|
Items in cart [0] |
Questions? Call 888-624-8373 |
| Copyright © 2009. National Academy of Sciences. All rights reserved. Terms of Use and Privacy Statement |
Below are the first 10 and last 10 pages of uncorrected machine-read text (when available) of this chapter, followed by the top 30 algorithmically extracted key phrases from the chapter as a whole.
Intended to provide our own search engines and external engines with highly rich, chapter-representative searchable text on the opening pages of each chapter.
Because it is UNCORRECTED material, please consider the following text as a useful but insufficient proxy for the authoritative book pages.
Do not use for reproduction, copying, pasting, or reading; exclusively for search engines.
OCR for page 2
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
OCR for page 3
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
OCR for page 4
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
Representative terms from entire chapter:
chemical communication
