Content uploaded by Rony Aharon Armon
Author content
All content in this area was uploaded by Rony Aharon Armon
Content may be subject to copyright.
Published by Maney Publishing (c) Society for the History of Alchemy and Chemistry
© Society for the History of Alchemy and Chemistry 2012 DOI 10.1179/174582312X13345259996056
ambix, Vol. 59 No. 2, July, 2012, 152–69
From Pathology to Chemistry and Back:
James W. Cook and Early Chemical
Carcinogenesis Research
Rony Armon
Technion — Israel Institute of Technology, Haifa
During the 1920s, concerns over occupational cancers in the tar, coal-gas
and synthetic dye industries stimulated investigations into the responsible
carcinogenic agents. Chemical pathologist Ernest L. Kennaway and organic
chemist James W. Cook at London’s Cancer Hospital Research Institute
were the first to identify pure carcinogenic coal-tar polyaromatic hydrocar-
bons. Cook, who joined Kennaway in 1929, synthesised and tested hundreds
of compounds, seeking to identify the exact relationship between chemical
constitution and cancer. This paper reviews Cook’s research programme
until the early 1940s, and the attempt of his collaborator, Cambridge bio-
chemist Joseph Needham, to identify the biological basis of carcinogenesis.
In this, they drew upon structural and functional analogies between recently
discovered hormones and carcinogens. Cook established novel ways of stud-
ying chemical carcinogenesis, although conflicting empirical results and
understandings of cancerous growth militated against the development of a
coherent mechanistic theory.
Introduction
The origins of chemical carcinogenesis research can be traced to the late 19th cen-
tury, when a growing incidence of cancer was observed in industries exploiting coal
tars. It was evident that occupational exposures to some newly introduced chemicals
had pronounced carcinogenic effects. Coal tar, the waste of coal-gas works, served as
the source for a diverse range of aromatic hydrocarbons and their derivatives. The
incidences of scrotal and skin cancers had increased significantly from around 1890
among manual workers distilling tar or working with its products, and to a lesser,
yet still significant, degree in all trades that involved exposure to tar, pitch or min-
eral oil and allied substances. As similar and long-known pathologies were prevalent
among chimney sweeps exposed to high-temperature soot, researchers began to
explore the carcinogenicity of the products of strongly heated tar. Following clinical
Published by Maney Publishing (c) Society for the History of Alchemy and Chemistry
153
FROM PATHOLOGY TO CHEMISTRY AND BACK
and epidemiological investigations, the first reported success in inducing tar cancers
experimentally by Japanese workers K. Yamagiwa and K. Ichikawa in 1915 set the
stage for their investigation under carefully controlled laboratory conditions.1
The study of tar-related carcinogenesis occupied the efforts of leading physiologists
and biochemists in Europe and the USA. British researchers, primarily Ernest L.
Kennaway (1881–1958) and his group at the Cancer Hospital Research Institute
(CHRI) in London, made the most determined attempt to investigate tars for their
carcinogenic constituents.2 The study of cancer was one of the top priorities in British
medical research, engaging the Medical Research Council and two dedicated founda-
tions, the Imperial Cancer Research Fund (ICRF) and the British Empire Cancer
Campaign (BECC).3 While clinicians, industrial hygienists and factory inspectors
grappled with the newly defined occupational pathology, leading researchers, such as
James A. Murray, director of the ICRF, and Archibald Leitch, director of the then
tiny CHRI, began testing tars and their extracts under laboratory conditions.4
Kennaway, who joined Leitch in 1921, later earned the support of the BECC, and
recruited a group of chemists who achieved considerable successes in the isolation of
pure compounds from coal tar and establishing the identities of chemical carcinogens.
Led by James W. Cook, and exploiting recently established spectroscopic methods
developed at the CHRI, Kennaway’s team made a major discovery in 1933, when they
identified pentacyclic 3,4-benzo[a]pyrene as a principal carcinogenic component in
coal tar.5
Kennaway had recruited Cook for a programme involving the synthesis of ana-
logues of coal-tar culprits in order to assist in their identification and characterisa-
tion. When Cook found highly active carcinogens among a number of his synthetic
compounds, he believed that they might well serve for elucidating the chemical basis
of cancer more broadly. During Cook’s intensive decade-long programme, he synthe-
sised and tested hundreds of compounds for their carcinogenic effects. Leaders in
cancer research credited his ability to induce cancer by pure substances as a major
achievement, because it enabled the reproduction of tumours under experimental
conditions. However, guided by prevalent conceptions of chemical carcinogenesis,
1 For useful background, see: H. A. Waldron, “A Brief History of Scrotal Cancer,” British Journal of Industrial
Medicine 40 (1983): 390–401; Anthony S. Travis, “A Woman in Biochemistry and Toxicology: The Polish–
British Refugee Regina Schoental,” Bulletin for the History of Chemistry 34 (2009): 92–104; Joan Austoker, A
History of the Imperial Cancer Research Fund, 1902–1986 (Oxford and New York: Oxford University Press,
1988), 120–22; Robert N. Proctor, The Nazi War on Cancer (Princeton, N.J.: Princeton University Press, 2000),
17–18; and Regina Schoental, “Carcinogenesis by Polycyclic Aromatic Hydrocarbons and by Certain Other
Carcinogens,” in Polycyclic Hydrocarbons, ed. E. Clar, 2 vols. (London: Academic Press, 1964), vol. 1,
133–60.
2 I. Hieger and G. M. Badger, “Ernest Laurence Kennaway, 1881–1958,” Journal of Pathology and Bacteriology
78 (1959): 593–606.
3 Austoker, A History.
4 W. J. O’Donovan, “Epitheliomatous Ulceration Among Tar Workers,” British Journal of Dermatology 32
(1920): 215–28; S. A. Henry, “Occupational Cutaneous Cancer Attributable to Certain Chemicals in Industry,”
British Medical Bulletin 4 (1947): 389–401.
5 David H. Phillips, “Fifty Years of Benzo(a)Pyrene,” Nature 303 (1983): 468–72; A. Luch, “Nature and Nurture
— Lessons from Chemical Carcinogenesis,” Nature Reviews. Cancer 5 (2005): 113–25.
Published by Maney Publishing (c) Society for the History of Alchemy and Chemistry
154 RONY ARMON
they saw in Cook’s carcinogens no more than subsidiary irritants, and strongly con-
tested his idea that they resembled cancer’s biological causes. The “chronic irritation”
theory, on which they tended to rely, dated back to Rudolf Virchow’s work in the
1870s, although it was now at some variance with more recent findings concerning
carcinogenic and irritating substances.6 Observations showing that agents sharing lit-
tle or no chemical or physical similarity (various chemicals and X-rays and other
radiations) induced tumours in a similar manner, and with only little temporal and
spatial correlation between stimulus and response, went against positing chemical
carcinogens as crucial factors in carcinogenesis.7
Cook persevered in his search despite the biological challenges to his claims, as well
as the fact that quite different organic compounds induced cancers to a similar degree.
These made it difficult to correlate chemical structure with pathological effects. After
a decade of intensive synthesis and testing of chemical analogues, Cook acknowl-
edged that chemical structures alone could not account for cancerous effects. As Joan
Austoker in her study of Britain’s cancer research in the period has observed,
Kennaway and his group highlighted “an elegant relationship between chemical con-
stitution and biological action” and influenced cancer research in many countries, but
they “offered no explanation of the mechanism of tumor induction.”8 In applying a
chemical approach to cancer, Cook placed chemical carcinogenesis at the cutting
edge of cancer research, challenging an initially indifferent research community.
Nevertheless, the findings of Cook and his followers in the end served to highlight
the great complexity of the issues at hand.
From pathology to chemistry
For Kennaway, James Wilfred Cook (1900–1975) was certainly the right chemist at
the right time. A graduate of University College London, Cook in 1920 became
lecturer in organic chemistry at London’s Sir John Cass Technical Institute (later Sir
John Cass College). During 1920–1928, he also served as assistant to Dr. E. de Barry
Barnett, whose laboratory at the college was a recognised centre for the study of
anthracenes and the important dye intermediates, the anthraquinones.9 While Cook
worked on these substances, not far away in London, Kennaway and Izrael Hieger
(who joined Kennaway in 1924) found clues suggesting that the carcinogens in tars
6 E. L. Kennaway, “Experiments on Cancer-Producing Substances,” British Medical Journal 2, no. 3366 (1925):
1–4, on 3; John P. Lockhart-Mummery, Letter to the Editor, Lancet 222 (1933): 323; Austoker, A History,
91–137.
7 A. Leitch, “Observations on the Effect of Cessation of the Irritant on the Development of Experimental Tar
Cancer,” British Medical Journal 2, no. 3232 (1922): 1101–3; A. Leitch, “A British Medical Association Lecture
on the Experimental Inquiry into the Causes of Cancer,” British Medical Journal 2, no. 3262 (1923): 1–7; J. A.
Murray, J. W. Cook, W. Cramer, C. H. Andrewes, P. R. Peacock, J. McIntosh, W. E. Gye and A. E. Boycott,
“Discussion on Experimental Production of Malignant Tumours,” Proceedings of the Royal Society of London,
Series B 113 (1933): 268–92, on 271–73.
8 Austoker, A History, 122.
9 J. W. Cook, “Polycyclic Aromatic Hydrocarbons,” Journal of the Chemical Society (1950): 1210–19, on 1210;
J. M. Robertson, “James Wilfred Cook. 10 December 1900–21 October 1975,” Biographical Memoirs of
Fellows of the Royal Society 22 (1976): 71–103, on 73–74.
Published by Maney Publishing (c) Society for the History of Alchemy and Chemistry
155
FROM PATHOLOGY TO CHEMISTRY AND BACK
might be of a very similar nature. Assisted by the hospital’s medical physicist, William
V. Mayneord, and exploiting a method of fluorescence spectroscopy that he intro-
duced, Hieger identified similar spectra for carcinogenic tars and 1,2-benzanthracene,
or benzo[a]anthracene, and related polyaromatic hydrocarbons.10 With this crucial
clue, in 1929 Kennaway invited Cook to synthesise analogues based on the then
suspected anthracenes that might serve as tools in identifying the carcinogens present
in tars.
Using samples supplied by de Barry Barnett and synthesising many others, Cook
began to conduct intensive testing of anthracene derivatives for carcinogenic activity.
Not only did Cook’s synthetic capabilities contribute to the identification of carcino-
genic substances in coal tar — he synthesised some sixty compounds by the end of
1930 — but he also aspired to establish “a relationship between cancer-producing
power and chemical constitution” that would hold true for other molecules.11 In
contrast to 1,2-benzanthracene, which Cook found to be a weak carcinogen, its pen-
tacyclic polyaromatic derivative, 1,2:5,6-dibenzanthracene (dibenz[a,h]anthracene;
first reported by Erich Clar in 1929), induced cancers in a high proportion of the test
animals. Taking the skeletal structures of 1,2-benzanthracene and 1,2:5,6-dibenzan-
thracene as starting points, he produced derivatives with both minor and major
chemical modifications, and, through comparative testing of their carcinogenic
effects, attempted to correlate carcinogenicity with particular chemical features.12
Somewhat confounding was his finding that the fluorescence spectrum of 1,2:5,6-
dibenzanthracene differed from that observed with coal tar. Nevertheless, because it
was effective in inducing cancers, Cook still held the anthracene derivative as the
ideal point of departure.
Seeking to “define precisely the conditions of substitution which are necessary for
carcinogenic power,” he offered tentative conclusions as and when they emerged.13
Thus, with the identification of the carcinogenic impact of specific substitutions and
modifications (such as methylation of 1,2:5,6-dibenzanthracene), he used them as
leads towards the production of novel derivatives. When higher ringed compounds
afforded negligible inducing capabilities, Cook concluded that carcinogenic activity
was bounded within fairly narrow limits of “molecular complexity.”14 While occu-
pied with identifying the cause of tar-related cancers, Cook believed that he could
approach, very accurately, the chemical basis of any form of the disease.
Among chemists, the study of polyaromatic hydrocarbons and of their carcino-
genic effects was extended significantly during the 1930s. Erich Clar and Louis F.
Fieser synthesised new chemicals that others, including Cook, tested for carcinogenic
10 Ernst Kennaway (Sir), “The Identification of a Carcinogenic Compound in Coal-Tar,” British Medical Journal
2, no. 4942 (1955): 749–52.
11 J. W. Cook, “The Production of Cancer by Pure Hydrocarbons. Part II,” Proceedings of the Royal Society of
London, Series B 111 (1932): 485–96, on 485.
12 James W. Cook, I. Hieger, E. L. Kennaway and W. V. Mayneord, “The Production of Cancer by Pure
Hydrocarbons. Part I,” Proceedings of the Royal Society of London, Series B 111 (1932): 455–84; Robertson,
“James Wilfred Cook,” 74–77.
13 Cook, “The Production. Part II,” 486.
14 Cook, Hieger, Kennaway and Mayneord, “The Production. Part I,” 478–80.
Published by Maney Publishing (c) Society for the History of Alchemy and Chemistry
156 RONY ARMON
activity. But while, as a chemical field of research, the study of polyaromatic
hydrocarbons remained highly promising, in terms of cancer research it became
rather isolated. Not only were Cook’s colleagues sceptical of the utility of his quest,
but they preferred to follow biological leads. From the turn of the century, research-
ers had focused on diverse microbes and parasites, and their toxins, and those during
the following decades developed immunological, metabolic and genetic programmes
aimed at elucidating cancer’s basic causes. Pyton Rous’s early studies of the transmis-
sion of tumours by cell-free filtrates raised the hope that viruses would be found as
the main culprits. However, by the early 1930s, researchers noted that all of the
theories proposed, including that of Rous, left many clinical and experimental aspects
of cancer unexplained.15 With the emphasis among cancer researchers on biological
rather than chemical causes, Kennaway’s laboratory remained the only site in Britain
where the chemical approach to carcinogens was dominant.16
Carcinogens and sterols
Although Cook conceded that his results provided no explanation for the mechanism
of tumour production, he retained a strong belief that substances similar to his
aromatic carcinogens would eventually be identified as major causes of cancer.17 His
confidence was mainly derived from the study of sterol hormones and other biologi-
cal substances, which became a major and exciting area for leading chemists and
biochemists in the late 1920s. Chemical studies by Adolf Windaus from Göttingen
University, 1928 Nobel Laureate in chemistry for his studies in the field, Adolf
Butenandt at Berlin’s Kaiser Wilhelm Institute für Biochemie, Otto Rosenheim and
Harold King, at Britain’s National Institute of Medical Research, established the
formula of the sterol backbone. In addition, they discovered that diverse natural
products, including vitamin D, ovarian hormones, bile acids, certain poisons, and
vegetable alkaloids, were sterols or related compounds.18
15 Austoker, A History, 91–138; Murray, Cook, Cramer, et al., “Discussion”; Victor A. Triolo, “Nineteenth
Century Foundations of Cancer Research: Origins of Experimental Research,” Cancer Research 24 (1964): 4–27;
Robert N. Proctor, Cancer Wars: How Politics Shapes What We Know and Don’t Know About Cancer
(New York: Basic Books, 1995), 26–34; E. Becsei-Kilborn, “Scientific Discovery and Scientific Reputation: The
Reception of Peyton Rous’ Discovery of the Chicken Sarcoma Virus,” Journal of the History of Biology 43
(2010): 111–57.
16 Murray, with William E. Gye and William Cramer, his co-workers at the ICRF, investigated tar-related carci-
nogenesis during the early 1920s. However, in the 1930s they focused on different aspects of cancer biology.
Gye saw the viral theory of cancer as highly promising; Cramer developed studies on the role of hormones as
well as metabolic changes; Murray promoted the study of transplanted and cultured tumour cells.
17 Murray, Cook, Cramer, et al., “Discussion,” 274–77.
18 George Wolf, “The Discovery of Vitamin D: The Contribution of Adolf Windaus,” Journal of Nutrition 134
(2004): 1299–302; Jean-Paul Gaudillière, “Hormones at Risk: Cancer and the Medical Uses of Industrially-
Produced Sex Steroids in Germany, 1930–1960,” in The Risks of Medical Innovation: Risk Perception and
Assessment in Historical Context, ed. T. Schlich and U. Tröhler (New York: Routledge, 2006), 148–69; Otto
Rosenheim and Harold King, “The Chemistry of the Sterols, Bile Acids, and Other Cyclic Constituents of
Natural Fats and Oils,” Annual Review of Biochemistry 3 (1934): 87–110.
Published by Maney Publishing (c) Society for the History of Alchemy and Chemistry
157
FROM PATHOLOGY TO CHEMISTRY AND BACK
Chemists, biochemists, clinicians and industrialists who were interested in
hormones and vitamins for their preventive or therapeutic promise joined forces in
isolating, synthesising and testing the newly discovered sterols.19 Cook entered into
these efforts with tremendous enthusiasm. Because the recently investigated sterols
were identified as sharing the same chemical backbone as polyaromatic hydrocar-
bons, he could exploit his expertise, novel compounds and synthetic methods in both
investigations.20 Like Rosenheim and King, Robert Robinson (Oxford), and Ian
Heilbron (Liverpool), Cook studied the fundamental chemistry of biologically impor-
tant sterols, side by side with devising novel techniques for the production of their
synthetic analogues.21
Structural analogies, Cook suggested, could imply functional relationships as well:
naturally occurring sterols might be precursors of carcinogenic hydrocarbons, which
in turn could be implicated in the causation of spontaneous cancers. Although highly
speculative, the idea was developed from similar propositions that Kennaway made
in 1925 after he produced highly carcinogenic tars from heated biological materials.
Certain metabolic processes in the human body, he proposed, could slowly produce
the very same carcinogens that, when the tissues were heated, appeared rapidly.
Citing known reactions that were difficult for the laboratory chemist to produce but
that the body’s enzymes produced with ease, Kennaway suggested that enzymatic
modifications of naturally occurring compounds might lead to the accumulation of
cancer-producing agents.22 The idea remained a somewhat wild speculation until, in
1928, Kennaway found that heating cholesterol also produced a cancer-producing
tar.23 He remained cautious in drawing far-reaching conclusions. Yet, his findings
convinced Cook that substances similar to his artificial carcinogens could emerge
naturally.
Cook’s dual occupation with the chemistry of sterols and carcinogens allowed him
to identify chemical routes that led to the formation of the 1,2-benzanthracene ring
system from naturally occurring sterols.24 Thus, while testing 1,2-cyclopentenophen-
anthrene for carcinogenicity, he found that this compound could arise from certain
oestrogens through the aromatisation of their rings.25 Methylcholanthrene, which he
19 Jean-Paul Gaudillière, “Genesis and Development of a Biomedical Object: Styles of Thought, Styles of Work
and the History of the Sex Steroids,” Studies in History and Philosophy of Biological and Biomedical Sciences
35 (2004): 525–43; Nelly Oudshoorn, Beyond the Natural Body: An Archaeology of Sex Hormones (London:
Routledge, 1994); Nicolas Rasmussen, “History of Science: Biomolecules and the Bomb,” Science 297 (2002):
2000–2001; M. Weatherall, In Search of a Cure: A History of Pharmaceutical Discovery (New York: Oxford
University Press, 1990), 83–102, on 117–40; John P. Swann, Academic Scientists and the Pharmaceutical Indus-
try: Cooperative Research in Twentieth-Century America (Baltimore, Md.: Johns Hopkins University Press,
1988).
20 Robertson, “James Wilfred Cook,” 77–78; J. W. Cook and C. L. Hewett, “The Synthesis of Compounds
Related to the Sterols, Bile Acids, and Oestrus-Producing Hormones. Part I. 1:2-Cyclopentenophenanthrene,”
Journal of the Chemical Society (1933): 1098–112, on 1100–1102; Rosenheim and King, “The Chemistry of the
Sterols,” 94, 107; Murray, Cook, Cramer, et al., “Discussion,” 276.
21 E. R. H. Jones, “Early English Steroid History,” Steroids 57 (1992): 357–62.
22 Kennaway, “Experiments on Cancer-Producing Substances,” 3.
23 E. L. Kennaway and Basil Sampson, “Tumours of the Skin and Mammary Gland Caused by Pyrogenous Prod-
ucts of Cholesterol,” Journal of Pathology and Bacteriology 31 (1928): 609–12.
24 Murray, Cook, Cramer, et al., “Discussion,” 275–77.
25 Murray, Cook, Cramer, et al., “Discussion,” 276.
Published by Maney Publishing (c) Society for the History of Alchemy and Chemistry
158 RONY ARMON
synthesised and found to be highly carcinogenic, could be derived (although based on
an intermediary stage) from bile acids (see Figures 1 and 2).26 These exemplars dem-
onstrated that relatively simple — and therefore physiologically feasible — chemical
processes could transform at least certain of the body’s sterols into highly potent
carcinogens. The biological plausibility of these transformations did not mean that
they actually took place in the human body. However, recent findings concerning the
involvement of oestrogen in the causation of cancer did serve as important indicators.
Cook’s contemporaries in hormone research found that oestrogens might cause, or at
least enhance, the development of spontaneous cancers, thus narrowing the border-
line between carcinogenesis and normal hormonal effects.27 He tried to test the
carcinogenic effects of the recently discovered oestrogens, but failed, owing to their
toxic effects on his test animals.28 Nevertheless, in close collaboration with Edward
C. Dodds, director of the Courtauld Institute of Biochemistry at London’s Middlesex
Hospital, they demonstrated that many of Cook’s carcinogens, such as 1,2:5,6-
dibenzanthracene, induced oestrous as well.29
Collaborating with the Cambridge biochemist Joseph Needham, Cook further
extended the testing of his carcinogens for biological effects. Needham was occupied
with the chemistry of embryonic development rather than the origin of tumours,
although he came to see normal and abnormal growth as closely related. In 1933,
along with experimental embryologist Conrad H. Waddington, Needham commenced
an ambitious exploration of the chemical inducers governing major stages in embry-
onic development.30 Inspired, as was Cook, by recent advances in the study of sterol
hormones and vitamins, Needham hypothesised that the inducing agents that he
sought might be structurally and functionally related to this group. Finding deep
interest in each other’s research topics, Cook sent Needham cancer-inducing sub-
stances from his recently synthesised stock.31 Testing these and finding them to be
efficient stimulators of the embryonic transformation, Needham sustained his claims
concerning the structure of the inducer that he sought. At the same time, his findings
supported Cook’s intuition that the carcinogens that he identified might reflect
central biological entities. While Cook’s chemical studies demonstrated hypothetical
links between sterols and carcinogens, Needham and Dodds provided biological
evidence, although in an indirect manner, for their physiological interrelationship.
26 G. Barry, J. W. Cook, G. A. D. Haslewood, C. L. Hewett, I. Hieger and E. L. Kennaway, “The Production of
Cancer by Pure Hydrocarbons. Part II,” Proceedings of the Royal Society of London, Series B 117 (1935):
318–51, on 340–41; W. E. Bachmann, J. W. Cook, A. Dansi, C. G. M. Worms, G. A. D. Haslewood, C. L.
Hewett and A. M. Robinson, “The Production of Cancer by Pure Hydrocarbons. Part IV,” Proceedings of the
Royal Society of London, Series B 123 (1937): 343–68, on 343–50.
27 Austoker, A History, 99–102; Gaudillière, “Hormones at Risk.”
28 Barry, Cook, Haslewood, et al., “The Production,” 344–47; Bachmann, Cook, Dansi, et al., “The Production,”
362–63.
29 J. W. Cook, E. C. Dodds, C. L. Hewett and W. Lawson, “The Oestrogenic Activity of Some Condensed-Ring
Compounds in Relation to Their Other Biological Activities,” Proceedings of the Royal Society of London,
Series B 114 (1934): 272–86; Robertson, “James Wilfred Cook,” 78–79.
30 Rony Armon, “Between Biochemists and Embryologists: The Biochemical Study of Embryonic Induction in the
1930s,” Journal of the History of Biology 45 (2012): 65–108.
31 J.W. Cook to J. Needham, 12 July 1934, Joseph Needham Papers, Cambridge University Library (JNP-CUL),
file M.142.
Published by Maney Publishing (c) Society for the History of Alchemy and Chemistry
159
FROM PATHOLOGY TO CHEMISTRY AND BACK
fi gure 1 Structures of pentacyclic aromatic hydrocarbons that were of interest to James
Cook. The diversity of these and related compounds emphasize the range of benzanthracenes
which his team explored for carcinogenic effects. (Barry, et al.,”The Production,” 328.
Courtesy of the Royal Society).
Published by Maney Publishing (c) Society for the History of Alchemy and Chemistry
160 RONY ARMON
Normal and abnormal growth
Initially exploiting carcinogens in his experiments, Needham came to explore the
relevance of his embryological theories in understanding cancerous growth. As a
chemist, Cook became somewhat hesitant in defending the biological relevance of
Needham’s findings. However, Needham, who had a strong biological background,
believed that the recently discovered artificial carcinogens pointed to naturally emerg-
ing toxic factors and tried to persuade the cancer research community of their
importance.
Needham saw Cook’s carcinogens as being related to a broader class of — normal
or pathological — growth modifiers. The documented ability of the hormone thyrox-
ine to induce metamorphosis in amphibians, and of vitamins A and E to guard against
developmental malformation in mammals, justified, in Needham’s view, the placing
of certain chemicals as triggers of gross physiological and morphological changes.
Noting the identification of hormones and vitamins as significant and highly specific
inducers of growth and development, and his own, Cook’s and Dodds’s findings
concerning the structural and functional overlap of carcinogens and sterol hormones,
Needham grouped these substances together.32 Kennaway had already proposed, in
1924, an analogy between hormones and carcinogens.33 However, Needham was the
first to extend such an analogy in order to offer a new framework for studying their
effects.
fi gure 2 Cook’s suggestion for the conversion of a bile (here referred to as deoxycholic)
acid into methylcholanthrene, which was closely related to the 1:2-benzanthracene group. The
arrows show simple reduction, dehydration, and dehydrogenation reactions which, it was
speculated, could occur in the human body. (Barry, et al.,”The Production,” 340. Courtesy of
the Royal Society).
32 Joseph Needham, “Substances Promoting Normal and Abnormal Growth,” British Medical Journal 2, no. 3953
(1936): 701–6.
33 Ernest L. Kennaway, “On cancer producing tars and tar fractions,” British Medical Journal 1, no.xxxx (1924):
564–67.
Published by Maney Publishing (c) Society for the History of Alchemy and Chemistry
161
FROM PATHOLOGY TO CHEMISTRY AND BACK
However, while placing emphasis on the role of triggering chemicals, Needham
also cautioned researchers against ignoring the many other interactions taking place
in the sick body. In cancer, as in embryogenesis, he emphasised, a chemical can have
an effect only if the tissue is “competent” to respond, and it is the responding tissue,
rather than chemical trigger, that governs “the regional character of what will be
induced.”34 Distinguishing “evocation,” denoting the triggering by chemical factors,
from “individuation,” denoting the whole set of interactions by which the induced
tissue reaches its pathological state, Needham suggested a novel research approach:
focused on chemical carcinogens while demanding that the biological factors involved
should not be neglected.
Needham’s ideas were, of course, very preliminary and supported by only scattered
empirical evidence. And yet, they raised significant interest among medical research-
ers. In 1934, Dodds invited Needham to address the biochemical section of the British
Empire Cancer Campaign. Two years later, Needham delivered his ideas at prestig-
ious lectures and annual meetings of British medical associations.35 Leading a session
entitled “Substances promoting normal and abnormal growth,” at the 1936 annual
meeting of the British Medical Association (BMA), he invited Cook and co-workers
to present their recent results.36 These addresses created diverse opportunities to
emphasise and discuss both biological and pathological implications of chemical
carcinogenesis research.
The broad interest in Needham’s ideas on cancer is somewhat surprising, bearing
in mind that embryologists, his main audience, were strongly critical of his biochem-
ical approach. However, the conception of normal and pathological growth as close-
ly related was broadly held among cancer researchers. For Leitch and Murray, the
demarcation between normal and pathological growth was clinical rather than bio-
logical. Embryogenesis and wound healing, both of which involve rapid growth, dem-
onstrated that this capacity was not limited to cancer. Researchers, they claimed,
should examine the break-up of growth constraints, rather than search for mecha-
nisms unique to the malignant state.37 As Needham learned from responses to his
ideas, the view that normal and pathological growth reflect similar mechanisms, and
the hope that embryology would offer insights into the mechanism of tumorigenesis,
were becoming prevalent, even if not widely accepted.38
At the same time, others warned Needham — and the medical research commu-
nity more broadly — of the dangers of extrapolating from embryology to cancer.
Thus, G. W. Pickering, who accepted Needham’s 1936 address to the BMA for
34 Joseph Needham, “New Advances in the Chemistry and Biology of Organized Growth,” Proceedings of the
Royal Society of Medicine 29 (1936): 1577–626, on 1580–81.
35 Armon, “Between Biochemists and Embryologists.”
36 G.W. Pickering to Needham, 16 May 1936; Harold Burrows to Needham, 16 June 1936; Needham, Bundle of
Notes, JNP-CUL-H.23-H.24.
37 A. Leitch, “Growth in its Pathological Relations,” British Medical Journal 2, no. 3489 (1927): 929–33; Murray,
Cook, Cramer, et al., “Discussion,” 268; Austoker, A History, 105–12.
38 H. E. Annett, “Substances Promoting Cell Growth,” British Medical Journal 2, no. 3957 (1936): 944–45; Willis
to Needham, 7 September 1937, JNP-CUL-M.148; C. A. Mawson to J. Needham, 2 November 1936 and W. E.
C. Dickson to J. Needham, 25 March 1939, JNP-CUL-E.140.
Published by Maney Publishing (c) Society for the History of Alchemy and Chemistry
162 RONY ARMON
publication in the British Medical Journal (BMJ), warned him of uncritically exploit-
ing embryological concepts to explain cancerous growth.39 Needham made only slight
modifications to his paper, and its publication led to a stormy debate within the
pages of the BMJ. Positing a sharp dividing line between normal and pathological
cells and processes, William Cramer contrasted the short and immediate transforma-
tion described in embryonic induction with the long process described as taking place
before the onset of a tumour.40 Accepting Needham’s explanation of tumorigenesis,
Cramer declared that “we should, in fact, have to change the accepted conception of
cancer.”41 Stimulated by Cramer’s letter, other commentators indicated a clear dis-
tinction between embryogenesis and cancer in terms of their growth patterns. They
warned against taking visible histological similarities as indicating biological simi-
larities between tumours and embryonic tissues.42 Cancer was a disease with peculiar
origins and ends, they proclaimed, and embryology could not present the keys for
deciphering its causes.
When Alexander Haddow, a recent (1936) recruit from Edinburgh to Cook’s team,
demonstrated that the chemicals that he synthesised retarded rather than enhanced
tumour growth, Needham’s ideas were challenged even further. Injecting 1,2:5,6-
dibenzanthracene, 3,4-benzpyrene and other carcinogenic substances into rats
carrying implanted tumours, Haddow discovered that all significantly inhibited the
growth of the implant, whereas noncarcinogenic compounds produced no such
effects.43 In contrast to Needham’s theory, Haddow claimed that carcinogens caused
cancer through inhibiting, rather than enhancing, growth and suggested that the in-
hibitory carcinogens brought about a selection pressure favouring the reproduction
of potentially malignant cells.44 Although this explanation was somewhat convoluted,
he and others dedicated major efforts to studying the growth-inhibitory effects of
additional carcinogens, and their testing as potential anticancer drugs.45 Some
researchers suspected that the carcinogens tested by Haddow inhibited the growth of
the whole animal rather than merely the growth of the transplanted tumours.46
But the allusion to the very same chemical factors with opposite biological effects
complicated the application of the growth analogy in explaining their pathological
impacts.
39 G.W. Pickering to J. Needham, 2 April 1936, JNP-CUL-H.23.
40 William Cramer, “Substances Promoting Cell Growth (2nd Letter),” British Medical Journal 2, no. 3958 (1936):
997–98.
41 Cramer, “Substances (2nd Letter),” 998.
42 William P. Kelly, “Substances Promoting Cell Growth,” British Medical Journal 1, no. 3967 (1937): 141–42;
Hastings Gilford, “Abnormal Growth and the Cancer Problem,” British Medical Journal 2, no. 3958 (1936):
999.
43 Alexander Haddow and A. M. Robinson, “The Influence of Various Polycyclic Hydrocarbons on the Growth
Rate of Transplantable Tumours,” Proceedings of the Royal Society of London. Series B, Biological Sciences
122 (1937): 442–76; F. Bergel, “Alexander Haddow. 18 January 1907–21 January 1976,” Biographical Memoirs
of Fellows of the Royal Society 23 (1977): 133–91, on 147–48.
44 Haddow and Robinson, “The Influence of Various Polycyclic Hydrocarbons,” 472–73.
45 Alexander Haddow and A. M. Robinson, “The Association of Carcinogenicity and Growth-Inhibitory Power
in the Polycyclic Hydrocarbons and Other Substances,” Proceedings of the Royal Society of London, Series B
127 (1939): 277–87; E. C. Dodds and F. Dickens, “The Biochemistry of Malignant Tissue,” Annual Review of
Biochemistry 9 (1940): 423–58, on 440–42; Bergel, “Alexander Haddow,” 147–48.
46 Joseph Needham, Biochemistry and Morphogenesis (Cambridge: Cambridge University Press, 1942), 266–67.
Published by Maney Publishing (c) Society for the History of Alchemy and Chemistry
163
FROM PATHOLOGY TO CHEMISTRY AND BACK
From chemistry to pathology
Not only did Needham’s drawing on embryology encounter resistance, but his insist-
ence that chemical carcinogens were major inducers of malignant tumours became
even harder to accept. Carcinogens were mostly seen as stimulants rather than as
main components in the mechanism of cancer pathogenesis. And so, Needham’s
emphasis on chemical factors went against the grain of the prevalent biological
approaches to the study of cancer. Thus, Leitch and Murray emphasised that cancer-
ous — like normal — cells possess an inherent capacity for infinite growth rather
than acquiring it upon contact with irritants.47 Cramer saw an emphasis on chemical
triggers as representing a misconception that was prevalent among biochemists.48
With other critics, he placed priority on the need to examine hitherto undiscovered
biological factors rather than artificial stimulants.49 Needham’s separation of evoca-
tion from individuation reflected the distinction that Murray and Cramer were draw-
ing between the irritation stage and a latent period during which the cancer was
actually forming. But, it was seen as overemphasising the role of chemical features in
inducing tumour formation.
While biologists were debating the role of chemical carcinogens in the causation of
cancer, Cook enhanced his search for the relationship between molecular structure
and pathological activity. Comparing the high activity of four-ringed and five-ringed
molecules with the lack of activity of newly tested hexacyclic, heptacyclic and
octacyclic compounds, he declared that “there is an optimum state of molecular
complexity for carcinogenic activity.”50 Expanding his synthesis and testing of
derivatives of 1,2-benzanthracene and 1,2:5,6-dibenzanthracene, he extended his
tentative rules. Thus, after testing derivatives with attached alkyl groups of different
lengths in different positions, he concluded that alkylation at positions 5 or 6 of
1,2-benzanthracene gave “molecular conditions which are favourable for cancer-
producing activity.”51 At the same time, tests with twenty derivatives of 1,2:5,6-
dibenzanthracene highlighted positions whose disturbance diminished carcinogenic
capacities.52 Finding carcinogenic effects primarily for substances related to 1,2-
benzanthracenes, as well as particular enhancing and diminishing modifications, he
demonstrated the validity of his original hypothesis and the utility of his approach.
However, Cook and others also identified exceptions to the rules that he was draw-
ing up, finding that very different compounds induced tumours to a similar degree.
Testing compounds containing four aromatic rings with quite different arrangements
to that found in 1,2-benzanthracene, Cook demonstrated, as he expected, negative
results. And yet, one molecule, 3,4-benzphenanthrene, proved to be highly active.
In fact, even the identification of 3,4-benzopyrene with the carcinogen in coal tar
47 A. Leitch, “Growth in Its Pathological Relations,” 931; Murray, Cook, Cramer, et al., “Discussion,” 268.
48 William Cramer, “Substances Promoting Cell Growth (1st Letter),” British Medical Journal 2, no. 3954 (1936):
781–82, on 782.
49 Cramer, “Substances (1st Letter)”; Kelly, “Substances Promoting Cell Growth”; Tom G. S. Harkness,
“Substances Promoting Cell Growth,” British Medical Journal 2, no. 3958 (1936): 998–99; J. P. McGowan,
“Substances Promoting Cell Growth,” British Medical Journal 2, no. 3964 (1936): 1334–35.
50 Barry, Cook, Haslewood, et al., “The Production,” 348.
51 Barry, Cook, Haslewood, et al., “The Production,” 323.
52 Barry, Cook, Haslewood, et al., “The Production,” 330.
Published by Maney Publishing (c) Society for the History of Alchemy and Chemistry
164 RONY ARMON
conflicted with his focus on the 1,2-benzanthracenes, as their chemical structures were
significantly different.53 Researchers elsewhere demonstrated carcinogenetic potential
for the water-soluble synthetic dye styryl 430 and for the open-ring compounds tri-
phenylbenzene and tetraphenylmethane. The then recent discoveries of carcinogens
that were very different from Cook’s substances militated against his emphasis on
1,2-benzanthracenes, and the polyaromatic hydrocarbons more broadly, as represent-
ing typical cancer-causing agents.54 While documenting successes, Cook admitted
“difficulties in arriving at any complete generalization regarding the molecular
conditions which are necessary for cancer-producing activity.”55
With the negative responses to Needham’s ideas and with the seemingly contrasting
findings of Cook and others, Cook’s chemical inroad into the pathology of cancers
was challenged on chemical as well as biological grounds. However, Cook and
Needham were not deterred. On the contrary, Cook, who was nominated professor
of chemistry at the University of London in 1935, soon began to examine additional
structures and molecular groupings that might induce cancer. Testing triphenylben-
zene and tetraphenylmethane, he found them not to be carcinogenic, thus overcoming
a major challenge from other researchers to his claims.56 Following on from his own
findings, he synthesised and tested derivatives of benzypyrenes, 3,4-benzphenanthrene,
and arcidine, thereby extending the chemical extent of his exploration beyond
the 1,2-benzanthracenes.57 Needham theorised that nonsterols might induce cancer
indirectly by stimulating the tissue to produce internal, sterol-like, carcinogens.58 Like
Cook, he remained convinced that the chemical approach to cancer would prove
useful in deciphering certain underlying mechanisms, and saw the recent objections
and contrasting findings as encouraging further research. In retrospect, it may seem
strange that Cook insisted on searching for the chemical determinants of carcino-
genic activity, despite all the evidence that appeared to negate his earlier convictions
and the great scepticism that he encountered. Nevertheless, as Austoker and
other historians have noted, other branches of cancer research encountered similar
difficulties in attempting to derive a single explanatory mechanism for all known
pathologies.
Furthermore, while leading British researchers emphasised biological elements,
their colleagues across the Atlantic saw that chemical factors were crucial as well.
James B. Murphy, director of the Cancer Laboratory at New York’s Rockefeller
Institute of Medical Research, who earlier worked with Rous, moved from studying
viruses to examining enzyme-like protein entities. Following Rous in analysing
53 Barry, Cook, Haslewood, et al., “The Production,” 330.
54 Needham, “New Advances,” 1600; C. H. Browning, R. Gulbransen and J. S. F. Niven, “Sarcoma Production
in Mice by a Single Subcutaneous Injection of a Benzoylamino Quinoline Styryl Compound,” Journal of
Pathology and Bacteriology 42 (1936): 155–59; Avery A. Morton, Daniel B. Clapp and Charles F. Branch, “New
Cancer-Producing Hydrocarbons,” Science 82 (1935): 134; Barry et al., “The Production,” 348; James W. Cook,
“Carcinogenic Chemical Agents,” Yale Journal of Biology and Medicine 11 (1938): 1–13, on 2–3.
55 Barry, Cook, Haslewood, et al., “The Production,” 334.
56 Bachmann, Cook, Dansi, et al., “The Production,” 364.
57 Barry, Cook, Haslewood, et al., “The Production”; Bachmann et al., “The Production”; G. M. Badger, J. W.
Cook, C. L. Hewett, E. L. Kennaway, N. M. Kennaway, R. H. Martin and A. M. Robinson, “The Production
of Cancer by Pure Hydrocarbons. V,” Proceedings of the Royal Society of London, Series B 129 (1940):
439–67.
58 Needham, “New Advances,” 1600.
Published by Maney Publishing (c) Society for the History of Alchemy and Chemistry
165
FROM PATHOLOGY TO CHEMISTRY AND BACK
extracts of transmissible fowl tumour, Murphy noted that the transmitting agents
survived ultraviolet radiation and purification procedures that were considered fatal
to living organisms. Finding that cancer-causing extracts contained chemical inhibi-
tory factors as well, he conceptualised normal and pathological growth as hinging on
a delicate balance — or imbalance — of stimulating and retarding factors in the cell.
While Cook and Needham focused on sterols as probable precursors of naturally
occurring carcinogens, Murphy and his researchers extracted the proteins of
cancerous, as well as embryonic, tissues in their search for cancer-causing and cancer-
inhibiting factors.59 Murphy’s results and the growing use of similar physicochemical
methodologies in analysing both proteins and viruses raised the possibility that Rous’s
agent might not be a virus after all, and made the distinction between chemical and
biological causes of cancer ever more difficult.60 Needham’s attempt to direct the
attention of the cancer research community in Britain towards chemical approaches
reflected similar trends in the USA.
Even in Britain, not all researchers were indifferent to the search for chemical
factors in the causation of cancer. William Gye, who was among the chief promoters
of the viral theory, believed that the specificity of the tumorigenic response was
determined by existing proteins in the infected cells. Although he failed to obtain
conclusive results, and physical and biological examinations of the infecting bodies
demonstrated that these were viruses rather than proteins, his colleagues saw his
claims as meriting further examination.61 The chemicals found were, in fact proteins,
and, as such, not related to the carcinogens on which Cook and Needham focused.62
However, Needham saw the focus on proteins as highly supportive, because he
believed that carcinogens, just like the embryonic hormone that he sought, were
protein-bound.63 Furthermore, a recently published study supported Cook’s and
Needham’s views that sterol-like substances needed to be considered as naturally
occurring carcinogens. While Murphy focused on the protein fractions of chicken
sarcoma filtrates, James W. Jobling, from Columbia University’s College of Physi-
cians and Surgeons, analysed their lipid fraction, demonstrating the presence of a
fat-soluble substance that produced tumours at a high rate.64
59 James B. Murphy, Ernest Sturm, Albert Claude and Oscar M. Helmer, “Properties of the Causative Agent of
a Chicken Tumor,” Journal of Experimental Medicine 56 (1932): 91–106, on 103–4; Douglas A. MacFadyen
and Ernest Sturm, “Further Observations on Factors from Normal Tissues Influencing the Growth of
Transplanted Cancer,” Science 84 (1936): 67–68; Hans-Jörg Rheinberger, “From Microsomes to Ribosomes:
‘Strategies’ of ‘Representation’,” Journal of the History of Biology 28 (1995): 49–89.
60 Rheinberger, “From Microsomes”; Angela N. H. Creager and Jean-Paul Gaudillière, “Experimental
Arrangements and Technologies of Visualization: Cancer as a Viral Epidemic (1930–1960),” in Heredity and
Infection: The History of Disease Transmission, ed. Jean-Paul Gaudillière and Ilana Löwy (London: Routledge,
2001), 203–41.
61 Max Schlesinger, “Substances Promoting Cell Growth,” British Medical Journal 2, no. 3958 (1936): 998;
Murray, Cook, Cramer, et al., “Discussion,” 290–91; C. H. Andrewes, “Viruses in Relation to the Aetiology
of Tumours,” Lancet 224 (1934): 117–24.
62 Cramer, “Substances (1st Letter),” 782.
63 Joseph Needham, “Substances Promoting Cell Growth,” British Medical Journal 2, no. 3956 (1936): 892–93,
on 893.
64 J. W. Jobling and E. E. Sproul, “The Transmissible Agent in the Rous Chicken Sarcoma No. I,” Science 84
(1936): 229–30; Dodds and Dickens, “The Biochemistry,” 449–50.
Published by Maney Publishing (c) Society for the History of Alchemy and Chemistry
166 RONY ARMON
A few researchers responded positively to Needham’s suggestions concerning the
morphogenetic function of sterols and carcinogens.65 Colin A. Mawson, a cancer
researcher at the Westminster Hospital Medical School, advised Needham that he
was deeply inspired by his ideas.66 Even Rous considered that Needham’s ideas reso-
nated well with his current identification of the involvement of chemical factors in
the aetiology of virus-induced tumours.67 Cook, as well as other researchers, contin-
ued to furnish Needham with newly synthesised sterols and carcinogens for testing of
their morphogenetic effects. At the same time, Needham noted growing difficulties
in convincing cancer researchers of the utility of his explanatory framework.68
Invited to address the 1937 annual meeting of the Association of Surgeons, Needham
declined, suggesting, for the first time, that another investigator should speak on
the topic.69 Although he was pioneering in his effort to conceptualise the biological
function of chemical carcinogens, Needham left behind the question of how these
substances brought about their effects.
In the meantime, the results of Cook and others made the correlation of carcino-
genicity and molecular structure not just difficult, but seemingly impossible. Although
many of Cook’s recent findings supported and extended the previous correlations that
he had formulated, in many other cases he found no relationship between the
molecular alterations and the shift in carcinogenic activity.70 In addition, recent tests
on aromatic amines, products of the dye industry, added compounds that were very
different to Cook’s polyaromatic hydrocarbons to the tally of carcinogens. While the
study of tar-related cancers was developed and extended, researchers on “aniline
cancers” were at first hampered by their limited ability to induce tumours under
experimental conditions. Only in the late 1930s did they began to overcome these
difficulties. In 1937, the pathologist Wilhelm Hueper, who conducted research for
the Du Pont Company on bladder cancer, demonstrated the carcinogenicity of
2-naphthylamine. His and other studies identifying aromatic amines as carcinogens
further eroded the hoped-for coherent relationship between molecular structure and
carcinogenic activity.71
Cook still expected that testing the wide range of carcinogenic and allied com-
pounds would offer insights concerning the chemical basis of cancer. He demon-
strated inductions of tumours by bile acids and additional methylcholanthrene
65 S. Pern, “Substances Promoting Cell Growth,” British Medical Journal 1, no. 3969 (1937): 245; F. E. Chidester
to J. Needham, 22 August 1939, JNP-CUL-M.152; L.B. Holt to J. Needham, 16 December 1936, JNP-CUL-
H.23.
66 C.A. Mawson to J. Needham, 29 October 1936, JNP-CUL-E.140.
67 P. Rous to J. Needham, 6 January 1937, JNP-CUL-M.147.
68 C.A. Mawson to J. Needham, 2 November 1936, JNP-CUL-E.140.
69 Secretary of the Association of Surgeons to J. Needham, 27 October and 6 November 1936, JNP-CUL-H.35.
70 Barry, Cook, Haslewood, et al., “The Production”; Bachmann et al., “The Production”; Badger et al., “The
Production.”
71 Cook, “Carcinogenic Chemical Agents,” 13; G. M. Bonser, “Experimental Cancer of the Bladder,” British
Medical Bulletin 4 (1946): 379; David A. Hounshell and John Kenly Smith, Jr., Science and Corporate Strategy:
Du Pont R&D, 1902–1980 (New York: Cambridge University Press, 1988), 561–63; Anthony S. Travis,
“Toxicological and Environmental Aspects of Anilines,” in Patai Series: The Chemistry of Functional Groups.
The Chemistry of Anilines, ed. Z. Rappoport (Chichester: Wiley, 2007), 2 parts, part 2, 835–70; Proctor,
Cancer Wars, 36–40.
Published by Maney Publishing (c) Society for the History of Alchemy and Chemistry
167
FROM PATHOLOGY TO CHEMISTRY AND BACK
derivatives that could hypothetically be derived from bile acids within the human
body. In 1942, concluding his studies, he acknowledged exceptions to his rules, but
highlighted the positive results as demonstrating that his search was far from
misguided.72 However, by then, he had departed both from his London institute and
from engaging with the problem that he had formulated there a decade ago. In 1939,
when the CHRI was renamed the Chester Beatty Research Institute, and moved to a
new and dedicated building, Cook (who was elected a fellow of the Royal Society in
1938) joined the University of Glasgow, where he was appointed Regius Professor of
Chemistry and director of the chemical laboratories. Also in 1939, Cook, Kennaway
and colleagues received the first Anna Fuller Memorial Prize for their pioneering
work on carcinogenic aromatic hydrocarbons. By then, however, Cook was no longer
engaged in full-time research, but was about to become responsible for heading a
central teaching department with hundreds of students. Despite the new administra-
tive obligations, Cook further pursued the studies of sterols and polyaromatic
hydrocarbons for which he had won his reputation as a chemist, while also develop-
ing research into alkaloids and troplones.73 However, these new studies focused on
structural elucidation and the development of synthetic routes rather than extending
the search for the mechanism of cancer that he had commenced a decade earlier.
Indeed, as Cook and colleagues noted in the late 1940s, such a search would by then
have been totally futile. The list of carcinogenic substances continued to extend to
include diverse aromatic and nitrogenous compounds, differing considerably from
1,2-dibenzanthracene, making efforts to correlate carcinogenic activity with the size,
shape and electronic characteristics of the molecule partially successful at best.74
But while Needham and Cook abandoned their hopes of explaining carcinogenic
effects biologically, others engaged the topic with vigour. Isaac Berenblum, at the
Department of Pathology, University of Oxford, commenced studies on “co-carcinogenic”
effects, and developed the concept of tumorigenesis as comprising a sudden and
irreversible initiation stage followed by a promotion stage in which the stimulated
— but still latent — cells were transformed.75 Most important in terms of the
future development of the field were novel findings that carcinogens might bring
about their effects through mutating genes in transformed cells. Although John P.
Lockhart-Mummery and others proposed a mutagenic theory of carcinogenesis in the
mid-1930s, only a decade later did researchers begin to gather supporting evidence.
Following the identification of DNA as the hereditary material (1953), researchers
72 Bachmann, Cook, Dansi, et al., “The Production,” 343–49; J. W. Cook, E. L. Kennaway and N. M. Kennaway,
“Production of Tumours in Mice by Deoxycholic Acid,” Nature 145 (1940): 627; G. M. Badger, J. W. Cook,
C. L. Hewett, E. L. Kennaway, N. M. Kennaway and R. H. Martin, “The Production of Cancer by Pure
Hydrocarbons. VI,” Proceedings of the Royal Society of London, Series B 131 (1942): 170–82, on 181–82.
73 Travis, “A Woman in Biochemistry.”
74 A. Haddow and G. A. R. Kon, “Chemistry of Carcinogenic Compounds,” British Medical Bulletin 4 (1946):
314–25; G. M. Badger, “The Carcinogenic Hydrocarbons: Chemical Constitution and Carcinogenic Activity,”
British Journal of Cancer 2 (1948): 309–50; I. Hieger, “Chemical Carcinogenesis: A Review,” British Journal of
Industrial Medicine 6 (1949): 1–23; Cook, “Polycyclic Aromatic Hydrocarbons.”
75 I. Berenblum and P. Shubik, “A New, Quantitative, Approach to the Study of the Stages of Chemical
Carcinogenesis in the Mouse’s Skin,” British Journal of Cancer 1 (1947): 383–91.
Published by Maney Publishing (c) Society for the History of Alchemy and Chemistry
168 RONY ARMON
documented interactions with carcinogens as leading to deleterious mutations, plac-
ing the genotoxic model as the dominant biological explanation of carcinogenicity.76
Cook’s emphasis on the chemical approach thus paid off in one respect. Its linking
with prevalent biological conceptions and experimental methods made the study
of chemical carcinogenesis a central component of cancer research, and gradually
eliminated the identification of his carcinogens as mere irritants.
Epilogue
James Cook, like Ernest Kennaway, received a knighthood for his pioneering studies,
and was widely recognised for his efforts in chemical carcinogenesis research. During
1949–1951, he was president of the Royal Institute of Chemistry. He also served on
various government committees, including, during 1962–1966, the Advisory Commit-
tee on Pesticides and Other Toxic Chemicals (see Hannah Gay’s article). But although
he opened up new areas of intensive chemical research into polyaromatic hydrocar-
bons, sterols, and allied substances, his main contribution to cancer research was
more instrumental than theoretical. From the outset, the carcinogens that Cook
synthesised served as important tools for cancer biologists, because, with these sub-
stances, they could reproduce tumours experimentally and study their underlying
factors under controlled laboratory conditions.77 As Cook rightly predicted in 1940,
once available as pure and efficient inducers of cancer, “the carcinogenic compounds
will continue to furnish useful material for the experimental study of cancer.”78 But,
while the use of 3,4-benzypyrene and 1,2:5,6-dibenzanthracene was significantly
extended, they were exploited for inducing cancer rather than as resembling its
underlying factors.
Cook believed that he could elucidate the chemical basis of carcinogenesis, but he
also acknowledged that his approach might limit the scope of his search. Identifying
diverse molecules as carcinogens, he recognised that his early choice to confine his
search to the 1,2-benzanthracenes led to the neglect of other classes of chemicals.79
Developments in organic synthesis and the ability to carry out biological tests by
relatively simple means made the study of chemical carcinogens a leading subfield
within cancer research. This, ironically, was complicated by the expanding range of
chemicals identified as carcinogens. In 1949, Hieger observed that the increase in
carcinogenic data only encumbered attempts to derive a single generalisation that
would account for the activity of diverse molecules.80 Proposing genotoxic and non-
genotoxic models, biologists aimed at explaining how carcinogens produced their
76 John P. Lockhart-Mummery, “Substances Promoting Cell Growth,” British Medical Journal 2, no. 3959 (1936):
1052; Needham, “New Advances,” 1621–22; L. C. Strong, “The Induction of Mutations by a Carcinogen,”
Hereditas 35 (1949): 486–99; Bruce N. Ames, E. G. Gurney, James A. Miller and H. Bartsch, “Carcinogens as
Frameshift Mutagens: Metabolites and Derivatives of 2-Acetylaminofluorene and Other Aromatic Amine
Carcinogens,” Proceedings of the National Academy of Sciences 69 (1972): 3128–32; Austoker, A History,
114–16.
77 Murray, Cook, Cramer, et al., “Discussion,” 273, 279.
78 James W. Cook, “Cancer-Producing Chemical Compounds,” Nature 145 (1940): 335–38, on 335.
79 Barry, Cook, Haslewood, et al., “The Production,” 319, 348.
80 Hieger, “Chemical Carcinogenesis,” 2.
Published by Maney Publishing (c) Society for the History of Alchemy and Chemistry
169
FROM PATHOLOGY TO CHEMISTRY AND BACK
effects; yet no chemical or biological model could predict which chemical would bring
about carcinogenic effects in the first place. Despite the hard work, massive invest-
ment, and uncompromising determination, Cook and his followers learned that
chemical rules could not reflect cancer’s fundamental causes.
Acknowledgements
This paper builds, in part, on my dissertation, written under the supervision of Oren
Harman at the Graduate Program for Science, Technology and Society at Bar-Ilan
University (April 2010), and in part on additional research conducted while I was a
research fellow at The Jacques Loeb Centre for the History and Philosophy of the
Life Sciences at Ben-Gurion University of the Negev. I thank The Jacques Loeb
Centre for the grant of a fellowship, and Oren Hraman and Ute Deichmann for their
helpful advice. The anonymous referee is thanked for critical and valuable comments,
and suggestions for improvement. I would also like to thank the staff at the
Cambridge University Library for their assistance in my archival research.
Notes on Contributor
Rony Armon is a research fellow at the Department of Education in Science and
Technology at the Technion — Israel Institute of Technology. His recent publications
include “Between Biochemists and Embryologists — The Biochemical Study of
Embryonic Induction in the 1930s,” Journal of the History of Biology, 45 (2012):
65–108 and “Beyond Darwinism’s Eclipse: Functional Evolution, Biochemical Reca-
pitulation and Spencerian Emergence in the 1920s and 1930s,” Journal for
General Philosophy of Science 41 (2010). Address: Department of Education in
Science and Technology, Technion — Israel Institute of Technology, Haifa 3200;
Email: armonr@bgu.ac.il
