Autobiography of Paul A Negulescu
I was born and raised in San Francisco, California. My parents immigrated to California from Romania following World War II. My father was a general surgeon who loved his work. Mom spoke four languages perfectly and took care of the business side of dad’s medical practice. Mom and dad liked to go to auctions and bring back old furniture, which dad would restore beautifully. I inherited a love of reading from my mom and an interest in learning how things worked and fixing them from my dad.
My parents took great interest in the education of my brother and me. Mom insisted we take Latin, which I did not appreciate at first, but later realized it was foundational for my understanding of language and western culture. When I was about six years old, my parents built a house into a hillside with views of the city, the bay and bridges. Perhaps because of these experiences I wanted to be an archeologist or an architect as a child. I have happy memories of growing up in San Francisco.
After high school I attended the University of California at Berkeley and was preparing to graduate with a degree in History. A turning point occurred in my third year when I enrolled in a Physiology class taught by a new faculty member named Roger Tsien. Roger was a brilliant scientist and teacher (and future Nobel Prize Laureate), and his explanation of how the human body worked fascinated me. Roger would have a great influence on my development and career. I obtained degrees in both History and Physiology and applied to graduate school in Physiology.
As a graduate student at Berkeley I studied epithelial cell physiology in Terry Machen’s lab which prepared me for later work in cystic fibrosis. Terry was very collaborative with other faculty, including Roger, who would generously provide samples of fluorescent indicators he had designed and access to cell imaging equipment that he developed for my studies of cell ion transport.
As a post-doc in Mike Cahalan’s lab at UC Irvine, I tried learning patch-clamp electrophysiology, but did not have the delicate touch needed for this technique. I continued using fluorescent dyes and imaging methods to study cell biology. I met my wife Debbie while at Irvine and I started to look for a job. I planned to accept a faculty position at the University of Connecticut when Roger contacted me unexpectedly to ask me to join a new Company he was forming to industrialize cell-based assays for pharmaceutical drug discovery. My experience with Roger’s dyes gave me faith in the concept and I was drawn to applied research. I moved to San Diego and joined Aurora Biosciences as the 5th employee in 1996, while Debbie completed her graduate work at UC.
Joining a start-up provided a quick education. We had collaborations with many companies, developing assays for different targets in many diseases. I learned about deadlines, and drug discovery and managing more than myself. One approach at Aurora was to use voltage sensing dyes in cells that Roger had invented with Tito Gonzalez to screen chemical libraries for modulators of ion channel targets. Bob Beall, President of the Cystic Fibrosis Foundation (CFF) heard about this and approached us to screen for CFTR modulators to treat cystic fibrosis. In 2000, we proposed a 5-year research project to discover CFTR corrector and potentiators which Bob and the CFF accepted following diligence. Bob was very intense but supportive throughout our collaboration, which extended to over more than a decade. He was a model for me of a focused and demanding, but fair, executive.
When Vertex acquired Aurora in 2001, I was responsible for transitioning Aurora’s research to Vertex and we continued both the CF project and a project to inhibit sodium channels to treat pain. In 2003 I was given the opportunity to lead the Vertex research site in San Diego and to build a wonderful team including Fred Van Goor, Sabine Hadida and Peter Grootenhuis and so many others. Although it took us about 5 years to identify the first CFTR modulator, we learned many lessons together and we continued to work together to apply these lessons to each subsequent modulator, resulting in four approved medicines. Drug discovery failures are more common than successes, and I realize how rare it is to lead a team for so long and to contribute to a project from the very beginning to a tangible result.
Looking back on my life and career, I feel fortunate to have been supported by family and teachers early on, and then by teams and organizations to contribute to a positive health outcome for many people with CF. I am grateful to all of those who supported me throughout my life and who shared this journey with me, including talented teammates at Aurora and Vertex, members of the CF community and my family.
29 September 2022 Hong Kong