At the dawn of genetics, in the work of Mendel and Morgan, there was a complete void between the genes and the characters they determine.During the first week, we will discuss the relationship between genes and enzymes. We will start with the description of alkaptonuria by Garrod, in 1902, which he called a few years later an inborn error of metabolism. This was the first documented example of a human recessive trait, the first association of a human condition with Mendel’s principles and the first link between a gene and an enzyme. This work and that of Cuénot on mice fur color were essentially forgotten in the biology community in the following decades.After working with great difficulty on the enzymatic cascade that leads to the formation of the pigmented eye of fruit flies, Beadle and Tatum founded the field of biochemical genetics by isolating conditional mutants that affect the synthesis of vitamins and amino acids. This was first done with a mold, and then extended to bacteria. These experiments lead to the “one gene, one enzyme” hypothesis. While the hypothesis is now proven in many cases, the exceptions, including multigene enzymes, structural and enzymatic RNAs have expanded the concept rather than invalidating it.

Most people believed that genes must be made of proteins because nucleic acids were considered too simple to carry genetic information. Avery worked all his life on Pneumococcus and bacterial pneumonia. Griffith showed that transformation of a non-virulent strain can be achieved in mice by coinjection of heat-killed virulent bacteria. Avery’s lab managed to obtain transformation in the test tube, but it took many years to establish a reliable assay and finally to purify the molecule responsible for this effect, which turned out to be DNA. Although this work was well known, most scientists were not convinced of the general implication of this phenomenon. Furthermore, many biochemists believed that even the purified DNA was contaminated with a protein. Finally, transformation was a very inefficient process and the mechanism of transformation remained mysterious for many years. The work of Hershey and Chase finally convinced the scientific community that genes are made of DNA. We now realize that exchange of DNA by transformation is very common, and participates to the horizontal transfer of DNA between at least bacterial species, and was a considerable accelerator of evolution

The origin of mutations was a field of heavy discussions between proponents of Darwinism and those of Lamarckism. The major issue was to define an experimental approach that would unambiguously discriminate between mutations occurring at random and mutations caused by the selective agent used to reveal their existence. In the case of bacteria that became resistant to the lytic action of a bacteriophage, the hypotheses were labeled “mutation to immunity” versus “acquired immunity”. Luria and Delbrück realized that the variations observed in the number of resistant bacteria in different parallel cultures were intimately linked to the mutation hypothesis. This exceptional collaboration between a theoretical physicist and a bacteriologist is a perfect example of interdisciplinary work, while these two “enemy aliens” were working in the USA. At that time, it was not even clear that bacteria had genes and most bacteriology work was only descriptive. The use of a quantitative approach allowed the authors to settle the question. The fluctuation test is a very powerful tool to calculate mutation rates. Soon after, Newcombe did a simple but elegant experiment to demonstrate that the increased number of resistant bacteria that are detected upon clonal expansion reflects both the amplification of preexisting mutants and the continuous occurrence of new mutations.

When DNA was found to be the genetic material, it was not known how this molecule could carry information. The structure of DNA thus became of critical importance. The available X-ray images obtained by M. Wilkins and R. Franklin only yielded a rough picture, and even R. Franklin, who had the clearest diffraction data, could not decide whether the molecules contained two or three strands. Both Pauling and Watson and Crick used molecular models with known inter-nuclear distances (bond length) and bond angles to predict a structure. While the model of Pauling was hardly realistic, since it used the protonated form of the phosphate, the model proposed by Watson and Crick proposed that DNA consists of a pair of DNA strands. Furthermore, it indicated that any nucleotide sequence could be accommodated in the structure. The only central biological issue that was addressed in the first paper was replication, and the famous sentence was really nothing more than a priority claim. Much more biology was discussed in the second paper. It was assumed that base pairing is sufficient to account for the fidelity of replication. The importance of DNA polymerase in replication fidelity was first demonstrated by Speyer.