Dr. David Arthur John Tyrrell (born 1925)

David Tyrrell (physician)

David Arthur John Tyrrell CBE FRS (19 June 1925 – 2 May 2005) was a British virologist who was the director of the Common Cold Unit, which investigated viruses that caused common colds. He discovered the first human coronavirus (designated B814) in 1965. With June Almeida he made the first comparative study of human and chicken coronaviruses in 1967, and invented the name coronavirus in 1968.

Biography[edit]

Tyrrell was born on 19 June 1925 to Sidney Tyrrell and Agnes Kate Blewett. He had a younger brother Andrew.[2] He attended elementary schools at Ashford, Middlesex. His family moved to Sheffield in 1940, where he completed secondary education at King Edward VII School. While studying medicine at the University of Sheffield he suffered from a detached retina, which meant he was exempted from military conscription, and had a lifelong preference for monocular microscopes.[3] He graduated in 1948 and earned membership of the Royal College of Physicians in 1949.[4] During those years he worked as a house physician at the Professorial Medical Unit of Sheffield Royal Hospital and at the City General Hospital in Sheffield. He was appointed as the first Research Registrar post under the Hospital Endowment Fund of Sheffield in 1950.[2]

He moved to the Rockefeller Institute in New York to work under Frank Horsfall as an assistant from 1951 to 1954. He was briefly enrolled in the US Army during the Korean War (1950–1953).[citation needed] In 1954, he gained an appointment as External Scientific Staff of the Medical Research Council at the Virus Research Laboratory in Sheffield, where he worked until 1957.[3] Upon an invitation from Sir Harold Himsworth, Secretary of MRC, he moved to the MRC's Common Cold Unit on the outskirts of Salisbury on 1 April 1957,[4] becoming its head from 1962 succeeding Christopher Andrewes.[5] He was also appointed as head of the Division of Communicable Diseases in 1967 and then deputy director of the MRC's Clinical Research Centre at Northwick Park Hospital, Harrow, Middlesex, in 1970, while still attached to CCU.[3] The Clinical Research Centre was closed in 1984 following which Tyrrell returned full time at CCU in 1985, and remained there until its official closure in 1990.[4]

In the 1960s, after June Almeida produced the first images of the rubella virus using immune-electronmicroscopy,[6] Tyrrell and Almeida worked on characterising a new type of viruses, now called coronaviruses.[7]

He retired from the Common Cold Unit in 1990[8] and subsequently carried out research at the Centre for Applied Microbiology and Research at Porton Down, where he also worked on his scientific autobiography, Cold Wars: The Fight Against the Common Cold.[2] He died of prostate cancer on 2 May 2005 at Salisbury.[4]

Personal life[edit]

Tyrrell married Moyra Wylie,[9] a general practitioner, in 1950.[3] They had one son and two daughters. He was a devoted Christian and served as an organist and choirmaster at his local church.[4]

Scientific achievements[edit]

Discovery and coinage of coronavirus[edit]

Soon after he joined CCU, Tyrrell developed a system of categorising cold viruses. Some viruses could be maintained only in human-embryo-kidney cell culture and were designated H strain, and others could be maintained both in human-embryo-kidney cell culture and monkey-embryo-kidney cell culture and were labelled M strain.[10][11] One nasal swab sample collected on 17 February 1961 from a schoolboy in Epsom, Surrey, was different as it could not be maintained in any of the culture media. The specimen designated B814 when experimented on healthy volunteers was highly contagious and produced the symptoms of cold within a few days.[12] Due to its unusual nature, they were uncertain whether the pathogen was a virus or a bacterium. Without any other method to study, the specimen was preserved for four years. Returning from a visit to the Lund University in Sweden in 1965, Andrewes told Tyrrell that there was a young Swedish surgeon who was able to grow complex viruses. The Swede was Bertil Hoorn who had developed a culture method using human trachea tissue.[13] Tyrrell immediately invited Hoorn to visit CCU, and after which they were was able to grow different viruses which could not be cultured earlier.[14] Specimen B814 could the be confirmed as a virus, but was unique from all known cold viruses based on its antigenic property and symptoms it produced.

Tyrrell and Malcolm L. Bynoe reported the discovery in the 5 June 1965 issue of the British Medical Journal, concluding: "After considerable initial doubts we now believe that the B814 strain is a virus virtually unrelated to any other known virus of the human respiratory tract, although, since it is ether-labile, it may be a myxovirus."[15] This was the discovery of human coronavirus. But the virus was difficult to maintain in culture and the structure was difficult to study. In 1966, June Dalziel Almeida had just joined as an electron microscopist at the St Thomas's Hospital Medical School in London. She had earlier developed techniques for studying viruses under electron microscope,[16][17] and had also studied the first two coronaviruses discovered, infectious bronchitis virus (IBV) and mouse hepatitis virus (MHV). Tyrrell sent her the specimen, including one new human virus called 229E, which was recently discovered by Dorothy Hamre and John J. Procknow at the University of Chicago.[18] Almeida revealed that the two human viruses were identical to each other, and to IBV as well. Almeida and Tyrrell reported in the April 1967 issue of the Journal of General Virology, writing: "Probably the most interesting finding from these experiments was that two human respiratory viruses, 229 E and B814 are morphologically identical with avian infectious bronchitis."[19]

The new discovery was supported by independent discovery of new human viruses (OC43) by Kenneth McIntosh and co-workers at the National Institute of Health, Bethesda, almost at the same time.[20] It was becoming evident that all these viruses including MHV were of the same kind. Almeida and Tyrrell came up with the name "coronavirus". As Tyrrell recollected in Cold Wars: The Fight Against the Common Cold:

We looked more closely at the appearance of the new viruses and noticed that they had a kind of halo surrounding them. Recourse to a dictionary produced the Latin equivalent, corona, and so the name coronavirus was born.[21]

Other works[edit]

At the Rockefeller Institute, Tyrrell worked on the epidemiology on poliomyelitis. He presented his findings at the second International Congress on Poliomyelitis in Copenhagen on 3–7 September 1951,[2] and published in The Lancet at the end of the year.[22] At CCU, he developed techniques for culturing different cold viruses. He was the first to grow certain cold viruses (rhinoviruses) using nasal epithelial cells. He published a series of papers on his new technique in The Lancet in 1960.[23][24][25] With researchers from University College London, he also investigated the role of human parvovirus B19 during 1985–1987. They discovered that the virus is the causative agent of erythematous rash illness and temporary stoppage of blood formation in persons with chronic haemolytic anaemia.[26][27]

Awards and honours[edit]

Tyrrell was elected a Fellow of the Royal Society in 1970, and was appointed Commander of the Order of British Empire (CBE) in 1980.[2] He held honorary degrees from the University of Sheffield (1979) and the University of Southampton (1990), and received the Stewart Prize (1977), the Ambuj Nath Bose prize (1983), and the Conway Evans Prize (1986).[2]

References[edit]

David Tyrrell

CBE FRS


Born

David Arthur John Tyrrell

19 June 1925

Ashford, Middlesex, England

Died

2 May 2005 (aged 79)

Salisbury, England

Nationality

British

Alma mater

University of Sheffield

Known for

Discovery and naming of coronaviruses

Spouse

Moyra Wylie ​(m. 1950)​

Children

3 (1 son and 2 daughters)

Scientific career


Institutions

Rockefeller Institute for Medical Research

Medical Research Council, Sheffield

Common Cold Unit

Northwick Park Hospital

Doctoral students

Wendy Barclay[1]

https://www.thelancet.com/journals/lancet/article/PIIS0140673605667220/fulltext

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OBITUARY| VOLUME 365, ISSUE 9477, P2084, JUNE 18, 2005

David Tyrrell

David Tyrrell

Published:June 18, 2005DOI:https://doi.org/10.1016/S0140-6736(05)66722-0

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Researcher who led efforts at the UK's Common Cold Unit from 1957 to 1990. Born on June 19, 1925, in Ashford, UK, he died in Salisbury, UK, on May 2, 2005, aged 79 years.

The UK's Common Cold Research Unit (later the Common Cold Unit), in Salisbury, came into being after World War II when Harvard University donated a wartime hospital it had set up for the British military. In 1957, David Tyrrell, who had worked at the Rockefeller Institute in New York, USA, and at the then-infant UK's Medical Research Council but was still a “reluctant young virologist”, as he would later describe himself, became head of the unit. He took over what was planned as a last-ditch effort to culture the virus responsible for the common cold to forestall the closure of the unit.

The assignment, scheduled to last 3 years, paid off in 1960 with the publication of three papers describing common cold virus isolates in The Lancet. The Common Cold Unit lasted until 1990, when it was shut down. In that time, Tyrrell became well known for isolating some of the early rhinoviruses, coronoviruses, and parainfluenza viruses, according to Ronald Eccles, who runs the Common Cold Centre in Cardiff, UK. Tyrrell studied treatment options, undertook studies of influenza and cold virus vaccines, and eventually studied the relation between stress and colds. “He saw the whole development of the common cold story from the discovery of the viruses right up to the treatments”, Eccles said, “which so far have not proven very effective”.

The Common Cold Unit produced 1006 papers from 1948 to 1989, according to Tom Jefferson, of the Cochrane Collaboration, who did a review of the unit's literature. Closing the unit, Jefferson said, was “scientific vandalism”. “It was very fashionable and very exciting in the 1960s when the rhinoviruses were discovered”, said Jack Gwaltney, a cold researcher at the University of Virginia, Charlottesville, USA. “Things change. Herpes virus came along, then AIDS. Colds are pretty much an area that doesn't get much attention right now.”

“Of course it is the failure to find a cure which has hit most strongly upon the public consciousness”, Tyrrell wrote in his memoir Cold Wars with co-author Michael Fielder in 2002. “Why, will people ask, in this age of advanced science, do we appear to have got nowhere in combating this age-old affliction? The truth is that we have made enormous progress, although it has needed detailed research in many centres. Knowing its causes, the mechanics of how it is caught and its variety of forms is a very significant advance. But it is this variety which is at the heart of the problem.” When the group found that there were about 100 different rhinovirus serotypes and that the body saw the “common cold virus” as 100 different viruses, they realised there was “no way you could start to discover a vaccine”, Eccles said. “Rhinoviruses are also rather unstable because they are RNA viruses—there's no spellchecker when it's produced.”

The Common Cold Unit was well-known for its uses of volunteers, some 20 000 of whom spent days or weeks taking part in trials after responding to advertisements such as “Free 10 Day Autumn or Winter Break: You May Not Win A Nobel Prize, But You Could Help Find a Cure for the Common Cold.” A character in Iris Murdoch's Under the Net met another character through volunteering there. Such volunteers “were often pleased to know that they would appear as a dot on a graph or a digit when the paper was published in The Lancet,” Tyrrell and Fielder wrote. In one experiment, colleague James Lovelock “built a rig that trickled a solution of a fluorescent dye out of the nose of one of the laboratory staff. They set it running and then played cards together. After that they turned out the lights and put on a fluorescent lamp. To their amazement they found that the dye had got onto the cards, tables, their fingers, and other parts of the room.”

“I suppose when everyone else was running around looking at impact factors and this sort of thing, David was thinking about what this meant for the patients”, said Jonathan Kerr, who worked with Tyrrell in the 1990s when his interests turned to chronic fatigue syndrome. “That's what motivated him and he was ultimately more successful for it.” He also had a wonderful sense of humour, Kerr told The Lancet. One of his favourite poems, by A P Herbert, spoke of physicians' knowledge of the common cold: “And I will eat my only hat; if they know anything of that!” Tyrrell is survived by his wife of 55 years, Moyra Wylie, and two daughters. A son predeceased him.

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Published: 18 June 2005

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DOI: https://doi.org/10.1016/S0140-6736(05)66722-0

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doi:10.1098/rsbm.2007.0014351 © 2007 The Royal Society



DAVID ARTHUR JOHN TYRRELL CBE

19 June 1925 — 2 May 2005

Biogr. Mems Fell. R. Soc. 53, 349–363 (2007)

DAVID ARTHUR JOHN TYRRELL CBE

19 June 1925 — 2 May 2005

Elected FRS 1970

BY J. R. KERR1 & D. TAYLOR-ROBINSON2

1 Department of Cellular and Molecular Medicine,

St George’s University of London, London SW17 0RE, UK

2 Division of Medicine, Imperial College London, St Mary’s Campus,

London W2 1NY, UK

David Tyrrell is remembered by physicians and scientists principally for his discovery of the

common cold viruses and elucidation of their pathogenesis, but also for his work in various

other areas, including influenza, bovine spongiform encephalopathy (BSE) and chronic

fatigue syndrome (CFS). David possessed a deep humanity, honesty, perseverance and a vision

of collaboration as a means of making discoveries that would contribute meaningfully to the

alleviation of human suffering. He also had a warmth and a mischievous sense of humour that

was frequently directed at bureaucracy, which he thoroughly disliked.

INTRODUCTION

The name David Tyrrell will forever be linked with the discovery of the common cold viruses

and elucidation of their disease pathogenesis. He was a physician and virologist who directed

his medical and scientific training towards the benefit of his fellow man. The area he finally

chose was that of respiratory virus infection and in particular the common cold.

After his graduation from medical school in Sheffield, and a three-year research fellowship

at the Virology Laboratory of the Rockefeller Institute under the direction of Frank Horsfall,

he was invited in 1957 by Sir Harold Himsworth FRS, Secretary of the Medical Research

Council (MRC), to work at the Common Cold Unit (CCU) in Wiltshire with the aim of growing

the common cold virus. David’s unique approach of using well-oxygenated nasal epithelial

cells grown at 33 °C (the temperature of the nose) enabled him to grow rhinoviruses for the

first time, as described in a series of exciting papers in The Lancet in 1960. He gained a


worldwide reputation, as did the unusual volunteer-based CCU. It soon became clear that there

were more than 100 different types of rhinovirus, and also other viruses that could cause the

common cold, for example, the coronaviruses.

In 1967, David became Head of the Division of Communicable Diseases at the MRC’s

Clinical Research Centre, built in association with Northwick Park Hospital, Harrow,

Middlesex, and was Deputy Director of the Centre from 1970. During this time, he studied

gastrointestinal infections in children, febrile convulsions, encephalitis and schizophrenia

while maintaining control of research at the CCU, part of which involved determining the

effectiveness of antiviral drugs.

ASHFORD

David was born on 19 June 1925, the first child of Sidney Tyrrell and Agnes Kate Blewett, and

grew up in a small bungalow in Ashford, Middlesex (now Surrey), in a ‘protected environment’

with his mother, father and brother, Andrew, who was 18 months younger than himself.

His father had served in the infantry in World War I; he had risen through the ranks to become

a captain and had served for almost the entire war, mainly in France, despite wounds and ‘shell

shock’. Later, he became an accountant and joined Parke Davis & Co. Ltd. at Hounslow as a

cost accountant. He later discovered that his father would have liked to have studied medicine

if funds had permitted. Sidney Tyrrell talked frequently about the development and testing of

drugs and the animal experiments at Hounslow and had a considerable intellectual influence

on David. Sidney was restless and talkative and was a great reader of history and biography,

‘yet a great debunker and hostile to the abstract, the academic and the intellectual who was

detached from real life’. He was very much against dishonesty in business and refused lucrative

posts rather than be compromised. David’s mother trained as a teacher at Hereford

College and had a special interest in French and mathematics; she taught for 5 years but then

stopped to take care of her family. Interestingly, in later life, David spoke French fluently, and

German too. In his childhood, he played with his brother and other friends; garden cricket, fantasy

games involving exploration and the circus, riding bicycles, swimming and boxing.

Swimming, and also sailing, he very much enjoyed in later life, although he freely admitted

that he had no aptitude for games that involved eye–hand or foot coordination. As a child, he

enjoyed reading, particularly stories about the sea, travel and animals. He learned to play the

ukulele and piano and played piano duets with his mother. He continued playing the piano

throughout his life, being at one time part of a musical quartet, and extended his musical experience

by learning to play the organ. When young, David and the family would go to church

and he and his brother attended the Crusaders on Sundays; this encouraged his personal commitment

to the Christian faith, which was maintained throughout his life.

He loved adventure stories and wanted to go to sea but could not because of his eyesight

(see below), but did enthuse his brother, Andrew, to go to sea; Andrew became a navigating

officer and was eventually in the senior management of his shipping line. At primary school

David was noted for being ‘dreamy, forgetful and untidy’. However, at grammar school, first

at County School, Ashford, David ‘enjoyed being top of the class’ in his studies of French,

Latin, geography and science.


SHEFFIELD

When World War II broke out in 1939, the family was on holiday in Scotland, and David and

Andrew were at school for a term in Greenock. The family returned to London but in 1940

moved to Sheffield. David attended the King Edward VII School and studied physics, chemistry,

mathematics, German and music, but later had to drop the music lessons to provide time

for the other subjects.

The Tyrrell family had been friendly with the family of Dr A. Sutherland, a general practitioner

(GP) in Ashford; David had, through them, been to the Royal Institution Christmas lectures

on ‘Young chemists and great discoveries’ and recalled the excitement of witnessing at

first hand the actual performance of historic experiments. This brought to life books like

Simple science, which David had received as a form prize and which he had read more than

once.

As a career, he wished to do something that would help people and initially considered

school teaching; however, this idea faded because he did not like the atmosphere of his school

or the personality of most of the masters. However, in the second year of his sixth form he

finally settled on medicine. An interview was arranged for him with the Dean of the Medical

School in Sheffield, Professor G. A. Clark, who was very encouraging and offered him a place

in his Honours BSc year, assuming that his exam results would be good, as they later were.

He was excused most of first MB and read physiology, anatomy and zoology for the first year,

and was accepted to enrol for an Honours BSc in physiology, in which he received lectures

from Dr H. A. (later Sir Hans) Krebs (FRS 1947) on intermediary metabolism but ‘could find

no account in our books of the cycle he described’! He later concluded that these lectures must

have been the earliest presentations of the citric acid cycle.

At the end of the first term, David had to take several months off for surgical management

of a detached retina, which was the reason why he was not accepted for military service after

his graduation. He enjoyed all the clinical subjects except forensic medicine and gynaecology,

and entered twice for the undergraduate Woodcock Essay Prize. His first attempt, on endotoxins,

met with criticism for lack of original ideas and interpretation, but two years later he

was awarded the prize for an essay on ‘The role of the hypothalamus in the phenomenon of

sleep’. Because of the war, students were spread out thinly and were able to do active clinical

work. David enjoyed casualty and orthopaedics and for a while wanted to do surgery. In his

last year of university, the war was over, Charles H. Stuart-Harris was appointed Professor of

Medicine and David visited him to make some complaints on behalf of his fellow final-year

medical students. David remembered him as very charming. Stuart-Harris was to have a big

influence on David’s career.

In 1948, as a house physician at the Professorial Medical Unit of Sheffield Royal Hospital,

he became interested in internal medicine and, encouraged to do clinical research, undertook

a small project on changes in cerebrospinal fluid pressure after lumbar puncture (1)*. Later,

from 1948 to 1949 as a house physician at the City General Hospital in Sheffield, he was

involved in a systematic clinical and microbiological study of influenza pneumonia in which

he saw and recorded the patients and collected the specimens (3). Thus he became interested

in clinical virology. Later he worked at the infirmary and did some research in organizing a

hypertension clinic with A. W. P. Leishmann, while he studied for and obtained his

* Numbers in this form refer to the bibliography at the end of the text.


membership of the Royal College of Physicians. During this time, during discussions with

Alick Isaacs (FRS 1966), he learned about the basic behaviour of viruses and cells. Alick

would discuss with David what he was doing, and on one occasion he was surprised that David

could interpret the results of an experiment on virus–cell interactions.

There was little chance for David to continue his training in internal medicine because so

many ex-servicemen took priority. He was tempted for a while by general practice and had

been befriended by his family GP, Dr H. N. Skelton of Chapeltown. However, after a discussion

with his clinical tutor, H. R. Vickers, he decided to try to remain in academic work, at

least for a while. He was offered the first Research Registrar post financed by the Hospital

Endowment Fund and, in 1950, began some benchwork in influenza virology accompanied by

a few diabetic clinics each week. In the same year, he married Dr Moyra Wylie, a GP.

He wanted a period of study abroad, so he wrote to A. J. Rhodes in Toronto for a fellowship;

however, he was told that they could not offer a large enough salary for a married man

with a baby ‘to have a pleasant time’. Then, in the spring of 1951, Dr C. H. (later Sir

Christopher) Andrewes FRS passed on to Professor Stuart-Harris a letter he had received from

Frank L. Horsfall Jr, who wanted to appoint an assistant in the Rockefeller Institute and assistant

physician at the Rockefeller Hospital in New York. With the agreement of Moyra, David

applied and was appointed with a smaller salary than had been available in Toronto. David had

done some epidemiology on poliomyelitis (2) in response to a request from a GP in

Lincolnshire, Dr Smallhorn, to Stuart-Harris and presented this work at the second

International Congress on Poliomyelitis in Copenhagen, where he ‘met the virological literature,

eg. Stanley, Enders & Salk, and my new chief, Horsfall’. This work on poliomyelitis was

published in The Lancet and was the first of many such papers by David (2).

THE ROCKEFELLER INSTITUTE, NEW YORK

Within a month of the Copenhagen conference, the family arrived in New York, living in an

apartment across the street from the Rockefeller Institute. He had planned to be there for nine

months but ended up staying for three years. His work was initially directed and supervised

closely by Horsfall, but later he was given much more freedom and, by the end of three years,

he merely kept his boss informed of progress and occasionally asked his advice. David was

taught the need for systematic and rigorous proof and a well-controlled experimental protocol,

and received an excellent training in virology and in research methods. He was surrounded

with eminent and stimulating people, whom he met at lunch and heard talk at the Friday sessions.

Those who made a deep impression and provided an example to follow were Stanford

Moore and William Stein (amino acid chromatography), George Palade (ForMemRS 1984)

and Keith Porter (electron-microscopic structure of cells), René Dubos (biology of infection),

and Robert Shope and Max Theiler (vertebrate viruses). There was little clinical work to do

but he occasionally visited the New York Hospital, which was next door. It was during this

time that he learned to think about the basic nature of the interaction between viruses and cells

and between viruses and inhibitors, and also about the mechanisms of virus interference and

synthetic antiviral chemicals.

During the Korean War, he was formally enrolled in the US Army, but he returned to

Sheffield in the summer of 1954.



VIRUS RESEARCH LABORATORY, UNIVERSITY OF SHEFFIELD

In Sheffield, Stuart-Harris and C. P. Beattie had started a Virus Research Laboratory at

Lodgemoor Hospital, and David began work there, mainly in clinical virology, setting up

many techniques from scratch. He worked with adenoviruses, which had just been discovered

at that time (4); he did one of the first studies in the UK on inactivated poliovirus vaccine (5)

and described an epidemic of a new enterovirus (6, 7). During this time, he had his first experience

of training other scientists and running a small team.

THE MRC COMMON COLD UNIT

During part of his time in Sheffield, he was on the External Scientific Staff of the MRC, and

in 1957 he was casually told by Stuart-Harris that the Secretary of the MRC would like to see

him. Sitting before Sir Harold Himsworth, the ‘dynamic head of the MRC’, David was asked

‘would you like to work at the Common Cold Research Unit’ (CCRU; later shortened to CCU)

to attempt to cultivate ‘the common cold virus’? It is appropriate to mention at this point that

the American Red Cross–Harvard Hospital was brought across the Atlantic in prefabricated

units to Salisbury at the beginning of World War II. After assembly, the hospital opened in

1941 to deal with epidemics of infectious disease that might occur during the war. Thereafter,

in disuse, Christopher Andrewes saw it as being ideal for housing volunteers who could be isolated

from each other and so facilitate work on the common cold. Thus, the CCU was born and

the first volunteers arrived in July 1946. In considering the offer to work there, he felt that he

had been so fortunate that it would do him no harm to struggle with this problem for a few

years. He had two ideas: one was to grow the virus in human kidney cells, which seemed very

susceptible to other viruses, and the other was to use the temperature of the human nose, which

he had once measured in himself and found to be 33 °C. At the CCU (figure 1), arriving on

All Fools Day, 1957, he enjoyed the space and quiet, and quickly adapted to the philosophy

of experimenting on human volunteers. He

planned to make a systematic attempt to find out more about the basic properties of the virus by experiments

in volunteers, to put tested specimens into a variety of cultures, on the assumption that only one combination

of cells and conditions might work, and to do other more quickly moving studies with known viruses to get

results of some sort and to learn about possible methods of virus detection and other cell–virus interactions.

The CCU quickly built up a substantial reputation for common cold research, but its fame

spread even more widely through its use of human volunteers, who came willingly in large

numbers for a 10-day holiday in the Wiltshire countryside, paid for by the CCU, in compensation

for the possibility that they might receive a cold virus intranasally. They were in strict

quarantine and they recorded any symptoms and the number of tissues they required, and so

on. Many used this solitude as an opportunity to study for examinations. Journalists sometimes

came to visit the unit when trials were running, and they sometimes came as volunteers; one

pretended she was a teacher but was exposed on receiving a telephone call from her editor.

One man, who had come to the unit nine times, on one occasion developed a ‘romantic feeling’

for a woman volunteer, an oboist who played with a London orchestra. ‘I had brought my

guitar down with me’, he said, ‘and we played duets at 30 feet while the trial lasted, and closer

at the end.’

'


Figure 1. An aerial view of the Common Cold Unit, Salisbury, Wiltshire.


At first, David was under the direction of Christopher Andrewes, who was then Head of the

Virology Division of the National Institute for Medical Research, but Charles (later Sir

Charles) Harington FRS, the Director of the Institute, said that David was to have a free hand

in planning the experiments. Andrewes came down from London about every two weeks to

discuss progress and David found him very stimulating, Andrewes’s idea of studying viruses

from an ecological or natural history point of view being particularly appealing.

Within a year or so, it was clear that ‘something’ was growing—and so the family sold their

house in Sheffield and moved to Salisbury. Early in 1960, David and his team published their

results showing that rhinoviruses, as they became known (figure 2), could be grown and

detected in tissue cultures (8–10). The notion of ‘the common cold virus’ was dispelled, as

subsequently different types of rhinovirus, more than 100, were discovered. The work

increased in volume and speed, and the group became interested both in basic questions on the

nature of the viruses and also in applied questions such as the possibility of making vaccines,

and studying the mode of spread from person to person.

Andrewes was also very good on taxonomy and international relations, and the unit subsequently

became a WHO Reference Laboratory. Andrewes retired in 1962 and came to live in

the vicinity of the CCU; he would call in to talk and use the library. Alick Isaacs formally

became Head of the Division but was too ill to take an active role, and in due course the Unit

became a Division of NIMR with David as Head.





David Arthur John Tyrrell 357

Figure 2. Electron micrograph of particles of rhinovirus type 9 clumped together by specific antibody. Some particles

are empty; in these the medium has entered the interior, which is normally occupied by nucleic acid.

(Photograph by Barry Dowsett, CAMR.)

David described his work as strenuous but very satisfying, and he particularly enjoyed several

aspects of it. One of these was the number of visiting workers who came through the laboratory,

and another was the development of the local and unofficial scientific society, the South

Wiltshire Virological Society, which grew from a dozen people sitting around a coffee table to

regular meetings with attendances of 60 or more. There were also the increasing contacts with

the Virus Unit of the WHO, Geneva, the development of the Reference Centre system and the

numerous international contacts and occasional working meetings that emerged from all of this

in the 1960s. Through the WHO, he and his team developed a particular relationship with the

laboratory of Dr Robert M. Chanock at the National Institutes of Health (NIH), Bethesda, MD,

USA, and Dr David Taylor-Robinson worked there for some time. There was a mixture of

rivalry and cooperation between the two laboratories as well as good personal relationships,

which kept the work moving forward. David tried to steer the work of the CCU so that his team

did not get into competition with the Chanock laboratory on aspects such as large-scale epidemiology

and serology, for which the Americans had superior resources and organization.

After an enquiry from Sweden to Andrewes, David was put in touch with Bertil Hoorn, an

ear, nose and throat surgeon interested in the function of cilia. Bertil had developed a simplified

form of organ culture, which he later set up at the CCU. This was then used to grow many

of the known respiratory viruses, using human fetal ciliated trachea, and with them he eventually

propagated and recognized a new group of viruses of colds, the coronaviruses (14).



THE MRC CLINICAL RESEARCH CENTRE

During David’s time at the CCU, he had been interviewed by Sir Harold Himsworth, who

enthused him with his concept of a Clinical Research Centre (CRC) to be built in close association

with a district general hospital. David began working at intervals in Birmingham with

a small group under Professor John Squire, the Director Designate, on the planning of the

whole complex, which was to be at Northwick Park in northwest London. He was particularly

involved with the animal house and the infectious disease wards and found it stimulating to

imagine the integration of clinical work and laboratory work and research. In the meantime,

he kept in touch with clinical work mainly by doing a medical out-patient clinic at Salisbury

Hospital.

In 1967, the family moved to London in anticipation of the opening of the CRC and at a

convenient time to move schools. He was made a consultant physician and looked after infectious

disease beds at Neasden Hospital, although he still managed to spend about two days a

week in Salisbury. He turned his attention to the problem of acute diarrhoea in infants and

adults, in which the bacteriology of the day could not explain most cases. He took over the

adult side of a small infectious disease unit at West Hendon Hospital and noticed the frequency

of gastroenteritis as a cause of admission and how often it was not possible to find causative

bacteria. In the laboratory, using intestinal specimens, he tried to grow viruses from them in

organ cultures of intestinal epithelium, although by then others had detected the rotaviruses

and other viruses.

The untimely death of John Squire in 1966 was followed by the appointment of Graham

Bull, who patiently and carefully supervised the planning of one division after another, and

generated an atmosphere of amiability and goodwill. Graham was especially good at managing

the complex relationships between the hospital staff and the CRC. David was made

Deputy Director, ‘which entailed little extra work’. For the first few years at the CRC, from

1970, there were many teething problems, laboratory work was difficult and there was no

infectious disease service. However, there was steady progress, and the development of work

on infectious diseases was such that it merited and attained divisional status as the Division of

Communicable Diseases. Apart from David, this comprised David Taylor-Robinson and Ten

Feizi. David Taylor-Robinson worked first with rhinoviruses and other respiratory viruses at

Salisbury (11–13); later he worked with mycoplasmas, in which field he achieved international

recognition, building up a group working on sexually transmitted diseases (which later

became the Division of Sexually Transmitted Diseases). Ten Feizi, who had collaborated with

Taylor-Robinson at Salisbury, came back from the Rockefeller Institute to set up an immunochemical

group, particularly to study Ii antigens.

During this time there was much collaborative work between Divisions in the CRC and

with physicians in the district general hospital at Northwick Park. Indeed, the philosophy

behind the existence of the CRC was that emphasis should be on the study of common diseases.

David, of course, was no stranger to this, having studied in Salisbury perhaps the most

common of common diseases. Thus, studies on gastrointestinal and respiratory infections in

children, as well as those on febrile convulsions, encephalitis and schizophrenia, were set up.

The possibility of a viral cause of schizophrenia, suggested by both David and Tim Crowe,

was intriguing and supported by the fact that specimens of cerebrospinal fluid from patients

with the disease produced changes in cell cultures, whereas those from other patients did not

(15, 16). However, despite considerable effort a virus could not be found, in sharp contrast to



the success in Salisbury and in other projects. Also, during this time, David gave quite a lot of

time to the virus diagnostic laboratory and directed, in a general way, the work of A. S. Beare

and S. E. Reed, who had remained at Salisbury.

While at the CRC, he made regular visits to scientific meetings abroad, in the USA, South

Africa and Australia. He built up a regular relationship and personal friendship with Robert

Chanock and A. Z. Kapikian at the NIH, and retained a friendship with Igor Tamm, with

whom he had worked at the Rockefeller Institute. David always valued the occasional updating

and strategic discussions he had with Tamm when he passed through New York. He

attended WHO meetings as a Director of a Reference Laboratory and as an occasional consultant.

He wrote about the WHO:

I always felt that I received more than I gave, though I was often unhappy that we were doing little to further

the health of the world as a whole. However, such international collaboration facilitated the work of establishing

rhinovirus serotypes and reagents for them.

The impending closure of the CRC, regarded by many as a political decision by the MRC

rather than a sound scientific one, was a major reason for David’s return full time to the CCU

in 1985. The closure of the CCU a few years later on David’s retirement, largely as a result of

financial constraints, came at a time when good work was still being undertaken, particularly

on antiviral drugs. He held the view that both decisions were not in the interests of scientific

progress, but he nevertheless recognized that the MRC had given him unrivalled opportunities

for research. He once said, ‘people say that place never found the cold cure, did it?’ Of course,

the enlightened realized that the finding of a plethora of different responsible viruses made the

possibility of an effective vaccine more or less hopeless. It is safe to say that as far as he was

concerned there could be no self-recrimination, and right to the end of his time at the CCU,

David made significant discoveries that were to change and inform the course of future

research in various areas.

With Mary Anderson and John Pattison from University College London, in 1985, David

led the seminal studies of experimental parvovirus B19 infection in human volunteers at the

CCU (17, 18). Healthy adult volunteers were inoculated intranasally with human parvovirus

obtained from an asymptomatic blood donor. One week after inoculation, intense viraemia

was observed in seronegative volunteers; this was accompanied by a flu-like illness. In the following

week volunteers suffered reticulocytopenia with an associated slight drop in haemoglobin

concentration, lymphopenia, neutropenia, and a drop in platelet count. Rash and

arthralgia occurred 17–18 days after inoculation, coincident with the appearance of specific

IgG, suggesting that these symptoms were mediated by an immunological mechanism. This

study confirmed the aetiological role of human parvovirus B19 in erythematous rash illness

and in the temporary arrest of erythropoiesis that leads to aplastic crisis in persons with

chronic haemolytic anaemia.

At the CCU, he studied the effect of psychological stress on the incidence of symptoms during

experimental infections of human volunteers with cold virus. After completing questionnaires

assessing degrees of psychological stress, 394 healthy subjects were given nasal drops

containing one of five respiratory viruses (rhinovirus type 2, 9 or 14, respiratory syncytial

virus, or coronavirus type 229E), and an additional 26 were given saline nasal drops. The subjects

were then quarantined and monitored for the development of evidence of infection and

symptoms. The rates of both respiratory infection and clinical colds increased in a

dose–response manner with increases in the degree of psychological stress. These effects were



not altered after taking into account a range of factors that could diminish their significance.

Moreover, the associations observed were similar for all five challenge viruses, and several

potential stress–illness mediators, such as smoking or alcohol consumption, did not explain

the association between stress and illness (19). This work has subsequently been reproduced

by Sheldon Cohen and colleagues at Carnegie Mellon University, Pittsburgh, PA, USA.

Psychological stress is now known to alter the effectiveness of the immune response markedly,

but the precise mechanisms involved have yet to be elucidated.

David’s many achievements were recognized by the award of a CBE in 1980, honorary

degrees from the universities of Sheffield in 1979 and Southampton in 1990, the Stewart Prize

by the British Medical Association in 1977, the Ambuj Nath Bose prize in 1983, and the

Conway Evans Prize of the Royal College of Pathologists in 1986.

PORTON DOWN

After his retirement, David moved to the Centre for Applied Microbiology and Research

(CAMR), Porton Down, where he had an office in which to research and prepare the writing

of his book, Cold wars (25). This is his scientific autobiography and provides a detailed history

of the CCU and the research on the common cold. One reviewer stated (Treanor 2004):

The book is written in a friendly, conversational tone, and one could imagine that this is the story one might

have heard from Dr. Tyrrell himself during, say, a long train ride. There is a wealth of anecdote here that one

could never find elsewhere, and anyone with more than a passing interest in the common cold would be well

advised to spend an afternoon in front of the fireplace with this book and a warm drink. I know I did that, and

I was glad afterward.

Also at this time, David took part in several research projects on infections with respiratory

viruses and their influence on bronchial reactivity and the presentation of asthma (21, 22), on

bovine spongiform encephalopathy (BSE) (20), and on respiratory syncytial virus (RSV) vaccine.

THE CFS RESEARCH FOUNDATION

While he was at Northwick Park he had a few patients who apparently had infectious illnesses

that were then followed by what seemed to be chronic fatigue syndrome (CFS). He was familiar

with the dogma that this condition was psychogenic in origin, but in some of his patients

this seemed not to be true. He was asked by Dr R. Sykes, Director of the charity Westcare,

which provided counselling for CFS patients, to participate in a National Task Force to review

the evidence that CFS was a real disease. David chaired the Task Force, which produced a

report, published by Westcare. This presented the case that CFS is a significant health problem

and reviewed the possible causes and disease processes. Following this, the Royal Colleges

produced reports that agreed that CFS is a significant health problem with no radical treatment:

they emphasized the psychiatric approach and proposed that there should be studies of various

management approaches such as cognitive behavioural therapy. The Department of Health and

an MRC report took the same view and were against research on biological factors.

David was not happy with these opinions and recalled his experience with Sudden Infant

Death Syndrome. He had been on the first Research Committee of the Foundation for the


Study of Infant Deaths (FSID). At the time this was a mysterious condition, often regarded as

child murder (or overlaying) with a possible viral cause and other contributing factors. David

and his colleagues had been told at an informal meeting of the MRC that the MRC ‘does not

work on non-existent diseases’. He remembered that the FSID had, despite being a small charity,

supported research on aetiology and environmental factors that was later confirmed by

larger charities and nationwide studies, followed by national campaigns to increase awareness

about the harmful effects of maternal smoking and overlaying, among others, which markedly

decreased the incidence of sudden infant deaths.

At about this time, in 1992, the medical charity the Chronic Fatigue Syndrome Research

Foundation (CFSRF) was registered; it was launched in the following year. David was invited

by its Honorary Director, Mr Hugh Faulkner, to join the Research Committee, and he was glad

to be a part of this small charity because of its commitment to the specific purpose of supporting

high-quality basic research into the pathogenesis of CFS. In 1998, he was appointed

Vice-Chairman and in 2001 he was made Trustee and Chairman of the Research Committee.

He was involved in all aspects of the Foundation’s business: fundraising, management, chairing

the research committee, and even with the research when required.

He was particularly involved in two studies, both also involving Jonathan Kerr. The first

showed that parvovirus B19 had a role in the pathogenesis of CFS in that it could trigger the

development of CFS in some subjects, and that B19-associated CFS was indistinguishable from

idiopathic CFS and was associated with raised levels of interferon-  and tumour necrosis factor-

  (23, 24). The second study concerned the molecular pathogenesis of CFS, in which David

was instrumental in setting up collaborative work. This began with a simple pilot study with

microarrays, identifying 16 genes that were at significantly different levels in CFS subjects

from those in normal controls (26). When David received news of the confirmation of these 16

genes by polymerase chain reaction technology, he said that he celebrated by mowing the lawn

while singing ‘Praise, my soul, the King of Heaven’! While he was still Chairman of the

Research Committee, a larger study was approved for funding, led by Jonathan Kerr at St

George’s University of London. This confirmed the involvement of 15 of the original 16 genes,

and found a total of 89 genes that were differentially expressed in CFS, including the original

16. The top functions of these genes include immunity, infection, cancer, neurological disease

and apoptosis, processes that have been documented previously in patients with CFS and present

several opportunities for experimental therapy (J. R. Kerr, R. Petty, B. Burke, J. Gough, D.

Fear, L. I. Sinclair, D. L. Mattey, J. Montgomery, S. C. M. Richards, D. A. Baldwin, P. Kellam,

T. J. Harrison, G. E. Griffin, D. Emlander, D. J. Nutt and S. T. Holgate, unpublished work).

However, shortly after the approval of this study, David died on 2 May 2005 of a complication

of a terminal illness. Two weeks before, he had met to discuss research progress, and

on the morning of the day he died he had discussed by telephone the future of the CFSRF.

ACKNOWLEDGEMENTS

We thank the various people who have given advice and information in preparing this memoir. These include Anne

Faulkner (Honorary Director, CFS Research Foundation), Peter Hammond (Site Historian, Centre for Applied

Microbiology and Research (CAMR)), Barry Dowsett (Centre for Applied Microbiology and Research (CAMR)), and

David’s surviving daughters Frances and Sue.

The frontispiece photograph was taken in 1978 by Godfrey Argent, and is reproduced with permission.



REFERENCE TO OTHER AUTHOR

Treanor, J. J. 2004 Cold wars. N. Engl. J. Med. 350, 522.

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