A Decade of Chemical Biology

nature chemical biology | VOL 6 | DECEMBER 2010 | www.nature.com/naturechemicalbiology 847

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A decade of chemical biologyWith insights from a panel of experts, the Nature Chemical Biology editors examine the evolution and current era of chemical biology.

Twenty years ago, chemical biology was just an idea. Since then, that idea has evolved into a global community of

scientists dedicated to understanding science at the intersections of chemistry and biology. How did this major transformation occur, and where is chemical biology going next?

To find out, we contacted 50 chemical biologists, all of whom have witnessed and participated in the field’s evolution over the past decades (see p. 854 for our final list of advisors). We invited them to share their thoughts on the scientific and cultural evolution of the field, to identify the major scientific contributions of chemical biology over the past decade and to outline current challenges for the field. Despite a diversity of opinions on how to define chemical biology, our panelists, working independently, arrived at a remarkably precise and coherent view of the discipline. For example, while they identified many significant papers published from 2000–2010—a selection of which are captured here in a timeline of chemical biology research (Fig. 1)—they quickly converged on the ten most influential papers of the decade, which are featured in short highlights throughout this article. They also described a changing scientific culture poised to influence chemical biology research in the coming decades.

origins of chemical biologyDefining ‘chemical biology’ has been a challenge since the term came into wide use in the 1990s. Even Stuart Schreiber, who is frequently credited with coining the term, has a difficult time identifying the origins of the name although he notes that it at least traces to Konrad Bloch1. Though our panelists had differing views on the precise definition, they generally agreed that chemical biology emerged over decades as a complex hybridization of bioorganic chemistry, biochemistry, cell biology and pharmacology. Each parent discipline has endowed chemical biology with specific scientific themes and methodological approaches, but in the current global, interdisciplinary scientific environment, they have blended to produce a distinct discipline defined by a practical desire

to understand and manipulate biological systems in new ways.

Bioorganic chemistry, which applies synthetic and physical organic chemistry to biological questions, is the primary disciplinary precursor of chemical biology. As Erick Carreira, one of our advisors, suggested, bioorganic chemistry was founded on the premise that “the ultimate currency of biology is molecules, large and small.” This philosophy highlights the important role that molecular studies have traditionally played in chemical biology research. Over time, bioorganic chemistry broadened its scientific purview, and in

doing so, served as the training ground for the first scientists who referred to themselves as chemical biologists.

During that period, bioorganic chemists used their ability to synthesize almost any desired molecule as a means to understand chemical mechanisms in biological systems with great success. Bioorganic chemistry provided new fundamental insights into enzymatic catalysis through the use of ‘biomimetic’ enzyme models and ushered in the molecular biology era by providing robust, automated methods for the synthesis of oligonucleotides and peptides of any sequence. Yet, these chemists offered more than powerful tools: they brought a new mindset to studying biology. “Chemists are quantitative and computational, and they know how to analyze problems in terms of structure, energetics, and kinetics,”

noted Thomas Cech. “Biology needs these approaches.” Chemists of all kinds—analytical, inorganic, organic and physical—saw the great potential of applying chemistry to important biological questions and began forging collaborations with biologists who had complementary interests.

Though chemical biology has its roots in chemistry, the fields of biochemistry, cell biology and pharmacology all contributed significantly to our modern conception of the discipline. Many panel members argued that biochemistry was the first discipline dedicated to explicating biology in chemical terms and that along with bioorganic chemistry, biochemistry stands as one of the most influential intellectual threads in modern chemical biology. Yet others pointed out that cell biology had adopted chemical biology approaches early on, using small molecules as tools to reversibly control cellular pathways or as reagents for cellular imaging. Cell biologists also were uniquely positioned to identify biological questions that were addressable by chemical approaches and thus provided significant direction for the burgeoning field. Pharmacology, a discipline devoted to understanding how small-molecule drugs function in cells and in organisms, in turn linked chemical biology to the realm of medicine. These various threads made chemical biology’s worldview broad, and they instilled it with an emphasis on the practical.

The 1990s were a formative era for the field. By the middle of the decade, the term ‘chemical biology’ was serving as an organizing idea for researchers with diverse scientific interests. The field’s global expansion was reflected in the inclusion of ‘chemical biology’ in the names of academic departments, the active recruitment of chemical biology faculty members and the development of chemical biology training programs. Publishers took note, and the first chemical biology journals, Chemistry & Biology and Current Opinion in Chemical Biology, were established to cater to researchers at the interface of chemistry and biology. Scientific conferences increasingly featured chemical biology sessions, and new meetings, such as the annual Yale Chemical

The multiple intellectual and methodological threads that have contributed to our view of modern chemical biology

have also made it a community of scientists open to new

ideas, willing to take on tough challenges and motivated to ensure that their science has

impact in the ‘real world’.

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848 nature chemical biology | VOL 6 | DECEMBER 2010 | www.nature.com/naturechemicalbiology

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are now an essential tool for examining the mechanisms of small-molecule action in cells.

Our panel also noted that structural biology, like molecular biology, has transformed chemical biology in the past decade. Technological developments that made it easier to produce large quantities of proteins and nucleic acids for structural studies and advances in instrumentation and computational power have streamlined the process of determining three-dimensional structures by NMR or crystallography. These have made it possible to obtain our first atomic-level snapshots of some of biology’s most complex and interesting machines. For instance, after decades of biochemical studies, the revelation of the three-dimensional structure of the ribosome3,4 was likened by many, including Gerald Joyce, to a “near-religious experience.” Seeing the

In addition to contributing a certain viewpoint and a toolbox to chemical biology, in the past decade molecular biology has also delivered game-changing new insights that have deeply influenced chemical biologists. The discovery of RNA interference pathways led to what Philip Cole calls an “RNAi revolution,” which reshaped our view of gene expression and the abundance and diversity of small RNAs in cells. In Cole’s view, the discovery of RNA interference “has to be seen as one of the major accomplishments of the decade.” A number of scientists on our panel identified a particular study from the Tuschl lab as a

landmark paper2 for chemical biologists. By providing evidence that synthetic small-interfering RNA (siRNA) duplexes could be used to target gene silencing in mammalian cells, the study laid the

foundation for ‘knockdown’ approaches that

Biology Symposium (initiated in 1998), were founded to facilitate conversations among chemists and biologists.

chemical biology in transitionIf chemical biology of the 1990s could be described as having a ‘molten globule’ state, the following decade (2000–2010) could be viewed as a steep energetic trajectory toward a stable but dynamic form of the field. A key driving force during this period, as our panel pointed out, was the unprecedented expansion in our understanding of complex biological systems made possible by new technologies and interdisciplinary efforts. Karen Allen remarks that “chemical biology has the potential to address what I believe is one of the greatest knowledge gaps facing us today: that between the atomic level and the cellular level.” The excitement engendered by this opportunity has lowered barriers to collaboration and encouraged scientists to take a more ‘problem-based’ approach in which ideas and technologies from a variety of disciplines are used to bridge this important gap.

Many of our panelists suggested that molecular biology had a transformative effect on the field by providing powerful biological tools that chemical biologists rapidly adopted. With its focus on informational macromolecules and a versatile toolbox for manipulating them, molecular biology endowed chemical biologists with straightforward access to genes, RNA and proteins. Benjamin Cravatt notes that these tools stimulated a “movement away from artificial model systems that only marginally replicate true biology toward the direct examination of complex biological systems themselves.”

2000 2001 2002 2003 2004 20102005 2006 2007 2008 2009

Modified Staudinger ligation8

Analog-sensitive kinases14

Ribosome structure3,4

Activity-based probes7

Streptomyces coelicolor genome5

Click chemistry in situ9

A TRP receptor senses temperature22

The druggable genome23

Personalized medicine27

Histone demethylation28

Yeast chemical genetic profiling29

shRNA screens30

The Connectivity Map19

Sub-di�raction-level imaging35

Discovery of platensimycin36

Inhibitors of lipid kinases16

Biology-inspired synthetic strategies37

Synthetic ubiquitylated histones13

Chemicals regulate stem cells42

Proteostasis defined43

High-content screening for target ID44

Reprogrammed bacteriaseek and destroy49

A new radical SAM mechanism50

Public antimalarial candidates51,52

PRIME fluorophore labeling53

UAG

MudPIT6

Genetic code reprogramming11

RNAi in mammals2

Imatinib becomes a drug15

Automated carbohydrate synthesis21

Design of a novel protein fold24

Semisynthetic Rab revealsits function25

Origins of amyloidogenesis26

Kinase inhibitor specificity assays31

Auxin receptor identified32

A mechanism-basedfemtomolar inhibitor33

Optical manipulation of neural activity34

Structure of theβ2-adrenergic receptor17,18

Brainbow38

In silico enzyme assignments39,40

Unprotected naturalproduct synthesis41

Chaperones facilitate neutral drift45

Chromatin-level regulationof biosynthesis46

Small-molecule activators47

Metabolic engineering in plants48

Figure 1 | Key chemical biology discoveries over the past decade.

mammalian rnai Nature 411, 494–498 (2001)RNA interference (RNAi) is a cellular mechanism in which gene expression is silenced by small-interfering RNAs (siRNAs) that have sequence complementarity to a target gene. The discovery of RNAi in organisms such as nematodes, fruit flies and plants in the late 1990s stimulated great interest in understanding how active siRNAs are produced from double-stranded RNA (dsRNA) and whether these pathways operate in other eukaryotes. At that time,

the prevailing view was that mammals lacked RNAi pathways because they already had a nonspecific dsRNA-dependent pathway that globally downregulated gene expression. Elbashir et al. changed that view in 2001. They first showed that mammals use RNAi pathways by demonstrating that exogenous application of chemically synthesized siRNA duplexes to mammalian cells can suppress expression of heterologously expressed or endogenous genes in a sequence-specific manner. They also demonstrated that the RNAi and nonspecific dsRNA pathways could operate orthogonally. Taken together, these results opened the door for functional genomics in mammalian cells using ‘knockdown’ approaches and energized efforts to apply siRNAs for therapeutic strategies.

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architecture of the ribosome at the atomic level allowed researchers to integrate years of data and more rapidly formulate and test specific hypotheses about molecular aspects of its function.

Finally, many panelists felt that the emergence of ‘big science’ initiatives and the era of ‘systems biology’ encouraged chemical biologists both to embrace the complexity of biological systems and to do so in an increasingly collaborative fashion. For instance, international genome sequencing collaborations transformed how chemical biologists understand natural product biosynthesis. The sequencing of the Streptomyces coelicolor genome in 2002 (ref. 5) revealed previously unseen

biosynthetic clusters, which inspired the community to turn to genome-wide approaches to learn about the structures and origins of

secondary metabolites in cells. As Jörn Piel recounts, “This insight has sparked the area of gene-based natural product discovery and resulted in methods such as genome mining and the activation of cryptic pathways.”

Taken together, these and many other intellectual and technological threads from molecular biology, structural biology and systems biology from the past decade provided an expanded view of the remit of chemical biology and launched the field in new scientific directions.

insights from a golden ageThe development of new chemical tools designed to probe biological systems has been a major theme of chemical biology research in the past decade. Tom Muir described the early days of tool development

2000 2001 2002 2003 2004 20102005 2006 2007 2008 2009

Modified Staudinger ligation8

Analog-sensitive kinases14

Ribosome structure3,4

Activity-based probes7

Streptomyces coelicolor genome5

Click chemistry in situ9

A TRP receptor senses temperature22

The druggable genome23

Personalized medicine27

Histone demethylation28

Yeast chemical genetic profiling29

shRNA screens30

The Connectivity Map19

Sub-di�raction-level imaging35

Discovery of platensimycin36

Inhibitors of lipid kinases16

Biology-inspired synthetic strategies37

Synthetic ubiquitylated histones13

Chemicals regulate stem cells42

Proteostasis defined43

High-content screening for target ID44

Reprogrammed bacteriaseek and destroy49

A new radical SAM mechanism50

Public antimalarial candidates51,52

PRIME fluorophore labeling53

UAG

MudPIT6

Genetic code reprogramming11

RNAi in mammals2

Imatinib becomes a drug15

Automated carbohydrate synthesis21

Design of a novel protein fold24

Semisynthetic Rab revealsits function25

Origins of amyloidogenesis26

Kinase inhibitor specificity assays31

Auxin receptor identified32

A mechanism-basedfemtomolar inhibitor33

Optical manipulation of neural activity34

Structure of theβ2-adrenergic receptor17,18

Brainbow38

In silico enzyme assignments39,40

Unprotected naturalproduct synthesis41

Chaperones facilitate neutral drift45

Chromatin-level regulationof biosynthesis46

Small-molecule activators47

Metabolic engineering in plants48

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Predictive power Nature 417, 141–147 (2002)When this paper was published, the rise of genome sequencing, and thus of comparative genomics, was just beginning to yield new

insights into relationships between species and adaptation to specific

environments. The Streptomyces coelicolor genome, containing more than 8.6 million base pairs and nearly 8,000 predicted genes (almost 25% of the number estimated for humans at that time), took the world by surprise. In this paper, Bentley et al. discovered that nearly half of the genome encoded “nonessential functions,” including more than 20 clusters of enzymes characteristic of secondary metabolism—most of which had not been assigned to a specific natural product, and several of which appeared to be recently laterally transferred insertions. When considered in combination with the enormous number (12%) of predicted proteins involved in regulation, this paper provided exciting evidence that microbes were harboring natural products produced in unknown circumstances and undetectable under laboratory conditions. These results, cited more than 1,100 times, not only revolutionized biosynthesis research and significantly influenced antibiotic discovery but also altered our understanding of genetic islands, antibiotic resistance and microevolution.

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by chemical biologists as something akin to the California gold rush: “many people jumped in, seeing an opportunity.” In this “mad rush to develop new technologies,” as Muir puts it, the community developed a reputation for being mere toolmakers. Yet our panel agreed that these tools were an important and necessary starting point for the field, and this early investment in chemical methodologies is now paying biological dividends. Indeed, in this context, Cravatt feels that we are “witnessing the emergence of a new breed of chemical biologists who are not only interested in

developing chemical tools and methods but also in applying them to make profound discoveries.” Our panel was quick to identify numerous chemical biology papers published between 2000 and 2010 that took the field in this important direction.

Mass spectrometry was the clear ‘winner’ as the most influential analytical technique of the past decade. Though mass spectrometry had been used to study small molecule systems for decades, the advent of new ionization techniques and detection methods made it possible to characterize large biological molecules with

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greater precision and throughput than was previously possible. Accordingly, during the past decade, mass spectrometry has become a workhorse for proteomic efforts; several of our advisors identified multidimensional protein identification technology (MudPIT)6 as an enabling

mass spectrometric approach that opened the door to high-throughput proteomics. In parallel, chemical biologists

designed new tools such as activity-based protein profiling (ABPP)7 to enhance the information content of these functional proteomic studies. To read more about mass spectrometry and its applications in chemical biology, see the Primer in this issue by Erin Carlson.

Driven by decades of knowledge of chemical reactivity and mechanism, organic chemists had turned their attention to developing selective chemical coupling reactions that proceed in cells without affecting cellular chemistry.

mudPit Nat. Biotechnol. 19, 242–247 (2001)Early in the postgenomic era, it became clear that characterizing the proteome—the abundance and activities of all proteins in a system at one time—was essential for a complete understanding of biology. Proteomics methods based on mass spectrometry and bioinformatic analysis had made it possible to identify proteins by analyzing peptide fragments resulting from enzymatic digestion of

proteome samples. However, most methods relied on two-dimensional gel electrophoresis, a low-throughput approach that provided a biased view of the proteome. Washburn et al. brought proteomics into the 21st century with multidimensional protein identification technology (MudPIT), in which two-dimensional liquid chromatography fed directly into a mass spectrometer, eliminating sample manipulation and enabling analyses in a high-throughput format. With this method, the authors reproducibly identified 1,484 proteins from the Saccharomyces cerevisae proteome in an unbiased manner, including low-abundance and membrane proteins that had previously been largely invisible to proteomic analyses. MudPIT was thus a formative technology that helped establish mass spectrometry as one of the central technologies for high-throughput proteomic analysis.

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a programmatic change Science 292, 498–500 (2001)The common 20 amino acids can perform an astonishing number of tasks, but expansion of their structural and functional breadth was of obvious interest. Progress toward this goal, in the form of in vitro protein synthesis using chemically aminoacylated tRNAs and the identification of a few orthogonal tRNA-synthetase

pairs, had been reported. However, to incorporate non-natural amino acids in a high-fidelity, site-specific manner in living organisms, Wang et al. needed to create an orthogonal tRNA synthetase that was selective for an unnatural residue that itself would not be used by host machinery. Random mutagenesis of an inactivated tyrosyl-tRNA synthetase from Methanococcus jannaschii coupled with clever selection experiments yielded a mutant enzyme capable of loading O-methyl-l-tyrosine onto a mutant nonsense suppressor tRNA and provided the first demonstration that the genetic code could be reprogrammed. With this precedent, scientists have expanded the scope of the method, and it now serves as a common technique to evolve enhanced polypeptides and investigate specific details of protein function.

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This strategy, termed ‘bioorthogonal chemistry,’ has enabled applications such as biomolecular labeling and was ranked highly by our panel as being one of the most unique and useful contributions of

chemical biology. Described by Stephen Caddick as an “impressive piece of molecular design to allow the chemical modification of cell surfaces,” the modified Staudinger

reaction developed by Carolyn Bertozzi and colleagues has been widely applied in many biomolecular labeling systems8. Another widely cited contribution in the bioorthogonal chemistry area is the application of ‘click’ chemistry to biologial systems by M.G. Finn and Barry Sharpless9. According to Piel, click chemistry “laid the foundation for the wide range of orthogonal reactions that are available today to study biochemical processes and to discover protein modulators in vitro and in vivo.”

Chemical biology also has combined techniques from molecular biology and chemical synthesis to create powerful methods for the synthesis of complex biopolymers. These approaches allow chemical biologists to introduce subtle structural modifications that are designed to probe and manipulate the functions of these large macromolecules. As Cole says, “the increasing ability to modify proteins with greater precision has been highly influential.” Two advances in this area were widely viewed as essential chemical biology technologies that have enabled new biological insights.

The first paper builds on work from numerous labs during the 1990s to incorporate non-natural amino acids into proteins using engineered in vitro

translation systems10. For many of our advisors, this area achieved a major milestone in a 2001 paper from the laboratory of Peter

Schultz11. By manipulating the cell’s protein translation machinery, Schultz and his colleagues truly expanded the genetic code of Escherichia coli to insert non-natural

chemistry clicks Science 287, 2007–2010 (2000); Angew. Chem. Int. Ed. 41, 1053–1057 (2002)

In the first example of truly bioorthogonal chemistry, Saxon and Bertozzi designed a modified reagent that would make the Staudinger ligation—a known reaction between phosphines

and azides—compatible with the aqueous cellular environment by trapping an unstable intermediate

through intramolecular cyclization. Incubation of mammalian cells with azide-derivatized mannosamine and the subsequent application of the new reagent delivered the ligation product, the yield of which varied with typical reaction parameters such as time and concentration, to cell-surface glycans labeled with the azido sugar. In the first application of ‘click’ chemistry to a biomolecule, Lewis et al. explored the effects of preorganization in their study of the Huisgen dipolar cycloaddition of azides and alkynes within an enzyme. The close confines of the acetylcholinesterase active site were expected to accelerate the

reaction of preferred building blocks from a small library. Out of 98 possible products, only one bivalent molecule—with a remarkable dissociation constant of 77 femtomolar—was detected. These powerful methods, cited a combined ~700 times, changed the perception of how chemical synthesis could impact biological research.

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or modified amino acids into proteins within cells. As was the case with earlier test-tube driven chemistries, the ability to tailor protein composition in vivo has far-reaching potential in all areas of biology.

A more recent study from Muir and colleagues also highlights the maturation of a chemical biology technology and its application to delivering new biological insights. During the 1990s, Stephen Kent and colleagues took inspiration from ‘intein’ protein splicing to develop the approach of ‘native chemical ligation’, in which synthetic (and later, expressed) protein fragments were coupled to produce functional proteins12. In 2008,

Muir and colleagues reported a highly refined semisynthetic approach to a ubiquitylated histone protein (uH2B)13. Using

this synthetic histone, they demonstrated how this post-translational modification of chromatin activates methylation of histone H3 and controls crosstalk within nucleosomes. Herbert Waldmann praises such applications of protein semisynthesis as exemplary cases of how chemists can directly explore biological questions: “The development of this field in the last decade has allowed scientists to solve problems that have resisted insight for more than a decade.”

Finally, chemical genetics—the application of small-molecule probes as tools for understanding and manipulating biological pathways—was widely noted

by our panel as an important area of chemical biology. Numerous scientists highlighted a paper from the laboratory of Kevan Shokat as

an exemplary demonstration of the power of chemical genetics14. This “bump-and-hole” strategy created modified kinases with enlarged active sites (‘holes’) that responded selectively to complementary ‘bumped’ kinase inhibitors. This bioorthogonal approach has been widely used to probe the functions of kinases and extended to other enzyme classes.

These examples highlight that chemical biology approaches, when paired with a pressing biological question, can provide important, physiologically relevant insights. Jeffery Kelly highlights this trend in the field, stating that “excellent chemical biology papers today address real biological problems, and this is critical for the perception of the field, the training of students and post-doctoral fellows and the impact that our papers have on the overall scientific community.” Similarly, Chris Walsh is confident that “chemical biology will not be limited to chemical tool creation and evaluation for biology

but will continue to evolve to a broad view encompassing all the chemistry that occurs in nature.”

links to drug discoveryWith historic influences from pharmacology and cell biology and strengths in small-molecule probe development, many chemical biologists have nurtured a keen interest in extending this knowledge to drug discovery efforts. Many panelists, including Hiroyuki Osada, Herbert Waldmann and Minoru Yoshida, emphasized the central role that chemical biology must play in target identification strategies that underpin chemical probe and drug development. A number of

scientists working at the intersection of chemical biology and drug design,

including Guilio Superti-Furga, identified several important drug discovery papers in which chemical biology is already making its

mark. First, the development of imatinib (Gleevec), a Bcr-Abl kinase inhibitor, into a widely used therapeutic agent in 2001 was cited as a major success story for chemical biology15. Several of our panelists also highlighted a transformational 2006 study from Shokat and colleagues in which they developed specific inhibitors of phosphoinositide 3-kinase (PI3-K) isoforms16. Paul Workman, in particular, felt that this work “had a huge influence

histones from scratch Nature 453, 812–816 (2008)Nuclear DNA is packaged on spool-like nucleosomes that are composed of histone proteins. Specific epigenetic modifications of histone proteins—

such as methylation or ubiquitylation—are known to modulate chromatin structure and alter gene expression. For instance, in humans, ubiquitylation of Lys120 of histone H2B (uH2B) is associated with an increase in methylation of Lys79 of histone H3. However, gaining insight into how these post-translational modifications are linked seemed an impossible task, given the complexity and the dynamic nature of the system. McGinty et al. turned to protein semisynthesis for help. Using a series of orthogonally expressed protein ligation reactions, the authors synthesized uH2B, assembled it into nucleosomes and showed that the presence of the ubiquitin modification enhanced the ability of methyltransferase hDot1L to mono- and dimethylate Lys79 of histone H3, but only within the same nucleosome. This recent study not only provides an excellent example of the sophistication of contemporary protein synthesis approaches but illustrates how the ability to make large molecules in a precise way can be used to directly test important biological hypotheses.

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inhibition in isolation Nature, 39, 395–401 (2000)Small-molecule inhibition of a target protein can have advantages over genetic manipulations. However, even with the most successful chemical optimization schemes, specificity can be difficult

to achieve if the target protein has features in common with other proteins within the biological system. Kinases, for example, contain a highly conserved ATP-binding site, and many known inhibitors bind to this site in an ATP-mimetic manner. Shokat and colleagues were able to overcome this obstacle by first identifying a large ‘gatekeeper’ residue that made contact with these ATP mimics. Modification of known inhibitors of four kinase subfamilies with a bulky functional group then yielded compounds designed to fit into a mutant kinase lacking this ‘gatekeeper’ and thus incompatible with wild-type kinases. This strategy, originally developed for kinases in the budding yeast Saccharomyces cerevisiae, provided an elegant example of the ‘bump-and-hole’ strategy and has been widely adopted to study individual kinases and other large protein families in multiple organisms.

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membrane proteins in view Nature, 450, 383–388 (2007); Science 318, 1258–1265 (2007)

G protein–coupled receptors (GPCRs) are responsible for the majority of transmembrane signal transduction in response to hormones and neurotransmitters. Like all membrane

proteins, GPCRs have been refractory to crystallization, which has limited insight into the mechanisms of GPCR activation, G protein coupling and downstream signaling, a fact that hindered drug design against these important targets. Conformational heterogeneity and structural instability of GPCRs in detergent complicated efforts to obtain high-resolution structures. The Kobilka lab overcame this problem for the adrenaline-responsive β2-adrenergic receptor (β2AR) in two papers by using a conformationally selective monoclonal antibody or by replacing an intracellular loop with lysozyme. Working with the Stevens group, they obtained a structure of this β2AR-lysozyme fusion protein in a lipid environment. Comparison to the rhodopsin structure—the only GPCR structure known at the time—allowed for critical insights into basal GPCR activity and the role of GPCR structural plasticity in recognition of diverse diffusible ligands.

and impact on the PI3-K field but also established an approach that is applicable more generally in chemical biology and drug discovery.” Workman goes further to argue that “academic or not-for-profit drug discovery will play an essential role in taking on high-risk projects and ‘derisking’ them for the pharma industry.”

Structural biology continues to provide a starting point for chemical biologists to investigate basic biological processes, many of which have important implications for drug development. Thus, it was no surprise that the recent determination of the three-dimensional structure of the β2-adrenergic receptor17,18—a G protein–coupled receptor (GPCR) family member—was viewed as a major breakthrough by chemical biologists interested in signaling and drug discovery. For Brian Shoichet, “the GPCR

structure papers out of Kobilka and Stevens’ lab really rocked my world.” Likewise, Joyce believes that these structures have

“enormous implications for understanding biological signal transduction and for opportunities in drug discovery.”

a changing cultureIn parallel with the scientific evolution of chemical biology since 2000, several cultural trends have significantly broadened the impact of chemical biology on the wider scientific community. First, the enhanced visibility of chemical biology in the scientific literature has brought the breadth and utility of studies at the chemistry-biology interface to a wider audience. Indeed, Peter Seeberger argues the expansion of chemical biology journals in the past decade has “helped to

amalgamate the community and has given it an identity.” Second, the rapid expansion of access to chemical compound libraries and high-throughput screening facilities has made it possible for researchers of any background to identify chemical probes and apply them to biological questions with greater success. In the view of René Bernards, this trend has been critical for the field’s development, in that “large compound libraries are no longer a privilege of pharmaceutical industries but are also available in larger academic centers.” Initiatives such as the US National Institutes of Health Roadmap for Medical Research (http://nihroadmap.nih.gov/) greatly supported such efforts in the United States and served as catalyst for broader efforts worldwide.

Similarly, other large-scale initiatives seeking to examine biological systems in a more integrated way are changing

how chemical biologists interact with data. Christopher Dobson highlights the transformative potential of systems biology: “The study of complex biological systems has been completely transformed by technological innovations that enable large amounts of data to be acquired and analyzed. These systems can now, for the first time, be addressed in their entirety,

and not just component by component as has traditionally been done.” In this area, our advisors highlighted the ‘Connectivity Map’, the result of

a collaborative effort led by Todd Golub, Justin Lamb and colleagues19, as a beautiful example that links bioactive compounds to a growing network of data on cellular processes. Put into an appropriate context, large datasets provide a more integrated view of systems and allow researchers to rapidly identify promising avenues for further exploration.

In conjunction with the growing expectation that large-scale datasets be made publicly available, our panelists argued that scientists are spending less time collecting data and devoting more time to making sense of it. Joshua Rabinowitz, who is quite familiar with the challenges of ‘omic’ datasets, suggests that for today’s researcher, “Sweat is less important, while thought becomes more critical.” This increasing emphasis on intellectual endeavors is related to changes that have influenced how scientists do research on a daily basis. For instance, commercial kits are convenient and widely used for routine procedures. University core facilities and companies providing services ranging from oligonucleotide synthesis to mass spectrometry have greatly facilitated access to chemical biology techniques. Rajesh Gokhale states that these trends “have increased the

able to target abl N. Engl. J. Med., 344, 1031–1037 (2001)The 1960 demonstration that human chronic myeloid leukemia was caused by the fusion of the Bcr and Abl genes led to the realization that the tyrosine kinase Abl was the relevant oncoprotein in the disease. In one of the first major success stories of rational drug design, researchers at Ciba-Geigy (now

Novartis) and Oregon Health & Science University found a compound, STI571, that could occupy the kinase active site and inhibit Abl activity. STI571, now called imatinib (Gleevec) went on to become the first drug specifically developed to target a kinase and is now classified as a type II kinase inhibitor that both prevents ATP binding and stabilizes the inactive kinase conformation. The clinical trial reported in this paper served to validate imatinib as a successful drug, heralding a new era of drug discovery. Not long after the drug was approved for clinical use in 2001, resistance started to emerge, which could be traced to mutations that interfered with imatinib binding. So, in addition to serving as a model for kinase inhibitor discovery, imatinib has also been critical in understanding drug resistance.

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throughput of research, allowing scientists to focus on important scientific questions,” and Brian Shoichet agrees that companies and centers “have had an important influence on our level of ambition.”

While acknowledging that this delocalization of effort has aided research progress, these and many other researchers have expressed concerns about the extent to which scientists fully comprehend the subtleties of their data and feel intellectual ownership of their scientific conclusions. Cech warns that, in this new era, “we need to be wary of situations in which most of the authors of a final paper are familiar with only a small slice of the project” and where perhaps only a few are fully versed in its methodological aspects. Yet the future, as viewed by Stephen Benkovic, is that “science will have to be increasingly collaborative—the problems are too complex generally for a single lab to execute the most meaningful research.” Balancing these desires and concerns will require that chemical biologists reformulate how we collaborate. Many of our advisors felt that this process is already underway, as the traditional model of collaboration, in which expertise-dependent tasks are subdivided (the chemist as a compound supplier or the biologist as an assay runner) is increasingly being supplanted by more balanced collaborations in which all parties are actively engaged in the scientific and methodological aspects of the study.

Finally, the major scientific advances of the last decade and the resultant cultural changes are precipitating a re-evaluation of what it means to be trained as a chemical biologist. Martin Feelisch notes that being conversant in diverse scientific areas including chemistry “has become a prerequisite for the proper training of a new generation of biologists.” However, our survey reflected uncertainty about whether contemporary scientific projects, such as screening of chemical libraries or pattern identification in complex datasets, are appropriate training for students. In addition, as chemical biology continues to encompass new scientific frontiers, many of our advisors expressed concerns as to how to train chemical biologists with sufficient breadth and depth so that they will be perceived as ‘equals’ with their colleagues in traditional disciplines. While this perception has plagued the field in the past, Muir is optimistic that this concern will fade and feels that the good science coming from chemical biology has already “trumped the skeptics.” Although it will be impossible to define a single ‘best’ academic training model, Kelly believes

that “multiple professors serving as day-to-day mentors to chemical biology students and post-doctoral associates seems essential for creating fearless, creative and capable scientists who can solve nearly any problem. If we as a field can be successful in this, then we will be held in very high regard by the scientific community as a whole.”

a bright future aheadThe past several decades have been a remarkable period for chemical biology, marked by major scientific advances and dramatic changes to the scope and sophistication of research at the interface of chemistry and biology. The multiple intellectual and methodological threads that have contributed to our view of modern chemical biology have also made it a community of scientists open to new ideas, willing to take on tough challenges and motivated to ensure that their science has impact in the ‘real world.’

Earlier this year, as part of the fifth anniversary celebration of Nature Chemical Biology, we announced an essay competition that welcomed contributions on the ‘grand challenges of chemical biology’ from scientists early in their careers20. We are delighted to present the winning essays in this issue (pp. 857–879) and are confident that you will agree that the field’s future is in good hands. We also discuss these pieces, along with some of the thoughts of our advisors on the future of chemical biology, in the editorial in this issue (p. 845). We hope that these

pieces will inspire conversation and debate about chemical biology’s past, present and promising future.

Mirella Bucci, Catherine Goodman & Terry L. Sheppard

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10919 (2010).

Karen Allen, Boston University

Stephen Benkovic, Pennsylvania State University

René Bernards, The Netherlands Cancer Institute

Stephen Caddick, University College London

Erick Carreira, Eidgenössische Technische Hochschule Zürich

Thomas Cech, University of Colorado, Boulder

Joanne Chory, Salk Institute for Biological Studies

Philip Cole, Johns Hopkins University

Benjamin Cravatt, The Scripps Research Institute

Christopher Dobson, University of Cambridge

Diana Downs, University of Wisconsin

Martin Feelisch, University of Warwick

Rajesh Gokhale, National Institute of Immunology

Phil Hajduk, Abbott Laboratories

Gerald Joyce, The Scripps Research Institute

Changwon Kang, Korea Advanced Institute of Science and Technology

Jeffery Kelly, The Scripps Research Institute

Stephen Michnick, University of Montreal

Tom Muir, The Rockefeller University

Hiroyuki Osada, RIKEN Advanced Science Institute

Francine Perler, New England Biolabs

Jörn Piel, University of Bonn

Joshua Rabinowitz, Princeton University

Peter Seeberger, Max Planck Institute of Colloids and Interfaces

Brian Shoichet, University of California, San Francisco

Stuart Schreiber, Broad Institute of Harvard and MIT

Guilio Superti-Furga, Austrian Academy of Sciences Center for Molecular Medicine

Dirk Trauner, University of Munich

Herbert Waldmann, Max Planck Institute of Molecular Physiology

Christopher T. Walsh, Harvard Medical School

Paul Workman, Cancer Research UK Centre for Cancer Therapeutics at The Institute of Cancer Research

Minoru Yoshida, RIKEN Advanced Science Institute

Biao Yu, Chinese Academy of Sciences Shanghai Institute for Organic Chemistry

advisory panel

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Documents

A Decade of Chemical Biology