Bacterial Transformation and the Origins of Epidemics in the Interwar Period: The Epidemiological Significance of Fred Griffith’s “Transforming Experiment”
Journal of the History of Biology
Bacterial Transformation and the Origins of Epidemics in the Interwar Period: The Epidemiological Significance of Fred Griffith's ''Transforming Experiment''*
0 Centre interuniversitaire de recherche sur la science et la technologie Universite ́ du Que ́bec a` Montre ́al C. P. 8888, succ. Centre-ville Montre ́al, QC H3C 3P8 Canada
1 PIERRE-OLIVIER ME
Frederick Griffith (1879-1941) was an English bacteriologist at the Pathological Laboratory of the Ministry of Health in London who believed that progress in the epidemiology and control of infectious diseases would come only with more precise knowledge of the identity of the causative microorganisms. Over the years, Griffith developed and expanded a serological technique for identifying pathogenic microorganisms, which allowed the tracing of the sources of infectious disease outbreaks: slide agglutination. Yet Griffith is not remembered for his contributions to the biology and epidemiology of infectious diseases so much as for discovering the phenomenon known as 'transformation'. Griffith's discovery, for many, was a pure case of serendipity whose biological relevance had also largely escaped him. In this paper, I argue that the key to understanding the significance of bacterial transformation - and the scientific legacy of Fred Griffith - rests not only on it initiating a cascade of events leading to molecular genetics but also on its implications for epidemiology based on the biology of host-parasite interactions. Looking at Griffith's entire career, instead of focusing only on the transformation study, we can better appreciate the place of the latter within Griffith's overall contributions. Presented in this way, Griffith's experiment on bacterial transformation also ceases to appear as an anomaly, which in turn leads us to rethink some of the most prevalent historical conceptions about his work.
* This paper is dedicated to the memory of Dr. Richard M. Krause (1925–2015),
director of the National Institute of Allergy and Infectious Diseases from 1975 to 1984,
‘‘amateur’’ historian of science (in the original sense of the word), and philanthropist.
‘‘Mutation of type among disease-producing bacteria’’ was, according
to Frederick Griffith (1879–1941), ‘‘a subject of obvious importance in
the study of epidemiological problems’’ (1928, p. 154). Working as a
public health officer at the Pathological Laboratory of the Ministry of
Health in London, Griffith was an English bacteriologist who strongly
believed that progress in the epidemiology of infectious diseases would
come only with more precise knowledge of the identity of the causative
microorganisms.1 A better understanding of the ways bacterial strains
undergo changes and variations, Griffith thought, was a precondition of
a better control of infectious diseases through the production of specific
vaccines and curative antisera. It was accordingly important to assess
the level of variability of specific bacterial strains. To this end, he
devoted three decades of his professional life to the classification of
pathogenic bacterial species, producing a systematic grouping of these
microorganisms through the use of an identification technique he had
developed and extended over the years: slide agglutination.2
From 1901 to 1941, Griffith investigated various disease outbreaks
across Britain and sought to identify the causative agents. His early
1 As medical microbiologist A.W. Downie emphasized in the Fourth Griffith
Memorial Lecture, ‘‘Griffith’s main scientific interests were related to the epidemiology
of infectious disease’’ (1972, p. 2). Historian of science Robert Olby pointed out,
similarly, that for Griffith ‘‘[t]o learn how to control the incidence and spread of chronic
lobar pneumonia called for a detailed knowledge of the host–bacterium relationship’’
(1994, p. 178). See also Wright (1941).
2 Bacterial strains of a same species usually display a wide array of antigenic dif
ferences expressed on the cell surface structures. To determine the type of strain under
study, Griffith used what is called the slide agglutination technique. This test proceeds
thus: the serum derived from infected animals (often a mouse, a guinea-pig, or a horse)
is cultivated and mixed with the type of cell used to cause the infection. Then, as the
antigen–antibody relation is specific, if the two agglutinate in the sera this means that
antibodies are binding with corresponding antigens in the bacterial strain. Using this
procedure, researchers could determine the identity of the strain they were dealing with
and could produce therapeutic serum to cure a patient or to induce immunity. This
method allowed for practical innovations, such as the identification of pathogenic and
non-pathogenic strains, and made possible the epidemiological study of infectious
diseases caused by microorganisms (see Dubos, 1976, p. 133).
major work focused on the relation between bovine and human
tuberculosis, a research conducted together with his older brother, Arthur
Stanley Griffith (1875–1941), as part of the ten-year long investigation
of the Royal Commission on Tuberculosis (on the Commission, see
Francis, 1959). During the following decades at the Pathological
Laboratory at the Ministry of Health, Griffith reported on several aspects of
the biology and epidemiology of meningococcus, pneumococcus, and
streptococcus. He also developed a new test for detecting syphilitic
infections. Griffith’s work on the classification of hemolytic
streptococcus is especially important from a public health point of view as the
typing of bacteriological strains permitted the identification of the
sources of various acute infections such as rheumatic fever, scarlet fever,
puerperal fever, and other minor wound infections such as sore throats
(see Hare, 1940, for the importance of this bacteriological work).
Yet Griffith is not remembered today for his contributions to the
biological understanding and classification of infectious diseases but for
a single ‘‘oddball’’ paper – his 1928 study in which he had shown that
nonvirulent bacteria could be transformed into virulent types when
mixed with previously heat-killed bacterial strains of a different virulent
type, a phenomenon known as transformation. As Sir Peter Medawar
(1915–1987) once put it, the behavior of pneumococci Griffith recorded
evoked the notion that ‘‘they could undergo something akin to a
transmutation of species’’ (1968). This was extremely puzzling at a time
where it was still unclear whether bacteria had genes and whether they
could evolve at all (see Creager, 2007).
Unsurprisingly, American researchers at the Rockefeller Institute in
New York, in particular Oswald T. Avery (1877–1955), initially
perceived Griffith’s experimental finding as a ‘‘bombshell’’ in the field of
immunology because it called into question the doctrine of
‘‘immunological specificity’’ (Dubos, 1956, p. 40; see Amsterdamska, 1993).
Thanks to his reputation as an excellent laboratory scientist, however,
Griffith’s results were fast-replicated in several laboratories across
Europe and in the United States. The hunt for the nature of the
‘‘transforming principle’’ culminated with the discovery that DNA was
the active molecule involved in transformation (Avery et al., 1944), and
placed researchers on the ‘‘path to the double helix’’ (Olby, 1974/1994;
Despite our familiarity with different aspects of this history, and the
later developments of molecular biology that ensued (Judson, 1996;
Kay, 2000), the conceptual foundations of the transforming experiment
remain poorly understood and have received little historical attention
(see Eichmann and Krause, 2013 for a renewed interest in the topic). As
bacterial geneticist and Nobel Prize laureate Joshua Lederberg (1925–
2008) reported after trying for several years to reconstruct the
‘‘conceptual antecedents’’ of the transformation study: ‘‘[w]e are at loss
trying to trace the intellectual influence behind his [Griffith’s]
experiment’’ (1992, p. 264).
To understand the significance of the transforming experiment, I
argue, we must place it within Griffith’s own research interests, which
were epidemiologically-oriented as well as based on the production of
detailed bacteriological knowledge. ‘‘Griffith’s primary concern’’ with
the results in the 1928 article, as Maclyn McCarty (1911–2005)
emphasized, ‘‘was with their implications for the epidemiology and
disease patterns of pneumonia’’ (1985, p. 77; emphasis added). Yet,
‘‘Griffith’s speculations on the epidemiological significance of the
interconvertibility of pneumococcal types,’’ Ren e´ Dubos (1901–1982)
previously noted, have ‘‘remained virtually unnoticed, and have been
largely forgotten,’’ while ‘‘his experimental findings had an immediate,
enormous impact on immunologists all over the world’’ (Dubos, 1976,
p. 136). This paper seeks to recuperate the ‘‘epidemiological
significance’’ of the interchangeability of pneumococcal types as studied by
Griffith. Historicizing the transforming experiment will show that it
cannot be divorced from the latter’s wider interests in the
epidemiological aspects of infectious diseases.
The significance of microbial transformation, in brief, rest not (only)
on it initiating a cascade of events leading to molecular genetics but also
– and perhaps especially – on its implications for epidemiological
approaches based on knowledge of the biology of host–parasite
interactions. Griffith’s thirty years of research on changes in disease virulence,
in fact, should be considered as a whole in which bacterial
transformation is an important part – and following the historian of science and
medicine J. Andrew Mendelsohn, certainly not some ‘‘quirky medical
idea’’ (2002, p. 29). The experiment on bacterial transformation, it turns
out, belongs to a wider scientific effort to understand the nature of
variation and the origins of epidemics in the interwar period (see
Amsterdamska, 2005). Understood in this way Griffith’s work on the
origin and disappearance of infectious diseases and the transforming
experiment cease to be considered merely as the ‘‘prelude’’ to the
discovery that genes are made of DNA. Placing his scientific contributions
within a longer time period also leads us to rethink and question some
of the most prevalent historical conceptions about Griffith’s work.
After introducing some biographical elements concerning Griffith’s
life, I situate his works within the wider context of epidemiological,
bacteriological, and medical research in the interwar period. I then
explore his earlier study at the Royal Commission for Tuberculosis and at
the Ministry of Health and I show how they are continuous with the
discovery of transformation in 1928. Following a detailed examination
of the transformation study and some aspects of its reception in Europe
and in the United States, I turn to Griffith’s later research on
streptococcus diseases in relation to rheumatic and scarlet fever, conducted
alongside bacteriologists and epidemiologists in the late 1920s and
mid1930s, which were of great public health significance at the time. The
paper concludes with a brief examination of the unpublished
correspondence between Griffith and American bacteriologist Rebecca
Lancefield (1935–1937), who developed an alternative system of
bacteriological classification based on precipitin-test reaction, in contrast to
Griffith who subdivided types by slide agglutination technique.
Elements of Fred Griffith’s Biography
‘‘There is so little information about Fred Griffith!’’ Lederberg lamented
(Letter from Lederberg to Pollock, 1970).3 Most of the sources related
to Griffith’s work, it should be noted, are largely based on memory, not
on first-hand statements or observations.4 Reconstructions of Griffith’s
contributions, furthermore, often sounds rather heroic and the general
lack of correspondence to and from Griffith poses a serious challenge to
any comprehensive reconstitution of his life and work. The following
section attempts at providing a more synthetic view of Griffith’s
biography that can help us gain a better understanding of his career path
and the evolution of his scientific ideas on infectious disease biology.
3 The Joshua Lederberg papers, deposited at the National Library of Medicine, can
be freely accessed here: http://profiles.nlm.nih.gov/BB/. All letters to and from
Lederberg, Winston Maxted, Martin Pollock, Graham Wilson, Rebecca Lancefield, Robert
Olby, and Alvin Coburn, unless otherwise stated, will be quoted from this online
4 Information in this section comes mostly from obituaries and letters about Griffith,
from the first four Griffith Memorial Lectures, and from Olby (1974/1994), Dubos
(1976), and McCarty (1985). Griffith’s personal papers and correspondence have almost
all disappeared during the war, when his house was flattened, and he had no offspring.
Some letters between him and Rebecca Lancefield at Rockefeller survived and are
available in the Rebecca Lancefield papers at the Rockefeller Institute.
The son of Joseph and Emily Louisa Griffith, Fred Griffith was born
at Hale in Cheshire in 1879. Trained in medicine, he graduated from
Victoria University in Liverpool in 1901. After being physician and then
a house surgeon, holding resident posts at the Liverpool Royal
Infirmary, he was appointed as Alexander Fellow in Pathology at the
Thompson Yates Laboratory in Liverpool in 1901, a private institution
dedicated to research in biochemistry, tropical medicine, experimental
medicine, and comparative pathology (Figure 1). Between 1903 and
1911, Griffith worked as a bacteriological investigator on the Royal
Commission of Tuberculosis, together with Arthur Stanley Griffith and
Arthur Eastwood (1867–1936). In 1910, he took the Diploma of Public
Health (D.P.H.) from Oxford University and one year later he joined
the Local Government Board as a medical officer at the Ministry of
Health in London where he stayed until he was killed during an air raid
in the Second World War.
Arthur Stanley Griffith, Fred’s older brother, was also a graduate from
Victoria University, which awarded him the Derby exhibition prize at the
Liverpool School of medicine. In 1901, two years after being the first
Alexander Fellow at Thompson Yates and Johnston Laboratory, Stanley
received his M.D. degree and the Diploma in Public Health of the Royal
English College, with a medical thesis on ‘‘The flora of the conjunctiva in
health and disease’’ (Griffith 1901). Arthur Griffith is particularly known
for his work on the typing of the tubercle bacilli and for his demonstration
of the potentially severe effects of bovine tuberculosis on man through
milk consumption, and especially for children, a work he carried out as
one of the principal investigators for the Royal Commission on
Tuberculosis. Once the work of the Commission was completed Stanley
continued his research on tuberculosis under the auspices of the Medical
Research Council at the University of Cambridge. In 1926, he was
awarded a PhD from Cambridge and in 1927 he received the
WeberParkes prize and medal of the Royal College of Physicians for his overall
contribution to the study of tuberculosis. His state of health fell out in the
early 1940s and he died in 1941, a few days before his younger brother was
killed during the London blitz.
After their participation in the Commission, Fred Griffith and
Arthur Eastwood both accepted positions at the Local Government Board
in London. In 1915 they were joined by William McDonald Scott
(1884–1941), a noted bacteriologist who was in charge of investigating
the spread of cerebrospinal fever in Britain. A graduate from Edinburgh
in public health, Scott studied tropical medicine and hygiene before
obtaining his M.D. degree in 1910. Scott and Griffith became close
collaborators and also good friends. Together, they developed a new
method to test for syphilitic infections (Griffith and Scott, 1920; see the
details in Gilbert, 1928). As the Local Government Board Laboratories
was taken over by the Ministry of Health during the First World War,
both Griffith and Scott moved to Dudley House, located on Endell
Street, in Soho, and converted in Pathological Laboratory.
It may be difficult to imagine the inner working of Scott and
Griffith’s laboratory but according to Hedley Wright, the author of one of
Griffith’s obituary in 1941, a foreign visitor might have been ‘‘short of
appalled’’ to see the internal functioning of this ‘‘chaotic environment’’;
and yet the quality of the contributions coming out of it was widely
recognized within and outside Britain (Wright, 1941, p. 588). Wright
noted further that not only Griffith and Scott ‘‘did all their own bench
work with very little up-to-date equipment’’ but that these two ‘‘could
do more with a kerosene tin and a primus stove than most men could do
with a Palace’’ (Ibid.). This is but one example of the heroic rhetoric that
is often employed to describe Griffith’s work.
Many have also reported on the generosity and modesty of Griffith and
Scott, who were keen to assist other bacteriologists investigating
infectious diseases and working in the country or abroad (Downie, 1972, p. 2).5
In 1931, for instance, Griffith helped American bacteriologist Alvin
Coburn in (1899–1975) identifying Streptococcus pyogenes serologically.
Five years later, on the occasion of the 2nd International Microbiology
Congress in London (July 25–August 1, 1936), Coburn visited Griffith at
which time he took the famous snapshot (Figure 2) of Griffith and his dog
Bobby on the Downs, near Brighton (Coburn, 1969; see also Dubos,
1976). The picture was sent to Oswald Avery at the Rockefeller Institute
when Coburn realized ‘‘how deeply Avery’s work was founded on the
discovery made by Fred Griffith’’ (Coburn, 1969, p. 627). Avery framed
the picture and kept it on its desk and after retirement, at his home,
throughout the ‘‘transforming’’ and ‘‘post-transforming years’’ (Letter
from Coburn to Lederberg, November 9th 1965, p. 2).
On the eve of the Second World War, as senior bacteriologist of the
Ministry of Health, Griffith was sent to Cambridge to create and
manage the Emergency Public Health Laboratory (EPHL), where he
teamed with Bruce White (1891–1949), the other senior bacteriologist
on the staff at the EPHL. Though some expected that Griffith would
take the lead in the organization of the EPHL, and apparently ‘‘Topley
always tried to force him into this,’’ Griffith was, it was said, ‘‘without
political ambition’’ and preferred to leave these matters to him (Letter
from Wilson to Pollock, 8th December 1969, p. 2). As it turned out,
Griffith also had apparently ‘‘no flair for organization’’ and his dislike
of constantly meeting new people made him want to return to London
(Letter from Maxted to Lederberg, no date). Thanks to Leonard
Colebrook’s help, another long-time scientific collaborator, he was able
to return to London where he established a streptococcal research unit
at Queen Charlotte’s Isolation Block at Hammersmith, which is where
he began working with Stuart Dunsmore Elliott (1907–1986).
5 ‘‘Few public-health bacteriologists in the British Isles do not owe to Griffith and
Scott gratitude for help received, some of it acknowledged here and there as a footnote
to a paper, yet more unexpressed, but living in the thousand and one details of their
daily life’’ (Wright, 1941, p. 589). Graham Wilson also emphasized in the late 1960s that
‘‘[a]nybody who went to them [Griffith and Scott] during life with a problem found them
a mine of information, imparted in the most modest fashion and accompanied by
helpful suggestions and wise criticism’’ (Letter from Wilson to Pollock, 8th December
1969, p. 1).
Upon his return in the capital, Griffith lived in his private house in
Eccleston Square, in which he stayed with a housekeeper and his niece.
Griffith’s collaborator and friend William Scott also shared his house.
When the Blitz began in April 1941, many friends and colleagues of
Griffith believed they should all move out of central London at once but
he apparently refused ‘‘to move for any German’’ (Letter from Maxted
to Lederberg, no date). A bomb flattened Griffith’s house a few days
later, killing him, Scott, and the housekeeper. Only Bobby and the niece
survived the raid. After Griffith’s death, Stuart Elliott became head of
the Streptococcal Research Laboratory (McCarty, 1985, p. 20).
Fred Griffith was often described as a ‘‘quiet and reticent’’ man who
was ‘‘always happiest at the bench’’ (Letter from Wilson to Pollock, 8th
December 1969), and ‘‘like his brother he was a recluse, known to few’’
(Wright, 1941, p. 588). Unlike his brother, however, he remained a
bachelor while Stanley Griffith married Anna Nellie Griffith, a graduate
in mathematics and physics. Together they had a son, John S. Griffith
(1928–1972), born the same year his uncle published his study on the
transforming principle.6 Fred Griffith ‘‘seldom attended meetings’’ and
was a ‘‘classical example of the backroom boy’’ (Letter from Wilson to
Pollock, 8th December 1969, p. 2). He disliked going to scientific
conferences and was almost forced into a cab by William Scott and V.D.
Allison to get to the International Congress in Microbiology in London
1936 (Olby, 1994, p. 171). During the delivery of his paper on ‘‘The
agglutination of hemolytic streptococci’’ (1937), he was nearly inaudible
as he apparently spoke too softly throughout the whole presentation
(Dubos, 1976, p. 132).
Outside of his work as a civil servant in bacteriology, Griffith enjoyed
walking his Irish Terrier Bobby and driving at high speed in narrow streets,
a behavior that impressed and scared his American guest Alvin Coburn in
1936 (Dubos, 1976). He owned a house in Brighton that was apparently
‘‘more modern in architecture than anything in Beverly Hills’’ (Letter from
Coburn to Lederberg, November 19th 1965), a fact standing in stark
contrast with his alleged conservative attitude. Indeed, Griffith was a member
of the Honorable Society of Gray’s Inn and many people who have known
him personally such as Winston Maxted (1911–1999) have described him as
being ‘‘patriotic’’ – for instance, Griffith was always the first with his
‘‘aluminium pots and pans for Spitfires, and with War Bonds and in
following other governmental exhortations.’’ In Maxted’s opinion, ‘‘Griffith’s
politics, social and professional attitudes and every aspect of his life’’ were
conservatives (Letter from Maxted to Lederberg, no date, p. 2). In a letter to
Lederberg, Coburn similarly refers to Griffith as ‘‘one of England’s most
conservative scientists’’ (Letter from Coburn to Lederberg, November 19th
1965). In a sense, this conservative attitude could be seen in Griffith’s
repeated emphasis on the biology of microorganisms to explain the rise and
fall of epidemics. Understanding epidemics through the biology of the
microorganism, indeed, is a classic image of scientific conservatism and, in
this respect his work remains close (in spirit at least) to Robert Koch’s
postulates (see Gradmann, 2014).
The snapshot with Bobby is often considered to be the only existing
photography of Fred Griffith (together with the one in Downie’s fourth
Griffith Memorial Lecture, 1972). Here (Figure 3), we can see him
6 John Griffith became a theoretical chemist and biophysicist, and while working at
Cambridge and Oxford, he played a critical role in calculating the helical structures of
DNA for James Watson (1928–) and Francis Crick (1916–2004). Afterwards, his interest
in biology and immunology led him to elucidate aspects of the nature of prions. Griffith
suggested that the active agent might be an infectious protein but his death in 1972
prevented him from witnessing the confirmation of his views (Lagnado, 2005).
enjoying himself during a ski trip in the Alps. Maclyn McCarty,
coauthored with Avery of the 1944 paper, discovered this picture of
Griffith on skis in Rebecca Lancefield’s office at the Rockefeller Institute
after she passed away in 1981.7 How she came into possession of this
7 When Griffith and Lancefield began to correspond in 1935 he was just returning
from a ski trip in the Swiss Alps (Letter from Fred Griffith to Rebecca Lancefield,
March 18th, Rebecca Lancefield papers, Rockefeller University, Series 450, L 221, box
3, folder 1). Griffith was a close friend to Colebrook, one of his long-term collaborators,
and the two of them used to go skiing together in the Alps (Letter from Winston to
Pollock, December 8th 1969, p. 2). Colebrook might have taken the picture. On
Lancefield, see the biographical memoir by McCarty (1987) and O’Hern (1975).
picture is not known. But as it happened, Griffith and Lancefield had
corresponded between 1935 and 1937, sending each other bottles of sera
and various microbial strains across the Atlantic while reflecting more
broadly on the significance of their different approaches to bacterial
classificatory systems. In the last letter of Lancefield to Griffith at the
Rockefeller Institute she invited him to visit her laboratory: ‘‘Why don’t
you make a trip over here sometime?’’8 Griffith’s response is lost. After
the war, it was Stuart Elliott who crossed the Atlantic Ocean and
reconciled the typing methods of Group A streptococcus (GAS) used by
Griffith and Lancefield (McCarty, 1985). Through his many visits to
New York, Elliott became a close friend of Lancefield and supported
her work throughout his life.9
Epidemiology and Bacteriology in the Pre- and Interwar Period
What happens when an epidemic slowly emerges, gathers
increasing momentum until it reaches its climax, and then dies gradually
away until the disease falls back to the endemic level it started
from? What are the respective shares of microbic virulence and host
resistance? Is the decline of an epidemic due to a falling off of
virulence, or to the exhaustion of susceptible materials? (Cushing,
1922, p. 429)
These foundational questions in epidemiology, formulated here in the
editorial of The Canadian Medical Association Journal in 1922, had
remained in large part of theoretical interest until the emergence of the
influenza pandemic in 1918–1919, from which flowed a general feeling
of powerlessness in face of its devastating effects (Mendelsohn, 1998; on
the history and epistemology of influenza pandemics, see M e´thot and
Alizon, 2014). At the turn of the past century, answers to these
questions were sought either in changes in the germ, the host, or in some
other environmental factors. Typically, while bacteriologists postulated
changes in the germ’s virulence, epidemiologists hypothesized wider,
historical changes in the social or cultural environment. The popular
8 Letter from Rebecca Lancefield to Fred Griffith, July 30th, 1937, Rebecca Lance
field Papers, Rockefeller University Series 450, L 221, box 3, folder 1.
9 For example: ‘‘Dear Stuart, This is to register the enthusiastic approval of everyone
consulted about arranging plans to get you to join our laboratory as soon as possible for
you to get away this spring and to stay until the money gives out or you feel you have to
go’’ (Letter from Rebecca Lancefield to Stuart D. Elliott, March 7th 1979, Rebecca
Lancefield Papers, Rockefeller University, Series 450, L 221, Box 9, folder 5).
hypothesis that a change in the germ’s virulence or infectivity could
account for the cyclical behavior of epidemics was widely discussed in
the first two decades of the twentieth century in England and in the
United States (Amsterdamska, 2004, p. 487).
Already in 1905, for instance, British medical statistician John
Brownlee (1868–1927) argued on the basis of his study of vital
statistics that ‘‘the number of cases must be due to the loss of
infectivity in the germ itself, and not in the lack of individuals who may be
supposed open to contagion’’ (1905–1906, p. 486). Brownlee, however,
did not inquire into what such a biological change may be. The
following year, British epidemiologist William Hamer (1858–1934), a
vocal critic of bacteriology, intended to account for the waxing and
waning of epidemics not as a ‘‘change in the number of the sick’’ but
as a change in the ‘‘rate of infection and the density of the
interactants’’ (Mendelsohn, 1998, p. 317). As Mendelsohn noted, this model
rendered bacteriological, immunological, and environmental variables
altogether ‘‘superfluous’’ in accounting for the epidemic. What
mattered in Hamer’s model was the continuous arrival of fresh susceptible
individuals (either from birth or from migration) and the ways in
which this flow of individuals could disturb a biological ‘‘equilibrium’’
established at the population level. Hamer’s mathematical model was
adopted by advocates of a more ‘‘experimental’’ approach to
epidemiology in England, such as statistician Major Greenwood (1880–
1949) and bacteriologist W.W.C. Topley (1886–1944) (Greenwood and
Topley, 1926; Amsterdamska, 2004).
Despite the prominence of statistical approaches to disease in the
interwar period, as historians have made us aware (Amsterdamska,
2005), it is important to underline that bacteriological studies have
continued to occupy a central place in terms of methodological
approaches and research questions, on the one side, and that this work was
often pursued ‘‘largely outside the institutions, research schools, and
journals of academic biology, in the predominantly hospital and public
health spheres of a most applied and medical laboratory science,’’ on
the other (Mendelsohn, 2002, p. 31). Fred Griffith, for instance, who
worked in the Pathological medical laboratory in London, did not train
as a statistician but as a medical bacteriologist. He viewed changes in a
germ’s virulence as a fundamental factor in explaining the origin of
epidemics and the geographical path of disease outbreaks more
generally. For him, the constant arrival of insusceptible individuals could not
provide – in itself – a complete explanation of the decline of epidemics;
scientific investigators also had to consider incremental changes in the
biology of the microorganism, and how these changes, in turn, could
affect the nature of its relation to the host and to the wider population.
As we will see, Griffith was convinced that modifications in the
biology of the causal germ not only had consequences on illness severity
at the patient level but also at the community level, as it changed the
epidemiological distribution of diseases, that is, it brought new disease to
the fore and caused others to recede in the background. Griffith’s view
of the origin and decline of epidemics were not based on a crude
bacteriological and reductionist doctrine but on a more subtle form of
biological adaptation being established between hosts and parasites. His
work indicates also that bacteriology and epidemiology were perhaps
much less in an antagonistic relation than what was often assumed in
the historiography (on this point, see Steere-Williams, 2015). But before,
let us go through some of the stages in the history of bacteriology to
contextualize Griffifth’s work on changes in serological types.
Conceptual Flux in Bacteriological Research: From Pasteur to Griffith
In the second half of the nineteenth century Louis Pasteur (1822–1895)
had shown the phenomenon known as ‘‘virulence’’ or disease severity to a
host could be decreased through specific attenuation techniques or again,
it could be enhanced by serial host passages (Moulin, 1992).
Understanding the nature and the significance of variable virulence continued to
be a fundamental research problem at the Pasteur Institute as well at the
Robert Koch’s Institute in Berlin, at the turn of the twentieth century
(Gayon, 1995; Mendelsohn, 2002). During the first three decades of the
past century, in fact, the ‘‘identity’’ of microbial organisms was in crisis.
Inherited from the last quarter of nineteenth century medical
bacteriology, the doctrines of ‘‘monomorphism’’ and ‘‘pleomorphism’’ still exerted
their influence on the concepts of variation and variability in microbial life
forms (Mazumdar, 1995; see also Gradmann, 2000).10
How to reconcile ‘‘the extraordinary persistence of types’’ during
epidemics with the ‘‘rapid transformation [of germs] under conditions
favorable to change’’ (Hamer, 1906, p. 570), for instance, was a thorny
10 The thesis of pleomorphism derives from the works of naturalist Karl Na¨ geli
(1817–1891) and stipulates that all microorganisms, in different states (e.g. virulent or
avirulent), form a single species. For Na¨ geli, microorganisms not only change
morphologically or physiologically but can also transform into one another. In contrast,
monomorphism, a thesis often attributed to Robert Koch (but cf. Mendelsohn, 2002),
claims that microbial species are well-defined in nature, and cannot transform (though
they admit intra-species variation).
issue at a time when the Darwinian concepts of natural selection and
evolution only began to be applied to the microbial world (see O’Malley,
2009). The concept (and scope) of ‘‘biological variation,’’ furthermore,
was itself unclear and variable as reflected by its usage in the context of
microbiological research at the time (see Cole and Wright, 1916, p. 212;
see also Eastwood, 1923, Hadley, 1927, and Arkwright, 1929, 1931. For a
historical account, see Amsterdamska, 1991, and Creager, 2007). The
conceptual flux in bacteriological research was increased by the problem
of delineating microbial species: not only was knowledge about bacteria
still fragmentary but also traditional biological concepts applied poorly to
bacteria and viruses (though the two were not distinguished yet). First, the
concept of ‘‘species’’ was difficult to operationalize because of the peculiar
mode of reproduction of microorganisms and also due to the speed at
which new generation could arise. Second, the problem of sorting out
microorganisms into species was accentuated due to their great
variability, functionally and morphologically as well as with respect to
pathogenicity or virulence to hosts (see, Topley and Wilson, 1934).
Initially, claims about the possibility for bacteria to undergo
physiological and morphological changes were regarded as suspect although
they exerted a clear fascination for researchers. As Ludiwk Fleck (1896–
1961) once commented, he used to regard words such as ‘‘vitalism’’ in
biology, ‘‘specificity’’ in immunology, or ‘‘bacterial transformation’’ in
bacteriology as ‘‘slogans’’ endowed with ‘‘magic power’’ (Fleck, 1979, p.
43). After bacteriologist Joseph Arkwright (1864–1944) from the Lister
Institute in London correlated the agglutinative behavior of enteric
bacteria to changes in virulence, the interest in studying bacterial variation
grew steadily (Amsterdamska, 1991, p. 193). Fred Griffith, for one, was
very curious about biological variation and wondered whether it was an
artefact or a ‘‘real’’ feature of biology (Letter from Coburn to Lederberg,
1972, p. 2). Yet even if the existence of the diversity of microbial variability
was progressively recognized, the distinctions between genetically stable
variability (i.e. the result of mutations) and momentary variations (i.e. the
result of adaptation to changes in the environment) were not firmly
established as far as 1927 (Lo¨ wy, 1988, p. 234). In fact, until the mid 1940s,
the possibility of drawing up an ‘‘operational distinction’’ between
mutation and adaptation did not seem possible to most microbiologists
(Hotchkiss, 1966, p. 182/2007; Creager, 2007).
Paramount examples of virulence modification with important
implications from a medical point of view included colonial changes from
‘‘smooth’’ (S) to ‘‘rough’’ (R) described by Arkwright for the dysentery
group (1921, 1929, 1930, 1931) and also by Griffith (1923). Indeed, these
gradual changes from S to R correlate with loss of virulence and altered
sensitivity to bacteriophage. The loss in virulence was due to the
disappearance of a polysaccharide capsule (giving the culture a ‘‘rough’’
outlook as opposed to a ‘‘smooth’’ or shiny, almost watery one) – which
permits bacteria to avoid phagocytosis – and corresponding antigenic
components. Directionality of changes in colonial aspects as described by
Arkwright was thought to go from smooth (virulent) to rough (avirulent),
a thesis Griffith’s 1928 paper on transformation called into question
(Topley and Wilson, 1934). Yet what was the nature of those observable
changes in bacterial colonies? Were they heritable, analogous to de Vries’
notion of ‘‘mutation,’’ or were they transient ‘‘physiological’’
adaptations? Clarifying the nature of those changes, Griffith (1928, 1934) and
others hoped, would help explaining the incidence of diseases such as
pneumonia at the epidemiological level (Olby, 1994, p. 170).
Pneumonia and the ‘‘Fixity’’ of Serological Types
Issues concerning the nature of changes in microorganisms were
intimately connected to the practical possibilities of developing effective
treatments against infectious diseases, particularly serum therapy. Since
Emil von Behring (1854–1917) and Shibasaburo Kitasato (1853–1931)
demonstrated the possibility to cure sick animals using anti-serum
previously obtained from animals immunized with the corresponding
bacterial toxins, much effort was devoted to producing antipneumococcus
sera and other therapeutic agents that would be useful against a number
of infectious diseases (Gradmann and Simon, 2010) including
pneumonia, a significant cause of death and morbidity (Podolsky, 2006).
While earlier attempts at producing effective serum-therapy were
unsuccessful, German bacteriologist Fred Neufeld at the Robert Koch
Institute in Berlin made a major theoretical advance of practical importance.
Neufeld believed that the classification of pneumococcus into serological
types was at the foundation of the science of immunity. Together with his
coworkers, he established the existence of immunologically distinct serological
types of pneumococci in 1909, showing that those pathogens do not form a
homogenous group (Neufeld and H a¨ndel, 1909). In 1912, they delineated
three such distinct groups of pneumococci (on Neufeld see, Mendelsohn,
1998, and Eichmann and Krause, 2013; on the standardization of serum
therapy see Mazumdar, 2010, and Hu¨ ntelmann, 2010).
Simon Flexner (1863–1946), then director of the Rockefeller Institute
in the United States, took notice of Neufeld’s work. Inspired by his results,
Flexner and Rufus Cole (1872–1966) provided much of the impetus to
classify the disease-causing organisms involved in pneumonia outbreaks,
and to look for the production of effective and standardized serum. To
organize pneumococcus research at the Rockefeller Institute, Cole
appointed a talented chemist, Oswald Avery, in 1913. For Avery, like for
Neufeld, the chemical basis of immunological specificity and the
differences in antigenic properties provided not only a ‘‘reliable method’’ to
determine the variety of bacterial strains but also ‘‘the only rational basis
for the study of immunotherapy in pneumococcal infection’’ (Avery, 1915,
p. 816). Avery stressed that serological types are based on ‘‘well defined
immunological differences’’ that reflect ‘‘the extraordinary uniformity and
comparative fixity of the specific groups’’ (Avery, 1915, p. 816). Upon his
arrival at the Rockefeller, Avery joined Alphonse R. Dochez (1882–1964)
with whom he reported on the relation between pneumococcal types and
human pneumonia (Dochez and Avery, 1915). In Acute Lombar
Pneumonia- Prevention and Serum Treatment (1917), Avery, Chickering, Cole,
and Dochez confirmed Neufeld’s results. The American team identified
four Types after the examination of cases of pneumonia: Types I, II, III,
and a heterogeneous named Type IV. In London, Griffith (1922) obtained
the same distribution of pneumococcus as the one observed by the
American researchers in New York. In addition, Griffith identified twelve
serological types within the Type IV group (Downie, 1972, p. 2).
Over the years, Avery and Griffith have looked at each other’s work
with great respect although they never met and (probably) never
corresponded either.11 Commentators have noted similarities between the
two bacteriologists: Both were interested in streptococci and
pneumococci; they were both bachelors; in terms of scientific practice, both were
modest and meticulous with their experimental work12 as well as
generous with their time in helping others; not to mention that they were
almost ‘‘obsessively cautious’’ in drawing conclusions (Pollock, 1970, p.
10). Avery and Griffith, however, entertained different views about the
biological and clinical meaning of type variation in pneumococcus:
‘‘For Avery the Types were distinct and separate forms, almost with the
status of species, while for Griffith they were unstable varieties’’ (Russel,
1988, p. 395).
11 ‘‘I probably was the source of Dr. Elliot’s ‘definite opinion’ that Dr. Avery and Dr.
Griffith never met or corresponded. I can only say that this certainly has always been my
impression and was doubtless casually stated around the laboratory’’ (Letter from
Lancefield to Lederberg, December 12th 1972).
12 Bacteriologist Stuart D. Elliott, who worked with Griffith for several years, noted
that he was ‘‘fanatic about techniques’’ so much so that his meticulousness ‘‘sometimes
aroused the exasperation, if not the fury, of his associates and assistants’’ (cited in
Dubos, 1976, p. 132).
Avery’s belief in the doctrine of immunological specificity explains, at
least partly, why he was at first reluctant of accepting Griffith’s claim that
pneumococci can change in their immunological signature (see Dubos,
1956). And while Avery refrained from speculating about the
evolutionary origins of serotypes, Griffith did not hesitate to explore ‘‘in the
light of evolutionary possibilities’’ the transformation of one type into
another (1917, p. 185).13 Examining Griffith’s research prior to the
transforming experiment and well as the 1928 study, the following
sections will illustrate his constant preoccupation with finding changes in
microorganisms that could explain the origins of epidemics and the
ecological paths of disease. Beginning with his work as part of the Royal
Commission on Tuberculosis and continuing throughout his career while
at the Ministry of Health in London, Griffith’s interest for changes in
microorganisms also provides insights into his dynamical views of
bacterial species and the evolution of serological races in nature. Taking a
longer view of his scientific career will help us see that Griffith was not
‘‘convinced of the fixity of bacterial types’’ until as late as 1928, contrary
to what was often supposed (Letter from Wilson to Pollock, December 8th
1969; see also Pollock, 1970, Downie, 1972) but that he contemplated the
possibility of bacterial transformation much earlier on.
Griffith’s Bacteriological Research Before the Transforming Experiment
The Royal Commission on Tuberculosis (1901–1911)
First identified by German bacteriologist Robert Koch (1843–1910) in
1882, American bacteriologist Theobald Smith (1859–1934) claimed,
fourteen years later, the existence of distinct bovine, avian, and human
13 For example, in a paper on the classification of pneumococci, Avery wrote: ‘‘In the
present discussion no attempt is made to interpret the experimental data in terms of
their phylogenetic significance. Whether the subvarieties of the second group of
pneumococci represent strains which have acquired independently certain adaptive
characters, or whether they are related to each other and to the fixed type by the lineage of
common descent is interesting. However, the limited nature of the present study precludes
the formulation of any hypothesis as to origin’’ (Avery, 1915, p. 818; emphasis added). In
contrast, as part of a study of pneumococcus, Griffith concluded: ‘‘[In] the light of
evolutionary possibilities […] one might speculate on the relationship to the
meningococcus group of the naso-phrayngeal organism which cannot be accepted as a
meningococcus but differs culturally from the true meningococcus only in the marked
production of pigment. […] According to one’s point of view, such strains might be
considered as the possible starting point or the possible end point in the process of
evolution of the meningococcus’’ (Griffith, 1917, p. 185; emphasis added).
types of tuberculosis bacillus – challenging Koch’s views of a unique
tubercle germ (on Th. Smith, see Me´ thot, 2012). During the British
Congress on Tuberculosis in London in 1901, Koch responded that the
bovine form of tuberculosis was not dangerous for human populations,
precisely because it differed from the human type (Rosenkrantz, 1985).
In the debate that ensued among participants the government conveyed
the Royal Commission on Tuberculosis, which was appointed on
August 3rd 1901 under the chairmanship of Sir Michael Foster (1836–
1907). Its purpose was to determine (1) ‘‘whether the disease in animals
and man is one and the same; (2) whether man and animals can be
reciprocally infected with it; and (3) under what conditions, if at all, the
transmission of the disease from animals to man takes place, and what
are the circumstances favorable or unfavorable to such transmission’’
(Ritchie, 1907, p. 3; see Francis, 1959).
The commission conducted two parallel investigations of the tubercle
bacillus in human and animal forms at two experimental farms in
Stansted, Essex, lent by Sir James Blyth (1841–1925), a British
businessman. A third series of comparative experiments was then carried out in
laboratory. Stanley Griffith, Arthur Eastwood, and Louis Cobbett (1863–
1947) were the senior resident investigators on the Royal Commission.
They were joined by Fred Griffith. During the investigation, the two
brothers worked closely together. Studying the cultural characters of the
bovine tubercle bacillus, they conducted a large number of modification
experiments of virulence with bacilli of bovine and human origin and
reported on their effects in different species including calves, goats,
monkeys, mice, rabbits, pigs, and guinea-pigs after subcutaneous
inoculations (Griffith and Griffith, 1907). During ten years, the commission
published a series of detailed interim reports (that appeared in 1904, 1907,
1909). As recommended by the Royal Commissioners, comparative
pathologist Theobald Smith’s experiments used to distinguish the bovine
from the human form were repeated. While he was able to confirm Smith’s
general statement about the different behavior of virulent tubercle
cultures of human and bovine origins, Stanley Griffith concluded that this did
not point to a physiological difference between the two (1907, p. 57).
‘‘Man,’’ the final report concluded, ‘‘must therefore be added to the list
of animals notably susceptible to bovine tubercle bacilli’’ (Final Report of
the Royal Commission, 1911, p. 122).14 As to the question of the identity
14 I am quoting from the summary of the report published in the British Medical
Journal. The complete report appeared in Her Majesty’s Stationary Office and was led by
Sir William Henry Power (1842–1916), who acted as Chairman of the Commission from
from 1907 after the death of Sir Michael Foster. The whole report contains various
appendix written by Stanley Griffith, Fred Griffith, Arthur Eastwood and Louis Cobbet.
of the disease, the commissioners considered that the human and bovine
types are ‘‘varieties of the same bacillus’’ and consist in ‘‘one and the same
disease’’ (Ibid., p. 123). Concerning the possibility of reciprocal infection
they stated that ‘‘mammals and man can be reciprocally infected with the
disease’’ (Ibid.); and as to the conditions facilitating the transmission, they
concluded that they are mainly dependent on the ‘‘susceptibility’’ of the
animals and the opportunities of transferring the infection to man (Ibid.,
p. 124). From a public health perspective, the authors of the report called
attention to the danger of drinking infected cow milk.
Of special interest here is the question of the difference of virulence
between bovine and human tubercle bacilli towards certain animals and
not others. Why, the commissioners asked, is the human bacillus more
virulent in monkeys than in goats, calves, and pigs? Is the human form a
‘‘modified’’ or ‘‘degraded’’ form of the bovine tubercle? Is its
degradation permanent? Drawing upon the works of the Griffith brothers, the
commissioners noted the following: ‘‘[R]epeated attempts were made to
transmute bovine into the human bacillus, and vice-versa’’ (Final Report
of the Royal Commission, 1911, p. 124; emphasis added). Most of these
experimental attempts, several of which were performed by Fred
Griffith (1911), were unsuccessful, however, and lent support to the claim
that both types were ‘‘remarkably stable.’’ The authors conceded that
‘‘transmutability of bacillary type’’ is ‘‘exceedingly difficult, if not
impracticable of accomplishment by laboratory procedures.’’ In spite of
the failure to experimentally transmute the bacillary type, the
commissioners also stated clearly that they were ‘‘not prepared to deny that
the transmutation of one type into another may occur in Nature’’ (Final
Report of the Royal Commission, 1911, p. 123; emphasis added).
This conclusion calls into question the view put forward by Downie
(and others) in the Fourth Griffith Memorial Lecture, that prior to 1928
‘‘Griffith was conditioned to believe that bacteria existed in immutable
types’’ (1972, p. 3).15 Indeed, although the tuberculosis bacillus appeared
remarkably stable and resistant to experimental transformation, the
investigators did not give up the possibility of transmutation in general.
The several experiments designed to test whether the human type of
tubercle bacillus could be transformed into a bovine type (and
vice15 According to Graham Wilson, ‘‘Many years before [the transforming experiment],
he [Griffith] had worked with his brother Stanley on the tubercle bacilli, and was
convinced of the fixity of the mammalian types; and yet here he had produced a change
in the types of pneumococci’’ (Letter from Wilson to Pollock, December 8th 1969). One
year later, Pollock nuanced Wilson’s words, however: ‘‘At the time, Graham Wilson has
pointed out, he [Griffith] was firmly convinced of the fixity of bacterial types – at least in
so far as the mammalian tubercle bacilli were concerned’’ (Pollock, 1970, p. 7).
cation in bacteriological diagnosis,’’ for instance in the development of
therapeutic sera for lobar pneumonia (1928, p. 148). He also
considered, however, that the findings he was reporting could bear on ‘‘others
issues, probably of greater importance’’ such as ‘‘the occurrence and
remission of epidemics,’’ ‘‘the appearance of epidemic types in certain
diseases,’’ and the ‘‘attenuation of the infecting agents’’ (1928, p. 148).
What is the ‘‘meaning’’ of the types defined by serologists, he asked.
Do they represent ‘‘stages in the normal life history of a bacterium’’ or
are they the ‘‘response on the part of the bacterium’’ to changes in the
host? (1928, p. 148) A solution to these questions, Griffith considered,
‘‘would be a valuable contribution to the epidemiology of disease’’ as it
would ‘‘explain some of the phenomena in the rise and fall of
epidemics’’ (Ibid.) Claiming that ‘‘a Type I could be changed into a Type
II or III,’’ Griffith said, ‘‘would have been received with greater
skepticism than at the present day.’’ Since it was shown that a
pneumococcus can be attenuated, ‘‘deprived of its type characters and
virulence,’’ which can then be restored under favorable conditions,
however, ‘‘the possibility appears less unlikely’’ (1928, p. 154). It is
thus the discovery of reversion from R to S that supported the
possibility of bacterial transformation itself.
How does this relate to the hypotheses set out at the beginning? Here,
Griffith remains a little unclear. ‘‘The apparent transformation,’’ he
says, ‘‘is not an abrupt change of one type into another but a process of
evolution through an intermediate stage, the R form, from which the
type characters have been obliterated’’ (1928, p. 154; emphasis added).
This phrasing seems to support the second hypothesis (i.e. mutation),
and the author then adds immediately that ‘‘[m]utation of type among
disease-producing bacteria is a subject of obvious importance in the
study of epidemiological problems’’ (1928, p. 154). However, Griffith
settled for the third hypothesis, namely that Group IV types are derived
from Type I. Although it had remained ‘‘purely speculative’’ so long as
the instability of pneumococcal types was not demonstrated, this
hypothesis could now be stated with more confidence: ‘‘the chief types
revert to the Group IV varieties from which they were derived during
the development of the disease in the individual’’ (1928, p. 155).
Griffith conceived those changes as transient, physiological
adaptations. ‘‘The formation of a Group IV strain from Type I,’’ he explains,
‘‘might be considered as an adaptation on the part of the Type I
pneumococcus to the altered conditions consequent on the development
of immune bodies’’ (1928, p. 156; emphasis added). Whereas most
writers had regarded the reversion to the R form as a ‘‘degenerative
change’’ (1928, p. 156), and while it implies ‘‘some sacrifice of its [Group
IV] antigenic complexity’’ Griffith interpreted this change as a ‘‘vital
adaptation,’’ as suggested previously by bacteriologist Philip Hadley
(1881–1963) (Hadley, 1927, p. 156; see Amsterdamska, 2004). Reversion
to the R (avirulent) form, thus, is not admitting defeat on the part of the
pneumococcus but an illustration of the efforts allowing the
microorganism to actively develop virulent potentialities anew in the future.
This biological adaptation, for Griffith, was to be understood as ‘‘the
final stage in the struggle of the bacterium to preserve its individuality
[…] against adverse cirumstances’’ (1928, p. 157). This is one of the most
important aspects of the 1928 paper for Griffith, as it could explain why
an apparently harmless saprophyte could suddenly turn into a virulent
pathogen and vice-versa.
Going back to the tensions between epidemiologists and
bacteriologists introduced earlier, Griffith located the cause of the decline of an
epidemic in the biology of the germ itself, that is, in the identity of the
causative microorganism. The possession of the S antigen, he argued, is
potentially capable of transforming a harmless saprophytic, rough-like
colony into a virulent smooth type endowed with what he called the
‘‘full equipment of virulence’’ of another type (1928, p. 157).
Transformation via an intermediate stage S offered an appealing mechanism
to account for the distribution of virulent and avirulent diseases in a
population. Beyond the interest in bacterial transmutation itself, this
experiment, overall, provided Griffith with an explanation of epidemic
outbreaks that was epidemiologically significant and grounded in
bacteriological knowledge, as the conclusion of the paper makes plain:
The experiments on enhancement of virulence and transformation
of type suggest an explanation of the manner in which
pneumococcus residing as an apparently harmless saprophyte in the
nasopharynx acquires disease producing powers. So long as it
retains certain potentialities, indicated by the possession of traces of
S antigen, the most attenuated pneumococcus may develop the full
equipment of virulence. These considerations which relate to an
individual case of pneumonia are capable of application to an
outbreak of epidemic disease in a community. Thus the
consequences which ensue on the decline of an epidemic are not only an
increase in the number of insusceptible individuals but also an
alteration in the character of the infective organism (1928, p. 157;
Historians have long been interested to know whether Griffith had any
understanding of the phenomenon he produced; and most concluded
that his discovery was a case of ‘‘pure serendipity.’’ 23 It has also often
been said that Griffith left to others the task of sorting out the nature of
the transforming principle and that he never returned to the problem
himself. 24 While it is the case that Griffith focused on other problems in
biology and medicine after 1928, he did not entirely leave
transformation aside. In ‘‘Serological Races of Pneumococci. Significance of
Types,’’ a paper which appeared in 1929 in A System of Bacteriology in
Relation to Medicine, he discussed ‘‘whether pneumococci may change
from one type to another under natural conditions’’ (1929, p. 209).
Although this had not been demonstrated in human infections, Griffith
said, ‘‘it is difficult to conceive that the chief types, as well as the
innumerable varieties of Group IV, are absolutely fixed and inalterable’’
(Ibid.). To make his point, he referred again to the variety of Group IV
strains found in the sputum of convalescent patients. Rejecting the
consensus according to which the chief types ‘‘die out’’ he advanced the
view (as in the 1928 paper) that under the influence of the immune S
substance formed during the recovery phase, the pneumococcus can
take on different serological characters: ‘‘Group IV strains may be
derived from one or other of the chief types’’ (1929, p. 209).
23 Graham Wilson claimed that he ‘‘doubted whether Fred Griffith ever realized the
greatness of his transformation discovery’’ (Letter from Wilson to Pollock, December
8th, 1969, p. 1). ‘‘Griffith seemed to have had little idea of how this transformation came
about, nor even of its great and ultimate significance,’’ Martin Pollock wrote in the
Third Griffith Memorial Lecture. ‘‘His discovery,’’ he continued, ‘‘was a classic instance
of pure serendipity’’ (Pollock, 1970, p. 8; emphasis added). Similarly, for Brock, ‘‘Fred
Griffith’s paper is a classical example of serendipity’’ (1990, p. 224; emphasis added). See
also Chen (2010).
24 In the First Griffith Memorial Lecture, microbiologist and geneticist William Hayes
wrote: ‘‘The story of this discovery [of transformation] is told in his [Griffith’s] 1928
paper, which is the only one he wrote on this topic. […] [N]o further references to it
appear among his rather scanty subsequent publications’’ (Hayes 1966, p. 386; emphasis
added). Brock also contends that ‘‘Fred Griffith’s observations on type transformation
in pneumococci are embedded in a lengthy paper on characteristics of pneumococcus
types (Griffith, 1928), the only paper Griffith published on transformation’’ (1990, p.
218; emphasis added). ‘‘My guess is,’’ American microbiologist Alvin Coburn once told
Lederberg ‘‘that Fred Griffith thought little of his experiment’’ (Letter from Coburn to
Lederberg, April 25th, 1966).
Griffith continued and discussed a number of ‘‘modifications
experiments,’’ while making clear reference to his own 1928 paper. Citing works
by Morgenroth et al. (1925) in which the authors were apparently able to
‘‘transform pneumococci into streptococci’’ Griffith went on to describe
the method he had used to show that ‘‘one type of pneumococcus can
apparently be converted into another’’ (1929, p. 209). Detailing another
case of transformation ‘‘in which a rough Type II was changing into a
virulent Type I’’ he referenced the use of his personal method by Fred
Neufeld and Levinthal (1929, p. 210). In 1927, Neufeld visited Griffith in
London. During his visit, he was informed of the intriguing results of
Griffith and the experimental procedures employed. Once back in Berlin,
Neufeld replicated the experiment and confirmed Griffith’s initial results.
This explains why he and his colleague Walter Levinthal (1886–1963)
published their results a few months only after Griffith’s own paper
appeared in print (Neufeld and Levinthal 1928).25
Griffith’s experimental results, though not immediately endorsed,
were regularly discussed at scientific meetings, in journals and in
encyclopedic works, and their implications for genetics were also explored (on
this see Olby, 1994). In his Bradshaw Lecture for example, Arkwright
reported on Griffith’s finding, which, ‘‘if fully corroborated will mean a
great advance in the theoretical position’’ (1929, p. 968). During the 1st
International Congress of Microbiology in Paris, he characterized
Griffith’s work on transformation as being of ‘‘fundamental importance in
the theory of variation and the change of virulence of bacteria and the
progress of epidemics’’ (Arkwright, 1931, p. 155). Topley and Wilson, in
their Principles of Bacteriology and Immunity (2nd edition), wrote that to
‘‘transmute a smooth Type I pneumococcus, via the non-capsulated
rough variant, into a smooth Type II or Type III pneumococcus,’’ as
suggested by Griffith, is ‘‘so important, in its biological interest and
implications’’ (1934, p. 209). One such implication was pondered by
geneticist Theodosius Dobzhansky (1900–1975) in the 2nd edition of his
Genetics and the Origins of Species, who added: ‘‘If this transformation is
described as being a genetic mutation – and it is difficult to avoid so
describing it’’ (1941, cited by McCarty in a Letter to Lederberg October
11th, 1972; see Olby 1994; Morgan, 1944).
25 ‘‘We used the one-cell cultures to reproduce the important experiment of F. Griffith
on the transformation of avirulent pneumococci (R-forms) into virulent (S-forms) of the
same but also of a foreign type […]. The communication of Griffith just appeared in the
Journal of Hygiene (1928, Vol. 27. p. 113); owing to the kindness of Dr. Griffith, who
communicated his results to one of us during a visit […] in London, we were enabled to
begin with our experiments before [Griffith’s paper appeared]’’ (Neufeld and Levinthal,
cited and translated in Eichmann and Krause, 2013, p. 2233).
The central problem raised by bacterial transformation was the
realization that changes in serological types entailed that the doctrine of
immunological specificity had to be reconsidered (Amsterdamska,
1993). Oswald Avery’s initial skepticism, thus, was likely due to the fact
that he devoted much of his professional life developing this doctrine
that Griffith’s findings were calling into question (Dubos, 1956, p. 40;
Downie, 1972, p. 3). In the United States, Reimann (1929) and Dawson
(1928, 1930) successively confirmed Griffith’s results. Dawson and Sia
(1931), then, replicated the transforming experiment in the test-tube,
succeeding in what Griffith had failed to achieve, while Alloway (1932,
1933) demonstrated transformation in vitro using cell-free extract of
pneumococci. Upon his return to Rockefeller after a sick leave, Avery
was made aware that his colleagues had confirmed Griffith’s results and
had even extended them. As is well known, after more than fifteen years
of experimentation they then established that the transformation of one
type of pneumococcus (avirulent) into another (virulent) was the result
of the action of a deoxyribonucleic acid, or DNA, and not protein
(Avery et al., 1944).26 Avery’s work underlined the need to bring
molecular and chemical approaches to bear on the study of infectious
diseases and, according to Nobel Prize laureate Frank Macfarlane
Burnet (1899–1985), it signposted a broad shift from the study of
infectious diseases to molecular biology (Burnet, 1968; see
Amsterdamska, 1993; Mendelsohn, 2002). Transformation was later
experimentally demonstrated to occur in the respiratory tract (Conant and
Sawyer, 1967) and although further works on transformation continued
as biochemistry and molecular biology developed in the 1960s the
medical domain largely ignored the phenomenon of transformation
discovered by Griffith (Downie, 1972).
The Accusation of Lamarckism
Early molecular biologists often saw as uninterrupted the line of intellectual
descent going from Karl N a¨geli (1817–1891) to Fred Griffith, and
interpreted bacteriology, by and large, as ‘‘one of the last strongholds of
Lamarckism’’ (Luria, 1947, p. 1; Olby, 1974; see also Morange, 1998). This
is partly due to the fact that bacteriologists often described bacteria’s
adaptation to their milieu in terms of acquired traits. ‘‘Transformation of
pneumococcus strains, as observed by Frederick Griffith,’’ Angela Creager
noted, ‘‘was commonly viewed as evidence of Lamarckian inheritance’’
(Creager, 2007, p. 173). According to Olby, for example, Griffith had a
‘‘Lamarckian scheme of intraspecific variation in his mind,’’ and he ‘‘was
not surprised by the discovery of the transformation of types’’ (Letter from
Olby to Lederberg, November 8th, 1972; emphasis added). ‘‘After having
established that R cells derived from Type 1 could be transformed into S
cells of Type II,’’ Dubos also concluded that ‘‘Griffith suggested a
Lamarckian explanation of the phenomenon’’ (1976, p. 135; emphasis added).
‘‘Strangely,’’ Thomas Brock observed fifteen years later, ‘‘Griffith did not
see his third (somewhat Lamarckian) hypothesis, interchangeability of type,
as particularly radical’’ (1990, p. 218; emphasis added).
In the post-face of his book, Olby maintains that ‘‘the
neo-Lamarckian account’’ he gave ‘‘is important for our understanding of the
whole transformation story’’ (Olby, 1994, p. 456). But what does it
mean to claim that Griffith’s interpretation of his result was
‘‘Lamarckian,’’ and why does it matter? For one thing, the Lamarckian reading
of the transforming experiment was important because historians used it
to explain scientists’ initial reluctance in accepting Griffith’s results.
According to Olby, for instance, ‘‘Griffith’s reputation was high, but his
‘Lamarckian’ ideas and his vague talk of a ‘pabulum’ could hardly have
appealed to Avery who […] was at least committed to strictly chemical
explanations’’ (1974, p. 178). Others, however, refrained from
attributing the label of Lamarckism to Griffith. In reading Olby’s
manuscript for his book on the history of molecular biology, Lederberg
felt that the author was trying to ‘‘force a theoretical outlook’’ on
Griffith’s interpretation of his own results. ‘‘It seems inappropriate,’’
Lederberg wrote in response to Olby, ‘‘to put the label Lamarckian in a
point of view that was not well informed about the nuances of the issue
that it presents nor about the elements of related controversy in other
fields of biology’’ (Letter from Lederberg to Olby, October 25th, 1972).
Lederberg also said he would ‘‘hesitate to call Griffith a Lamarckian for
this would imply some greater clarity […] than I believe he exhibited in
his earlier paper’’ (Letter from Lederberg to Olby, October 25th 1972).
While it is easy to go from ‘‘transformation’’ to ‘‘transformism’’ to
‘‘Lamarckism,’’ bacterial transformation bears little in common with
what became known as the inheritance of acquired characters, typically
(and often misleadingly) associated with the name of Lamarck – but
that Darwin and several other biologists of the nineteenth and early
twentieth century also accepted (for a recent study on neo-Lamarckism,
see Loison, 2011). According to Lamarck, for example, variations
always go from the less complex to the more complex (Jacob, 1973, p.
145). This scheme does not apply to Griffith’s work that explored how
bacteria could both lose and gain in antigenic complexity. Griffith’s
paper, furthermore, is rather silent about the fact that induced
modifications via transformation are heritable (Downie, 1972; McCarty, 1985).
This is not surprising, though, given that most bacteriologists of the
1920s ‘‘were unconcerned with whether bacterial variation was
hereditary’’ an issue that seem far off from their practical concerns (Creager,
2007, p. 163; see Amsterdamska, 1987). Furthermore, scientists working
in the 1920s did not sharply distinguish the concepts (nor the cause) of
mutation and adaptation as we do today; but the most important point
is that Lamarckism and Darwinism did not yet stand out as competing
explanatory schemes – at least in bacteriology and microbiology – when
Griffith discovered transformation: the genetic (and selectionnist)
interpretation of transformation would take shape only during the
1940s within the neo-Darwinian framework (Creager, 2007). If one truly
wants to relate Griffith to the transformist tradition in microbiology,
one should probably look into N a¨geli’s microbiological works rather
than in Lamarck’s.27
After the Transforming Experiment: Griffith’s Work on Streptococcus
pyogenes and the Decline of Rheumatic and Scarlet Fever in Britain
Next to his research on pneumococcus and meningococcus, Griffith has
been involved in a series of epidemiological and bacteriological projects
investigating the etiology of rheumatic fever and streptococcal
infections. Though its virulence was progressively declining since the late
nineteenth century (Swedlund and Donta, 2003), rheumatic fever was
still a serious cause of morbidity and mortality in the first three decades
of the twentieth century. In the interwar period, researchers attempted
to correlate the presence of a specific microorganism with the disease in
order to devise an antisera-based treatment similar to those developed
for pneumococcal diseases. Identifying the causative organism through
slide agglutination was not straightforward, however. What germs and
under what conditions they were normally found in humans was
27 Griffith, indeed, did not place rigid limitations on the changes in serological types,
as he considered that the emergence of one type rather than another depends more
fundamentally on the material being provided, not on the species. He noted that, for
instance, ‘‘in its ultimate form’’ the R pneumococcus ‘‘is the same, no matter from what
type it is derived.’’ The R pneumococcus posses antigens of both Types I and II and
‘‘could develop either S form according to the available material’’ (1928, p. 153;
problematic. The situation was also complicated due to the fact that
precise classifications of bacteria (pathogenic and non-pathogenic) were
lacking (English, 1989), which is what Griffith sought to remedy.
In the early 1920s, attempts at isolating the bacteria responsible for
the disease had thus largely failed although the conviction that cases of
rheumatic fevers were due to members of the streptococcus family
remained widely held. As historian Peter C. English has described, several
research strategies devoted to identifying the crucial factor(s) in the
etiology of rheumatic fever emerged in the interwar period, including
allergy, heredity, environment, and infection with group A hemolytic
streptococcus (2002, p. 89). Griffith’s study on group A streptococcus
(GAS) was a turning point in the epidemiology of GAS and rheumatic
fever in the twentieth century. He pursued this research, forming the last
part of his written work, sometimes alone but often also alongside other
scientific investigators who made decisive contributions to the
elucidation of the bacteriological or to the epidemiological aspect of the disease
in England and in the United States. These advances, in turn, allowed
scientists to trace the sources of infection with greater precision and
accuracy, prior to the advent of antibiotics.
Beginning in 1926, Griffith studied hemolytic streptococci of human
origin in relation to scarlet fever, one of the outcomes of streptococcal
infections. Classification of types, as always, was a prerequisite to
‘‘more intimate knowledge of the interrelationship between the various
forms of streptococcal infections’’ (Griffith, 1927, p. 372). The variety of
bacteria was so great that without a proper way of sorting pathogenic
from non-pathogenic form, attempts to locate the sources of infection
were largely improbable. Using slide agglutination technique, Griffith
demonstrated that the family of streptococcus comprises four main
serological types and one heterogeneous group (Ibid.). Together with
British bacteriologist William Gunn, he conducted an extensive and
intensive study of one hundred cases of scarlet fever in Britain, mostly
from schools, in a combined bacteriological and clinical perspective. In
their paper, Gunn and Griffith emphasized the correlation between
types of streptococcus, the level of toxin production, and the severity of
scarlet fever infections (Gunn and Griffith, 1926). For half of the cases,
the same serological type was found throughout the hospital treatment
of patients. For the other half, however, there was an ‘‘apparent change
of type’’ during the course of the disease (Gunn and Griffith, 1926, p.
253). Gunn and Griffith proposed three hypotheses: the serological
types were too instable to warrant a useful classification; the bacterium
may be stable outside the body but was liable to change in contact with
antibodies formed to resist infection; reinfection occurred as the patients
were close to one another. In contrast with the other paper published in
1928, Griffith did not decide for type-transformation: ‘‘While the
possibility of modification of type cannot be excluded,’’ they settled for the
last hypothesis: reinfection (Gunn and Griffith, 1926, p. 253).
British epidemiologist J. Alison Glover (1874–1963), author of the droplet
infection theory of transmission of rheumatic fever, was one of the main
scientists to document the decline of this disease in Britain during the
1930s and 1940s. In his Milroy Lectures, Glover concluded that rheumatic
fever was becoming an ‘‘obsolescent disease,’’ apart for children (Glover,
1930). Together with Griffith, he investigated several cases of tonsillitis
outbreaks in relation to scarlet fever in boarding schools in England in the
early 1930s (Glover and Griffith, 1930a, b; Glover and Griffith, 1931). In a
paper on the sequel of tonsillitis, they established that scarlet fever is only
one of the possible outcomes of hemolytic streptococcal infections,
though streptococci were unified as a species. This conclusion was put
forward thanks to Griffith’s method of serological analysis that allowed
classifying the chief types involved in outbreaks of streptococcal
infections under study. This method also helped clarifying the epidemiological
importance of types as well as their actual association with clinical
conditions. Their results and public health recommendations appeared in the
pages of the Lancet and the British Medical Journal.
Griffith’s fundamental paper related to rheumatic and scarlet fever
was published in 1934 in the Journal of Hygiene. There, he exposed how
he patiently sorted the species Streptococcus pyogenes into 27 distinct
serological types. He noted that like pneumococcus, streptococcus had
become differentiated into a number of ‘‘serological races’’ with
different pathological and epidemiological values though they continued to
form a ‘‘well-defined bacterial species’’ (Griffith, 1934, p. 578). What
was the motivation behind this large-scale project carried out by slide
agglutination technique? In his 1972 note to Lederberg, Coburn
remarked that one important ‘‘conceptual antecedent’’ to Griffith’s
‘‘colossal task of identifying hemolytic streptococcus serologically’’ was
the identification of variants that had great ‘‘infectivity.’’ For Griffith,
typing might provide valuable insights about the transformation of
harmless saprophytes into virulent pathogens.
There is no doubt in my mind that Griffith, the bachelor, was
inspired by the romance of a concept, i.e. one variant of
Streptococcus pyogenes with great ‘infectivity’ (commonly called virulence)
for man could produce a devastating epidemic. And believe me
when one is inspired with this concept all other matters seem
momentarily insignificant (Letter from Coburn to Lederberg
September 28th 1972, p. 2, emphasis added).28
As usual, Griffith thought that a better differentiation of bacterial
strains should come first. ‘‘The importance in epidemiological studies of
a reliable method of identification of a bacterial species,’’ as he put it in
his talk at the 2nd International Congress in Microbiology, ‘‘is
unquestionable’’ (1937, p. 132). Aligned with his prior interest in finding
how a common saprophyte may be able to propagate an epidemic under
appropriate conditions or how a virulent type was reverting to a rather
inoffensive one, as for instance during convalescence, Griffith tried to
pin down the multiple causes of changes in virulence. In the conclusion
of his 1934 lengthy paper, he related the loss of severity in scarlet fever
to a change in the ‘‘serological constitution’’ of the population.
The evolution of serological types in nature is an interesting subject
for speculation. It seems probable from the severity of scarlatinal
epidemics in the past was originally much more virulent and
toxigenic […] In consequence of experience of streptococcal infection
being more common in crowded urban communities man has
developed a considerable degree of herd immunity, and it may be
that the resistance which the streptococcus has had to contend with
has resulted in the development of the existing multiplicity of
serological races. Each of these races or types differs, however slightly,
from another in infectivity, invasiveness and toxigenic capacity in
virtue of its individual antigenic constitution (Griffith, 1934, p. 582).
Epidemics of scarlet fever were much more devastating in the late
nineteenth century, as Glover and others had demonstrated, and as
clinicians had also observed (English, 2002). For Griffith, however, the
decline in virulence was not only due to the global increased in
resistance on the part of the population (‘‘herd immunity’’) but also the
result of the germ’s loss in infective capacity. Griffith derived a lesson of
28 Topley offered a similar view about Griffith: ‘‘Many field epidemiologists, and in
particularly the late Dr. Fred Griffith, have been convinced that the observed behavior
of certain human infections, such as those due to haemolytic streptococci, demand the
hypothesis of the existence of special epidemic strains of the parasite concerned, with
heightened power of producing disease by contact infection’’ (Topley, 1941, p. 352).
epidemiological significance from this two-way process, very much
along the lines of his paper on transformation: the ‘‘spread of disease in
a community,’’ he argued, ‘‘means ultimately not only increased
resistance on the part of the host but also alteration and attenuation of the
parasite’’ (1934, p. 583). According to Griffith, a susceptible human
population and a pathogen that was once very virulent were locked in a
long-term process of adaptation that might lead to a harmless relation.
Indeed, the English bacteriologist claimed that while most epidemics of
scarlet fever in Britain were caused by type I and II, some types were
increasingly causing tonsillitis without rashes meaning that serological
types can ‘‘lose their toxigenicity’’ (1934, p. 583). ‘‘If the present
tendency is maintained,’’ Griffith continued, scarlet fever ‘‘will disappear as
a clinical entity’’ (Ibid.). In sum, there was a process towards decreased
levels of virulence as humans’ immunity rose and the streptococcus’s
pathogenic power declined over time. Did Griffith consider the
described changes in bacterial virulence to be the result of physiological
adaptation of the bacteria or of a selection of less virulent variants?
Given his constant emphasis on changes in the biology of the parasites
to account for the spread of diseases, it is likely that such physiological
explanation might have appeal to him, perhaps even more than a purely
selectionnist hypothesis sorting out strains that varied in virulence
power (on the distinction between adaptation and selection, see Creager,
In the early 1930s, two rival methods existed for identifying
pneumococcal strains (Parker, 2001; see Lancefield 1933): Griffith’s type
agglutination technique and Lancefield’s precipitin test reactions (where
strains were identified on the basis of C-carbohydrates and M protein).
Correspondence between Griffith and Lancefield located at the
Rockefeller Institute in New York bring additional light on the
methodological issues arising in the classification of pneumococcus during that
period. It was the possibility of classifying Streptococcus pyogenes into
27 distinct types as proposed by Griffith led to a letter of interest by
Rebecca Lancefield to the British bacteriologist in 1935.
pyogenes into so small a number as 27. It certainly makes a much
more workable situation in this group if one can do that (Letter
from Lancefield to Griffith, January 22nd 1935).29
Griffith responded quickly and positively to Lancefield’s letter, who turned
out to be right in the end – there were more than 27 strains. Between 1935
and 1937 the two bacteriologists corresponded frequently. Most of their
letters bore on the methods of typing pneumococci. The letters do not
mention, however, whether they met in person during the International
Congress in Microbiology in London in 1936 to which both participated.
Lancefield and Griffith were keen to know whether their methods
were compatible in typing streptococcus stains. ‘‘I have not finished
checking some of our strains against your sera yet,’’ wrote Lancefield,
‘‘but enough is done to show the general agreement between these two
methods of typing Group A strains’’ (Letter from Lancefield to Griffith
August 14th 1935, p. 1).30 This was a reassuring finding as scientists had
been wondering whether the two methods would indeed yield the same
result: ‘‘It seems to me’’ Lancefield continued, ‘‘that wherever I have
had good anti-M sera for making the comparison, the results of typing
by these different techniques agreed very well. This was, of course, what
I expected, but so many people have asked me whether our method
would give the same results that I am very glad to have definite
information on the subject’’ (Letter from Lancefield to Griffith, August 14th
1935, p. 1).31 To achieve uniformity, Lancefield also adopted the
numerical classification proposed by Griffith (McCarty, 1987).
Despite general agreement in typing, discrepancy arose sometimes
between their different methods, and they endeavored to account for it: ‘‘Our
results then with these strains are opposed ‘‘Griffith pointed out,’’ and it is
necessary to seek some explanation of this divergence’’ (Letter from Griffith
to Lancefield, April 29th 1937).32 Though they had deep respect for one
another Griffith and Lancefield ‘‘did not see eye to eye on methodology’’
and ‘‘were never converted to each other’s approaches’’ (McCarty, 1987, p.
235). The exchange of letters between the two bacteriologists, interrupted
by Griffith’s death, however, shows that despite his skepticism to ‘‘new
claims in streptococcal work’’ he was beginning to acccept other
bacteriological systems of classification that were then commonly in use for many
years (Letter from Maxted to Lederberg, no date).
Fred Griffith was a medical bacteriologist and public health officer by
training whose work was deeply rooted in epidemiological
considerations, as he was acutely interested in the biological study of
host–parasite relations and their consequences for diseases at the population
level. Questions of epidemiology, in fact, fundamentally drove his
bacteriological work rather than the other way round. Epidemiology
broadly understood provided him with an interface between biological
and medical understanding of host–parasites relations. Interested in
unraveling the emerging patterns as well as the sources of infections,
most of his reports attempted to relate bacteriological knowledge with
the epidemiological path of the disease under study. As Topley once put
it, Griffith was a ‘‘field epidemiologist’’ (1941, p. 352). Griffith’s
approach differed from the ‘‘experimental epidemiology’’ defended by
Greenwood and Topley at the School of Tropical Medicine and
Hygiene in London, however. In contrast with mathematical approaches to
epidemiology that would be prevalent after the Second World War, and
would become the hallmark of modern epidemiological practice
(Amsterdamska, 2005), Griffith did not draw on statistical methods or
mathematical tools. What he did was generate detailed tables in which
he meticulously reported the results of his numerous experiments with
animal models into which he inoculated various bacterial strains. In this
respect, he was not an epidemiologist working with ‘‘modern’’
mathematical tools but rather a medical bacteriologist of the ‘‘old school’’ that
was still prevalent in the interwar period.
The serum type agglutination technique Griffith developed on a
largescale was devoted to advance a more precise differentiation of
microorganisms and to the production of serum therapy and vaccines. The
differentiation of hemolytic streptococci into types he accomplished was likely
one of his most valuable scientific contributions though it is most of the time
ignored by commentators, who concentrated almost exclusively on the
transformation study. This work on classification, continued and
broadened by Lancefield’s method after Griffith’s death, permitted scientists and
public health officers to identify the sources of infection for deadly diseases
such as scarlet fever, rheumatic fever, sore throats, puerperal fever as well as
wound infections and to develop preventive and prophylactic measures
(Hare, 1940). After the introduction of penicillin and sulfa drugs in the early
1940s, serum therapy became soon obsolete – although this technique
recently surfaced in the context of the Ebola epidemics in West Africa to cure
an American doctor infected with the virus.
Despite his practical achievement with typing hemolytic streptococci,
Griffith’s name became closely associated with the phenomenon of
transformation. Considering Griffith’s earlier studies has helped
revisiting long-established historical narratives and has permitted unraveling
some of the ‘‘conceptual antecedents’’ of the transforming experiment
Lederberg was after. First, Griffith’s classification of serological races
was informed by evolutionary thinking about the variation in types,
although his understanding of the phenomenon remained intellectually
closer to natural history than to modern bacterial and molecular
genetics. For instance, Griffith was less interested in the heritable
dimension of the R to S changes he experimentally provoked than in
their current adaptive effect and their wider epidemiological
significance. Griffith, furthermore, was open to the possibility of witnessing
changes in serological types several years before his studies on the R and
S forms published in 1923. Yet if Griffith was ‘‘prepared’’ to observe
transformation in 1928, as Olby pointed out, it was not, however,
because he was committed to neo-Lamarckian explanations but rather
because he had an evolutionary scheme of biological variation in his
mind. The indeterminacy of terms such as ‘‘variation,’’
‘‘transmutation,’’ and even ‘‘adaptation,’’ as employed by Griffith and other
bacteriologists and microbiologists in the 1920s and 1930s, together with his
lack of emphasis on intergenerational change, prevent a strict
‘‘Lamarckian’’ interpretation of his results.33
Second, in contrast with most accounts of Griffith’s achievements, we
have seen that the English bacteriologist returned to the topic of
transformation one year after his 1928 study and discussed other works
in relation to it. Whereas some bacteriologists claimed that microbial
strains are very stable, already in 1911, while he was an investigator
during the Royal Commission on Tuberculosis, Griffith considered the
possibility of ‘‘transmutation’’ of one type of bacteria into another. This
finding extends Robert Olby’s suggestion that Griffith’s discovery of
transformation was perhaps ‘‘quite deliberate’’ (1994, p. 446; emphasis
in original). His finding that one strain of pneumococcus can revert into
another of a different type, in retrospect was not a mere accidental
33 It would be interesting to contrast Griffith’s view of ‘‘adaptation’’ with the one
developed by French microbiologist Charles Nicolle (1866–1936), laureate of the Nobel
Prize in 1928 and pioneer of ecological approaches in medicine.
observation, but a direct continuation of his earlier ideas on the
possibility of transmutability of bacteria. A consequence of taking into
consideration Griffith’s career as a bacteriologist interested in the origin
and disappearance of infectious diseases is that transformation does not
come across as a ‘‘quirky medical idea’’ but as part of a broader
research tradition – starting with Pasteur in the second half of then
nineteenth century – aimed at understanding the coming and going of
infectious diseases, the changes in virulence, and the nature and scope of
biological variation more generally (Mendelsohn, 2002).
Thirdly, it is worth mentioning that Griffith’s working methods,
located at the border between the bacteriological laboratory, field
experiments, and epidemiology are reminiscent of the meticulous works
of comparative pathologist Theobald Smith who investigated diseases
such as tuberculosis and Texas fever at the turn of the past century in
the United States. Not unlike Smith, Griffith attempted to study host–
parasite relations and infectious diseases not only at the ‘‘lab-field
border’’ (Kohler, 2002) but from all points of view; he wanted to
understand the details of the biology of host and parasites precisely,
although he did not believe that ‘‘exhaustion of susceptible materials’’
was sufficient to account for the decline of an outbreak. As to the effects
of a prolonged relation between a host and a pathogen, Griffith’s
discussion in the 1934 paper illustrates the evolutionary underpinning of
his views on the matter. In the 1960s, when molecular biologists applied
their tools to unpack the biology of the streptococcus organism
responsible for rheumatic and scarlet fever, clinicians and
bacteriologists had long documented their decline. The long history of scarlet
fever to which Griffith explained some central epidemiological features
provides finally an illustration of Theobald Smith’s perspective on
which harmlessness on both sides is the expected outcome of long-term
biological associations – a position endorsed by several pioneers of the
ecological approach to disease far into the second half of the twentieth
century (M e´thot, 2012).
The final version of this paper was written during a research stay at
the Institut universitaire d’histoire de la m e´decine et de la sant e´
publique in Lausanne in the summer 2015. An earlier version was
presented at the History of Science Society conference in Boston in
November 2013 as part of a session on ‘‘Infection as Host–Parasite
Interaction: Studying Parasites at the Interface of Biology and
Medicine’’ I co-organized with Rachel Mason Dentinger. In addition to
the participants, I am particularly grateful to Richard Krause for
allowing the reproduction of the picture of Griffith on skis in this
journal and for the many discussions on Fred Griffith. Archivists at
the Rockefeller Institute in Sleepy Hollow (New York) are also
warmly thanked for their assistance during my research in the
Lancefield papers in January 2013. I extend my thanks to Barbara King
and Sir Peter Lachmann at the Department of Veterinary Medicine at
Cambridge University (UK) for their help in finding documents about
Fred and Stanley Griffith, and to Christoph Gradmann, Rachel
Mason Dentinger, Gladys Kostyrka, and an anonymous reviewer for
their critical reading and comments on the manuscript. Special thanks
go to Catherine M e´thot for her assistance in locating the 1937
Griffith paper at the McGill Library in Montreal and to Jean Gayon,
Sabina Leonelli, and Michel Morange for their encouragements in
writing this paper. Finally, I would like to thank Michael Dietrich for
accepting the symposium as a special issue in this journal and
gratefully acknowledge funding from the FRQ-SC.
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