Ronald W. Davis: Honors & Awards

Davis was one of the first scientists to begin mapping and cloning DNA. His first research project developed physical gene mapping by electron microscopy of heteroduplex DNA molecules. He constructed the first physical gene map for any organism using the bacteriophage lambda during his PhD thesis at Caltech. This was a study ahead of its time that paved the way for future genetic mapping efforts. His later work with David Botstein built the revolutionary proposal to map the human genome using DNA as a marker, in the form of restriction fragment length polymorphisms (RFLPs; see Publications). Their method was used to generate the first map of the human genome, on which Davis consulted. This map enabled the discovery and cloning of numerous disease genes and forensic markers. Davis also developed a new instrument (CHEF) for electrophoretic separation of very large DNA molecules and cloning of very large DNA molecules as artificial chromosomes in yeast. These genetic and physical mapping efforts were crucial groundwork for the Human Genome Project.

As an Assistant Professor, Davis discovered that the cleavage of DNA with the restriction enzyme EcoRI yielded DNA with cohesive ends, such that two different DNA molecules could easily be ‘recombined’ into a single molecule (see Publications). This simple method ushered in the era of DNA cloning in E. coli and animal cells and sparked the recombinant DNA revolution. Davis used his physical gene map of bacteriophage lambda to convert it into a cloning vector for DNA from any organism. He developed several biochemical methods that made cloning into lambda much easier and more efficient than the previously used plasmid vectors. The cloning of genes from any organism spurred the revolution in molecular analysis of higher organisms. Davis and Robert Lehman were the first to overexpress a protein (DNA ligase) from cloned DNA. Overexpression of human and other proteins propelled the biotechnology industry. This approach allowed numerous yeast genes to be cloned and led to the construction of yeast vectors and DNA transformation of yeast, as well as phenotypic selection for recombinant yeast clones based on genetic markers. DNA transformation of yeast revolutionized yeast genetics, allowing a large number of genes to be molecularly characterized for the first time. In 1977, Davis co-authored a paper describing the very first case of genome editing, the ability to replace any nucleotide in the yeast genome with any other nucleotide. Davis and Stewart Scherer then developed methods for targeted gene deletion, pioneering the use of reverse genetics on a eukaryote in 1979. Forward and reverse genetics were the hallmark of yeast genetics for years to come. Davis identified DNA replication origins and centromeric DNA sequences that allowed the construction of yeast artificial chromosomes out of large DNA segments from other organisms. These technologies collectively made yeast the premier genetics model organism and spawned a whole generation of superb geneticists. 

Davis was a key participant in the Human Genome Project (HGP) and one of its earliest advocates. Facing great skepticism from the scientific community and funding agencies about feasibility and costs, Davis was a strong voice for cost reduction through technology and automation. His SGTC laboratory developed a revolutionary oligonucleotide synthesizer, which reduced the cost of oligonucleotides (essential for DNA sequencing, PCR, and more) by 20-fold. It became the dominant instrument worldwide within 6 months of its release in 1995, and is still the basis of most synthesis today. He was the first to propose extensive modular automation, which proved essential for sequencing the human genome. He developed numerous instruments for modular automation of high-throughput DNA sequencing, many of which are still used today. From the start of the HGP in 1989 until the announcement of its completion in 2004, the cost of DNA sequencing was reduced by 2000-fold, which was instrumental in the project’s success. In addition to the HGP, Davis’ laboratory sequenced numerous additional organisms like yeast.

Scaling up his pioneering work in reverse genetics, Davis introduced the now widespread use of molecular barcodes for high-throughput genetic analysis to build his yeast whole genome deletion collection, which was the first complete mutational analysis of any genome (see Publications). He invented new genetic technologies such as chemogenomic profiling to identify drug mechanisms of action and reciprocal hemizygosity scanning for quantitative trait mapping. These technologies allow high-throughput analyses of genetic variation and its interaction with the environment – key concepts for precision medicine. 

Davis has also contributed to analyzing sequenced genomes and patterns of gene expression. He pioneered the development of the DNA microarray for DNA analysis in collaboration with Steve Fodor of Affymetrix and was the first to show its use for gene expression. He subsequently automated DNA microarray technology to reduce costs for clinical applications. He performed the first whole genome genetic analysis using yeast and single nucleotide polymorphisms (SNP) on the DNA microarray. He developed molecular inversion probe technology for genotyping and applied it to identify individual species in the microbiome without culturing them. SGTC’s large clinical study analyzing human trauma patients’ blood demonstrated common gene expression signatures to various types of trauma, identified major problems with mouse models of trauma that could accelerate drug development, and helped to establish standards for clinical genomics (see Publications).