The origins of chemical biology

Kim L Morrison & Gregory A Weiss

Chemical biology has historical roots that date back to the birth of chemistry and biology as distinct sciences.
The origins of chemical biology can be traced
to the enormous technological and scientific
advances of the nineteenth century, resulting
in the fields ascent in the twentieth century.
Examining the nineteenth-century origins
of chemical biology serves at least two pur-
poses. First, the history of science provides a
framework for teaching. Descriptions of clas-
sic experiments and breakthroughs can equip
teachers and students with examples illustrat-
ing key concepts. Second, the historical roots
of chemical biology inform us that the field has
always identified exciting new research ques-
tions and challenges. Such a record promises
a bright future for the field.
Nature Chemical Biology defines chemical
biology as both the use of chemistry to advance
a molecular understanding of biology and the
harnessing of biology to advance chemistry
1
.
Despite the veneer of newness associated with
the term, chemical biology has early, albeit
modest, beginnings, extending back at least
two centuries to the masterworks considered
the foundations of chemistry and biology. This
brief article presents a few intriguing histories
that define the beginnings of chemical biol-
ogy. Given its limited scope, however, many
examples of the hard work, heartbreak, inno-
vation and patience integral to the field have
had to be omitted.
The history of nitrous oxide, discovered
in 1772 by Joseph Priestley, provides a classic
example of the yin and the yang of chemical
biology. Inspired by Benjamin Franklins work
on electricity, the radical theologian Joseph
Priestley (17331804) began to perform his
own experiments on gases, referred to as airs
in the parlance of the time
2
. Priestley, perhaps
most identified with the discovery of oxygen,
also isolated at least ten other gases, includ-
ing nitrous oxide. Using biology to advance
chemistry, Priestley incubated mice with these
gases. The approach provided a primitive
characterization method (upon exposure to a
compound, does a mouse live or die?) that has
since fallen into disfavor with synthetic chem-
ists. The experiments also inspired early ani-
mal-rights sentiments, including The Mouses
Petition, a poem by Priestleys friend Anna
Laetitia Aikin Barbauld (Box 1)
3
. Widespread
condemnation of Priestley followed publi-
cation of the poem, fueling discontent with
his radical political leanings, which included
sympathy for the American colonies. Thus, an
angry mob torched the home of perhaps the
first chemical biologist.
Turning the tables on Priestleys approach
to chemical biology by using chemistry to
advance biology, Sir Humphrey Davys experi-
ments with newly isolated, unfamiliar gases
omitted the mouse entirely. In what must be
considered an act of either lunacy or egotism,
Davy (17781829) carried out his experiments
on himself. Not surprisingly, his experiments
with carbon monoxide almost proved fatal. In
one experiment, Davy inhaled four quarts of
nitrous oxide isolated in a silk bag. The pleas-
ant intoxicating effect of the gas inspired Davy
to name it laughing gas. A popular drug in
the late eighteenth century (and to a lesser
extent today), nitrous oxide is believed to have
influenced many of the celebrated works of
one pleasure seeker, the author Samuel Taylor
Coleridge
4
. Although Davy had noted the
possible advantages of using nitrous oxide
in surgical procedures, medical uses for the
gas remained unexplored until experiments
by the American dentist Horace Wells in 1844
(ref. 5). Application of the chemistry of nitro-
gen oxides to advance biology and medicine
continues to the present day, reaching a high
point with the 1998 Nobel Prize won by Robert
Furchgott, Louis Ignarro and Ferid Murad for
demonstrating the key roles played by nitric
oxide in cell signaling.
Establishing the importance of synthetic
chemistry to chemical biology, Friedrich
Whlers fortuitous accident in 1828 led the
way to the formulation of a chemical basis for
life. During an attempt to synthesize ammo-
nium cyanate, Whler (18001882) heated
a solution of silver cyanate and ammonium
chloride. Separately, he also heated lead cya-
nate and aqueous ammonia. In both cases, he
obtained not the expected product, but urea
(Scheme 1)
6,7
. Whlers synthesis showed that
inorganic starting materials could be used to
synthesize substances previously associated
Gregory A. Weiss is in the Departments of
Chemistry, Molecular Biology and Biochemistry,
and Kim L. Morrison is in the Department of
History at the University of California, Irvine,
California 92697-2025, USA.
e-mail: [email protected]
Figure 1 A cyanotype from British and Foreign
Flowering Plants and Ferns by Anna Atkins (circa
1854). With characteristic artistry, Atkins captured
two stages of feathery dandelion blossoms.

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only with living organisms. In other words,
chemical synthesis requires no living or vital
force to make biologically active compounds.
Remarkably, some belief in vitalism still per-
sists within current popular culture. For exam-
ple, the public continues to pay a premium for
vitamins and other supplements isolated from
natural sources
8
. Synthesis, of course, continues
to play a key role in chemical biology, includ-
ing the present frontiers of diversity-oriented
synthesis and chemical genomics.
Another prevalent theme in contemporary
chemical biology, cellular imaging, was revo-
lutionized by chemical approaches first devel-
oped during the nineteenth century. One early
innovator, Anna Atkins (17991871), learned
science firsthand from her father, a prominent
botanist, and his circle of friends, including
Sir Humphry Davy, Sir John Herschel and
William Henry Fox Talbot (the father of pho-
tography). Herschel invented the cyanotype
process for an intensely blue, monochromatic
color photography
9
. The cyanotype process
relies on light-sensitive paper doped with
iron salts to produce negative images where
the imaged sample blocks exposure to light. In
her own time, Atkins established a solid repu-
tation as a collector, botanist and scientific
illustrator. Elected a member of the Botanical
Society of London in 1839, a remarkable
accomplishment for a woman in the mid-
nineteenth century, Atkins applied Herschels
cyanotype process to document delicate
botanical specimens (Fig. 1). Atkins published
her images in the first photographically illus-
trated book (either scientific or nonscientific),
British Algae: Cyanotype Impressions (1843)
10
.
Atkinss photograms render a transparency to
the stained objects, making the intricate details
of her specimens remarkably clear. Art galler-
ies, such as the Getty Museum in Los Angeles,
still display her work
11
.
Synthetic chemistry in the nineteenth century,
especially the synthesis of aniline dyes, is inextri-
cably linked to early cell biology. As improvements
to microscopy and chemical dyes uncovered fine
structures within the cell, Rudolf Virchow (1821
1902) published Die Cellularpathologie in 1858.
This text established two key principles. First, all
cells descend from other living cells, and, second,
cellular changes can result in disease. Virchows
theory of cellular pathology transformed scien-
tific understanding of biology and revolution-
ized the field of medicine. Virchow also bravely
served in the German Reichstag in opposition
to the Chancellor of blood and iron, Otto
von Bismarck
12
. Equally undaunted by hostility
from his scientific peers, Virchow vehemently
opposed germ theory, arguing instead that the
causes of disease lay within the cells themselves.
Discouraged and exasperated, Virchow eventu-
ally abandoned both politics and science for
the seemingly more attainable goal of finding
Homers Troy. Nonetheless, Virchows studies,
particularly on leukemia, resulted in an explosion
of interest in cell physiology and structure
13
.
In 1856, as the Austrian monk Gregor Mendel
began his studies of the genetic basis for hered-
ity, an 18-year-old British chemist, William
Perkin (18381907), worked diligently through
the night in his laboratory seeking a treatment
for malaria. While attempting to synthesize the
alkaloid quinine, Perkin serendipitously dis-
covered the first aniline dye, which he called
mauveine for its brilliant violet color (Fig. 2a)
14
.
Whereas the dazzle of mass-produced pigments
transformed the fashion houses of Europe, the
1856 discovery of mauve had far-reaching
implications for biological research, sparking
the development of modern medicine
15
. For
example, Paul Ehrlich realized the pharmaceu-
tical potential of coal tar derivatives and sug-
gested such treatments could provide magic
bullets for precise targeting of disease.
The cigar-smoking Ehrlich (18541915)
devoted his early lifes work to applying a
chemical approach to the visualization of living
cells. Ehrlich experimented with the newly
discovered aniline dyes derived from coal tar
and found that some dyes could differentially
stain specific cells and tissues. He correctly
surmised that this difference resulted from
a chemical reaction of the dyes with specific
substances within the cells
16
. For example,
the predominant basicity of dyes capable of
staining cell nuclei led Ehrlich to term the
nucleus basophilic. Applying the aniline
methylene blue dyes for diagnostics, Ehrlich
identified a tiny rod-shaped bacterium as the
culprit responsible for tuberculosis. Ehrlichs
insight into the intracellular reduction of
various synthetic dyes led to amazing leaps
in medicine, pioneering the earliest form of
chemotherapy and drug therapy. For example,
Ehrlich proposed the development of magic
bullets or toxins capable of targeting specific
pathogens. In the first example of a magic
bullet, Ehrlich discovered a chemical, Salvarsan
or Ehrlichs 606
th
(named in tribute to the 605
preceding failed compounds; Fig. 2b), to treat
syphilis. Salvarsan became a blockbuster in
its time and replaced the earlier treatment of
mercury, which caused blackened teeth and
baldness
17
. The success of Salvarsan paved
the way for new drugs, ultimately fulfilling
Perkins initial experimental goal of finding
a treatment for malaria.
+
NH
4

OCN + AgCl
AgOCN +
+
NH
4

Cl

AgOCN +
+
NH
4

Cl

O
H
2
N NH
2
Expected
Obtained
Scheme 1 Whlers synthesis of urea. Yielding
a chemical previously isolated only from man
or dog, the synthesis of urea represented a
landmark achievement in organic synthesis and
chemical biology.
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Sir Humphry Davy (right, with bellows) presents his newly isolated airs to the Royal Institution,
London. Caricature by James Gillray (1802). Image copyright and used with permission of the
Wellcome Library, London.
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Contemporaneously, Swiss biochemist
Friedrich Miescher (18441895) took the first
concrete steps toward the eventual discovery of
the double helical structure of DNA by James
Watson and Francis Crick. Interested in the
substructure of the cell, Miescher focused on
the identification of proteins in the nucleus.
Miescher made the practical, though slightly
unpleasant, decision to use human leukocytes
readily available in copious quantities from the
pus-soaked bandages of a nearby surgical clinic.
After working out conditions to separate intact
cells from the bandages, Miescher next devised
a procedure to isolate their nuclei, through
treatment with warm alcohol to remove lipids
of the plasma membrane, followed by proteo-
lytic digestion of the cytoplasm with pepsin and
sedimentation of intact nuclei. Using chemistry
to advance biology, Miescher analyzed the con-
tents of his purified nuclei with the chemical
tools of the dayelemental analysis, digestion
by various proteases and solubility in various
solutions. In 1869, he recorded the following in
a lab notebook (translated from German):
In the experiment with the weakly alka-
line fluids, I obtained, by neutralization
of the solutions, precipitates which were
insoluble in water, acetic acid, very dilute
hydrochloric acid, or sodium chloride solu-
tions; consequently, they could not belong
to any of the known albuminoid substances.
Where did this substance come from?
18
Miescher called this substance nuclein and
found that its elemental composition included
not only the usual assortment of carbon, hydro-
gen, oxygen and nitrogen of known organic
chemicals but also, surprisingly, phosphorus.
Mieschers use of chemistry to initiate the faint
beginnings of molecular biology did not cause
the sensation that one might expect for such a
key advance. Indeed, publication of Mieschers
exciting results was delayed by the editor of the
first biochemistry journal, Ernst Felix Hoppe-
Seyler, who insisted on repeating and verify-
ing the experimental results. Although many
in the field disputed his discovery, Miescher
continued to use chemical methods to unravel
the mysteries of the cell. Mieschers student,
Richard Altmann, coined the term nucleic
acid to more accurately describe nuclein in
1889 (ref. 19).
The explosion of research at the chemis-
try-biology interface continues to the present
day. The field remains driven by emerging
technologies, such as microarrays, molecular
display libraries, single-molecule techniques
and combinatorial biosynthesis. Many current
chemical biologists emphasize the use of small
molecules to control cellular processes
20
.
This approach to chemical biology would be
familiar to its earliest practitioners, such as the
magic bullet proponent, Paul Ehrlich. Similarly,
using chemistry to enhance imaging has been
a longstanding interest of chemical biologists
from Anna Atkins onward. Of course, much
has changed since the nineteenth century, from
the analytical tools to the addition of powerful
molecular biology techniques.
In summary, although the term would
not be coined for at least a century, the roots
of our field can be found in both biological
and chemical experiments that today would
clearly be classified under the heading of
chemical biology. Examining history uncovers
other interesting trends. First, several promi-
nent early chemical biologists staked out con-
troversial, public positions in the political
debates of the day. Though their views were
quite unpopular at the time, such courage
illustrates the role leading-edge scientists can
play in the national discourse. For example,
many contemporary chemical biology experi-
ments make use of in vitro molecular evolu-
tion, and could offer a useful counterpoint to
the ongoing debates over teaching evolution.
Second, our present considerably advanced
state of knowledge in chemical biology did
not emerge from a smooth arc of progress.
In fact, serendipity played a key role in sev-
eral key advances cited here. Third and most
importantly, the historical record and current
studies show the effectiveness of the chemical
biology approach for advancing both chem-
istry and biology.
As As
OH
HO
NH
2
NH
2
N
N
N
H
R
H
3
C
H
2
N
CH
3
a b
Figure 2 Structures. (a) Mauveine (R = mixture of CH
3
and H). (b) Salvarsan. Although it was
structurally characterized only recently
13
, mauveine sparked a nineteenth-century revolution in
chemistry and chemical biology. Discovered by Paul Ehrlich, Salvarsan demonstrated the efficacy
of the magic bullet approach to treating disease.
BOX 1 EXCERPT FROM
THE MOUSES PETITION
OH! hear a pensive captives prayer,
For liberty that sighs;
And never let thine heart be shut
Against the prisoners cries.
For here forlorn and sad I sit,
Within the wiry grate;
And tremble at th approaching morn,
Which brings impending fate.
If eer thy breast with freedom glowd,
And spurnd a tyrants chain,
Let not thy strong oppressive force
A free-born mouse detain.
Anna Laetitia Aikin Barbauld
Aikin, A.L. The mouses petition in Poems (Joseph Johnson, London,
1773). Reprinted online in Romantic Circles (Vargo, L. & Muri, A.,
eds.). Accessed 15 November 2005 (http://www.rc.umd.edu/editions/
contemps/barbauld/poems1773/mouses_petition.html/).
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Paul Ehrlich (circa 1913) in his laboratory.
Winner of the Nobel Prize (in 1908, which
he shared with lie Metchnikoff), Ehrlich
contributed groundbreaking discoveries in several
areas, including cell imaging with aniline dyes,
development of the magic bullet concept and
antigen-mediated immune response. Image
Wellcome Library, London. Used with permission.
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ACKNOWLEDGMENTS
We thank G. Fenteany, R. Martin and other readers
for their helpful comments.
1. Anonymous. Nat. Chem. Biol. 1, 3 (2005).
2. Priestley, J. Experiments and Observations on Different
Kinds of Air (Johnson Press, London, 1774).
3. Ready, K.J. Eighteenth-Cent. Life 28, 92114 (2004).
4. Hoover, S.R. B. Res. Humanities 81, 927 (1978).
5. Wright, A.J. J. Clin. Anesth. 7, 347355 (1995).
6. Whler, F. Poggendorffs Ann. 12, 253256 (1828).
7. Whler, F. Ann. Chim. Phys. 37, 330333 (1828).
8. Cohen, P.S. & Cohen, S.M. J. Chem. Ed. 73, 883886
(1996).
9. Schaaf, L. Out of the Shadows: Herschel, Talbot and the
Invention of Photography (Yale Univ. Press, New Haven,
1992).
10. Atkins, A.A. Photographs of British Algae: Cyanotype
Impressions Vols. 13 (privately published, Halstead
Place, Sevenoaks, 18431853).
11. Gribbin, J. The Scientists: A History of Science Told
Through the Lives of its Greatest Inventors (Random
House, New York, 2004).
12. Toulmin, S. & Goodfield, J. The Architecture of Matter
(Univ. Chicago Press, Chicago, 1962).
13. Meth-Cohn, O. & Smith, M. J. Chem. Soc. Perkin Trans.
1, 57 (1994).
14. Garfield, S. Mauve: How One Man Invented a Color that
Changed the World (W.W. Norton, New York, 2000).
15. Ehrlich, P. Arch. Mikr. Anat. 13, 263277 (1877).
16. Schiller, F. Clio Med. 5, 145155 (1970).
17. Miescher, F. Die Histochemischen und Physiologischen
Arbeiten (Vogel, Leipzig, 1897).
18. Miescher, F. Hoppe-Seylers Med. Chem. Unt. 13, 441
460 (1871).
19. Fruton, J.S. Proteins, Enzymes, Genes: The Interplay of
Chemistry and Biology (Yale Univ. Press, New Haven,
1999).
20. Schreiber, S.L. Nat. Chem. Biol. 1, 6466 (2005).
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