ABSTRACT
A chapter describing my formative years working from a young age at an abattoir where there were many lessons to be learned about the people who wore white coats and those in blue denims. I explain how I survived medical school by following my professor's advice to pursue a career in science, and why I was intent on doing so. Then, I switch to the years after I left MIT when there was no job or funding offered to continue my work on the Z-DNA binding protein I had discovered and how I acquired the skills I would eventually use to answer the question I had initially started out on. My work at the Framingham Heart Study (FHS) in genetics led to a significant paper in the journal Science, but my tendency to put the science ahead of the politics led to my firing. The tensions arose due to the different ways science is conducted by each discipline, with molecular biologists wanting to publish quickly and epidemiologists taking years to collect and analyze data. I also learned other key skills for the time I worked at Merck on the identification of medically important targets before being “separated” during yet another reorganization. Again, I successfully failed the politics.
Here, I describe the new methods I learned and helped develop that allow the analysis of large datasets in a way that overcame the statistical problems associated with multiple testing. In FHS, we used around half a million sequence variants to map a genetic cause for obesity. The approach was deemed infeasible and the NIH actually held back funding for the study because of the peer reviews received. Despite this judgment, we were successful in achieving our goal. I will describe the politics involved and its limitations.
I was hired at Merck to use these genetic approaches to find new drug targets. The work was based on a novel approach and did identify targets, but these at the time lacked genetic validation. I describe how that all worked out. Best of all, when I left Merck, I was then in a position where I had time and money to return to the Z-DNA story. At this time, I started InsideOutBio to work on therapeutics for cancers that were not responsive to the new class of immune checkpoint inhibitors that Merck had just brought to market.
