Chemical Biology: Powerful Synergy Between Two Cultures

Abstract

Dear Reader, the explosive growth of the young field of Chemical Biology (CB) is evident from its high-profile journals, including Nature Chemical Biology, ACS Chemical Biology, Cell Chemical Biology and ChemBioChem, and from its popular conferences, such as EMBO biannual chemical biology meeting, which attract increasing audiences from both academia and industry. Several prestigious Chemistry Departments have changed their names to Department of Chemistry and Chemical Biology to accommodate the glory and appeal of CB to the young generation of scientists. Obviously, no singly authored view could serve as an authoritative statement about the perspective and prospect of the field of CB, its history, strength, amazing diversity, contribution to other fields, to humankind, its predicted future, etc. Therefore, in order to create an integrated collage of personal opinions by several authors, we approached prominent scientists who are active in the field, and requested their personal views and reflections, offering some guiding questions: How do you view the historical development of CB, and of your specific field in particular? What have been the most significant contributions of CB to science/humankind? How would you respond to comments that CB is service technologies rather than independent science? In retrospect, were the key achievements of CB predictable? Where may CB go in the next 20–30 years, and what are the open questions? The resultant compilation of personal opinions could inspire and influence not only scientists and corporate decision makers, but also administrators of research funding agencies and even journalists and politicians. This Rosarium Philosophorum on CB joins this growing series of Rosaria, which focused on Physical Organic Chemistry (2016),1 Structural Chemistry (2017)2 and Organic Synthesis (2018).3 In 1987, Arthur Kornberg, who won the 1959 Nobel Prize in Physiology or Medicine for his discovery of the mechanisms in the biological synthesis of DNA, published a monumental article in Biochemistry, titled “The Two Cultures: Chemistry and Biology.” Kornberg4 made a dramatic plea for unification of these cultures for the benefit of science and humankind. As Peter Dervan pointed out, in 1987 there has been already substantial evidence for the realization of the desired unification. Nevertheless, these early signs were probably overlooked by Kornberg, who expressed his rather pessimistic view, criticizing both biochemistry and molecular biology for failing to bridge the gap: “Chemistry and biology are two distinctive cultures and the rift between them is serious, generally unappreciated, and counterproductive… I was led to wonder whether a sociological study of chemists and biologists might be helpful in understanding their different styles. Are chemists more conservative, analytical, and clannish than biologists? Are biologists more artistic, eclectic, and right-brain dominated than chemists? Which of the language barriers is more formidable and needs earlier imprinting? How much of the cultural difference between chemists and biologists is attributable to highly evolved training and vocational patterns? What are the consequences of most chemists being employed in industry and most biologists in academia? Insights gained from such a study might be useful for science training and practice in the future.” “Despite its enormous success in solving these and other problems, biochemistry has nevertheless failed to fill the gulf between chemistry and biology. Instead, as I shall discuss, biochemistry itself is being pulled apart by the separate drifts of the two cultures from which it was assembled.” “In its rapid and turbulent growth, molecular biology has washed away much of the bridge to chemistry. In the rush and excitement over the new mastery over DNA, attention in biochemistry departments has been sharply shifted to major biological problems of cell growth and development and away from chemistry… Molecular biology falters when it ignores the chemistry of the products of the DNA blueprint - the enzymes and proteins, and their products… We now have the paradox of the two cultures, chemistry and biology, growing farther apart even as they discover more common ground.” We thank Peter Dervan and Chaitan Khosla for essentially adding Kornberg's article as an integral part of this Rosarium. One could speculate on what would Kornberg write 3 decades later, vis-à-vis the overwhelming evidence for the realization of his desired unification of the two cultures. Dervan argues that the organic and physical chemists, who were blamed for creating and maintaining the gap, where those who eventually bridged it. And these early pioneers, who started with very limited experimental toolbox, didn't realize they are creating a new field in science. We collected some selected quotes made by the “philosophers” of this Rosarium, and this collage of opinions creates a colorful, informative picture of the field. By no means these quotes fully represent their authors and respective articles; we just found them interesting, worth sharing, and useful curiosity triggers. Peter Dervan: “In the 1980s the early pathfinders were trained as organic chemists, not biochemists, and applied chemical thinking to biologic processes… the beginning of chemical biology was CHEMICAL not quite full biology… the next generation of chemists who would balance the chemical-biology portfolio… third generation were true hybrid chemists-biologists.” “The phrase service technology sounds somewhat subservient and suggests chemical biology makes tools and reagents which biologists use to make the important and significant discoveries. In my view there is no problem here! New methods drive and enable new discoveries often in a neighboring interdisciplinary field.” Christopher Walsh: “The term chemical biology emerged about 25 years ago and encompasses a set of research inquiries at the intersections of chemistry and biology. Before chemical biology there was biological chemistry for 100 years or more, but the traverse from one to the other has not just been a switching of noun and adjective. Over the past quarter century chemists, many from organic synthetic lineages, have become convinced that the open systems of biology have become appropriate venues to bring chemical thinking for library design, screening, and molecular scaffold optimization. Whereas biological chemistry may be described as the universe of chemistry that happens in nature, chemical biologists often bring new, unnatural molecular scaffolds to decipher the logics of biology. That seems a limiting definition and I prefer the mantra: think chemically, act biologically.” Benjamin G. Davis: “Until now the accomplishments of Chemical Biology have been predictable in part, more enabling but now finally tending towards uniquely revealing – it is key that the future will not be solely in ‘tool delivery'. Without chemical mechanism, Biology and Medicine will stumble increasingly into an intellectual bankruptcy based on reductionism… It has never been a better time to be a Chemist. The subject's unparalleled sophistication may, however, be stimulating an intellectual crisis that could necessitate new analytical frameworks that serve to stimulate new knowledge. So how do we address the dilemma of a greater need to describe well our science, on one hand, and even greater detail in that science, on the other? This is therefore a tension in breadth and depth. I present here, using some strategic examples, an opinion that such frameworks should also embrace sophistication rather than merely simplification if they are to succeed.” Chaitan Khosla: “It appears that Nature's core principle for assembly line polyketide synthase diversification has been to evolve new manifolds for channeling reactive intermediates between pairs of pre-existing active sites. How a chemical biologist can be expected to reconstruct this evolutionary feat in the laboratory is beyond the scope of any established paradigm in physical organic chemistry. As the legendary Albert Eschenmoser once remarked in a private conversation after a lecture I gave in his presence, ‘I feel sorry for those of you who study biological processes that seem so dependent on non-covalent bonding. As if covalent bond chemistry isn't complicated enough'… Notwithstanding the fact that the time-honored language of physical organic chemistry can teach us a lot, it is often insufficient to describe many of these events, and must therefore evolve.” Dan Tawfik: “For many, Chemical Biology regards the development of chemical tools for biological applications: analytical tools, and most typically synthesis of molecules that probe or modulate various biological processes. However, for me, there is much more to Chemical Biology than the development and application of chemical probes. Rather, by my own, personal definition, Chemical Biology regards the implementation of a chemist's mindset to biological questions: obtaining mechanistic insights by applying the laws of physical chemistry paired with quantitative, molecular structure-function analyses.” Floyd Romesberg: “Chemical biology is usually thought of as the effort to develop synthetic small molecules that in some way interact with biological systems. But what if the synthetic small molecules are designed to be “parts” that function in living cells to create new organisms with new attributes? This has been called “xenobiology,” but it seems to just be the chemist's approach to synthetic biology, and I will refer to it as such… The fundamental difference between the biologist's and chemist's approach to synthetic biology is in the natural versus unnatural nature of the “parts” being used. In some respects, the chemist's approach is more challenging – unnatural parts do not have the benefit of eons of evolution for at least a similar function.” Stuart L. Schreiber: “My goal in this essay is to point readers to a possible solution to these challenges – a novel drug-discovery path that bypasses traditional biochemical activity-based screens or cell or animal-based phenotypic screens. I am imagining that this path is complementary to the two well-established ones – it may be well suited for the types of challenging non-traditional targets emphasized in this essay, whereas there will be drug-discovery efforts, for example those requiring “simple” enzyme inhibitors, that may be adequately served by the traditional approaches. The binding-based path will benefit from innovations in organic synthetic chemistry and chemical biology and provides a conceptual framework for a more general approach to drug discovery – extending to small-molecule drugs that target critical regulatory proteins that function inside of cells and that are therefore less easily modulated with protein therapeutics.” Chi-Huey Wong: “Chemical biology is an interdisciplinary field that uses chemistry (especially synthetic chemistry and other chemical techniques) to dissect the complexity of biological systems. Chemical biology is different from biochemistry, a study of the chemical processes of the biological systems at the molecular level (e. g., biosynthesis and metabolism), but the two fields often overlap. For example, the origin of “chemical biology” could be traced back to the classic biochemical study by Bloch on the dehydration mechanism of fatty acids… Later on, the terms of suicide substrates and enzyme inactivators were introduced to describe this type of enzyme inhibitors, though Bloch preferred the use of Trojan horse inhibitor. In any event, his work stimulated the development of the cholesterol-lowing agents, statins, which acted as HMG-CoA inhibitors. In a more general sense, this research represented a new approach to develop drugs targeting specific enzymes using the techniques of chemical biology, which incorporated methods and knowledge of synthetic organic chemistry, biochemistry, cell biology, and pharmacology.” Andreas Marx: “During recent years, the field of Chemical Biology has undergone a continuous maturation process driven by the advent of new technologies and increasing awareness that insights into complex biological systems require interdisciplinary efforts. In consequence, Chemical Biology evolved into a multidisciplinary research area where novel tools and methods are developed to make profound scientific discoveries. This became possible by impressive advancements in the Chemical Biology repertoire generating sophisticated probes that allow to analyze, modulate, and monitor biomolecules and complex biological processes at the atomic and molecular level, respectively. The conceptual transition from a single-edge discipline to an integrated research field, where key scientific questions are addressed by multiple, interdisciplinary and complementing approaches, puts Chemical Biology into a prime position to make significant contributions to the understanding of the intricate network of cellular pathways and how they are regulated and fine-tuned in a concerted manner.” Carsten Schultz: “Long before the term chemical biology was created, there was the desire to use chemistry for unraveling the endlessly complex world of biology. The impact of this work has been tremendous, as we are now able to follow and switch biological processes at will and in real time. In fact, without these tools it will be very difficult to address the complexity of biology in the future… During my postdoc in Roger Tsien's lab, I was amazed how much biology expertise and biological diversity was in place… we started collaborations with scientists in the clinics around the UCSD campus. More than anything else, these possibilities for collaborations and the experiences in labs with an entirely different background changed my view on science and my desire to dive deeper into biology and medicine. I am therefore a very strong believer that it is most useful for researchers at any career level to get physically exposed to research in neighboring disciplines. In fact, the traditional department structures as well as physical separation of institutes at times prohibit exchange between disciplines.” Oliver Plettenburg: “Today chemical biology is defined as applying sophisticated chemical methods, both, synthetic and analytic, to address specific biological questions. In this context, chemistry now also serves as a facilitator to generate tailored tools to visualize and understand dynamic physiological processes, study biochemical pathways or cell-cell communication, shed light on the development of pathology and unravel the origins of the development of specific phenotypes… It is clear that chemistry with respect to optimizing compound series by means of medicinal chemistry will remain at the core of drug development. However, this work is now complemented in an ideal fashion by efforts to generate probes and enable target validation by means of chemistry at the interface of chemistry and biology. This new discipline quickly turned into an integral and indispensable part of the drug discovery process that will contribute to the development of new and effective medications to improve on current treatment and to enable the treatment of previously incurable diseases.” Herbert Waldmann: “Phenotypic screening is currently undergoing a renaissance in chemical biology and drug discovery research. New assays that truly mimic a disease state are still challenging to develop. However, advances in the culture and use of induced pluripotent stem cells and organoids are very promising steps in the right direction. For instance, the introduction of the high content phenotypic ‘‘cell-painting assay'' platform has provided a powerful tool to broadly assess biological compound profiles, provided that they induce changes in cellular morphology. Diverse fingerprints obtained from this assay can be used as a metric for the construction of focused chemical libraries that cover a broad range of biological space. However, identification and validation of the biological target(s) and uncovering the underlying mode of action of the hit compound(s) is an extensive, time- and cost-intensive exercise and a formidable challenge in chemical biology. This arguably may be the most limiting factor in many chemical biology and drug discovery efforts.” Lei Liu: “Biology can be regarded as a system of biomacromolecules that is far from being completely understood. To improve our understanding of biology, we need to accurately reconstitute and selectively perturb biochemical processes – a task requiring of, amongst other things, proteins. Because neither biosynthesis nor engineered biosynthesis can deliver all the requisite proteins, synthetic chemistry is needed for their synthesis. That said, chemical protein synthesis remains a challenging subject in the disciplines of both synthetic chemistry and chemical biology. Despite significant progress, many proteins cannot be readily synthesized. New synthetic methods are needed, and more complete testing of current chemical protein synthesis technologies needs to be conducted. More importantly, the applications of these non-recombinant proteins need to be explored and used to confront pragmatic biological problems; the protein post-translational modification biochemical and biophysical studies and peptide/mini-protein-based diagnostics and therapeutics are particularly exciting.” Shuichi Takayama: “…my first point which is the “counter-intuitive” importance of heterogeneity… this heterogeneity is not just noise or due to unwanted biological mistakes, but may be due to a programmed system of fate determination… my second point which is the “counter-intuitive” importance of disorder. My chemical biology background in targeting enzymes for inhibition as well as using them as catalysts to facilitate key chemical transformations required to synthesize potential inhibitors, the usefulness and value of proteins were linked strongly to their defined structures. How surprising then to learn that many proteins in the cell exert their function, not in spite of, but thanks to disorder.” We invite you to dive into this unique special issue and read the detailed opinions of our “CB Philosophers”. Finally, we wish to thank all those who took part in this important endeavor, particularly the authors who shared with us their thoughts and perspectives, the reviewers and the highly professional team at Wiley-VCH. Enjoy your reading! Ashraf Brik and Ehud Keinan