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Introduction Understancling the chemistry of chemical communication: Are we there yet? Jerrold Meinwald* Department of Chemistry and Chemical Biology, Baker Laboratory, Cornell University, Ithaca, NY 14853-1301 Small molecules often carry vital information. Compounds as simple as nitric oxide, carbon dioxide, and ethylene play essential roles as hormones or pheromones in plants and ani- mals. Extensive research during the past century has revealed that chemical signaling is not only the primary means whereby organisms coordinate and regulate their internal activities, but also the chief channel through which organisms interact with one another. In this Introduction, I will examine briefly the evolution of the science of organic chemistry, which lies at the heart of chemical communication, and consider what some future goals for organic chemistry in a postgenomic world may be. By the start of the 19th century, chemists had begun to make sense of the inorganic world. Elements were being discovered at a rapid rate, and the importance of quantitative research had become apparent. Chemists' curiosity naturally extended to the study of compounds making up living organisms as well, but "organic" chemistry, the chemical study of the biotic world, presented essentially insurmountable difficulties. In the preface to his pioneering treatise, Lectures on Animal Chem- istry (1806), J. J. Berzelius wrote ". . . Of all of the sciences contributing to medicine, chemistry is the primary one, and apart from the general light it throws on the entire art of healing, it will soon bestow on some of its branches a perfec- tion such as one never could have anticipated." Despite this exuberance, worthy of the introductory section of any con- temporary chemist's National Institutes of Health research grant application, it was only 4 years later that Berzelius himself became deeply discouraged with the unreliability of his own analytical work on animal products, declaring in 1810 that he had written his last paper on nasal mucus, bile, urine, and related subjects (1~. Although by 1831 Justus Liebig was able to report elemental analyses of such fascinating and important plant-derived natural products as morphine, quinine, and strychnine, the results he obtained were disorienting, because there was no understanding of what the complex ratios of carbon to hydrogen, oxygen, and nitrogen in these alkaloids implied about their chemical nature. The prevailing confusion was dramatically summarized in an 1835 letter to Berzelius by his distinguished student, colleague, and friend, Friedrich Wohler, who wrote ". . . Organic chemistry just now is enough to drive one mad. It gives me an impression of a primeval tropical forest, full of the most remarkable things, a monstrous and boundless thicket, with no way to escape, into which one may well dread to enter. . ." (24. The problem with organic chemistry was 2-fold. On the experimental front, only the crudest techniques of distillation and crystallization were available for the isolation and purification of organic com- pounds, and combustion analyses required grams of material simply for the determination of carbon, hydrogen, and nitro- gen percentages in an unknown sample. On the theoretical side, matters were even worse. It was not until 1859 that August Kekule provided a clear insight into molecular structure theory, thereby explaining the nature of structural isomerism and providing a rationale for structure determination. And it 14514-14516 1 PNAS 1 November 25, 2003 1 vol. 100 1 suppl. 2 was only in 1874 that J. A. LeBel and J. H. van's Hoff discerned the fundamentals of stereochemistry, which proved indispens- able for the modeling of essentially all biologically relevant chemistry. With the realization that organic compounds are almost universally compounds of carbon, and that carbon-based chem- istry offers a practically limitless domain of study entirely independent of biology, the subject of organic chemistry rede- fined itself much more broadly as simply the chemistry of carbon compounds. Methods for making and breaking carbon-carbon bonds, assembling natural and non-natural structures by rational synthesis, determining both molecular structures and stereo- chemistry, relating molecular structures to chemical and physical properties, and understanding the detailed mechanisms by which organic reactions occur all took center stage. Organic chemistry blossomed into a self-contained, inward-looking science, bring- ing order and understanding to the synthesis and reactions of millions of compounds. Pursuit of this young science also led to the discovery of synthetic dyes, plastics, fibers, pesticides, ex- plosives, and pharmaceuticals that have repeatedly changed the quality of human life on Earth. It may not be going too far to suggest that the appeal of the abstract logic of organic chemistry, closely akin to that of Euclidean geometry, combined with the intriguing aromas of volatile compounds and the visual beauty of various crystals, inspires a sense of chemiphilia in many chemists, analogous in some ways to E. O. Wilson's biophilia (3~. It is impossible to overestimate the extent to which the spectacular development of organic chemistry has depended on a relatively small number of experimental techniques that were discovered or significantly improved during the 20th century. Chromatography in its various forms permits undreamed-of separations of complex mixtures from large-scale preparative experiments down to the nanogram scale. UV, IR, and NMR spectroscopy, MS, and single crystal x-ray crystallography have revolutionized the art of structure determination. The amount of compound required for a structure determination in Kekule's time compared with ours has decreased at least a million-fold. Furthermore, a structure determination that might have re- quired 20 or more years, starting in 1900, might be accomplished in <1 hour today, using readily available NMR spectroscopic techniques. The advances in separation and structure determination de- veloped chiefly in the second half of the 20th century had a special impact on the subdiscipline of "natural products" chem- istry. They made possible the isolation and characterization of tens of thousands of the most important "secondary metabo- lites" found in nature. Even more significant from the biologist's This paper serves as an introduction to the following papers, which result from the Arthur M. Sackier Colloquium of the National Academy of Sciences, "Chemical Communication in a Post-Genomic World," held January 17-19, 2003, at the Arnold and Mabel Beckman Center of the National Academies of Science and Engineering in Irvine, CA. *E-mail: circe~cornell.edu. 2003 by The National Academy of Sciences of the USA www.pnas.org/cgi/doi/10. 1 073/pnas.24361 68100

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Table 1. The relationship of sample mass of a hypothetical compound (molecular weight of ~300) to the number of molecules In the sample, and to the applicability of the three most powerful experimental techniques for structure determination Sample size, 9 Sample size, no. of molecules X-ray NMR crystal lography spectroscopy ~300 x 10 Sox 10 50x 10-3 50x 10-6 50x 10-9 50 x to-do 50 x 10-~s So x 10- 50 x 10-2' 6.23 x 1023 + 1 o23 1 o20 1017 1 014 1033 108 105 1o2 + +, applicable; -, inapplicable. viewpoint, these novel techniques could be coupled not only with one another but also with newly developed biological experi- mental methods, such as the "electroantennogram" technique, to provide insights into interactions at the molecular level, thereby supporting the emergent discipline of chemical ecology. It is instructive to contrast present-day research techniques with Butenandt's pioneering research on chemical communi- cation, carried out over a roughly two-decade period in the mid-20th century and leading to the characterization of bom- bykol, the first pheromone to be chemically characterized. His painstaking preparation of ~10 mg of the pure 4'- nitroazobenzene-4-carboxylic ester of bombykol from extracts of the terminal segments of a half million virgin female silkworm moths (Bombyx mori) is a classic of natural products chemistry (4~. With these beautiful red-orange crystals, he was able to carry out a microscale oxidative degradation that allowed him to deduce the structure of bombykol itself. (Significantly, the stereochemistry of natural bombykol could only be established on the basis of stereospecific syntheses of all four of the possible E/Z isomers.) A contemporary researcher would find a problem of this sort vastly easier to solve. Using the combined techniques of gas chromatography, electroantennogram detection, and MS, a typ- ical moth sex pheromone might be chemically characterized in a day's work by using only a microgram or less of material obtainable from a single female. (Again, synthetic work might be needed to ascertain stereochemistry and provide quantities useful for further studies, such as field trapping experiments.) Clearly, we have come a long way in recent decades. Does this mean that chemists have completed their part of the job, and that the chemical aspects of chemical communi- cation research are essentially routine? If we examine chemical signaling from the viewpoint of numbers of signal molecules required for state-of-the-art structure determination, we can see that we have the potential to do very much better. Consider a signal compound (pheromone, allomone, kairomone, hor- mone, or neurotransmitter) with a modest molecular mass of ~300. In 1950, structure proof for such a compound might have been carried out by using a sample size of ~50 ma. Today, this task might be accomplished by using only ~50 ,ug or perhaps even 50 ng for a moderately complex unknown, which would represent a reduction of between 103 and 106 in sample size. However, even as little as 50~ ng of our hypothetical signal compound corresponds to a hundred trillion (10~4) molecules (see Table 1~. If we wanted to study chemical communication in mites, or pursue the chemistry of still smaller organisms that Meinwald are not readily cultured, these quantities would be difficult to obtain. Because 109 or fewer signal molecules are certainly sufficient in many situations to trigger behavioral responses, there is still a quantitative gap of at least a factor of 10~2 between biologically significant quantities of a molecular messenger and the quantities that a chemist skilled in the art can characterize today. MS Of course, any chemist working with natural products will recognize that up to this point we have completely ignored several extremely important factors in our discussion, thereby greatly oversimplifying the task at hand. Most natural com- pounds of interest are found in a matrix of other compounds, from which they need to be separated or else analyzed in situ (for example by UV, IR, or NMR spectroscopy) (5, 6~. In situ analysis has significant advantages over any procedure involving a pre- liminary separation (chromatographic or otherwise) during which unstable, volatile, or irreversibly absorbed components might be lost. Unfortunately, such a direct anDroach is not universally applicable. In any case, it is important to bear in mind that the handling of ultra-small quantities becomes increasingly difficult as sample size decreases. Finally, the fact that biological information transfer frequently depends on mixtures of two or more components, sometimes in well-defined ratios, adds still another level of complexity to the analysis of chemical commu- nication systems. Overall, recent technical advances in analytical techniques enable the characterization of chemical signals with a facility that could not have been anticipated even a few decades ago. There is every reason to assume that future advances will continue to make the chemist's job easier, ultimately permitting both sepa- rations and chemical characterization to be achieved by using a small number of molecules. Although it is not within the scope of this discussion, it is also likely that chemical biologists will soon be able to model the interactions of many signal molecules with their receptor proteins, which should provide invaluable insights into the workings of any chemical communication system. We can further expect that genomic and proteomic research will go a long way toward elucidating the evolution and regulation of biosynthetic pathways and toward defining the mechanisms of reception and transduction. What kinds of problems are accessible with the techniques already in hand? If a quantitative bioassay can be designed, it should be possible to characterize any biologically active natural product that can be obtained in microgram quantities. One example taken from the current literature illustrates the kind of opportunity that is open to imaginative researchers. In an exciting reversal of the traditional approach of natural products chemists, Spehr et al. (7) have found and character- ized an olfactory receptor protein in the tails of human spermatozoa. Those researchers could demonstrate that a simple aromatic aldehyde, bourgeonal, at a concentration as low as 10-7 M, can guide sperm swimming. They have also shown that this response is blocked by a low concentration of n-undecanal. However, it still remains to find and characterize the natural ligand for this olfactory receptor, presumably a low molecular weight pheromone secreted by the human egg. This intriguing task will very likely test the limits of small-scale chemical characterization. And it will certainly not be without wide-ranging impact! There can be no doubt that Berzelius, Liebig, Wohler, et al., were they with us today, would be absolutely delighted to take up once again the original mission of organic chemistry, i.e., to provide the chemical basis for the understanding of life. They would certainly be amazed by the incredibly powerful experi- mental and theoretical tools now at hand and available for this purpose. Those of us who have had the privilege of pursuing problems involving natural products chemistry and chemical communication have enjoyed the endeavor immensely. It is hard PNAS 1 November25, 2003 1 vol. 100 1 suppl. 2 1 14515

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to imagine that future generations of chemiphiles will not be at least equally intrigued by the opportunities that the explorations of future biophiles are sure to provide. If one were to ask whether chemistry right now is anywhere near reaching its ultimate goal with respect to providing a full molecular understanding of chemical communication, the answer must be a resounding NO! Future opportunities far outweigh present accomplishments, 1. Jorpes, J. E. (1966) Jac. Berzelius, His Life and Work (Almqvist and Wiksell, Stockholm). 2. Fieser, L. F. & Fieser, M. (1961)Advanced Organic Chemistry (Reinhold, New York) p. 11. 3. Wilson, E. O. (1984) Biophilia (Harvard Univ. Press, Cam- bridge, MA). 4. Hecker, E. & Butenandt, A. (1984) in Techniques in Pheromone Research, eds. 14516 1 www.pnas.org/cgi/doi/1 0.1 073/pnas.24361681 00 which are best viewed as a promising start. So, we are not there yet, but we are certainly on our way! My research in chemical communication, pursued for more than four decades in close collaboration with Dr. Thomas Eisner, along with many dozens of dedicated predoctoral and postdoctoral students, has been generously supported by National Institutes of Health Grant GM53830 and the Schering Plough Research Institute. Hummel, H. E. & Miller, T. A. (Springer, New York), pp. 1-44. 5. Schroder, F. C., Sinnwell, V., Bauman, H., Kaib, M. & Francke, W. (1997) Angew. Chem. Int. Ed. 36, 77-80. 6. Schroder, F. C., Farmer, J. J., Attygalle, A. B., Smedley, S. R., Eisner, T. & 7. Meinwald, J. (1998) Science 281, 428-431. Spehr, M., Gisselman, G., Poplawski, A., Riffell, J. A., Wetzel, C. H., Zimmer, R. K. & Hatt, H. (2003) Science 299, 2054-2058. Meinwald