In the spring of 1933 a team of Medical Research Council (MRC) staff gathered nasal fluids and throat garglings from a sick researcher, filtered them, and dripped them into ferrets. Within forty-eight hours the ferrets would start sneezing and displaying signs of an influenza-like disease. This research formed the basis of an extraordinarily important Lancet paper by Wilson Smith, Christopher H Andrewes and Patrick Laidlaw, published on 8 July 1933, identifying a 'virus' as the primary causative agent for influenza. This was no serendipitous finding, but the result of a sustained campaign of funding and research.

The 1918-9 influenza pandemic and virus research

The 1918-19 influenza pandemic challenged ideas about influenza, as at the time most microbiologists believed that influenza was caused by a bacteria. But during the pandemic, pathologists failed to consistently find the bacillus. This undermined claims about its primary role and jeopardised the prospect of producing a vaccine.

Walter Morley Fletcher, Secretary of the MRC, suggested to the War Office and Army Medical Services that attention should be turned to the possible role of a so-called 'filter-passing virus', and in November 1918 the search for the virus began. The first British investigations into the role of a virus in influenza were carried out by two teams in France and within weeks both claimed they had identified a filterable agent from sick servicemen.

These findings were controversial - there was no test for a virus, so its presence had to be inferred: it could not be seen with light microscopes, retained by bacterial filters or studied using culture methods. Only the presence of symptoms, and traces in serological tests suggested any 'thing' was present in infected people (and animals).

In the summer of 1922 Laidlaw was recruited to the MRC's National Institute of Medical Research (NIMR) to develop a project on "diseases probably caused by filter-passing organisms." Although such organisms had been identified as the probable causes of many infectious diseases they had eluded standard laboratory techniques, so new methods had to be developed using 'model' diseases in animals. Canine distemper was selected as the model for influenza, and for over a decade Laidlaw and the resident veterinary pathologist, G. W. Dunkin, used distemper to build virus research at the Institute.

The Distemper Experience

The research attracted some powerful patrons. The Field, a country and field sports magazine, already had a Distemper fund to finance work on the disease, and in October 1922 The Field's editor, Sir Theodore Crooke, proposed to Fletcher that the fund should be devoted to supporting Laidlaw and Dunkin.

This money enabled the MRC to develop new laboratories on a forty-acre agricultural site at Mill Hill , which included space to breed and house dogs, as well as a laboratory and isolation/quarantine unit. Until 1924, Laidlaw and Dunkin used puppies bred at Mill Hill to experiment on distemper, but dogs were not ideal experimental animals. Dogs presented an awkwardly variable clinical picture, they were expensive and slow to breed, sometimes hard to handle, and attracted vociferous antivivisection protests. So in late 1924, they introduced the ferret as a new experimental animal, marking the start of a long scientific career.

Laidlaw and Dunkin attributed much of their success on distemper to their work with the ferret; they developed an experimental vaccine for ferret distemper in 1926, then modified for dogs in 1927. Burroughs-Wellcome started commercial production in 1928, and by 1931 the vaccine was protecting the nation's dogs. This scientific and commercial success legitimised the NIMR's approach to virus diseases. Its primary goal became virus identification and control through the production of serological assays, therapeutic sera, and vaccines.

New interest in applying this approach to influenza was sparked in 1931, when the American researcher, Richard E. Shope announced that a combination of a bacillus and a filterable virus produced a disease in pigs – 'hog flu' – analogous to human influenza.

Ferret Flu

In late 1932 the MRC decided to concentrate on influenza, placing the research under Laidlaw's control, with experienced virus researchers Smith and Andrewes. At the time, the main obstacle for virus researchers was that they lacked a viable experimental animal to study influenza. Solving this problem was the team's first task.

Through January 1933 they tested nasal and lung material taken from influenza patients on rats, mice, guinea pigs, monkeys, pigs and horses. These efforts failed. They then turned to the ferrets at Mill Hill. In early February 1933, Smith dripped ("instilled") filtered nasal and throat garglings taken from Andrewes, who had himself caught influenza, into the noses of two ferrets. Unfortunately, before Smith could isolate the virus a distemper out-break destroyed the experiment. By chance, Smith himself caught influenza on 4 March, and this time Andrewes used his throat garglings and his instillation method to infect some ferrets.

They quickly identified the infecting agent as a virus on the basis that it was filterable, invisible, and not cultivable, but still produced disease in the animal. They named it "W.S." and it became the NIMR's master strain. Through spring 1933, they traced "the full course of [the] illness" in 64 ferrets, noting the analogies of "ferret flu" to human influenza. They were now able to develop a serological test showing that recovered ferrets had antibodies which inhibited the disease, an important piece of evidence in establishing the identity and role of the virus. With this test it was possible to trace neutralising antibodies in sick and healthy Londoners, and thus determine the presence of the virus in the human population. At the same time, they compared their virus antibodies with those identified by Shope in hog flu, to show that their virus specifically produced human influenza.

Smith, Andrewes and Laidlaw made a cautious claim in their report to the Lancet that,

the evidence strongly suggests that there is a virus element in epidemic influenza, and we believe that the virus is of great importance in the aetiology of the human disease.



The report caused a minor media sensation. The Lancet editorialized that it "offered almost conclusive evidence that the primary cause of human influenza is a filterable virus."

Within the year, researchers in other parts of the world confirmed the research. In 1934 mice began to be used in research, followed in 1940 by the developing chick egg, but the ferret and the virus model have become integral to new ways of understanding and controlling influenza. Experimental vaccines were produced in 1936 by Smith, Andrewes and Charles Herbert Stuart-Harris, and in 1947 the NIMR was designated as the World Influenza Centre of the World Health Organization. Work on the 'flu virus also spawned unexpected findings, such as the discovery of Interferon – a protein associated with immune responses – by NIMR researchers Alick Isaacs and Jean Lindenmann in 1957.

The NIMR's success came so quickly only because so much had been put in place in the previous decade. The experience of the 1918-19 pandemic and the MRC's development of virus research created the conditions for the success of 1933. The story is a reminder of the crucial role of the MRC and government-supported research in spurring scientific innovation through sustained funding.

Michael Bresalier is a historian of medicine at Imperial College London. His forthcoming book, "Making Flu: British Medical Science and the Definition of a Virus Disease", will be published by Palgrave. You can read more about his work on influenza and viruses here