A Look Back

49 years ago, when I was 16 years old, I wanted to do exactly what I am doing now. The only subject in school that held my interest was biology. As soon as I learned about DNA and RNA, I wanted to be a molecular biologist. I wanted to use molecular biology to create drugs. However, that was 1972, and the biotechnology industry did not exist. Growing up in Shrewsbury, Massachusetts, it was natural for me to attempt to get a summer job up the road at the Worcester Foundation for Biomedical Research, where the first oral contraceptive was created. After telling one of the more senior scientists about my goal, he told me to forget it and find another interest – “you will never get a job.”

I am now at the end of a career that has comprised nearly 10 years of academic research and 35 years in biotechnology. I am retiring at age 65, a decision that seems both traditional and a bit arbitrary. But, as my retirement date has crept closer, it seems increasingly appropriate to step aside and give way to the next generation of leaders.

Last stops at RNA

My last roles in biotech were where my original passion began: DNA and RNA. Both companies were founded to explore new space for drug discovery related to RNA, representing the revolution in RNA-focused drug discovery that has happened in the past decade or so. My last stop at Arrakis Therapeutics is with a company targeting RNA with small molecules. Prior to that, I was CSO at RaNA Therapeutics (now Translate Bio), initially focused on targeting the function of long noncoding RNA in epigenetic regulation, and later transitioning to an mRNA therapeutics company.

Arrakis is the capstone of my career. I was enticed by Arrakis’ founder Jen Petter to serve in one more operational role, leading the research group at Arrakis as the company launched as one of the first biotechs to target RNA with drug-like small molecules. It was exhilarating to pioneer new drug discovery territory, by targeting structures in mRNA to modulate the splicing, translation or degradation of mRNA encoding undruggable proteins such as transcription factors and other oncoproteins. The Arrakis platform has combined two of the key threads of my career: keeping me in the RNA field, while also applying traditional medicinal chemistry for small molecule drug discovery. It also captures what drives me and others like me – the opportunity to create a new class of drugs to address diseases not currently treated effectively, but to do so in a novel way. It also takes advantage of the evolution of “big data” that has changed the landscape of drug discovery, as we can globally interrogate all RNAs in human cells at once. Our approach has high risk but tremendously broad potential. I am happy that I will remain associated with Arrakis as a member of the Scientific Advisory Board.

Falling in love with an industry and a protein

My first industry position was at Biogen, and I was incredibly fortunate to be a part of the successful growth of the biotechnology industry during my 16 years there. Biogen initially started in Geneva as the second biotech company after Genentech. The founders decided to locate the company in Europe since it was not clear at the time whether the biotechnology industry could support two companies; therefore, Genentech would be the US company and Biogen the European biotech. Although this thought seems absurd now, it provides a perspective on the uncertainties facing this new industry in the 1970s.

At Biogen, my group’s work covered a range of technology development areas including protein production in mammalian cells, intracellular protein delivery (our work on HIV Tat started the field of cell-penetrating peptides) and novel gene delivery vehicles, as well as biological drug discovery and development. The specific area in which my group focused most was type I interferons, most notably IFN-β. Here, like other scientists, I found that it is possible to fall in love with a protein.

Along with work on IFN-β protein, which became the multiple sclerosis drug Avonex^®, my team worked extensively on adenovirus-mediated IFN-β gene therapy. Delivering the IFN-β gene into tumors caused cancer cell apoptosis and activated both innate and adaptive anti-tumor immune responses. Ad-IFN-β was an early immuno-oncology program before the great success of the checkpoint inhibitors. This agent displayed spectacular efficacy in a wide variety of mouse cancer models, some of the best results that my team and our academic collaborators ever produced, and this program remains one of my favorites. Unfortunately, the program was terminated, resulting in one of many disappointments that anyone in biotech is bound to encounter. It also highlights the need for resilience in the face of setbacks and a deep well of fresh ideas. As any good idea tends to have a long life, Ad-IFN is currently in a phase 3 clinical trial in mesothelioma patients.

One of the major growth experiences at Biogen was learning how to manage people. This is an area in which most academic postdocs have little to no experience. Mentoring scientists is one of the most important and rewarding experiences, and can be one of the more challenging responsibilities. One must learn to adapt to the interests, motivations, anxieties and ambitions of each individual. As scientists who are managers, we must recognize the frustratingly non-uniform nature of human beings and create our own management style.

The most important event for me at Biogen was meeting my wife Sue. Biogen was a close family in which employees stayed for decades. I was not alone in meeting the love of my life at Biogen.

Small molecule drug discovery and the wonder of biotech start-ups

After my time at Biogen, I went to Synta Pharmaceuticals, first as VP/Biology and then SVP/Research. Synta was focused on small molecule drug discovery and development in oncology and inflammatory diseases. This started my long-term preference for smaller companies – from start-up to ~100 employees.

The start-up atmosphere is particularly thrilling. At smaller companies, I could learn more because my job required me to play a greater variety of roles. We advanced multiple compounds against a variety of targets into clinical trials. We saw a new phenomenon with the emergence of social media that enabled us to follow the experiences of patients through their blogs and social media postings. I had a first-hand role in raising money from Wall Street by being part of an IPO roadshow as Synta went public in 2007. Unfortunately, I also experienced the tribulations of biotech with the devastating experience of late-stage failures in clinical trials, as two drug candidates that had promising phase 2 clinical data failed in phase 3. Having to lay off hard-working researchers after a phase 3 failure and loss of a pharma partnership was the low point in my career, but one of the sobering realities of biotech start-ups.

Drugs are not hunted or discovered

Through my time at Synta and other companies, I learned to enjoy the progress along the way and to appreciate the breakthroughs. Sir James Black, one of our advisors at Synta, was one of the greatest drug hunters in the history of the pharmaceutical industry. But, he did not like to be called a “drug hunter”, and he even recoiled at the term “drug discovery”. He would say that “drugs are not hunted or discovered”. They are created through the innovative thinking and tireless efforts of scientists. As a creation, they can have beauty as well as utility. I have had the privilege of working with a large number of brilliant scientists who are dedicated to this calling.

Brilliant scientists were there during my graduate and postdoctoral work, fostering research topics that remained a focus during my industry career over decades: transcriptional regulation, epigenetics and gene therapy. I obtained my Ph.D. at MIT in Alex Varshavsky’s lab, focusing my primary research on the effect of histone modifications and chromatin structure on transcription, which later became known as epigenetics. I did a postdoc with Paul Berg at Stanford, studying transcriptional regulation. Having an interest in the emerging field of gene therapy, I did a brief postdoc with Richard Mulligan at the Whitehead Institute.

Drug discovery is my passion. What we do is difficult. Failure is common. The ultimate success is incredibly rewarding. We need to be driven to help patients. However, it is such a long path to an approved drug that, on a day-to-day basis, one needs to be motivated by the love of science and the enjoyment of our colleagues. It is most critical that we respect and support the co-workers at each side of us at the bench and in the conference room. I am thankful to have worked with so many wonderful colleagues, and I am confident in the prospects that we created at Arrakis.