Chemical Biology and the Limits of Reductionism
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COMMENTARY Chemical biology and the limits of reductionism Randall T Peterson Chemical biology and systems biology have grown and evolved in parallel during the past decade, but the mindsets of the two disciplines remain quite different. As the inevitable intersections between the disciplines become more frequent, chemical biology has an opportunity to assimilate the most powerful ideas from systems biology. Can the integrationist mindset of systems biology liberate chemical biology from the compulsion to reduce everything to individual small molecule–target pairings? Anyone following rock and roll music over the biological research necessitated the creation of Systematic screens for integration, not last three decades may have faced the challeng- systems biology as a discipline. Clearly, chemical pairing ing and sometimes entertaining task of keeping biology and systems biology do share much in Both systems biology and chemical biology track of Prince Rogers Nelson. This musician common with more traditional disciplines. But have turned to systematic, large-scale studies led fans through a complex series of name the new names appear to have endowed both as their discovery engines. Using many of the changes, adopting at various times the names disciplines with a feeling of newness that is same technologies, studies in both disciplines Prince, Jamie Starr, Camille, Christopher Tracey, attracting bright trainees, research funding and often begin by developing simple, robust assays Madhouse, The Artist Formerly Known as institutional investment (not to mention new and churning through large collections of Prince, and even at one point an unpronounce- journals). Will history view the emergence of small molecules, genes or proteins. However, able ‘love symbol’. Debate continues today about chemical biology and systems biology as inflec- the purposes are usually quite different in the whether the name changes reflected substantial tion points in scientific progress, or will the two disciplines. Systems biology seeks to use creative differences in a rapidly evolving artist terms simply be viewed as generation-specific comparison between conditions as a means of or simply a marketing strategy aimed at creating monikers for pharmacology and physiology? understanding relationships, revealing higher Nature Publishing Group http://www.nature.com/naturechemicalbiology 8 the impression of newness. Regardless of what we call them, the disci- order network structure and modeling the com- In a similar way, the christening of new sci- plines of chemical biology and systems biology plexity. By contrast, chemical biology in general entific disciplines can spark debate about the encompass a great deal of progressive, cutting- is still dominated by the mindset of pairing indi- © 200 significance and meaning of the new names, edge science. The fact that the terms are poorly vidual compounds and targets. In fact, one of and neither chemical biology nor systems biol- defined and have vague boundaries can be an the often-quoted overarching goals of chemical ogy has been exempt. In a job interview with asset, encouraging innovation and overlap with biology—to identify a small-molecule partner a Nobel prize–winning pharmacologist, I once other disciplines. As the disciplines co-evolve for every gene product in the genome—seems unwittingly touched off a polite tirade by declar- and intersect, both will benefit from a frequent to reflect a ‘one compound/one target’ mindset. ing my interest in chemical biology. Like other exchange of ideas. One of the most obvious As a result, systematic chemical biology stud- pharmacologists long involved in the study of opportunities for this is the borrowing by chem- ies (for example, high-throughput screens) the chemistry-biology interface, he questioned ical biology of systems biology’s integrationist are frequently focused on grinding through whether the name chemical biology truly mindset. Systems biologists generally seek to large libraries to identify interactions between reflected a substantially different field of study replace the reductionist ‘one student/one gene’ specific small molecules and a single target or was simply an attempt to dress pharmacology approach with an integrative approach that (Fig. 1a). Additionally, our preferred descriptors up in new clothes. Similarly, some physiologists strives to understand entire systems in their for compounds depend on this simplification. who have long advocated integrative approaches complexity. This integrationist mindset has not We describe aspirin as a cyclooxygenase inhibi- question why the influx of new techniques into yet permeated chemical biology very deeply, tor, atorvastatin as a 3-hydroxy-3-methylglu- although it is beginning to do so. Assimilating taryl (HMG) coenzyme A reductase inhibitor, Randall T. Peterson is at the Massachusetts more integrationist thinking could have posi- and lithium as a glycogen synthase kinase 3β General Hospital, Harvard Medical School, tive effects on many aspects of chemical biol- (GSK3β) inhibitor. These descriptors are useful 149 13th Street, Charlestown, Massachusetts ogy, including the ways we utilize screening data, and carry some information, but in reality these 02129, USA, and the Broad Institute of MIT describe compounds and use animal models. small molecules do much more than inhibit a and Harvard, 7 Cambridge Center, Cambridge, Ultimately, the most important impact may be single enzyme, and neither their beneficial nor Massachusetts 02142, USA. to lessen our dependence on reducing biology to their negative effects in humans are explained e-mail: [email protected] a series of small molecule–target pairings. fully by their actions on a single enzyme. NATURE CHEMICAL BIOLOGY VOLUME 4 NUMBER 11 NOVEMBER 2008 635 COMMENTARY by the diversity of assays, which may use radically Assays different experimental conditions, compound a b 123456789 A doses or readouts and may be conducted by B C Functional classes labs with differing data standards. Nevertheless, D E integration of a compound’s data across numer- F G ous assays creates a ‘biological fingerprint’ (also H I J called a ‘chemical genomic profile’) that serves as K L a functional descriptor for the compound, with M N more information than the structural or text O Small molecules P Q descriptors we typically use (Fig. 1b). R S Biological fingerprints can be used to cal- T culate the degree of functional similarity Systems biology Chemical biology Biological fingerprints between two compounds. More importantly, by comparing across both small-molecule and Figure 1 Evolving uses for systematic data collection. (a) The large-scale, systematic screens of genomic screens, it may become increasingly systems biology and chemical biology generally have different objectives. Whereas systems biology feasible to determine the relationship between seeks to understand the complex relationship of one biological element (for example, protein) to all a compound’s effects and the effects of genetic others, chemical biology has focused on pairing individual small molecules with a single target. (b) By comparing small-molecule activities across a spectrum of assays, biological fingerprints can be perturbations. The power of combined chemi- established that reflect the true, often complex, activity of a small molecule. cal and genomic screens and their potential for determining small-molecule mechanisms of action have been highlighted by recent proof- So, how might a systems biology mindset help originally intended to discover compound- of-concept studies in yeast and Drosophila mel- us relinquish our dependence on forcing every target pairs, can be used to create an integra- anogaster cells6–9. Importantly, describing and small molecule into a neat compound-target tive picture of a small molecule’s biological comparing small molecules using biological fin- pair? Hopefully, it will provide tools and lan- activity1–5. Databases such as PubChem and gerprints does not require the simplified pairing guage to help us conceptualize the simultaneous ChemBank that collect systematic assay data of a compound with a single protein target, but effects of a small molecule on numerous targets. enable assessment of an individual compound’s rather reflects some of the complexity present in Several groups have begun to demonstrate that activity across diverse biological assays. Of the bioactivity of most small molecules. high-throughput screening data, even those course, interassay comparisons are complicated Although biological fingerprints may be the most accurate way of describing the true func- tion of a compound, there is danger that they may be the equivalent of an unpronounceable a Biology ‘love symbol’—unique, but too unwieldy for Chemical biology regular use. Until we find better ways to visual- ize and verbalize the richness of these biologi- cal fingerprints, their utility is likely to remain Reduction Integration Nature Publishing Group http://www.nature.com/naturechemicalbiology 8 restricted to sophisticated computational or predictive settings with minimal impact on how b Nature’s bias O O MeO NH we think about small-molecule mechanisms of © 200 HN O MeO H action on a daily basis. OMe O O OH OMe O O O O 6 O MeO O Spreading out along the reduction- O H integration continuum H OH H O O O O Albert Einstein once advised, “Make everything HO OH as simple as possible, but not simpler.” Systems All possible naturally Selected for ability to target Natural products with produced