on a national panel to award graduate students with financial aid, he would not let any of his own students apply. They had to get their money the hard way."

In 1944, after the initial experiments with Neurospora, Tatum, working with C.H. Gray, a Stanford undergraduate, demonstrated that it was possible to get mutations in bacteria similar to those in Neurospora. This surprised many scientists, who considered bacteria to be primitive, without genetic material or real structure. It set the stage for the birth of bacterial genetics and all it has led to in genetic engineering and recombinant DNA.

In parallel efforts, other scientists were tackling the puzzle of genetic functioning from different angles. Microbiologists Max Delbruck and Alfred Hershey discovered that the genetic material of different viruses could be combined to form a new virus. They and Salvador Luria studied bacteriophages -- viruses that infest bacterial cells. In 1952, Hershey proved that it was the DNA of the phage that entered the bacterial cell, further indicating that the genetic material was nucleic acid, not protein.

Meanwhile, Oswald Avery, Maclyn McCarty and Colin McLeod worked with the pneumonia-causing bacteria pneumococci. Their work also showed that DNA was the key genetic material. Then, in 1953, Francis Crick and James Watson described the structure of the DNA molecule and its chemical composition.

In little over a decade, two new sciences were born: biochemical genetics and molecular biology. The molecular basis of life began to be revealed.

Upon leaving Stanford in 1946, Beadle joined the faculty of the California Institute of Technology. There he chaired the biology department and later became president. In 1961, he became chancellor of the University of Chicago. He returned to science years later, tackling the question of the origin of maize. Horowitz reflected that Beadle never seemed so happy as when he was in the lab or the corn fields he planted in Hawaii and Mexico.

Tatum, after completing his work with Beadle, was not offered a faculty position at Stanford. He went on to Yale, returning to Stanford as a full professor in 1948. While at Yale, Tatum and graduate student Joshua Lederberg discovered genetic recombination of bacteria.

Beadle, Tatum and Lederberg shared the 1958 Nobel Prize in medicine and physiology, Beadle and Tatum for their work in showing that genes regulate definite chemical events, Lederberg for his genetic work with bacteria.

Horowitz said, "Beadle and Tatum began a revolution which in a few years transformed genetics from a science with virtually no ties to the physical sciences -- to atoms and molecules -- into a science that could not be discussed apart from the physical sciences."

Robert Simoni, chair of Stanford's department of biological sciences, said, "Advances as profound as those Beadle and Tatum made will occur again, and for the same reason -- the bringing together of two perhaps different groups of people, who look at a common problem in a way that is outside of the traditional disciplines."

In 1957, in an article for the journal Science about the future of scientific discovery, Beadle wrote, "Man's evolutionary future biologically and culturally is unlimited. . . . He has won the knowledge that makes it possible deliberately to determine the course of his own biological evolution.

"But knowledge alone is not sufficient. To carry the human species on to a future of biological and cultural freedom, knowledge must be accompanied by collective wisdom and courage of an order not yet demonstrated by any society of men. And beyond knowledge wisdom and courage faith too will be essential."



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