key: cord-0042309-luayiig9
authors: Andrewes, Christopher
title: Colds, flu and memories
date: 2003-10-01
journal: Trends Biochem Sci
DOI: 10.1016/0968-0004(76)90303-0
sha: 509645c5593aa1b48783667266011024e5e9860a
doc_id: 42309
cord_uid: luayiig9

nan

N 100 pheral model ,' (P/rj,.s. Kcr. .4 hstr. ( I97 1 ) 2 (19) ). Some other delightful quotes that I have enjoyed:

'The concept of the bladder as an inert container of urine no longer holds water.' (Lancet (1973) 'Paleontology is a science which deals with the study of extinct plants and animals that survive today as fossils.' (Weber & Taylor (1968) Gene4 Biology, p. 3. Van Nostrand, N. J.);

'It is doubtful that regular people-eating had much nutritional meaning.' (Amer.

'Communication is an important daily aspect of a librarian's profession. The horizontal relationship is described and a distinction is drawn between it and the vertical relationship. The horizontal relationship is an important communication concept which when mastered by the librarian accrues many personal satisfactions. ' (Spec. Libr. (1975) 

Early in the history of the JIR, in order to make its existence respectable, I and the co-founder of the journal, H. J. Lipkin of the Weizmann Institute, established the Society for Basic Irreproducible Research (SBIR) and nominated Dr X. Perry Mental as the Secretary. Special indentity cards were issued to the members. The valuable assets these cards were to their proud owners is proved by the story related to me by R.A. Lewin of LaJolla. The saleswoman in a department store in San Diego refused to accept a personal cheque in payment for Lewin's purchases unless he could establish his identity. She turned down his drivingbcence and social security card, so Lewin in some perplexity handed her his wallet. She flipped with a disapproving expression through his many identification cards, then finally chose the ID card No. 576 of SBIR (issued by X. Perry Mental on 30 February 1960), expressed her satisfaction and accepted the cheque. 

Many must have noticed the contrast between our success in controlling some of the more devastating plagues and our relative failure with the minor, nuisance diseases, particularly infections of the upper respiratory tract. The difficulties they present offer a challenge; that, I suppose, is why I have spent about 45 years of my working life largely in the study of two of the most important and obstinate, namely influenza and the common cold.

The year 1933 was ushered in by a brisk influenza epidemic. With two colleagues, P. P. Laidlaw and Wilson Smith, a serious attempt was made to reproduce the disease in experimental animals. The first material to be tested was a washing from my own throat. Using rabbits, mice and guinea pigs the first experiments were negative. We were then told of a flu-like illness among the staff and also among ferrets at the Wellcome laboratories at Beckenham. Following this clue, washings were dropped up the noses of ferrets and these soon developed fever and nasal discharges [l] . They had, indeed, been infected with influenza virus. It turned out, however, that this success had depended on a sheer fluke: the Beckenham ferrets had not had flu at all, but an abnormal form of dog distemper. Anyway the fluke set us on the right lines. At first there were difficulties: our experimental ferrets came down with accidentally-introduced distemper as well as flu and we were greatly confused. Fortunately for our work, Wilson Smith caught the flu, almost certainly from a

N 101 sneezing ferret and, not being susceptible to distemper, he 'filtered' that virus out and we thus obtained uncomplicated influenza virus.

Influenza in ferrets proved to be quite infectious;

indeed we had a 'ferret hospital' with 32 isolation cubicles built for us. Thereafter discoveries came thick and fast. Infection was transmitted to mice, then grown in fertile eggs and in tissue culture. Hirst [2] showed that the virus would agglutinate red blood cells and a simple in vitro test for antibodies became available. Francis and Magi11 [3] showed that influenza viruses were of more than one serological type. Vaccines were made from lungs of infected mice and tested in man. These, however, were soon superseded by much better ones prepared ffom virus grown in the allantoic cavities of infected eggs.

Two important things gradually became evident : the antigenic make-up of flu virus strains was changing from year to year; and the changes were much the same in one country as in another. It soon became obvious that novel flu strains were moving from country to country. Accordingly in 1947 the World Health Organization was persuaded to set up a network of influenza laboratories to collect and study strains and monitor the spread of new ones. This was clearly necessary if manufacturers were to be able to provide vaccines effective against novel variants of the virus. When a change was recognized, all countries would be alerted so that, with luck, an appropriate vaccine could be made in good time.

Inactivated vaccines, if made against current strains, can reduce the incidence of influenza, though less decisively than one could wish. They are, however, well worth giving to people in key positions and to the elderly and infirm. They are not cheap, not of long-lasting efficacy, and there are practical difficulties about administering them universally. Living, attenuated vaccines have been given extensively in the U.S.S.R. and are under intensive study here and elsewhere. They could be made much more cheaply than inactivated vaccines and administered by spray or nose-drops instead of 'jabs'. They are certain to be used extensively in the future, especially when, as seems to happen every 10 or I I years, a major 'antigenic shift' occurs in the antigenic composition of the prevalent viruses. There is increasing belief that when very novel strains appear, there has been recombination or hybridization between viruses of human origin and one from another species, perhaps a bird, because influenza viruses affect not only man but many species ofvertebrate as well. in 1946 the time seemed ripe for a renewed attack on the common cold and a research unit was set up under the Medical Research Council at Salisbury. Here, two dozen volunteers at a time could be housed, usually in pairs under conditions of isolation, and used to test materials for the presence of the 'cold' virus [4] . The primary object was to discover a laboratory technique for recognizing the presence of the virus; it took about 14 years before this object was achieved. At first we tried, in vain, to confirm reports from three laboratories that the virus could be grown in eggs; we failed also to infect experimental animals of many different species. Finally, efforts were concentrated on trying to grow the virus in tissue culture. In 1953 we were apparently successful, using cultures of human embryonic tissues [5] . Having published the results, we then failed to confirm our own findings. But after some frustrating years, success was snatched from failure and ways were found of regularly cultivating cold viruses [6] .

There was a forward step when it was found that infectivity survived in cultures better at 33' C than at more conventional temperatures.

Later, actual multiplication was indicated when it was found that coldinfected cultures would no longer support the growth of an added virus of another sort. The real break, however, came through another of those happy accidents. One week, the complex salt mixture, 199, used in the cultures, went wrong and some had to be borrowed from another laboratory. When this was used, the cultures showed areas of degeneration in the cells and these were shown to be due to multiplication of our cold virus. It turned out that the borrowed 199 contained less buffer and was more acid than the original: and that did the trick.

Just as rapid advances followed the discovery that influenza could be transmitted to ferrets so the success in growing a cold virus opened up research in that field. But, alas, it was not a question of cultivating 'the common cold virus' but of growing more than 100 different ones. Most of them were small RNA-containing 'rhinoviruses', resembling poliomyelitis and other enteric viruses in many ways but more acid-labile. Some were larger and of quite a different virus family, the coronaviruses.

Great as have been the difficulties in making a successful flu vaccine, a common cold vaccine seems far less attainable.

One can immunize against any one of the many rhinoviruses, but to make a vaccine effective against 100 or more antigenically different ones is, at present, impracticable. Each valuable component would have to be diluted to a point at which it was no longer effective.

This sad finding does not mean that we must throw up our hands in despair. Much work is going on in the field of virus chemotherapy. This presents a far harder problem than the chemotherapy of bacterial infections, but results already achieved show that there are no theoretical reasons why success should not come. There has been limited success against small-pox and ocular infections with herpes. Amantidine is certainly successful against some strains of influenza in mice, though its efficacy in man is very limited. Claims for the value of ascorbic acid against colds have been heard over many years and have been much proclaimed recently. Controlled trials seem to show that it has no prophylactic value against colds, but has a slight beneficial effect in relieving symptoms. This does not seem to be a specific effect against cold viruses in particular. Statistics have to be invoked to show that there is not any effect at all, so its widespread use is hardly indicated.

Research into respiratory infections has by no means been confined to the search for effective vaccines or drugs. The epidemiology of colds and flu presents many problems.

Work has been going on into how these viruses spread, why they are prevalent at certain seasons of the year and where the viruses hide between outbreaks. In most of these ways colds and flu probably behave very differently.

There has been no space to write about numerous other viruses affecting our respiratory tracts. There are four parainfluenza viruses, many serotypes of adenovirus, the respiratory syncytial virus and others, each having its own characteristics and presenting its own problems.

Pursuit of'the Common Cold

Sir Christopher Andrewes FRS who wus ,formerl)

deput_v director of'the National Institute for Medical Re.vearc,lt, Mill Hill and for manl' j'ear.s head of the Medical Re