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Published February 2019 | public
Journal Article

A Personal Perspective on Chemical Biology: Before the Beginning


This perspective represents a brief personal account of early days before "chemical biology" emerged as a field of inquiry. Imagine a time when oligomers of DNA could not be synthesized and the order of the TACG letters in DNA could not be sequenced. Even the high resolution structure of the DNA double helix was not yet determined. 1975 was a time when there was a deep chasm between chemistry and biology. Chemists with precise knowledge of all the atoms in natural product architectures looked with dismay at the imprecise messy world of biology. Water was to be avoided! My view was that the power of synthetic organic chemistry should be used to create function, synthesis with a purpose. Our organic group at Caltech would embrace molecular recognition of biologics in water as a frontier for chemistry. We dreamed of inventing small molecules that would control the activity of macromolecules such as DNA, proteins and carbohydrates in living cells. We chemists would sky dive into the messy world of biology.

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© 2019 Wiley‐VCH Verlag GmbH & Co. KGaA, Weinheim. Manuscript received: November 30, 2018; Version of record online: January 23, 2019. Special Issue: Rosarium Philosophorum – Chemical Biology. I wish to thank the Editors in particular Ehud Keinan for the invitation to participate in this Rosarium Philosophorum on Chemical Biology. I am grateful to the National Institutes of Health (General Medical) for 45 years of uninterrupted financial support and, more recently, the Prostate Cancer Foundation. I am grateful for the contributions by the 192 graduate students and postdoctoral fellows who passed through my laboratory at Caltech 1973–2018. It was difficult for them to have an advisor who was always the learner and never the expert in the room as we migrated from biophysical chemistry to cell biology to xenograft mouse experiments. There was risk and many projects failed but I believe the experience fortified my former coworkers for success later in their careers. I am grateful to my collaborators, David Wemmer, Doug Rees, Joel Gottesfeld, Karolin Luger, Aseem Ansari, Michael Phelps and Dong Wang. I am indebted for the support of our program and encouragement over the years by Michael Waring, Hiroshi Sugiyama and Bengt Nordén. This personal essay is dedicated to Claude Hélène who shared our passion for discovery in nucleic acids and who passed away too young. I am grateful to my coworker Alexis Kurmis who helped prepare graphics.

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