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An historical note on Gram's famous stain

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Hans Christian Joachim Gram was a Danish bacteriologist born in 1853 who graduated from medical school in 1883 and developed his staining procedure in 1884. Subsequently this stain became known as Gram's Stain or the Gram Stain. Although the usefulness of this stain means that it continues to be a standard microbiological procedure it is threatened by new molecular biology techniques.


Usefulness of the stain

The Gram Stain's usefulness centres on its ability to distinguish two of the major types of bacteria which differ in the composition and structure of their cell walls. This proved useful for taxonomists but also had a major impact on medical treatment because certain antibiotics which are active against Gram negative bacteria have no effect on infections caused by Gram positive bacteria. In the early days of antibiotic therapy this became an important tool but the advance of antibiotic resistance has reduced its impact somewhat.


Hans Christian Joachim Gram


Gram's original aim



An interesting historical observation is that Gram did not set out to discover these major differences in cell wall structure that his staining method ultimately differentiated. He wanted to discover a better method to reveal bacteria in sputum especially in patients with pneumonia.


Friedlander & Fraenkel

At the beginning of the 19th Century Carl Friedlander, a German pathologist, was trying to discover the cause of pneumonia and published a couple of papers in 1882 and 1883 which described the histological appearance of micro-organisms in the fibrous exudate from infected lungs of patients dying of lobar pneumonia and the isolation of what was called the "micrococcus". The bacteriology was actually performed by a chap called Frobenius who trained under Robert Koch. In these papers Friedlander placed great emphasis on the presence of a capsule around the cells. There is little doubt today that what Friedlander was describing and what he had isolated was Streptococcus pneumoniae.

Friedlander's articles and, in particlular his emphasis on the presence of a capsule, seemed to have irritated another worker in the field called Albert Fraenkel. Fraenkel had also isolated a microbe from patients with lobar pneumoniae but it seemed to be quite different. Ironically it now appears that Fraenkel was describing Klebsiella pneumoniae, an organism orginally isolated and described by Friedlander.


Pneumonia is an inflammation of the lung which is caused by a variety of different micro-organisms. It can affect one or more lobes and is still a common disease in the UK, affecting approximately 1% of the adult population. About half of all cases are caused by a bacterial infection.

Lobar pneumonia is the infection of a discrete lobe of the lung and is invariably caused by Streptococcus pneumoniae. Although lobar pneumonia may occur in young adults it is most common in the elderly. Before the discovery of antibiotics the death rate in patients with this condition was very high. Death also followed quickly after onset of symptoms and because the disease was often secondary to another, possibly long and terminal disease, it was somethimes referred to as "the old man's friend" and was likened by Sir William Osler to Bunyan's "the Captain of the men of death".





Enter Dr Gram

One of the big problems both these researchers had was visualising the micro-organisms in sputum, pus aspirated from infected lungs and tissue sections. The reason being that cell nuclei and fibrin, a protein present in pus aspirated from infected lungs and also present in tissue, reacted with the histological stains used at that time in a way which was very similar to bacteria. This made it very difficult to see the bacteria among all the other biological material present.

As it happens, this was the problem that Carl Gram was addressing and he happened to be working in Friedlander's laboratory. Clearly, Friedlander made use of Gram's new staining method and he even made reference to it in his papers. However, in 1884, Gram published a paper himself in which he set out details of the stain.

The picture opposite is a fairly recent image of some sputum from a patient with lobar pneumonia. What Friedlander originally called the "micrococcus", what was subsequently called the diplococcus and what we now call Streptococcus pneumoniae are clearly identifiable from the background material.








The rest, as they say, is history

A further irony is that Gram's stain as we use it today would have clearly differentiated Friedlander's micrococcus and Fraenkel's isolate, ultimately identified as Klebsiella pneumoniae because the former is Gram positive and the latter Gram negative.

Undoubtedly Carl Friedlander made the greatest contribution but who remembers his name and not Gram's? The reason being, of course, that Gram's stain was later shown to be useful in differentiating the two major types of bacterial cell walls. This had significance in taxonomic studies but, perhaps more significantly, it helped treatment planning - once antibiotics had been discovered, but that didn't happen for another 50 years.



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