NEWS FEATURE NATURE|Vol 442|3 August 2006

WHAT CHEMISTS WANT TO KNOW Chemistry is a key component in all the scientific disciplines. But does that mean it is nothing more than a handy tool — or are there still major chemical questions to crack? Philip Ball finds out.

hysicists do not shy away from promot- threatened with closure. It has so far resisted The strongly synthetic character of chem- ing the big questions that drive their an attempt to remodel it as a ‘chemical biology’ istry sets it apart from the ‘discovery’ sciences field — how the Universe began, say, adjunct of the life-sciences division; but several such as physics, biology, astronomy and the MAGEE J. Por what governs the behaviour of space, other UK chemistry departments have failed Earth sciences. “Chemistry creates its object,” time and matter over scales from the atomic to to evade the axe. Following similar moves and as the French chemist Marcelin Berthelot wrote the cosmic. Biologists, too, are happy to point concerns in the United States, a 2004 editorial in 1860. to Erwin Schrödinger’s question ‘What is life?’, in Chemical and Engineering News, published Many chemists still see this creativity as one which they are attempting to answer by unrav- by the American Chemical Society (ACS), of the field’s strengths. “It makes chemistry able elling DNA and mapping out the structures proposed changing the organization’s name, to set goals of a type most other sciences cannot and interactions of proteins. rebranding it as the Society for Molecular Sci- hope to attain,” says Ron Breslow, an organic But what of the third basic science in the ences and Engineering. chemist at Columbia University in New York curriculum? To judge from the scant attention With departments closing and student num- and a past president of the ACS. “Where is chemistry gets in the public media, you could bers dwindling, can today’s chemists be sure synthetic astronomy — changing the gravita- be forgiven for thinking that it is a discipline that their discipline will continue to be seen tional constant to see what effect that has on whose time has passed, its grand puzzles all as a core science? Some of them complain the properties of the Universe, and thus per- now answered. Does chemistry have any big that many of its most important questions haps improving it?” questions left? are being framed in terms of the ‘chemical’ And although synthetic biology is now Identifying such frontier questions seems all aspect of another discipline, rather than being emerging as a genuine discipline, to many chem- the more urgent because university chemistry seen as central to chemistry itself. In an attempt ists this is just another branch of applied chem- departments are facing an uncertain future. to gauge the prospects for academic chemis- istry, relying as it does on chemical techniques The department at the University of Sussex try, Nature asked many leading chemists what such as DNA synthesis and protein design. “We in Britain, for many years home to Nobel the field’s big questions are, and whether in are the only science where things can be made laureate Harry Kroto, co-discoverer of buck- fact chemistry needs big questions to maintain that were never made before,” says nucleic-acid minsterfullerene, was the latest in a long line a sense of coherence and identity. chemist Jacqueline Barton at the California

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at the frontiers of physics and biology? transduction, identified as a key question by Chemists certainly have the tools and chemical engineer Matthew Tirrell at the Uni- 1 concepts to help answer some of the frontier versity of California, Santa Barbara, is one of QQ1 questions arising in these other disciplines. the issues that is positioning chemistry as an The clearest consensus among the chem- information science. The concept of a lock ists approached by Nature was that many of and key to explain biomolecular recognition, chemistry’s most urgent questions are ones proposed by German chemist Emil Fischer that address aspects of biology. “To me, the in 1894, can now be seen as the start of what big unanswered questions concern the chem- supramolecular chemist and Nobel laureate istry of life processes,” says physical chemist Jean-Marie Lehn of the University Louis Pas- Richard Zare of Stanford University. Barton teur in Strasbourg, France, has called the sci- agrees: “A real understanding of biological ence of informed matter. processes always comes down to understand- The concepts behind self-assembly have ? ing the chemistry.” accustomed chemists to the idea that mol- How do we design molecules with ecules can be programmed to interact and specific functions and dynamics Essence of life come together in very specific ways, and arti- Institute of Tech- Harvard University chemist George Whitesides ficial replicating molecules have demonstrated nology in Pasadena. goes further. “The nature of the cell is an entirely the principles by which chemical information The downside of this focus on making stuff molecular problem,” he says. “It has nothing to can be transmitted and amplified. “For me, is that chemists can be portrayed as inveterate do with biology, really.” Whitesides suggests that chemistry has a most impor- tinkerers — tweaking the molecular world to the “really intellectual” parts of biology, such as tant contribution to make to satisfy their curiosity, sometimes for fun and its more quantitative and molecular aspects, are

PHOTOTAKE/ALAMY sometimes for profit. And it makes it espe- overlooked whenever biologists study whole 2 cially hard to see where industrial chemistry organisms. These are strong claims, which QQ2 ends and academic chemistry begins, because biologists might contest. One can claim that the important practical challenges provide the cell has nothing to do with biology, points out motivation for much academic creativity. molecular biologist and Nobel laureate Sydney “Chemistry is the scientific enterprise that Brenner at the Salk Institute for Biological Stud- fuels industry,” notes Barton. “Not just petro- ies in San Diego, California, but by the same chemicals, but pharmaceu- token, one could say that all ticals, biotechnology and “The nature of the cell of chemistry is just quantum computer chips.” Breslow is an entirely molecular mechanics. agrees that chemistry faces Still, many of the gaps in not so much big questions problem. It has nothing scientific understanding of as big practical challenges, to do with biology.” the fundamental processes What is the chemical basis such as “to devise a practi- — George Whitesides of molecular biology, such of the cell? cal method to derive our as protein folding, genetic needed energy from sunlight; to create a room- encoding of biomolecular function, and highly the biggest temperature superconductor that can carry selective molecular recognition, are fundamen- question of all: how does self-organiza- large currents; to learn now to perform the tally chemical problems. And although molecu- tion arise and how does it lead the Universe to manufacturing we need without damaging lar biologists may assume that these things are generate an entity that is able to reflect on its the environment”. broadly understood, from a chemical viewpoint own origin?” Lehn says. they get more puzzling the closer one looks. Sci- Lehn believes the next step is the design of PHOTOTAKE/ALAMY Be specific entific understanding is still not good enough chemical ‘learning systems’ that are not just No one would deny the importance of applied to provide a rational and predictive basis for the programmed for assembly but can be trained. and industrial chemistry. But if chemistry’s kind of molecular-scale interventions needed in Indeed, another of the key questions in chemi- questions aren’t so much about what we can biomedicine and drug development. cal biology raised by several chemists was the know but about what we can do, does that make Meanwhile, the chemical nature of biomo- chemical basis of memory. it a form of engineering — a quest for particu- lecular processes such as signal “Once we know the answer, maybe we can lar solutions to particular problems? design new thoughts and memories, or even According to inorganic chemist John just learn how to retain old ones,” Barton sug- Meurig Thomas of the Royal Institution in gests. Whitesides wants to know how to use London, it is in the nature of chemistry to QQ33 chemistry to merge silicon electronics with be a science of particulars. One can identify grey matter. “How do I plug my computer into

T. VAN SANT/NASA VAN T. general principles of chemical bonding, for my brain?” he asks. That might sound like a example, but what often matters is how these matter for neuroscientists and electrical engi- are enacted and modified in specific mol- neers — but as the signals between neurons are ecules. Similarly, he says, “it would be ludi- chemically mediated, this kind of interfacing crous to look for a general theory of catalysis demands command of a chemical language. that applies to all enzymes, materials, surfaces These are appealing directions for chemists and so on.” to study, but do they qualify as truly chemical With so many chemists happily focused questions? To Whitesides, that couldn’t be more on practical goals, and with other disciplines the case. “I take the view that most of what is nibbling away at the edges of chemistry, are How do we make the materials interesting in science is now chemistry,” he says. there any big questions left at the academic needed for the future, in energy, He argues that even some of the key questions core of the subject? And if there are, do aerospace or medicine? in a field as apparently remote from chemistry they have the intellectual excitement of those as astronomy, such as ‘How many Earth-like

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planets are there?’ or ‘What is on Saturn’s moon A big question for Zewail is how to control Titan?’ are fundamentally molecular ones. chemical function through dynamics. Com- When addressing interdisciplinary questions, pared with their ability to determine molecu- QQ66 what truly distinguishes chemists from physi- lar structure, chemists have only just begun to cists and biologists is that they are not content understand what can be done to control reac- to ignore molecular-scale mechanisms. Tack- tion pathways in this energy landscape. In prin- ling these issues confronts chemists with what ciple, this can be done by guiding molecules, is perhaps the core challenge of their discipline: perhaps using laser beams, into particular to understand and predict the relationship quantum states. So far this has been achieved between molecular structure and function. for simple molecules, but looks extremely Structure–property relationships are crucial daunting for larger, ‘floppier’ ones. to drug design, for example — one of chem- And even if they crack the principles of istry’s major concerns. “How do molecular design, how do chemists apply them? “Until we reach the stage when someone How can we explore all the can go in the lab and synthesize an arbitrary possible permutations of molecule in 100% yield in pure form without all the elements? QQ44 having a graduate student spend a year working it out, we have not really mastered synthesis,” about says Barton. “So the big question concerns the 1040 possible molecules that nature and rules governing how to assemble could be made from common elements with a atoms into new molecules in a predictable and molecular size comparable to that of a typical effective way. Then we could make whatever drug. “The known chemical world, including

substances we want.” the expansion of the natural world that chem- 429–438 (2004) 2, ists have achieved, is nowhere near 1% of that,” Creative force says Breslow. Only chemists know how truly difficult it is It is this profusion that defies attempts to

to engineer atoms and molecules — some- reduce chemistry to a handful of objectives. “Its MATER. NATURE What is the chemical basis of thing that many other scientific disciplines universe is defined not by reduction to a few thought and memory? rely on. If room-temperature superconduc- elementary particles, or even the hundred or so tors or synthetic bacteria are ever created, it elements,” says theoretical chemist and Nobel we encode specificity for particu- will not be physicists and biologists who make laureate Roald Hoffmann of Cornell University lar cells, organelles or tissues into molecules?” them. And if chemistry is chopped up and par- in Ithaca, New York, “but by reaching out to the asks Barton. “How do we make molecules go celled off to other disciplines, there will be no infinities of molecules that can be synthesized. where we want them to go?” It is also essential training ground for those who achieve such There is no end to the range of structure and & I. TEKEUCHI H. KOINUMA for designing catalysts for use in industrial syn- mastery over matter. function that molecules exhibit.” thesis. But at present, a full understanding of It would be wrong, moreover, to suggest that Most chemists seem content to work with- PHOTOTAKE/ALAMY the link between structure and function is often the heart of chemistry — rational synthesis — out big frontier questions to guide them. Such possible only for relatively simple, small mol- lacks intellectual appeal. Some argue that, rather questions can be helpful to a discipline’s sense of ecules — and even then there are many details than trying to understand the world, chemists identity and direction, but they risk narrowing of the problem that have yet to be clarified. are attempting to understand all possible worlds. the possibilities of an inherently creative disci- “Chemistry has a useful aspect, but that is not pline. Some might argue that an excessive focus Action heroes the basic science,” says Breslow. “The basic sci- (at least in the public eye) on ‘theories of every- For example, Nobel laureate Ahmed Zewail, ence is clear once we realize that the limited thing’ or decoding the human genome has not a physical chemist at the California Institute examples of molecules and reactions that nature been terribly productive for physics or biology. of Technology, points out that the dynamic has supplied are a microdrop in an enormous Besides, in chemistry, as in any science, the behaviour of molecules can play as big a role bucket compared with the wonderful chemical biggest breakthroughs often come from unex- in their reactivity as their molecular structure. world still to be created and examined.” pected directions. “I do not think that I have It is now clear that the interactions between It has been estimated that there are ever identified in advance any of the major biomolecules aren’t simply a matter of fit- directions or key questions of chemical research ting a key into a lock — getting a good geo- that I witnessed in the past half century,” con- metric match between the binding site and 5 fesses inorganic chemist Hubert Schmidbaur its target — but may depend on the dynamics QQ5 at the Technical University of Munich in Ger- of the interacting molecules and the solvent. many. “And it seems to me that the situation will Chemists now think of reactions as hap- be not very different in the next five decades.” pening on a complex, multidimensional “There is no Holy Grail in chemistry,” Hoff- NASA/JPL/SPACE SCI. INST. NASA/JPL/SPACE energy surface, or landscape, which can be as mann admits happily. “Occasionally some are rugged as a mountain range. So understand- held up for public view,” he says, but they are ing protein folding is a question of how the just “gimmicky candidates for the chalice”. He molecule’s peptide chain negotiates a trajec- adds that in a fundamentally creative field, tory across this energy landscape so that it the satisfaction comes from the chase, not the ends up in the ‘valley’ corresponding to the catch. “My natural philosophical disposition is correctly folded conformation. “In biology, not to work on big questions,” says Hoffmann. thinking about the relationship between “I like working on many detailed small prob- structure and function is not enough,” says How did life on Earth begin, and lems in this wonderful chemical garden, while Thomas. “You’ve got to think about move- how and where might it begin keeping my eyes open for the connections.” ■ ment around the energy landscape.” In other on other worlds? Philip Ball is a consultant editor for Nature. words the dynamics are key. For more on this topic, see Editorial, page 486.

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