The discovery of bacterial sex grew directly out of the biochemical genetics of Neurospora, developed by Beadle and Tatum in the early 1940s. Both Esther Zimmer and Joshua Lederberg, the first genetic explorers who ventured into the exotic world of bacterial sex, carefully followed the Beadle and Tatum approach of using nutritional mutants to investigate the odd genetics of bacteria.
During the 1920s and 30s, Bernard Ogilvie Dodge and Carl Lindgren worked out the details of the mold’s life cycle and genetic processes, preparing the stage for Beadle and Tatum’s breakthrough in 1941.
That year, Esther Zimmer, an 18-year old undergraduate at Hunter College, rebelled against her professor’s expectations that she pursue a career in foreign languages. Instead, she chose genetics. But Zimmer had to look outside the Hunter College campus to find a mentor. Nearby, at the New York Botanical Garden, she found plant pathologist Bernard Ogilvie Dodge, the pre-eminent expert on Neurospora.
Over the final three semesters at Hunter College, Esther Zimmer interned in Dodge’s lab, learning to cultivate and experiment with Neurospora. Following graduation, Zimmer continued her research by studying radiation-induced mutations in Neurospora at the US Public Health Service. And her Master’s research and dissertation at Stanford–supervised by George Beadle–dealt with Neurospora genetics. Therefore, before teaming up with Joshua Lederberg in 1947, Esther Zimmer had spent more than five years acquiring an in-depth knowledge and technical expertise in Neurospora genetics. The next year she and Joshua established the first laboratory of bacterial genetics at the University of Wisconsin.
Why Neurospora? A little history of genetics provides the context for the rapid developments in the1940s and 50s that revealed the biochemical secrets of The Gene for the first time.
A little Genetics History
After the rediscovery of Mendellian inheritance at the turn of the 20th century, geneticists set about verifying Mendel’s principles in plants and animals. Maize and fruit flies became the standard model organisms that helped establish the chromosomal theory of inheritance, and clarified the processes of mitosis and meiosis. But The Gene itself remained an abstract concept. Genes “resided” on chromosomes–that much was clear–but what was the chemical structure of the gene? Researchers wondered what genes were made of, and how genes were expressed in physical traits, the inherited features that geneticists analyzed to make chromosomal maps. Answering these basic questions required new technologies and new model organisms.
The pathway of discovery to the double helix led through x-ray crystallography, the technology mastered by Rosalind Franklin, who provided the central evidence verifying Watson and Crick’s double helix model of DNA. Proving that DNA was the molecular identity of The Gene, and demonstrating how genes were translated into proteins that controlled the expression of traits, required the new model systems of Neurospora and E. coli.
The year before he started teaching genetics at Columbia University in 1942, Francis Ryan trained as a post-doctoral fellow in the Beadle and Tatum laboratory at Stanford University. There, Ryan learned a biochemical approach to genetics, the experimental model system of Neurospora crassa, which he brought back to Columbia. Joshua Lederberg, a callow 17-year old undergraduate, met Ryan in September of 1942, and began working in his laboratory.
Even though most scientists in 1945 doubted that bacteria even had real genes, young Lederberg thought that he could use the Beadle and Tatum approach to see if bacteria could recombine their genes. Tatum, a biochemist trained in the study of biochemical pathways in microbes, understood that Neurospora were capable of converting simple glucose into all of the molecular building blocks of life: lipids, proteins and complex carbohydrates. The hardy bread mold naturally possessed all of the enzymes necessary for biochemically converting glucose into each of the building blocks.
Beadle and Tatum wondered if genes controlled each of these enzymes. If so, then a certain mutation would inactivate a specific enzyme and block its essential biochemical function. To test their idea, Beadle and Tatum created a bunch of mutant strains by zapping the fungal spores with x-rays. They hunted through thousands of mutant strains looking for one that failed to grow, except when the culture broth was supplemented with the specific vitamin or amino acid that the mutant could not synthesize. This approach yielded three strains that required specific supplements: one strain could not make vitamin B4; another could not synthesize B1; and a third failed to make para-aminobenzoic acid. These mutant traits were shown to be inherited in cross-breeding experiments, i.e., the mutated traits were heritable, like genes worked in plants and animals. Thus, for the first time, Beadle and Tatum demonstrated what a gene actually did at the biochemical level: a gene controlled an enzyme. Hence their famous one gene : one enzyme hypothesis.
For this discovery, George Beadle and Edward Tatum were awarded the 1958 Nobel prize in physiology or medicine. The other half of the 1958 Nobel prize went to Joshua Lederberg, for demonstrating that bacterial genes controlled nutritional functions, and that these genes could be transferred between bacteria.
The specific model system introduced by Lederberg was E. coli, the K-12 strain. The K-12 strain was the only one that was fertile, and therefore useful for the initial bacterial mating experiments. Esther Lederberg discovered the fertility factor , the first plasmid, in K-12, and also the bacteriophage lambda, which became the most-studied bacterial virus for revealing the molecular regulation of genes. Bacterial model systems dominated molecular biology research for decades, facilitating the rapid growth of the biotechnology revolution.