One of the things that drew me into biology was the recombinant DNA revolution. I was studying chemistry at the University of Illinois in 1977 when I took a class that discussed the new methods to rearrange DNA. I was amazed by this and decided that I would like to work on recombinant DNA and so left chemistry to follow this new wave of biological discoveries waiting to happen. I did my graduate work at MIT working on DNA repair and found time for side projects on the development of new methods for generating recombinant DNA, essentially my hobby. During this period I developed the first phasmid cloning vectors that contained both a plasmid and phage origin, and this understanding of phage biology became the crux of many future discoveries.

I was a post-doctoral fellow in the Biochemistry Department at Stanford University and by complete accident I cloned a gene involved in synthesizing dNTPs needed for DNA replication. Since it was an accident, I wasn't very interested in it. However, since I was prone to working on extremely high-risk projects in hopes of doing something important, I was in need of a safe project in case I ever hoped to actually get a faculty position after my post-doc. So I followed up on the ribonucleotide reductase genes, eventually discovering that they were induced by DNA damage. This was an important discovery because it became the basis for a number of genetic screens that led to the discovery of a signal transduction pathway that senses and responds to DNA damage. However, that was not the most important aspect of this gene with respect to this story; it was also cell-cycle regulated, which got me thinking about the cell cycle. Not long after that, Paul Nurse, a leader of the cell-cycle field and co-winner of the 2001 Nobel Prize in medicine, gave a talk at UCSF and described isolating the human homolog of a key cell-cycle kinase gene, Cdc2, by introducing a human cDNA library into an S.pombe mutant. The methods were primitive but the message was clear, that the core of the cell cycle was functionally conserved and many human genes could be isolated by complementation cloning in yeast. This led to a marriage of my two interests, cloning technology and the cell cycle, and I further developed new cloning methods to make human cDNA libraries in yeast expression vectors and streamlined them to make them easy to use.

When I started my faculty position at the Baylor College of Medicine in Houston, the first experiment I performed was to introduce these new libraries into yeast cell-cycle mutants. The first gene I discovered was the human Cdc2 gene isolated by Nurse two years previously. However, I also isolated in that screen a relative of this kinase, Cdk2, which work from my lab and others subsequently revealed to be the key protein controlling the G1 to S phase transition, the critical transition for cancer. This was a key discovery and began my lab's involvement in human cell-cycle control. I then applied my newly developed cloning technologies to an emerging method for detecting protein-protein interactions called the two-hybrid system. I converted that system from a method for detecting interactions into a method for cloning cDNAs encoding proteins that associate with a target protein. Using Cdk2 as bait, my colleague Wade Harper and I isolated the p21CIP1 gene and showed it to be the first of a family of Cdk inhibitors. Bert Vogelstein's lab also identified the same gene as a gene regulated by p53 and we published our papers back-to-back in November of 1993. This was a watershed event in cell-cycle research and helped forge the connection between p53 and cell-cycle control. Our studies showed that p21 was a member of a family of inhibitors that the whole field began to work on. We also discovered that one member of this family, p57KIP2, was found to be mutant in individuals with the familial overgrowth and cancer predisposition disease Beckwith-Weidemann Syndrome. Our group was the first to demonstrate that these inhibitors were key regulators of developmental growth control being involved in everything from lens to muscle development.