2000 Professor John Oxford: The search for permafrost and other victims of the 1918 Influenza

The Influenza story has parallels with the search for the origin of many other infections. Cholera, still present in Europe at the turn of the twentieth century, was the subject of huge debate about its origins. Dr John Snow’s methodical approach in the 1850s solved the mystery of its transmission, laying the way open for future microbiological discoveries, culminating in the publication, in August 2000, of the cholera pathogen sequence (Nature, 3 August)

Dr John Snow would have been delighted, although little realising that it would take this long and that cholera would still be a major infection problem in many countries in the late 20th century. In reaching a full understanding of the pathogen, it is not so much an end to cholera as an ‘end to the beginning’. Snow’s major contribution in cholera was, of course, the demonstration of the water link. Water plays a part in the Influenza story too, not least in its origins. Influenza was possibly an early example of a virus jumping between species. It appears to have moved from an aquatic bird to humans around 10,000 years ago.

By the late nineteenth century, ‘flu was a familiar winter visitor although the viral cause was not understood. The epidemic of 1899 was known as “Russian Flu” and coincided with another wave of cholera in Europe. Recently Professor Oxford and his colleagues have been given permission to exhume some of the victims of the 1899 epidemic, to attempt to identify the nature of the Influenza virus responsible. This is not merely an academic exercise: no laboratory samples survive from the 1899 wave of the disease. This makes it very difficult to be precise about the specific virus responsible.

Most of the epidemics and pandemics are due to shifts or drifts in the Influenza A virus types, and the modern issue is when or whether another major shift will occur, causing widespread illness, since neither vaccination nor immunity to previous Influenza types would afford adequate protection. The 1918 pandemic, following so closely the exhausting end of the First World War, was devastating in its effects. In epidemiological terms, it was a huge natural experiment, and its study helps in the understanding of this pandemic disease, just as Dr John Snow’s scientific approach assisted in the control of cholera. To help us to imagine the times of the “Forgotten Plague”, Professor Oxford showed the page of deaths from the London Hospital’s children’s ward in November 1918, at the start of the pandemic. In addition to deaths from ‘marasmus’ (severe malnutrition), there were several listed as “Influenza-pneumonia”. One, Ivy Goddard, was only eight when she succumbed to the disease. The combination of widespread malnutrition and a new infection was inevitably lethal for this East London population, as in many other countries hit by the pandemic. Typically, death was heralded by cyanosis (blue appearance) of the lips and ears. This was matched by grave pathology in the lungs, resembling the effects of gassing, a problem familiar to the pathologists of the time from examination of war victims. The predominant theory was that the disease was due to a bacterial infection. The rapid deterioration of victims was also a reminder of the bubonic and pneumonic plague years of the distant past: a Breughal painting from the time of the Black Death (Plague), The Triumph of Death, showed Death on a pale horse, striking randomly with his scythe. The 1918 pandemic inspired many such images in cartoons and contemporary reports; it was also vividly described in the novel, ‘Pale Horse, Pale Rider’ by Katherine Anne Porter. Families were parted by death, including many couples who married shortly after the First World War, leaving widows and widowers all over the world. Worldwide, it is estimated that the pandemic caused 40 million deaths, the largest outbreak ever experienced.

The death toll did not stop with the decline of the pandemic: the ‘drift year load’ of subsequent epidemics, with slightly different types of the virus, also had high fatality. The famous actress and royal mistress, Lily Langtree, was one of the later victims. A cartoon of the Millennium Dome being punctured with needles was a reminder of the continuing drift year loads: around 19,000 deaths were attributed to Influenza over the 1999-2000 New Year period.

In 1933, there was a major breakthrough in understanding Influenza, when Charles Stuart Harris, Wilson Smith and their team isolated the virus in North London. This meant that physicians and scientists could now go back and examine fixed specimens from previous epidemics, as well as investigating the possibility of exhuming people who had died. Because the virus deteriorates rapidly in dead tissue, this latter route produced little initial success. What was needed was deep frozen tissue, where the virus might have survived or to have persisted, at least, in a state to allow identification. So began the story of the research into a group of miners who died from the pandemic in Spitzbergen, in the far north of Norway. Spitzbergen was a small mining community well used to Arctic hazards: citizens kept rifles to hand in case of attacks by polar bears and accident-related mortality was high. In October 1918, a ship arrived with miners to serve in the mines in the area. They caught ‘flu en route and seven of the miners died before arrival, 10% of those on board. These victims were hurriedly buried in the frozen ground. Decades later, a Canadian researcher, Dr Kirsty Duncan identified the probable location of the graves. Ground penetrating radar was used to pinpoint the site, picking up signals from the victims’ bones.

The next step was to obtain sponsorship and permission to exhume the bodies. A project of this type required considerable sensitivity and respect for the deceased miners, as well as permission from surviving relatives and the Norwegian authorities: it also needed research sponsorship of around £250,000. An international team returned to the site with 17 tons of equipment, and with expertise ranging from virology to professional grave digging. Local people were amused to find that the equipment taken to this polar region included a large fridge: but this was not a case of ‘coals to Newcastle’: any specimens would need to be kept at a constant low temperature (-20°C) during the research and return journey. A BBC documentary showed the disappointment of this team when they discovered that the Influenza victims had not been buried as far down as the permafrost, the permanently frozen layer. The bodies were higher up, in a layer that froze and thawed each year. But all was not lost. Previous experience with exhumations had shown that viruses could survive in identifiable form within sealed lead coffins, in formalin fixed specimens and in frozen bodies. Despite the deterioration during the thaws, some tissue had survived. In later examinations of specimens, signals of RNA – the nucleic acid of the virus – were detected. The celebration of this, in an issue of Esquire as “Virus beaters: the answer is buried in the ice”, belied the months of painstaking research required to uncover the secrets of the 1918 virus. While the RNA signal was detected in parts of the lungs and kidneys, the best signal was from brain samples. Research is underway to see whether the 1918 virus (Influenza A HA1/HA2) had an extra ‘pathogenic’ sequence giving it additional virulence. A sample from a surviving victim of the encephalitis lethargica epidemic of the 1920s (as fictionalised in the 1990 film ‘Awakenings’), suggested that this virus could have caused the strange disease, with its propensity for the brain. Because of the widespread pathology and severe pneumonia, possible early outbreaks of this strain were not attributed to ‘flu. Thus an outbreak in France in 1917 was described as “purulent bronchitis”: the virus responsible was Influenza and, to match the Spanish Lady of 1918, this one has been dubbed “The French Lady”. The strain that hit the Spitzbergen miners in October 1918 was particularly lethal: it may be no coincidence that the bodies of victims in Alaska and Carolina, also exhumed for viral study, relate to deaths in the same month.

Articles on emerging diseases often include the possibility of another pandemic. If it comes, have we made sufficient progress? What, in short, have we been doing to fight ‘flu since 1918? This is a question that perhaps the victims, like little Ivy Goddard, would have asked. Apart from vaccination, which necessarily has to be based on previous circulating strains, there have been developments that offer hope of effective treatment. The neuraminidase molecule was identified in the 1970s, leading to the development of a drug against Influenza, acting by binding to the amino acid on the neuraminidase spike of the virus. Its safety is still being tested on a large scale, but animal and human studies already suggest it could act as a prophylactic (preventing infection in around 90% of cases) as well as a treatment. In general, we are also far better nourished than the victims of 1918, so that the progress of the disease would be less rapid and less fatal in its course.So, vaccines and advanced drug therapy may be the future ‘Pump Handle’ for this virus, along with the established public health lessons regarding respiratory transmission in crowded spaces and the need to keep up surveillance and early warning systems. This was a worthy topic and lecture in the John Snow Society tradition, and Professor Oxford concluded the talk with the accustomed ritual of removing the Handle from the Society’s ceremonial Pump. The Handle was then returned to the Pump, as neither Influenza, nor many other diseases, have been vanquished yet. The meeting ended with another regular ritual: celebrating the memory of Dr John Snow at the John Snow Pub in Soho.

1997 Professor Pennington: E. coli in Scotland- the relevance of John Snow and William Whewell’s consilience of induction

The following paper from Professor Pennington is based on a lecture he gave for the John Snow Society at the London School of Hygiene and Tropical Medicine in September 1997.The following paper from Professor Pennington is based on a lecture he gave for the John Snow Society at the London School of Hygiene and Tropical Medicine in September 1997.

At the end of a week of myth-making, with the funeral of Diana Princess of Wales only two days before, I felt it appropriate to start the Pump Handle Lecture by looking at John Snow through the eyes of the artist who painted his portrait in 1851, because of its vivid contrast with the well-known photograph by Maull and Polybank taken not long before he died. The idealised image of the former showed no signs of the ravages of hypertension and bad kidneys that can be read into the latter.

To continue with the theme of images, Snow’s 1855 “On the mode of communication of cholera” was revolutionary not only in what he said but in the way that he said it. The significance of the pump handle removal apart, the force of the street map showing the location of cases around Broad Street is overwhelming, not only in its originality in its historical context but for its strength as an investigative and demonstrative tool. Its heuristic power continues. What about Wishaw? What lessons has the 1996 Scottish E. Coli 0157 outbreak taught us? The legal process there is still active with all the constraints that that brings. To protect myself against an inadvertent breach of the sub judice rules I describe the events there through the eyes of the press.

The first cases in the outbreak came to the notice of the local public health department on Friday 22 November 1996. The hidden hand, which determines that the earliest – and therefore the most important – events and activities in an outbreak always occur over a weekend, was clearly acting with full force here! Its evolution over the next fortnight was marked by the headlines: “Town in fear” (25 November, 35 cases), “Food bug outbreak spreading” (26 November, 65 cases), “Traders warned, killer meats still a threat” (29 November). At this point 120 cases had been reported in Lanarkshire, 13 in Forth Valley (30 miles away), 2 in Glasgow, and 1 in Edinburgh, and five attendees at a meal provided for the frail elderly at the Wishaw parish church hall on 17 November had died. By this time it was clear that the butcher’s shop at the centre of the outbreak supplied not only Wishaw, a small run down industrial revolution town in th Lanarkshire badlands, but used its 40 staff to prepare meat and meat products for many outlets across central Scotland.

At this point, the Secretary of State for Scotland asked me to chair an expert group to enquire into the circumstances of the outbreak, learn lessons from it, and make recommendations. Needless to say, this administrative move had no effect on the evolution of the outbreak. Neither did it diminish press coverage. Rather, it intensified it and made it more, rather than less, political, with headlines like “Cutback fears of the food doctors” (30 November, 173 cases; expressing the fear that the categorisation of public health doctors in Scotland as administrators would make them even easier targets for downsizing) and “Raw deal from food police” (1 December, 232 cases; a right-wing attack: “food police already have enough powers … what is needed is a more sophisticated intelligence system to track the when and how of sporadic outbreaks”). The cartoons were also appropriate (figure 1). By mid-December the outbreak was over (figure 2), and the hogmanay my expert group’s interim report with priority recommendations was on the Secretary of State’s desk. It was published in mid-January and accepted in toto by the government. How was it received? To quote my actual words “there’s been an enormous amount of jumping up and down and shouting about what was being done and what wasn’t being done … but as soon as it was suggested that butchers should tighten up their act, especially with the physical separation of raw and cooked meats, we got some moderately hostile publicity” (figure 3). Events moved on, particularly on the policial scene – a row about the alleged rewriting of an official report on conditions in abattoirs received full media coverage. Without a doubt this publicity was good for the expert group (figure 4). Our final report was published on 8 April. It has 32 wide-ranging “plough to plate” recommendations.

At this point I addressed the title of my lecture, which was about the philosophical principles underpinning our work. I epitomised a particular and critical view of epidemiology by quoting Macaulay’s 1837 analysis of Bacon’s scientific method: a plain man finds his stomach out of order. He’s never heard of Lord Bacon’s name but he proceeds in the strictest conformity with the rules laid down in the second book of the Novum Organum, and satisfies himself that minced pies have done the mischief. “I ate minced pies on Monday and Wednesday, and I was kept awake by indigestion all night,” “I did not eat any on Tuesday and Friday, and I was quite well.” “I ate very sparingly of them on Sunday, and was very slightly indisposed in the evening. But on Christmas day I dined on them, and was so ill that I was in great danger.” “It cannot have been the brandy, which I took with them, for I have drunk brandy daily for years without being the worse for it.” Our invalid then proceeds to what is termed by Bacon the Vindemiatio, and pronounces that mince pies do not agree with him.

After raising the issue that much of epidemiology is obliged to rest on such old-fashioned inductive scientific principles – with all the problems attendant on that approach – I went on to ride a personal hobby-horse, which is to emphasise the power of another scientific principle first enunciated by the Victorian polymath, William Whewell. He called it the Consilience of Inductions. Whewell proposed that where “inductions from classes of facts altogether different have jumped together … [this] impresses us with a conviction that the truth of our hypothesis is certain. No accident could give rise to such an extraordinary coincidence. No false supposition could, after being adjusted to one class of phenomena, exactly represent a different class, where the agreement was unforeseen and uncontemplated. That rules springing from remote and unconnected quarters should thus leap to the same point, can only arise from that being the point where truth resides”. The relevance for epidemiology of the Consilience of Inductions is that through its application conclusions cannot just be further supported, but enormously strengthened. This happens when supplementary, non-epidemiological evidence is found that independently supports an epidemiological conclusion. For E. coli 0157, evidence of this kind is produced when strain typing is done by pulse-field gel electrophoresis – a variant of the new classical genotyping approach which compares the bar-code like patterns obtained by cutting the DNA in a gel. During the 1996 outbreak this method of clonal analysis allowed a clear and unequivocal distinction to be made between strains linked epidemiologically to the outbreak and the others that were being isolated in central Scotland at the same time. All the outbreak strains (>200) that were isolated had identical gel profiles.

Did William Whewell and John Snow ever become acquainted? Maybe. They were both members of the Royal Medico-Chirurgical Society in London in the 1850s. Whether they met or not, they lived parallel lives with many similarities.

 WhewellSnow
BornLancaster 1794York 1831
FatherCarpenterLabourer
SiblingsOldest of 7Oldest of 9
PatronLocal headmaster (scholarship to Cambridge 1812)Uncle (apprentiship Newcastle 1829)
Position at deathMaster of Trinity College CambridgeAnaesthetist in London
Cause of deathFell from a horse 1866Stroke 1858

Was Whewell interested in public health? Despite his polymathic tendencies (he wrote books on mechanics, gothic architecture, moral philosophy, the history and philosophy of science, translated Plato, was ordained, preached regularly, wrote poetry and science fiction, and at one time was a Professor of Mineralogy) probably not. Nevertheless, the relevant anecdote about him, Cambridge, toilet paper, and Queen Victoria still amuses. Queen Victoria, standing on a bridge over the Cam: “What are all those pieces of paper floating down the river?” The Master of Trinity (Whewell): “Those Ma’am, are notices that bathing is forbidden”.

I felt obliged to finish my lecture with a Scottish connection because I come forth of there. Two came readily to hand. The Aberdeen University Library copy of John Snow’s account of the 1854 cholera outbreak and the Broad Street pump is not on the open shelves because it bears John Snow’s signature. It was presented by Snow to Sir John Forbes. Forbes trained in Aberdeen and Edinburgh, eventually becoming a physician to the Royal household. He was a pioneer stethoscopist. I speculated that this background and these connections may have helped and influenced Snow. I concluded by commenting on John Snow’s explanation of the different patterns of cholera seasonality in Scotland and England – that it could be due to the English preference for beer and the Scots for spirits – by paying tribute to the continuing importance of the symbolism of the pump and the removal of its handle, and I reinforced this by physically removing the handle of a pump placed before me by the Pump Handle President.

1995 Dr Sandy Cairncross: Turning the Worm- The Guinea Worm eradication programme

The Manson Lecture Theatre at the London School of Hygiene and Tropical Medicine (LSHTM) was crowded on Wednesday 8th September 1995, with Society members and other interested parties, keen to hear Dr Sandy Cairncross of the LSHTM deliver the third annual Pumphandle Lecture, entitled “Turning the Worm”, on the Guinea Worm eradication programme.The Manson Lecture Theatre at the London School of Hygiene and Tropical Medicine (LSHTM) was crowded on Wednesday 8th September 1995, with Society members and other interested parties, keen to hear Dr Sandy Cairncross of the LSHTM deliver the third annual Pumphandle Lecture, entitled “Turning the Worm”, on the Guinea Worm eradication programme.

Dr Cairncross was a member of a UNICEF/WHO joint eradication team who worked in Ouagadougou between 1992 and 1995. The guinea worm is a “good” parasite in that it does not kill its host but nevertheless 0.5% of patients are handicapped for life and 30% have some degree of pain and suffering even after losing the worm. The economic consequences for regions where it is found are vast.

Larvae escape from infected humans into water where they are ingested by water fleas (Cyclops spp.). Humans who ingest an infected water flea in their drinking water are likely to become infected, the worm, which may reach two feet long maturing a year later ready to shed larvae. The whole life cycle outside humans therefore takes place in water, the only human parasite in which this is the case.

This parasite is widely distributed throughout central Africa and into central Asia. The slave trade led to its brief introduction into the Americas. The disease is seasonal. In the Sahel belt of Africa cases peak in the rainy season, but in forest areas, where water is always present, it peaks in the dry season. Its seasonality and lack of annual vector mean that eradication programmes can be targeted at that time of year.

No vaccine has been developed against the disease; eradication programmes are aimed either at the vector or the human host. Two major methods have been used:

Insecticidal treatment aimed at the vector. Insecticides such as Temephos, which are harmless to humans, are effective against Cyclops and can provide effective cover at a local level. However, the costs of staff, equipment and insecticide for treatment of large areas is prohibitive.

Production of safe water. This has two components, the first involving educating infected persons not to go into water – and hence not transmit the larvae; and the second the provision of simple water filter to remove Cyclops from drinking water and break the chain of transmission.

These measures, particularly the latter, combined with a detailed community based surveillance programme have proved successful in reducing the incidence of the disease. A valuable sideline of the eradication programme, which trains local people to undertake the work, has been that the availability of these trained personnel has had an impact on other diseases and has improved local health care.

Dr Stanwell-Smith gave the vote of thanks after which the meeting was formally brought to an end by the ceremonial removal of the handle of the society’s pump. A large group then moved to the John Snow pub in Broadwick Street, Soho, for the customary toast to Snow’s name, examination and signing of the visitor’s book.

1994 Dr Spence Galbraith: Dr John Snow – Early Life and Later Triumphs

Professor Paul Fine, the Pumphandle President, welcomed members and non-members alike to an overflowing Manson theatre at the London School of Hygiene and Tropical Medicine on Thursday 8th September 1994 to commemorate the 140th anniversary of John Snow’s removal of the pump handle.

He introduced the speaker, Dr Spence Galbraith, who founded the Epidemiological Research laboratory (later CDSC) of which he was the director for a decade. Dr Galbraith gave a scintillating lecture entitled “Dr John Snow – Early Life and Later Triumphs. An exploration of Snow’s work from the epidemiological perspective”, a talk based on his original researches around the country.

Dr Galbraith had obtained photographs of Snow’s birth certificate and gravestone thus confirming at last the correct date of Snow’s birth. In fact, Snow was born on 15th March 1813 in York, near the site of the Rowntrees chocolate factory. After living on a farm near York during his childhood, he was apprenticed to a surgeon in Newcastle, where he attended tuition at Bell’s Court, the doorway of which is now incorporated into the structure of Newcastle Medical School. Whilst in Newcastle, Snow first encountered cholera which had spread from Sunderland in 1831/32. Later he was to write graphically about the impact of cholera in the coal pits at Killingworth, where he may have met Robert and George Stevenson of railway fame.

After spells in County Durham and Pateley Bridge, where he developed his taste for nature walks and teetotalism, Snow moved to London. He collected qualifications (LRCS May 1838, LSA October 1838, MB 1843, MD 1844), contracted nephritis (for which he was treated by Richard Bright), and started giving anaesthetics, mainly at St George’s Hospital. He continued his interest in cholera, writing very accurately about the transmission of the infection in 1849, and becoming involved in the Golden Square outbreak in 1854. The story is too well known to need repeating but Dr Galbraith pointed out how Snow founded “boot leather” epidemiology by actually visiting the area, drawing a map, using a questionnaire and conducting retrospective etiological study. It is intriguing that no mention is made of the outbreak in Snow’s own casebooks for the period, nor is there any mention of his famous visit to the local vestry records. He later went on to show by use of a cohort study that the incidence of cholera was ten-fold higher in households supplied by one water company (the Vauxhall and Southwark) as compared to those supplied by another (the Lambeth), the water extraction point of the former being close to a major sewer.

Snow became president of the Medical Society of London in 1855 and, according to his memorial, died on June 16th 1858.

Dr Ros Stanwell-Smith proposed the vote of thanks and presented Dr Galbraith with a silver pump tie pin on behalf of the Society. Professor Fine then removed the handle of the Society’s pump, thus declaring the meeting over. Many of the members then repaired to the John Snow public house in Soho for a convivial member’s evening, with refreshments courtesy of the Open University Press, who were promoting “The Epidemiological Imagination”, a recently published book by Professor John Ashton, a member of the Society, which features a section on Snow.

1993 Dr Nick Ward: Global Polio Eradication- a call for action

There was an expectant buzz of excitement around the crowded Manson Lecture Theatre at the London School of Hygiene and Tropical Medicine on Wednesday 8th September 1993.

On the bench in front of the audience stood the society’s ceremonial cast iron water pump. There was standing room only as Professor Paul Fine, the Inaugural President, opened the first annual Pumphandle Lecture of the newly formed John Snow Society. This meeting commemorated the 139th anniversary of what may be the most famous action in the history of public health – the removal by John Snow of the handle of the water pump in Broad Street which was at the centre of the cholera epidemic in Soho in 1854.

The guest speaker was Dr Nick Ward of the World Health Organization Polio Eradication Task Force, whose title was ‘Global Polio Eradication: a call for action’.

Dr Ward gave an inspiring and erudite speech in which he discussed the history and implications of the smallpox eradication campaign and the considerable achievements to date of the polio campaign, that there has not been a single case of polio reported from the Americans in the past two years. He did not shrink from discussing the problems that remain if the disease is to be eradicated elsewhere, in particular the cost and poor infrastructures. He identified practical achievable targets and measures for the road ahead.

Dr Ros Stanwell-Smith, secretary of the society, gave the vote of thanks, after which the President ceremoniously removed the handle of the pump thus bringing the meeting to an end.

A large group then moved on to the John Snow pub in Broadwick Street, Soho, for the rest of the evening. Plans were laid for future meetings – including the Blessed Chloroform lecture (to be arranged by anaesthetist members of the society and to be held on or about 7th April to commemorate John Snow’s administration of chloroform to Queen Victoria at the birth of Prince Leopold).