Frederick Griffith
Frederick Griffith
Born	c. 1879 (1879-07-29T17:10:16)
Died	1941 (1942) London, England
Nationality	British
Occupation	physician, pathologist, bacteriologist
Known for	discovery of pneumococcal transformation

Frederick Griffith (c. 1879 - 1941) was a British scientist whose focus was microbiology, especially as to the epidemiology and pathology of bacterial infectious disease. In 1927, in London, at the Ministry of Health, he conducted what is now known as Griffith's Experiment. Published in 1928 by the Journal of Hygiene, his paper carries the first widely accepted demonstrations of bacterial transformation, whereby a bacterium can distinctly change its form and function. The phenomenon was then attributed to an unidentified transforming principle or transforming factor.

In his experiments, Streptococcus pneumoniae, known medically as pneumococcus, implicated in most cases of lobar pneumonia ^[1], was induced by various means to transform from one strain into a different strain, previously held to be of separate evolutionary lineage. These findings stood to significantly revise prevailing interpretations of pneumonia epidemiology.

The findings prompted Oswald T. Avery, in New York at the Hospital of the Rockefeller Institute of Medical Research, where America's pneumococcal research was centered, to speculate that Griffith had failed to apply adequate controls. Known as a cautious and thorough researcher, and further as a reticent individual, however, Fred Griffith's tendency was to submit for publication only findings that he believed truly significant to science, and so his transformation findings endured.^[2]

Over the next decade, Oswald Avery's laboratory proceeded upon these findings to eventually demonstrate, in 1944, that DNA was the transforming factor, a finding that Avery remains renowned for and an understanding that steered molecular genetics.^[3][2]

Early life

Fred Griffith was born in Hale, Cheshire county, England, in about 1879 (exact year uncertain), and attended Liverpool University where he studied genetics. Thereafter, he held positions at the Liverpool Royal Infirmary, the Joseph Tie Laboratory, and the Royal Commission on Tuberculosis.

Office at Ministry of Health

In 1910, he was hired by the Local Government Board. During WWI, the laboratory was assumed by the national government and became the Pathological Laboratory of the Ministry of Health. In this capacity, Griffith was sent pneumococci samples taken from patients throughout the country. The British government spent money on the laboratory sparingly, and the laboratory used by Griffith and his colleague William M. Scott, who was also his enduring friend, remained very basic, and yet it was later said that these two "could do more with a kerosene tin and a primus stove than most men could do with a palace".^[4] With the outbreak of WWII, the laboratory was expanded into the Emergency Public Health Laboratory Service.

Griffith's Experiment

Pneumococci in culture—rough form (left) & smooth form (right)

The pivotal experiment occurred among many performed by Fred Griffith, in the 1920s, as medical officer at the Pathological Laboratory of the Ministry of Health. Toward establishing greater and more precise scientific understanding, Griffith would type—in other words classify—each pneumococci sample to search for overall patterns to clarify the epidemiology of lobar pneumonia. Meanwhile, testing various pneumococci on mice, he sought improved understanding of the pathology enacted by pneumococci on the individual.

Most significantly as to pathology, pneumococci has two general forms—smooth and rough. Pneumococci's smooth form, denoted by S, has a capsule, associated with the smooth form's virulence; this form was known to result in the host's pneumonia and death within a couple of days after its subcutaneous injection into mice. The capsule is a slippery polysaccharide coat—atop and outside the peptidoglycan cell wall common among the differing forms studied—which allows those bacterial cells bearing capsules to evade efficient phagocytosis by the host's immune cells. On the other hand, the rough form, R, lacking a capsule—having its outer surface as cell wall—was considered avirulent, unknown to prompt pneumonia.

In Griffith's Experiment, as expected, when S was killed by heat and then injected into mice, it caused no illness despite it being a virulent strain. When a large amount of heat-killed S was injected along with live R, however, Griffith observed pneumonia and death; this was a generally unexpected finding since R, the only live bacteria injected in that experiment, was considered avirulent. Recovering pneumococcus from the bodies, Griffith found that the live R had acquired capsules to become S, and thereafter it maintained this phenotype over many generations.

The above is often characterized as Griffith's Experiment. In any case, Griffith hypothesized that a transforming principle—derived from the killed S—had helped transform the live R into S. Yet more accurately, point six of his paper's abstract reports that R tended to transform into S if a large amount of live R, alone, were injected. Griffith then notes that adding a large amount of heat-killed S to the injection of live R merely made this transformation most certain. Further, in other experiments, Griffith could induce some pneumococci to transform back and forth.

Other findings in the paper concerned transformation of serological type, a matter distinct from the presence or absence of a capsule. Type is determined by bacterial antigenicity. Bacteriologist Fred Neufeld, of the Robert Koch Institute in Germany, had earlier discovered the pneumococcal types, and these were confirmed and expanded by Alphonse Dochez at Oswald Avery's laboratory in America at the Hospital of the Rockefeller Institute for Medical Research. Types I, II, and III were each a distinct antigenic grouping, whereas type IV was a catchall of varying antigenicities not matching any of the other three types. Illustrating S. pneumoniae's plasticity, the abstract of Griffith's paper reports, "The S form of Type I has been produced from the R form of Type II, and the R form of Type I has been transformed into the S form of Type II".^[5]

Direct Significance

Many bacteriologists, including Griffith previously, believed that a bacterium's form and function were in essence fixed, a changeless pair. Thus, in this belief, each strain had emerged from an identical progenitor, itself the result of an evolutionary lineage determined by Darwinian selection of fit bacterial cells amid mere death to and extinction of unfit bacterial cells. Besides this belief implying that a strain of bacteria could be vanquished by strong competition against it, many bacteriologists and physicians thus believed that any particular strain of bacteria, as for instance cultured from a patient, had necessarily multiplied from only that very strain acquired as such by the patient.

Fred Griffith's findings, though they remained generally neglected after the initial contention against them had subsided, showed that this assumption was incorrect. His paper's abstract summarizes, "The results of the experiments on enhancement of virulence and on transformation of type are discussed and their significance in regard to questions of epidemiology is indicated".^[6]

Posthumous Identification of the Transforming Principle

Despite doubt by Oswald Avery, America's then most noted figure on pneumococci, of Griffith's findings in the Journal of Hygiene, Avery's associate Martin Dawson of the Rockefeller Hospital verified each of Griffith's findings ^[7]. Even before publication of Griffith's paper, Fred Neufeld, of Germany's Robert Koch Institute, who had visited Griffith's laboratory and had been thereby told of Griffith's findings, had verified them as well, Neufeld waiting merely for Griffith's findings to be published before Neufeld published verification. Avery's illness, Grave's disease, kept him much out of his laboratory as other researchers in it experimented to determine, largely by process of elimination, which constituent was the transforming factor.

The first Griffith Memorial Lecture indicates that Fred Griffith died on the night of 17 April 1941^[8]—though the fourth annual lecture indicates that he died in his apartment in February 1941—alongside friend and colleague William M. Scott amid an air raid during WWII's London Blitz. At the time, a few weeks after Scott had become director of the laboratory, which had become Emergency Public Health Laboratory Service with the outbreak of WWII, Griffith's finding of pneumococcal transformation had drawn little overall notice from the medical sector. Both dated 3 May 1941, his obituary in The Lancet mentions the historical discovery briefly, and his obituary in British Medical Journal does not mention it at all.^[9]

In 1944, identification of the transforming principle or transforming factor was published in the Journal of Experimental Medicine in a paper by Oswald Avery, Colin MacLeod, and Maclyn McCarty of Rockefeller Hospital.^[10] The paper offered this identification as a departure from the prevailing belief that the protein content of chromosomes probably made up genes, although it would take another decade—till after Watson and Crick's 1953 paper in the journal Nature revealing DNA's molecular structure suggesting how a molecule as seemingly simple as DNA could store complex biological information—for the interpretation of DNA as genes to become widely accepted.^[11]

Thus the track toward modern molecular genetics, based on molecular biology of DNA, was set by the search for the transforming factor, acquired from dead pneumococci, that live pneumococci utilized to transform themselves, as shown by Griffith. As a microbiologist, Fred Griffith presumably recognized the genetic import of his findings—that not only could a bacterium transform itself but that it could apply something from dead bacteria to enact or enhance this—and yet Griffith's main concern, in conducting his experiments and then submitting the findings for publication, was improved understanding of the epidemiology and pathology of illness associated with pneumoccoci.

Further Work and Legacy

Fred Griffith in 1936

In 1934, Fred Griffith published a lengthy paper carrying his findings on the serological typing of Streptococcus pyogenes.^[12] More casually as well as medically called simply streptococcus,^[13] S. pyogenes is implicated in conditions ranging from the usually minor strep throat, to the sometimes fatal scarlet fever, to the often fatal puerperal fever, to the usually fatal streptococcal sepsis.^[14] In the 1930s, streptococci infection was already known as a frequent coinfection complicating recovery from lobar pneumonia by pneumococci infection.^[15]

In 1966, the Griffith Memorial Lecture, published thereafter by the Journal of General Microbiology (now Microbiology), was begun, suggesting the relevance of Fred Griffith's findings not only to steering the hunt for the specific genetic determinant, thereby contributing to molecular biology and molecular genetics, yet also to modern microbiology.

By 1967, pneumococcal transformation had been evidenced to occur in vivo naturally, and it was shown that treatment with streptomycin during dual infection by two pneumococcal strains could increase transformation—and increase virulence—while for the first time pneumococcal transformation was shown to indeed occur in the respiratory tract.^[16] In 1969, it was shown in vivo that, during drug treatment of a host, pneumococci could acquire genes from antibiotic-resistant streptococci, already in the host, and thereby the pneumococci could newly attain resistance to erythromycin.^[17] Such findings suggest the enduring relevance of Fred Griffith's findings also to epidemiology, pathology, and medicine.

References

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