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Postgrad Med J: first published as 10.1136/pgmj.50.579.1 on 1 January 1974. Downloaded from

Postgraduate Medical Journal (January 1974) 50, 1-8.

Whither ? and prospects in medical research*

SIR CHARLES STUART-HARRIS C.B.E., M.D., D.Sc., F.R.C.P.

Postgraduate Dean, University of Sheffield

FOR just over three-quarters of a century the study was regarded as the corner-stone of proof of the has furnished a most exciting chapter in that the material contained the actual causative the growth of the natural sciences. The story began of the particular under study. Later it became with the observations of Ivanovsky upon tobacco a method for artificial cultivation of the virus but mosaic disease in 1892 and of Loeffler and Frosch alas, available experimental were far too upon foot and mouth disease in 1898. Both studies frequently resistant to the transfer of infection from showed that the respective could be trans- man. Only the monkey, the ferret, the hamster, the mitted by filtered extracts from the affected or mouse and the fertile hen's egg remained to en- animals containing no recognizable . Yet courage the virologists of the pre-tissue culture era. the contagious material in the filtrates could neither the Latterly volunteer has been of inestimable value by copyright. be visualized nor cultivated. A similar mystery in permitting work upon the common cold, live surrounded Reed's transmission of yellow fever to vaccines and even hepatitis. Nevertheless, all work man in 1902 and that of poliomyelitis to monkeys by involving man as an experimental has Landsteiner and Popper in 1908. Though history immense drawbacks and can never do more than credits Buist (1886) and Paschen (1906) with the first supplement that of the laboratory. demonstrations of virus particles in vaccinial lymph, The new technical methods available for the further progress awaited technical advances in cultivation in tissue and organ cultures have microscopy. greatly extended the recovery of viruses both from When I was first initiated into virus research at the diseased animals and humans and from apparently National Institute for Medical Research at Hamp- healthy persons. A vast array of viruses recovered http://pmj.bmj.com/ stead in 1935, Dr J. E. Barnard was using ultraviolet from the animal kingdom stands revealed, many of photomicrography to demonstrate the elementary which have been obtained from man (Andrewes and bodies of the pox viruses. Also W. F. Elford was Pereira, 1972). The viruses of animals and particu- studying the measurement of size based upon graded larly of those in contact with man through domes- collodion filters. The then known particles including ticity, share many characters in common with viruses were arranged in order ofsize from bacterium human agents. A new science ofcomparative virology to molecule and Sir Henry Dale, in his Huxley lecture is thus being written at the present time which in- on September 23, 2021 by guest. Protected at Imperial College in 1935 entitled 'Viruses and cludes certain of the respiratory viruses of man Heterogenesis', relied upon such evidence to dispose including . Thus far it has proved impossible of the argument that viruses are products of the cells to say whether these animal viruses are derived from of other living organisms-an argument which recurs contact with man or vice versa but it is a fact that the periodically right up to the present day. former hard line of distinction between the viruses of The techniques which have been pressed into use animals and of men no longer exists. The bearing of in the study of viruses are many and varied but this upon the origin of human viruses is no mere periodically all virologists return from their chemical academic matter for it involves so practical an issue or physical technicalities to the question of the trans- as the source of the virus of the next influenza mission of infection, for it has been this above all pandemic. which has characterized the virus as an object Meanwhile the universality of virus parasitism worthy of study. In the early studies, transmission of encourages the belief that viruses are ancient in an * Inaugural address to the British Postgraduate Medical evolutionary sense and that human viruses may well Federation series on the Scientific Basis of Medicine, 11 have evolved hand-in-hand with man in his ascent October 1973. from the animal kingdom. Postgrad Med J: first published as 10.1136/pgmj.50.579.1 on 1 January 1974. Downloaded from

2 C. Stuart-Harris

TABLE 1. Some human viruses and their animal homologues

RNA Virus group Human virus Animal viruses

f Poliomyelitis Theiler's mouse encephalomyelitis Picornaviridae.Enterovirus P Echovirus Bovine, porcine, simian enterovirus Rhinovirus Equine rhino; foot and mouth virus Togaviridae (Arbovirus) Yellow fever (urban) Yellow fever (jungle) Sporadic virus from insects 200 insect, avian and mammalian hosts Orthomyxovirus Influenza virus A Fowl plague and many avian, porcine, equine Paramyxovirus Parainfluenza I-IV Parainfluenza III (bovine). Parainfluenza I murine, simian Measles Distemper; rinderpest Respiratory syncytial (RS) Bovine RS Other RNA viruses Coronavirus Avian inf: bronchitis Acute gastroenteritis Porcine gastroenteritis Oncornavirus (leukovirus) ?? ; mammary carcinoma Leukaemia viruses mouse, leukosis-sarcoma complex, Bittner virus mouse mammary carcinoma

TABLE 2. DNA Virus Group Human Animal Papovavirus Papilloma (wart) Papilloma rabbit (Shope), porcine, bovine, equine Virus of progressive multifocal leucoencephalopathy Polyoma mice Adenovirus 313 Serotypes Simian, bovine, porcine, murine, avian, canine adenovirus Herpesvirus Herpesvirus hominis 1 and 2 B virus monkeys, herpes III rabbit, Herpesvirus by copyright. suis (pseudorabies) Cytomegalic inclusion virus Salivary gland guinea-pigs mice Poxvirus Variola-vaccinia Cowpox monkey, pox, ectromelia (mice)

Viruses as causal agents of human disease species of variola, yellow fever, measles and rubella The impact of the tissue culture method upon the viruses are the exception rather than the rule. The cultivation ofviruses from human specimens has been three serotypes of poliovirus do not constitute a very great. The list of viruses recovered either from serious problem for prophylaxis, but the merry-go- patients or from apparently healthy persons is very round of the surface antigens of the influenza viruses http://pmj.bmj.com/ long and the task of associating viruses with clinical is one of the important reasons for the relative illnesses has sometimes proved difficult. The simple failure of influenza vaccine to control the disease and view of one virus, one disease, which held during the the specific prevention of the common cold seems first half of the twentieth century broke down with now to be insoluble even by means of a multivalent the discovery of the numerous viruses found in the vaccine. respiratory and gastro-intestinal systems. It is now Nevertheless, looked at from the point of view of obvious that the various clinical categories of respi- the causes of human illnesses, the viruses thus far ratory illnesses are syndromes even though certain recovered appear to account for most of the acute on September 23, 2021 by guest. Protected virus groups more commonly prefer to attack non-bacterial non-parasitic infections. Where viruses certain areas of the respiratory epithelium. It is also cannot be cultivated, their particles may sometimes obvious that most of the enterovirus infections be seen within the affected cells as, for instance, of originating from the pharynx or intestine are sub- warts or molluscum contagiosum. Some undis- clinical and rarely invoke virus invasion of the body covered virus species may exist as, for instance, in generally or of the CNS. addition to the rhinoviruses and coronaviruses there Another major consequence of the virus explosion may be other causes of the common cold. But most is the discovery that many viruses exist in the form of instances of viruses as determinants of acute disease multiple serotypes with little cross-immunity. The 33 including hepatitis and acute gastroenteritis are adenoviruses, 100 or so rhinoviruses, 30 coxsackie- probably known. viruses and 34 echoviruses constitute an immuno- The relationship of the virus to host in these logical jungle which, though it helps the virus as a acute infections is one involving varying degrees of parasite, nullifies the efforts of those seeking to damage to the host followed usually by repair. At develop vaccines. In retrospect, the single antigenic the same time replication of the virus particles within Postgrad Med J: first published as 10.1136/pgmj.50.579.1 on 1 January 1974. Downloaded from

Whither virology? 3

infected cells produces thousands of new particles then latency may change to overt infection as with identical to the original ones. As this progeny seeks cytomegalovirus and the newly described polyoma release from the host to the exterior, its transmission virus. from one infected host to the next follows the lines Reference must now be made to the chronic in- familiar in bacterial diseases. Vertical transmission fections induced by viruses. This of course raises the from mother to foetus is an important additional role of viruses in relation to tumours-a subject to corollary to horizontal transmission within the which reference will be made later. The only chronic human herd. All such aspects of virus infection could virus infections of man on which there is certain be described as 'orthodox' and the immunity which knowledge are those which occur in the nervous is invoked, if effective, is specific. But in the past few system. The herpes group of viruses again require years exploration of virus-cell relationships has mention in that congenitally acquired cytomegalo- revealed unusual patterns of infection. virus infection causes a chronic encephalitis with mental subnormality. The curious case of inclusion Latent, recurrent and chronic virus infections or subacute sclerosing panencephalitis is another A latent infection by a virus is one in which the example of a relatively slow infection, this time of virus persists but causes no outward evidence of its measles virus (Dayan et al., 1967; Legg, 1967). This presence. Herpesvirus hominis acquired probably in uncommon neurological condition which begins as a infancy as an acute infection of the mouth or behaviour disorder and progresses inexorably to pharynx, has the capacity to remain in its host death, seems to be the consequence of a resurgence of throughout life and in an obscure locus. The measles virus infection acquired months or even recurrent herpes blisters of the lips and face consti- several years before. No explanation of the exact tute the proof that the virus is still active and is pathogenesis is yet forthcoming. capable of being provoked into attack by some shock The possibility that chronic forms of neurological or adverse condition of the host. The whereabouts of disease are due to viruses was first canvassed in the virus' habitat within the body during the latent. explanation of the New Guinea Islanders' disease by copyright. phase of infection was for long a matter of surmize. kuru. The transmission of kuru to chimpanzees has Grouping of the recurrent skin lesions in the distri- done little to clarify this issue though the chronic bution of sensory nerves strongly suggested that character of both the human and animal disease nerve cells might be the locus of the hidden virus. suggests a similarity with scrapie of sheep. This Very recently proof of the correctness of this view disease, though transmissible to mice and several has been obtained by histological examination of the other species, still remains obscure. The hypothetical Gasserian ganglion and cultivation of virus from the virus has not been demonstrated and though it can latter at autopsy (Bastian et al., 1972). persist in cultures ofbrain cells from infected animals,

Other examples of virus latency are now known. it has not been transferred to other cultured cells. http://pmj.bmj.com/ Both hepatitis virus B and cytomegalovirus are The resistance of the scrapie agent to heat and ultra- known to be transmitted by blood from apparently violet light is so remarkable that doubt has been healthy blood donors. Yet we do not know where raised as to whether the agent contains nucleic acid. such latent viruses exist in the body though the The prospect of a transmissible self-replicating poly- liver and spleen may be involved in maintaining saccharide is not, however, one to which I subscribe viraemia. Latent adenovirus infection of the tonsils with enthusiasm. The lesson surely for us clinicians is and adenoids is perhaps of a different nature from that some forms of neurological disease hitherto that of herpesvirus for it appears not to be trans- regarded as degenerative in nature may be trans- on September 23, 2021 by guest. Protected mitted to others nor to cause recurrent infection. The missible infections due to virus-like agents. The virus merely survives locked within cells of the Jakob-Kreuzfeld disease and progressive leucoen- tonsils or adenoids to which it gained access at an cephalopathy already belong to this category but the unknown previous time. Perhaps it is because the hunt is on and no one can tell whither it may lead. adenovirus develops a close cell-relationship and Meanwhile it is necessary to turn away from human does not have a severely destructive cellular effect disease to describe some of the trends in virology that it can become latent. Indeed the ability of a occasioned by developments in molecular biological latent virus to survive even when adequate serum techniques. antibodies exist to prevent its spread, suggests a failure of immune mechanisms. It is thought, how- ever, that the virus particles in the latent state repli- The virus and the cell cate at an exceedingly slow rate and transfer directly (a) The nature of viruses from one cell to another through contiguous cell mem- The development of methods for the mass culti- branes without ever becoming extra-cellular. When vation of viruses led naturally to a study of the the parent host is subjected to immuno-suppression structure and composition of their particles. The late Postgrad Med J: first published as 10.1136/pgmj.50.579.1 on 1 January 1974. Downloaded from

4 C. Stuart-Harris

Rosalind Franklin of Birkbeck College was the first But the application of refined biochemical techniques to apply X-ray diffraction analysis techniques to to virus particles or fragments is still in its infancy. virus particles and her concept of the tobacco mosaic Biochemical molecular virology is uncovering the virus as a helical strand of RNA on which protein nature of the structural proteins including their poly- sub-units are assembled externally, has stood the test peptide constitution and is adding greatly to the of time. Coupled with advanced electron microsco- knowledge derived previously from immunological pical techniques the ultra-structure has now been analysis. Thus 7 or 8 polypeptide species have now studied in many viruses ofplants, insects, animals and been identified as virus-coded proteins of the in- man and certain basic patterns have emerged. Put the fluenza virus (Skehel and Schild, 1971); 4 are glyco- TMV rod as a skein inside a host capsule of lipo- proteins including the surface haemagglutinins and protein and embed in the envelope other virus- neuraminidase . A new membrane protein has specified protein units with specific functions and one been found and this is associated with the lipid which has the particle of a myxovirus typified by influenza encloses the ribonucleoprotein. An enzyme-an or parainfluenza viruses. Less knowledge exists in RNA-dependent, RNA polymerase-is contained the case of the virus particles exhibiting cubic within the virus particle and is presumably concerned symmetry resulting in a compact type of icosahedral with the replication of the virus nucleic acid (In- virus particle. This is adopted by many viruses fluenza Workshop, 1972). This information has yet to including , insect and mammalian viruses. As be put to definitive use but it may help to define a typified by the human adenovirus the icosahedron method of attack by chemicals on those virus con- has been intensively studied and in spite of much stituents not shared by the host cell and thus lead to probing the exact form of the DNA of this virus still antiviral . Dr Oxford, working in escapes definition. It is located as an internal 'core' Canberra, has recently studied the influenza ribo- on which the protein sub-units are arranged along nucleic acid polymerase and believes it to be suscep- defined radial axes of symmetry forming the cap- tible to chelating agents. Someone, somewhere, must

someres. The fibre-like antennae with their terminal surely break open the problem of a rational chemo- by copyright. knobs appear to provide for virus-specified proteins therapy of viruses, which still lags and prevents the which serve as additional antigens. In addition to development of the treatment of virus infections of these two basic structures there are many other man. individual variations. It may well be asked what the past 20 years of (b) Virus multiplication and virus genetics study of the structure of viruses as macromolecules It is now universally accepted that virus replica- has contributed in terms of understanding. A major tion depends upon virus nucleic acid. Indeed in the consequence is the uncovering of the essential unity case of the , the protein coat remains

of the viruses of plants and animals for there is now on the exterior of the bacterial host and only the http://pmj.bmj.com/ no sharp line of distinction between these. In spite of DNA enters the cell. particles enter the fact that plant viruses are all RNA-containing, host cells intact but are rapidly taken apart by whereas roughly half the animal viruses contain uncoating so that the RNA or DNA is RNA and the rest DNA, their morphological resem- released into the cell. Indeed infection has been blances are truly remarkable. That all viruses con- successfully accomplished in a number of cases by tain only one form of nucleic acid and not both, extracting free nucleic acid. The latter is highly marks them out as being fundamentally distinct from sensitive to destruction by cell nucleases and pre- all free-living micro- or macro-organisms (Lwow, sumably the virus protein is its chief protector. The on September 23, 2021 by guest. Protected 1957). Gone is the concept that a virus is a minute cycle of replication initiated by the viral nucleic acid bacterium rendered degenerate by intensive parasi- within the cell is a highly complex process and is as tism. True that viruses are parasitic and that their yet only poorly understood. ability to multiply depends on their penetration into In spite of its close intracellular relationship with a host cell but this alone is not unique to viruses. We the host cell in which it merges, the virus maintains now use a combination of physical structure in- its genetic independence though being subject to cluding the type of symmetry of the particle, the variation and error during replication. Spontaneous number of capsomeres belonging to each particle, the or induced mutation is occurring all the time but type of nucleic acid and the presence or absence of variants will only be detected when they enable the an envelope as the bases for the classification of virus to take advantage of selective environmental viruses whether these are plant, bacterial or animal. circumstances. Thus many variant particles perish Such a classification takes no account of the patho- because they are defective unless, like certain strains logical effects engendered by viruses on their hosts. of the fowl Rous sarcoma virus, they can borrow Much of what has just been said is comparatively facilities from a latent virus present in the same cell. well-established and by no means recent knowledge. Much studied of recent years are the mutants termed Postgrad Med J: first published as 10.1136/pgmj.50.579.1 on 1 January 1974. Downloaded from

Whither virology? 5

temperature-sensitive (ts). These are usually less processes. In one, the nucleic acid sets about repro- pathogenic than normal wild viruses. Sabin's atten- ducing a swarm of phage particles which ultimately uated polioviruses thus exhibit the property of re- burst the bacterium. Or, the phage DNA enters the stricted multiplication at temperatures in excess of DNA ring of the bacterium and is replicated when 390 C which suit virulent polioviruses quite well. the latter divides. In this case the bacterium and its Deliberate induction of mutation by chemical progeny are termed lysogenic. Under appropriate agents such as fluorouracil and selection by exposure circumstances such as UV irradiation the phage to temperatures which restrict multiplication has led nucleic acid is freed and produces a host of phage to the development of 'ts' attenuated influenza and particles with resultant lysis ofthe bacterium. Is this a respiratory syncytial viruses for use as vaccines. This phenomenon peculiar to the bacterial world or do has been done by Dr Chanock and others at Bethesda similar events occur with mammalian viruses? (Wright et al., 1973; Murphy, et al., 1972). However, The event most likely to be initiated by entry of a 'ts' mutants selected by exposure to graded environ- mammalian virus into susceptible cells growing in mental conditions are preferred by some for the tissue culture is that the virus will reproduce and the preparation of live virus vaccines (Beare and Bynoe, cell will be destroyed. This, however, is only one 1969). This is because of the importance of genetic consequence and there are plenty of instances of stability in a virus which actually replicates in the virus replication inside host cells which remain un- host. altered. When tissue cultures are prepared from In nature and certainly in the laboratory, anti- normal embryonic tissues andcarried serially through genic variation of some viruses, such as the influenza many generations they ultimately undergo cell virus, appears to be the usual method of survival in transformation. This is a phenomenon of increased the face of the selective pressure of host antibodies. capacity for growth, lack of contact-inhibition and A small change in the surface proteins-the haemag- change in the number of chromosomes. It can occur glutinin or neuraminidase-will enable the emerging in normal cultures in one step if one of the RNA or altered virus to resist neutralization by the host's DNA tumour viruses is added. Thus a third form of by copyright. antibody system. Repeated transfer thus results in virus-cell relationship exists in that the virus trans- the occurrence of '' and this accounts forms the cell but does not itself replicate. The host for the small year-by-year variations in the antigens cells, however, multiply freely and if either they or of influenza A and B viruses. But the mechanism the original virus are inoculated into an animal host whereby the sudden very large antigenic change in such as a weanling hamster there results a tumour, the surface proteins occurs every 10 years with in- usually a sarcoma which can be subsequently fluenza A virus is still unknown. It is this genetic propagated by grafts. variation to a previously unknown virus that brings What then has become of the virus? The current

disaster to our attempts to build up a sound system view that a fragment of viral RNA or DNA has http://pmj.bmj.com/ of prophylaxis with vaccines. In Canberra, bio- become integrated with the cell genome is largely chemical techniques have been used to analyse the based on immunological work. The transformed or haemagglutinins of different influenza virus strains. tumour cells develop new specific proteins known Polypeptide chains thus finger-printed are compared as 'T' antigens and these also appear in normal and possible sources of new combinations glimpsed. tissue cultures infected by the homologous virus in Laver and Webster (1972, 1973) have recently shown the usual way. Yet these 'T' antigens can only be that the haemagglutinin of the Hong Kong influenza detected by tests which employ antisera in the shape virus variant thus differs chemically from that of the of serum from tumourized animals so that they are on September 23, 2021 by guest. Protected forerunner Asian viruses. Its light chain resembles not structural components of the virus. Probably 'T' closely that of an equine influenza virus and it is now antigens are specified by the integrated virus nucleic suggested that antigenically new influenza viruses acid within the nucleus of the host cell. They are which arise at intervals may be produced by genetic certainly specific for the virus concerned whether this interchange between human and animal viruses. is the SV40, polyoma or adenovirus 12. Such a mechanism exists in the laboratory as genetic Arising from the flurry of new work occasioned recombination and is used to prepare new com- by study of viruses as carcinogens has come the binations of strains. It is Burnet's aphorism that concept of a virus-precursor built into the nucleus of anything which occurs in the laboratory probably normal cells. It was work with the RNA leukaemia occurs in nature that has added weight to this hypo- viruses of avian and murine origin which suggested thesis. that leukaemic or lymphomatous viruses were fre- quently to be found in apparently healthy animals (c) Changes in the host cell possessing a high leukaemia risk. Known as a C. A bacteriophage particle which injects its nucleic RNA virus (Bernhard and Guerin, 1968) and termed acid into a susceptible bacterium causes one of two oncornavirus by American authors, it is suggested Postgrad Med J: first published as 10.1136/pgmj.50.579.1 on 1 January 1974. Downloaded from

6 C. Stuart-Harris

that these single-stranded RNA viruses are trans- search in spite of the obvious benefits derived from mitted vertically from mother to offspring but that vaccines such as those in use against smallpox, they do not manifest their presence because of the yellow fever and poliomyelitis. activity of repressor genes. When de-repression Another facet concerned with the r6le of cellular occurs the portion of the genome produces a immunity has been derived from observations on transforming protein responsible for transformation patients with renal transplants treated with immuno- of the cell into a tumour cell. This virogene theory of suppressive drugs such as cyclophosphamide or anti- (Huebner) postulates that ageing, irradiation lymphocytic serum. Prolonged or carcinogenic agents ofany sort act as de-repressors appears to enable certain latent viruses to become and 'switch-on' the oncogene. The existence of a actively infective. Extensive lung lesions due to virus enzyme-RNA-mediated DNA polymerase or cytomegalovirus, the urinary excretion of particles of -has furthered the oncogene a hitherto unknown polyoma-like virus (Coleman, theory (Todaro, 1973). Though reverse transcrip- Gardiner and Field, 1973) and tumours of a lympho- tases are found in normal cells, those present in matous type are all found in such treated patients. tumour viruses are antigenically distinct and yet Nevertheless natural resistance to viruses, the curious share relationships with similar agents from different fact of species resistance to viruses not normally mammalian species. The virus theory of human found as infecting agents, remains unexplained. Also cancer is certainly beyond the scope of this lecture but the relative importance of antibodies, cellular activity it should be abundantly clear by analogy with mam- and the secretion of in the recovery of a mals that at least some human are almost host from infection is still far from obvious. certainly caused by viruses. What has been said A new trend is that upon the investigation of about virus-cell relationships should also indicate possible harmful actions of immunological mecha- how tough is the problem of detecting within a nisms. Such actions are of a varied nature. The first tumour cell a virus fragment which is not self- clue that antiviral antibodies may sometimes be replicating. It seems obvious that the hints and harmful came from studies on children in America by copyright. evidences thus far obtained are just a prelude to a given inactivated measles vaccine. Upon subsequent remarkable new chapter in the story of human exposure to natural measles infection, some children virology. developed fever and a peculiar rash unlike measles. As live measles vaccine does not seem to give rise to The pathogenesis of virus diseases this risk, it has been suggested that inactivated Let us turn from a consideration of the virus at a vaccine produces antibodies which attach to and cellular level to some trends of research upon infec- sensitize cells to a later exposure to measles virus tion of the whole animal host. The first of these antigen. A second clue is that derived from exper-

arises from the development of immunology in- ience with inactivated respiratory syncytial (RS) http://pmj.bmj.com/ cluding new work upon the immunoglobulins found virus vaccine. In the U.S.A. a controlled experiment in the blood and upon surface secretions and en- in which infants were given either inactivated RS or dowed with the properties of antiviral antibodies. parainfluenza virus vaccines ended during the But much concern is also being shown to cellular succeeding RS epidemic season with more instances factors concerned in immunity and to the relative of RS bronchiolitis in those receiving the holomogous importance of cells and of antibodies in the deter- vaccine. Chanock of the National Institutes of mination of an effective immunity. The observed Health (Chanock et al., 1970) considers that RS differences between the effectiveness of immunity infant bronchiolitis occurring between 3 and 9 on September 23, 2021 by guest. Protected induced by live virus vaccines which mimic infection months of age may be a disease in which maternal and that provoked by killed or inactivated vaccines antibody of IgG type has sensitized the epithelial are now becoming amenable to analysis. Sometimes cells to subsequent RS virus infection. He thinks that the advantage of a live vaccine seems to be related to the more usual consequence of RS infection is to the local surface immunoglobulin A induced in the induce local IgA at the epithelial surface which blocks secretions of the alimentary or respiratory tracts. any harmful sensitizing action and that the clinical But cellular immunity involving the lymphocytes is disease is due to a Type 2 or Type 3 allergic reaction also concerned even in a superficial condition such as in certain individual infants. Gardner in Newcastle influenza so that the mechanism of immunity is disputes this view and has suggested that a Type 1 complex. It is still a remarkable fact that the suscep- reaction mediated by local IgE is the explanation of tibility or the resistance of the individual human bronchiolitis (Gardner, McQuillin and Court, 1970). to influenza during an epidemic is not fully under- This conflict of the experts' views should not obscure stood, and that more work upon vaccines is therefore the fact that both agree that clinical RS disease is not required. Efforts to evolve and apply safe and just the result of cellular epithelial necrosis as in the effective immunizing agents still involve basic re- case of influenza. Postgrad Med J: first published as 10.1136/pgmj.50.579.1 on 1 January 1974. Downloaded from

Whither virology ? 7

Two further instances exist of immunopathological basic research at a cellular level and I for one do not effects in virus infection. A complement-mediated share the views of those who question the develop- form of cell destruction has been uncovered in some ment of molecular virology and its possible contri- experiments with myxoviruses and even herpes virus bution in the future. (Porter, 1971). Secondly, an immune-complexcapable What then of the outstanding problems ofvirology of causing pathological effects such as those of in relation to human disease? Chronic pathological nephritis has been suggested in relation to serum processes, particularly of the nervous system, are now hepatitis B. The discovery of the Australia antigen in in the limelight. Clinicians are at last realizing that the serum of carriers and in patients with acute or virology is not just a branch of bacteriology and that chronic liver disease has brought a flood of specu- viruses are not just the cause of acute self-limited lation. Almeida and Waterson suggested some time infections. But the reasons for the adoption by the ago (1969), when they observed clumping of Au par- virus of a chronic form of parasitism and the failure ticles by rabbit anti-Au-antigen serum, that immune of the host to eliminate the virus particles furnish complexes existed in the serum of patients with problems which need a great deal of research. Here hepatitis. Lately an unexpected discovery of Au- immunological techniques and animal models are antigen in the serum and blood vessels of patients called for in addition to the human patient. The team with polyarteritis nodosa has raised the concept of which will investigate viral of this type damage from serum-virus complexes (Gocke et al., must include some who have experience and 1970). It is, in my view, too early to form a judgment knowledge of the human patient. But the techniques on this matter largely because the nature of the are those of the laboratory and the team must include Au-antigen is still obscure. those with knowledge of ultrastructure and of immunology. I hold no brief for the lone research worker in this field nor for the scientist bereft of Conclusion assistance from the medical virologist. It is timely to attempt some remarks on the future. I hope this brief outline of the way ahead may by copyright. The prospect for the solution of any scientific prob- prove an exciting prospect to those young men and lem must be unpredictable until initial clues have women whose careers are undecided. Virology has been obtained. In the case of the outstanding prob- been an exciting discipline for me and I believe it lems of human virology which have been described should continue to be so for others for many years there are promising pointers yet no one can foretell yet. There is much talk of the present as the golden when solutions will be obtained. Thus, attempts to age of virology. I venture to prophesy that diamonds, formulate antiviral chemotherapy have been made not gold, lie ahead. repeatedly for more than 20 years with relatively slight success. Now with the better knowledge of the biochemical basis of virus multiplication more References http://pmj.bmj.com/ rapid progress ALMEIDA, J.D. & WATERSON, A.P. (1969) Immune complexes seems likely. But chemotherapy or in hepatitis. Lancet, ii, 983. chemoprophylaxis will not come about by staring ANDREWES, SIR C. & PEREIRA, H.G. (1972) Viruses of at patients or testing rows of synthetic compounds Vertebrates. 3rd edition. Balliere Tindall: London. even though serendipity can be fruitful. Research BASTIAN, F.O., RABSON, A.S., YEE, C.L. & TRALKA, T.S. must be pursued at a cellular or (1972) Herpesvirus hominis: isolation from human tri- intracellular level geminal ganglion. Science, 178, 306. and this is one reason why molecular biochemistry's BEARE, A.S. & BYNOE, M.L. (1969) Attenuation of human

alliance with virology must be applauded. influenza A viruses. British Medical Journal, 4, 198. on September 23, 2021 by guest. Protected Consider next the relationship between viruses and BERNHARD, W. & GUERIN, W. (1968) Presence de particules tumours. The hypothesis of the oncogene has been d'aspect virusal dans les tissus tumoraux de souris atteintes de leucemie spontanee. Compte Rendu hebdomadaire les followed by a hectic pursuit of virus-specific nucleic Seance de l'Academie des sciences, 247, 1802. acid polymerases. Study of these reverse transcrip- BUIST, J.B. (1886) The life history of the micro-organisms tases requires highly complex techniques and pro- associated with variola and vaccinia. An abstract of the gress must therefore be slow. At the moment it seems results obtained from a study of smallpox and vaccination in the surgical laboratory of the University of Edinburgh. possible that the transcriptases of the oncogenic Proceedings of the Royal Society of Edinburgh, 13, 603. viruses are recognizably dissimilar from those of CHANOCK, R.M., KAPIKIAN, A.Z., MILLS, J., KIM, H.W. & normal cells. More cannot be said except that the PARROTT, R.H. (1970) Influence of immunological factors theory of the virus as a in respiratory syncytial virus disease. Archives of Environ- cause of some human mental Health, 21, 347. cancers seems to have gained ground steadily over COLEMAN, D.V., GARDNER, S.D. & FIELD, A.M. (1973) the past 10 years. The ups and downs of this aspect of Human polyoma virus infection in renal allograft recip- cancer research have, however, been considerable in ients. British Medical Journal, 3, 371. the past and the prophet of the future needs must be DALE, H.H. (1935) 'Viruses and Heterogenesis'. Huxley Memorial Lecture, Imperial College Science and Tech- cautious. Meanwhile this problem again demands nology. Macmillan & Co. Ltd: London. Postgrad Med J: first published as 10.1136/pgmj.50.579.1 on 1 January 1974. Downloaded from

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DAYAN, A.D., GOSTLING, J.V.T., GREAVES, J.L., STEVENS, LOEFFLER, F. & FROSCH, P. (1898) Berichte der Kommission D.W. & WOODHOUSE, M.A. (1967) Evidence of a pseudo- zur Erforschung der Maul und Klauenseuche bei dem myxovirus in the brain in subacute sclerosing leucoence- Institut fuir Infectionskrankheiten in Berlin. Zentralblatt phalitis. Lancet, i, 980. fur allgemeine Pathologie und pathologische Anatomie, 23, GARDNER, P.S., MCQUILLIN, J. & COURT, S.D.M. (1970) 371. Speculation on pathogenesis in death from respiratory Lwow, A. (1957) The concept of virus. Journal of Genetics syncytial virus infection. British Medical Journal, 1, 327. and , 17, 239. GOCKE, D.J., Hsu, K., MORGAN, C., BOMBARDIERI, S., MURPHY, B.R., CHALBUB, E.G., NUSINOFF, S.R. & LOCKSHIN, M. & CHRISTIAN, C.L. (1970) Association CHANOCK, R.M. (1972) Temperature-sensitive mutants of between polyarteritis and Australia antigen. Lancet, ii, influenza virus. II. Attenuation of ts recombinants for man. 1149. Journal of Infectious Diseases, 126, 170. INFLUENZA WORKSHOP 1. (1972) Influenza virus polypeptides PASCHEN, E. (1906) Was wissen wir fiber den Vakzineerreger? and antigens. Journal of Infectious Diseases, 125, 447. Munchen Medizinische Wochensch rift, 49, 2391. IVANOVSKY, D. (1892) Uber die Mosaikkrankheit du Tabak- PORTER, D.D. (1971) Destruction of virus-infected cells by splanze. Bulletin of the Academy of Imperial Science, 3, 67. immunological mechanisms. AnnualRevue ofMicrobiology, LANDSTEINER, K. & POPPER, E. (1908) Mikroscopische 25, 283. praparate von einem menschlichen und zwei Affenruicken- marken. Weiner Klinische Wochenshrift, 21, 1830. REED, W. (1902) Recent researches concerning the etiology, LAVER, W.G. & WEBSTER, R.G. (1972) Studies on the origin propagation and prevention of yellow fever by the U.S. of pandemic influenza. II. Peptide maps of the light and Army Commission, Journal of Hygiene, 2, 101. heavy polypeptide chains from the haemagglutinin sub- SKEHEL, J.J. & SCHILD, G.C. (1971) The polypeptide com- units of A2 influenza viruses isolated before and after the position of influenza A viruses. Virology, 44, 396. appearance of Hong Kong Influenza. Virology, 48, 445. TODARO, G.J. (1973) Detection and characterization of RNA LAVER, W.G. & WEBSTER, R.G. (1973) Studies on the origin tumour viruses in normal and transformed cells. Persp. of pandemic influenza. III. Evidence implicating duck and Virol. viii, 81. Persistent virus infections. : equine influenza viruses as possible progenitors of the N. York and London. Hong Kong strain of influenza virus. Virology, 51, 383. WRIGHT, P.F., GHARPURE, M.A., HODES, D.S. & CHANOCK, LEGG, N.J. (1967) Virus antibodies in subacute sclerosing R.M. (1973) Genetic studies of respiratory syncytial virus panencephalitis: a study of twenty-two patients. British temperature-sensitive mutants. Archiv. fuir die gesamte Medical Journal, 3, 350. Virusforschung, 41, 238. by copyright. http://pmj.bmj.com/ on September 23, 2021 by guest. Protected