My first interest in Ras biology was inspired by my long-time friend Dr. Chris Marshall, from the Chester Beatty Laboratories in London. Chris and I were enjoying a glass of Dave’s Tea (vodka and iced tea mix) on a hot afternoon on the island of Spetses, Greece. I was at the Spetses meeting in my capacity as Staff Scientist, Cetus Corporation, where I worked on developing mammalian expression systems for recombinant proteins for therapy. Senior management at Cetus was somehow affiliated with the Spetses meeting organizing committee, chaired by Dr. Brian Clarke from Aarhus, Denmark. Through this connection, Cetus scientists were assured slots at the Spetses meeting, and I was delighted to take the opportunity to spend a week there. Chris was excited by the recent discovery that Ras oncoproteins differed from their normal counterparts by a single amino acid, and by the possibility that drugs could be developed based on this difference. This was 1983, early days in recombinant DNA technology, and Chris saw an opportunity to collaborate with a group with access to these new tools to facilitate production of recombinant proteins at unprecedented levels. We agreed to collaborate on this project, and would focus on N-Ras, as this gene had been cloned by Dr. Alan Hall in Chris’ group, and would give us a different angle relative to other groups working on H-Ras and K-Ras. One of these groups was headed by Dr. Art Levinson, then a junior scientist at Genentech, now CEO.

Returning to Cetus in California, I proposed a pilot project on oncogenes as diagnostic and therapeutic targets. For diagnostics, we developed a panel of antibodies that recognized position 12 substitutions. We also launched an effort to detect BRC-ABL fusion proteins for CML, amongst other projects. Both these efforts we later shelved when Dr. Kary Mullis in the laboratory next door, invented PCR: we switched to this new technology to detect Ras mutations in genomic DNA and, in collaboration with Dr. Owen Witte from UCLA, BCR-ABL fusion transcripts. The Holiday Inn, Emeryville, was soon filled with collaborators from all over the world, who brought DNA samples from tumors and cell lines, for amplification and analysis at Cetus. This was before Taq Polymerase, and PCR was a cumbersome process that required addition of fresh Klenow polymerase at each cycle. To streamline the process, Cetus developed an enormous liquid handling machine and obtained a million dollars worth of Klenow polymerase. The Klenow Monster ran round the clock, amplifying samples from collaborators and internal projects. Chris Marshall sent a young post doc, Dr. Christine Farr, with a large collection of samples from human AML. In two weeks, she performed hundreds of reactions, and, as far as we could tell, she spent all this time either at Cetus or in the Holiday Inn. Despite this activity and urgency, the first major analysis of Ras mutations in human tumors came from the lab of Dr. Hans Bos in Holland, who had constructed his own PCR set up on a smaller scale. His brilliant analysis earned him the reputation as The Amplifying Dutchman. Our effort to launch a therapeutic attack on mutant Ras began by cloning Alan Hall’s N-Ras cDNAs into bacterial expression vectors, and producing high levels of recombinant protein. Our plan was to develop drugs based on biochemical and structural analysis of these proteins. My new technician Meg Trahey led this part of the project. We first tried to confirm that oncogenic mutants were defective in GTPase activity, as others had reported for H-RAS G12V mutants in a series of classic papers. To our surprise, the G12D mutant of N-RAS, a fully transforming …