Discovering a Career Path on the Road to Drug Discovery

By Alan Wahl, PhD, Principal of Westwahl LLC and previous VP of Discovery at Ambrx Inc

In graduate school I remember coming across a quote taken from Tolkien and carved into the rocky shore of Lake Ontario somewhere near Webster NY: ‘All that is gold does not glitter, Not all those who wander are lost’. The past few decades have made me appreciate its significance. I trained at Rochester in the early ‘80s with two excellent advisors at University of Rochester Medical Center: Dr. Robert Bambara, studying the nucleic acid enzymology of DNA replication, and with Dr. Edith Lord, learning the immunology of monoclonal antibody production.

Following my Biochemistry thesis defense, I moved on to a fellowship in Experimental Oncology at Stanford, continuing to study the cellular mechanisms that control DNA replication, with the expectation that I would eventually pursue an academic path. However, a growing desire to discover new drugs to treat disease, cancer in particular, slowly but strongly surpassed my overarching interest in teaching and the basic sciences. In 1989, I moved from exploring university opportunities and signed on with Bristol Myers Squibb Research (BMS). In doing so, I transitioned from the more theoretical to the very practical and applied: How does one actually make drugs that help people with life-threatening disease? At BMS I learned the trade. I worked in two preclinical teams on compounds that have now become the established and highly effective anticancer agents Carboplatin and Taxol. There was always the underlying basic research, which was great fun and a formidable challenge. Our work, for example, elucidated the cancer-selective mechanism of Taxol provided by a tumor’s lack of cell cycle checkpoint control, but the data and experience were directly applied to improving the efficacy of anticancer treatment.  Bob Bambara had often admonished that a well-trained biochemist should be able to tackle anything and so in parallel I took on a side project, well outside of my prior experience and comfort zone, that eventually led to clinical entry of an early immuno-modulating cytokine.

Over my decade at BMS, I wandered from DNA damage to cell cycle control to cytokines, re-examining what I had missed in the field of immunology along the way. In 1998, I left the relative stability of BMS to build the departments of Oncology and Immunology at a new company, Seattle Genetics, which focused on antibody-targeted cancer therapies. I can admit now that I was likely one of the worst graduate students to ever haunt Edith Lord’s lab, but over the decade at Seattle Genetics I paid close attention to the immunology that I should have paid attention to in Rochester. My efforts led to many of the early and current Seattle Genetics’ programs for therapeutic antibodies and conjugates including several -CD19, CD30, CD33, CD40, and CD70 that have entered the cancer clinic. Each of these has shown therapeutic promise, and one, the anti-CD30 antibody-drug conjugate ADCETRIS, is now an approved and highly effective treatment for refractory Hodgkin’s Disease.

In 2007, I wandered again, this time to another small Seattle biotech, Trubion, to work on highly engineered antibody derivatives. These therapeutic molecules had their roots in antibodies but no longer looked much like antibodies. Very cool science and engineering, but I was always concerned with the questions of will they be useful, and will they work in the clinic? Our efforts at Trubion led to clinical entries of single-chain antibodies targeting CD20 and CD37, for autoimmune disease and lymphoma respectively, and of a structurally new bispecific antibody to redirect effector T cells to tumor markers. Following the company’s acquisition in 2010, I joined Abbott Labs (now Abbvie) to oversee their Oncology Biologics Discovery (Redwood City, California), and explore new therapeutic opportunities in the exciting field of immuno-oncology. At the end of 2013, I returned to another small biotech, Ambrx (San Diego, California) to apply a new protein engineering technology to the science of linking a protein to a small molecule drug through the incorporation of non-natural amino acids. The technology was successful, new molecules have entered clinical testing and the company was acquired in 2015.

Today, I advise multiple healthcare-based venture capital firms on forward-looking biotechnology, and can look back on a career thus far with some guiding notes:

• Remarkably, for students and fellows, your mentors and colleagues today may well be your mentors and colleagues 30 years from now. Stay in touch, help each other, and show them what you can do.
• In science, don’t search for the stability and the glitter of what is already established. Big pharma has an allure of unlimited resources and global reach in which much can be accomplished, but can be bureaucratically constraining. Biotech has the full-bore excitement of small team exploration but can change dramatically with a single success, or a single failure. Both environments are vehicles to drug discovery. Find what drives your passion, and which environment best enables your pursuits.
• It’s important to remember that you don’t know what’s important to remember. As a graduate student, I was all about the mechanisms of DNA replication and did some good work in that field, but eventually found my greatest impact has been in the field of immunology. Who knew?
• If your interest is in drug discovery, don’t be afraid to wander into tough areas, areas of unmet needs. Seek out science and medicine’s hard problems. There are plenty that still need to be tackled. Find what really needs to be done and go do it. Prepare your mind for a journey, then explore and invent!

Tracey Baas | 10/11/2016

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