1-15 Studying microbes provides insight into life at the molecular level

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• Microbes have been critical tools for the understanding of basic biology at the molecular level.
• Fred Griffith performed transformation experiments that suggested that DNA was the hereditary material. His student, Avery Oswald, later demonstrated this conclusively.
• Beadle and Tatum developed the one gene-one enzyme hypothesis using Neuropsora crassa as the test microbe.
• Many scientists working with E. coli deciphered the nature of DNA, RNA and protein. These experiments lead to our understanding of how information in the cell is stored and how it is converted into proteins.

In the early part of the 20^th century techniques were developed to examine the inner workings of the cell and much of the work was performed in bacteria due to their experimental accessibility. Before this period, the method of turning genetic information into the proteins that carry out cellular processes was completely unknown. Indeed, the chemical composition of the genetic material was being hotly debated. From Gregor Mendel's work with pea plants, the nature of inheritance and heredity was understood. However, it was unclear what molecule in the cell maintained and passed hereditary information on to subsequent generations. The leading contender for this role was protein, when in 1928 Fred Griffith discovered transformation in bacteria.

Griffith knew that when Streptococcus pneumoniae strains are injected into mice, they cause rapid deterioration and death. Griffith isolated strains of the bacteria that were no longer capable of producing an outer slime layer and appeared rough when grown on solid medium in contrast to the smooth colonies of the original isolate. When these rough strains were injected into mice, no illness resulted. Similarly, when a smooth microbe was heat-killed and then injected, the mice showed no signs of infection. A surprise was waiting for Griffith when he injected into mice a mixture of dead cells of a smooth isolate with live cells of a rough isolate: they died. When bacteria were isolated from these dead mice, they formed smooth colonies. Griffith hypothesized that the ability to create the slime layer was passed from the dead smooth cells to the viable rough cells, making them pathogenic again. The process became known as transformation.

Griffith was ridiculed, as most scientists believed his preparation were contaminated with viable smooth cells. It was not until 1944 that his student Oswald Avery and coworkers repeated the experiments of Griffith, reproducing his results and discovering that DNA was the material from the dead smooth cells that transformed the rough mutant. This was strong proof that the hereditary material in cells was DNA. Further experiments in the 1940's clearly established this observation with Joshua Lederberg discovering two more ways that DNA could be transferred between bacterial cells, conjugation and transduction. For more information on these experiments, see the chapter on Genomics and Genetics

In 1943 Beadle and Tatum reported experiments with the fungus Neuropsora crassa that eventually established the idea that each gene in the DNA typically codes for one protein (the one gene-one enzyme hypothesis). About 10 years later, Francis Crick, Rosalind Franklin, James Watson and Maurice Wilkins worked on experiments describing the structure of DNA and making predictions about how it was replicated. It was now clear that DNA stored the information for proteins and that proteins performed the many functions of the cell.

The important question now became, how does one convert the information in DNA into protein. A major contribution in understanding this puzzle was made by Paul Zemecnik and his laboratory who developed cell-free systems, first with rat liver and later using the bacterium E. coli. This allowed the study of translation in the test tube and he and other scientists used these systems to discover the important molecules involved in the process. An intense effort to describe these molecular events then ensued. The first insight came when Crick, Sydney Brenner and colleagues proposed the existence of transfer RNA (tRNA), a molecule that helps to create amino acid polymers based on nucleic acid sequence. Another critical player in the processing of information was revealed when Brenner, Francois Jacob and Matthew Meselson discovered that translation of genetic material into protein takes place on the ribosome and that the molecule being translated at the ribosome is RNA, not DNA. The next mystery was solved by Marshall Nirenberg and J. H. Matthaei when they developed methods to decipher the genetic code that dictates the correspondence of nucleic acids to amino acids. After the stunningly productive decade of the 1960's, the nature of the framework for the conversion of the genetic information into proteins was now understood and the basic mechanism has since been shown to be conserved across all biology. For more information on the process of transcription and translation, see the chapter on the Central Dogma

Figure 1-25 lists important events in learning about the central molecular events in biology. Note that almost all of this work occurred in microorganisms.

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