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I shall restrict my remarks to some papers on poliomyelitis

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I shall restrict my remarks to some papers on poliomyelitis ...

    PROFESSOR STEFAN S. NICOLAU (1896-1967)

    A FOUNDER OF VIROLOGY IN ROMANIA*

    COSTIN CERNESCU

    “St. S. Nicolau “ Institute of Virology

    285, sos Mihai Bravu, Bucharest 030304

    cernescu@valhalla.racai.ro Abstract. Forty years have passed since Professor Stefan S. Nicolau deceased. He was the founder of the Institute

    of Virology in to Romanian Academy structure. As assistant of outstanding scientist Constantin Levaditi (1874-1953), Nicolau was trained at the Pasteur Institute. Their collaboration was exceptionally fruitful, producing new

    concepts in virology. Between their most cited contributions was the concept of viral oncolysis. Oncolytic viruses

    are capable of selective replication in malignant cells and therefore offer levels of potency and specificity that are

    potentially far higher than conventional treatments for tumour. Viral oncolytic therapy is to day under intense

    investigation as a novel anticancer strategy, both alone and in combination with other conventional treatment

    modalities. Nicolau was between the first to observe a possible analogy between viruses and gene, and hence to

    anticipate the future importance of molecular biology. In Romania, it was in his Institute were people from

    different specialities, biologists, biochemists, and doctors were debated the implications of genetic engineering

    long before it was in practice possible that science fiction became fact, as the use of DNA synthesis, restriction

    enzymes and plasmids.

    Key words: Stefan S. Nicolau, ultravirus, viral oncolysis, Borna disease.

* In commemoration of 40 years since the time of Stefan S. Nicolau death

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    INTRODUCTION to isolate and cultivate as true microbes.

    Levaditi and Nicolau coined the term of

     In the history of virology, ultravirus instead the label of filterable circumscribed to the first half of a viruses or invisible viruses, the label twentieth century sequence, the th century in France used throughout the 19

    contribution of Romanian scientists as a blanket term for new, unorthodox,

    Constantin Levaditi and Stefan S. Nicolau infectious agents. In fact, Levaditi and

    played an important role. As faithful Pierre Lepine published the first textbook

    followers of Pasteur they assumed that of virology in 1938: “Les ultravirus des new filterable agents of infectious diseases 2maladies humaines”. It is to be noted that discovered by botanists (D.I. Ivanovski the term “virology” became established in

    Tobacco Mosaic Disease), by its own right only after the World War II

    veterinarians (F. Loeffler, and P. Frosch with the apparition of the S. E. Luria’s

    foot and mouth disease) or by physicians classic manual “General Virology” (1953)

    (W. Reed, and J. Carroll yellow fever; K. and of the first issue of the journal 1Landsteiner, and C. Levaditi - Virology (1955).

    poliomyelitis) were small bacteria unable

Fig.1. Jubilant “Nicolau Medal awarded for excellence in PhD works at the Institute of

    Virology, Bucharest (a craftwork of outstanding Romanian sculptor Ion Jalea).

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    Nicolau was a natural organizer and, relationships), Elena Oprescu (respirtory together with Radu Portocalã and Nicolae viral infections), Radu Portocala Cajal, he began to recruit people to work (biochemistry of the viral nucleic acids), on isolation and cultivation of human and Dan Sarateanu (ornithoses), Constantin animal viruses. He developed a group of Surdan (Rickettsia), Nicolae Cajal - his devotees and students who adopted his succesor at the Institute and Chair of view points on the important problems of virology direction. The Institute bridges virus diseases of humans and domesticated the gap between clinical investigation and animals in parallel with research in the application of basic science in order to theoretical and experimental virology. understand the pathogenesis of the

    infectious diseases, their diagnosis and

     Stefan S. Nicolau founded the optimal management, prevention and Institute of Inframicrobiology of the control. Romanian Academy. The Institute has its

    origin in the nucleus of the Chair of SHORT BIOGRAPHIC NOTE Virology, which began its activity in 1942

     Stefan S. Nicolau obtained in in the framework of the Faculty of

    1920 the MD degree at the Faculty of Medicine in Bucharest. For the first time

    Medicine in Cluj, where he began this in the world, in the higher medical

    collaboration with professor Moldoveanu. education, a separate discipline was

    From his student years in Cluj, Nicolau devoted to the study of the ultrafiltrable

    showed his tendency towards laboratory infectious agents. Afterwards, a team of

    research. After having spent one year in inframicrobiology of the Academy was

    Cluj, he began to work at Levaditi’s created, which developed into the actual

    laboratory in the Pasteur Institute. Nicolau “Nicolau” Institute of Virology. The

    studied for two decades at The Pasteur ?Stefan S. Nicolau? Institute of Virology,

    Institute in Paris (1920-1939). During this which chronologically is one of the first

    interval he passed his PhD at Sorbonne institutions in this speciality in Europe,

    (1925) and visited National Institute for has celebrated in 1999 the 50th

    Medical Research London (1927-1931). anniversary of its foundation. Many

    He received many awards from Paris disciples of the school created by

    Academy of Sciences and also important professor Nicolau distinguished

    prizes: Prize Bellion, 1926, Prize Breant, themselves by significant contributions:

    1930, Prize Montyon, 1935. Out of the Adelina Derevic (respiratory viral

    country until 1939, Nicolau authored infections), Elisabeta Nastac (virus-cancer

     3

    7pioneering studies regarding viral diseases ; the introduction of arbovirus infection

    34such as: herpesthe synchronophylaxis concept, a fact , rabies, poxvirus

     5, 6which promotes him as a, precursor of the infections (especially vaccinia),

    78interference phenomenon descriptionaphthous fever, Borna disease, ; the Aujeszky’s disease, ?looping illness? and discovery of the photodynamic action of

    others. Among the worldwide stains (which is nowadays widely used in

    acknowledged priorities we mention: the viral mutagenesis research on); the

    9first detection of inclusions in the yellow description of the septic neuritis and fever a diagnostic criterion of this others.

    .

    Fig 2. The office block of “Nicolau” Institute of Virology (www.virology.ro)

     In 1939, Nicolau returned in Iasi Medical School, and in 1942, as

    Romania as professor of Microbiology at professor of Inframicrobiology at

     4

    Bucharest Medical School. In the these objects by newly available electron recognition of his outstanding publications microscope in the early 1940’.

    he was elected member of Romanian

     In a broad prospective view of the Academy of Medical Sciences and of

    pathogenesis of viral infections, Levaditi Romanian Academy.

    and Nicolau underlined the cell-mediated He was director of the Institute of

    character of the antiviral immunity. Beside Inframicrobiology in Bucharest (to day,

    the viral cytocidal effect, Nicolau revealed “St. S. Nicolau” Institute of Virology),

    the participation of the cellular immune where he have the opportunity to create

    response of the host in the triggering of the many independent laboratories in which

    symptomatology. his co-workers served national public

     In a critical review of the literature health and medical school. As a teacher he on the antigenic propertiesof the was the editor of remarkable manuals

    ultraviruses, Nicolau and co-workers translated in French, Russian, Chinese etc. 11 (1928) called attention to thefact that

    these agents of disease, as far as they have EARLY WORKS been studied,seem to exhibit antigenic

     In 1922, Levaditi and Nicolau properties which suggest placing themin

    published a series of articles in which new the general group of bacteria and other properties of the viral agents were more highly organized proteinaceous

     demonstrated: ultrafiltrability (passage bodies.They observed that vaccinia virus through the pores of a collodion inoculated into the brain of an immunized membrane), antigenic properties of killed rabbit could not be demonstrated two and replicative viruses etc. Nicolau and hours after the injection. While vaccinia Levaditi elaborated experiments on the virus persisted in the circulation of a filterability of viruses with a very original susceptible rabbit for as long as 8 days and more constructive interpretation. They following intravenous infection, it opposed to the concept of non-particulate disappeared from circulation of an infective organism. In the debate about immune rabbit within 4 to 6 hours. whether the viruses were living or Nicolau and Kopciowska made a similar nonliving, or perhaps were the primordial observation regarding herpes virus stuff from which life itself originated, introduced into the brain of immunized

    7Nicolau underscored the macromolecular rabbits. nature of viruses and the significance of The same as the classic of Romanian their tiny component - the genomic nucleic medicine Victor Babeº - Nicolau’ early

    acid. The structure of viruses was soon research works were connected with rabies. amply confirmed by direct observation of He described extremely important lesions

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    in the central nervous system of animal Between the most cited Nicolau’ dead of rabies or of other neurotropic publications were papers referring the role

    viruses. Although described by Victor of Borna virus infection in

    Babeº as far back as 1886, the cytoplasmic neurobehavioural diseases. Borna disease inclusions in rabies were given the name virus (BDV) is the prototype of the family

    11of “Negri bodies”. The priority of Babeº Bornaviridae, genus Bornavirus, within was recognized owing to the well the nonsegmented negative-strand

    documented works of St. S. Nicolau and ribonucleic acid (RNA) viruses (order

    Mircea Babeº. Nicolau was the editor of Mononegavirales). Nicolau and Galloway two volumes of V. Babeº selected works were the firsts to conduct experimental and of many monographs which created a study of Borna disease in sheep and cattle

    true virology library in Romanian. (see and describe the characteristics of this

    13books at the references) This enzootic encephalo-myelitis.

    neurotropic virus appears to be distributed

     In regard to the immunological worldwide and has the potential to infect conditions existing inherpes disease, his most, if not all, warm-blooded hosts. The

    experiments have reaffirmed that herpes name Borna refers to the city of Borna, viruscan be neutralized with the serum of Germany, the site of an equine epidemic in actively immunized animalsand have 18951896 that crippled the Saxon cavalry. offered an explanation for the irregularity Natural infection has been reported of theresults of others. Nicolau et al. primarily in Europe, but recent reports found thatbrain extracts from inoculated also include North America and parts of

    rabbits possess some virus-neutralizing Asia (Japan, Israel and Iran). Reports of power, but considerablyless than the asymptomatic, naturally infected animals

    serum of the corresponding control suggest that the virus may be more animals. It hasbeen shown that active widespread than previously appreciated.

     immunity can be attained only when someReports of BDV nucleic acid and proteins

    degree of reaction to the living virus has in peripheral blood mononuclear cells also occurred. Rabbitswhich survived indicate a potential for haematogenous

    neutralized serum-virus mixtures did not transmission.

     acquireimmunity nor did those treated Although there is consensus that

     with virus phenolized to theextent of humans are likely to be susceptible to

    9actual destruction. BDV infection, the epidemiology and

    clinical consequences of human infection

     remain controversial. After 1990, German

    THE MOST CITED WORKS scientists reported that Borna infectious

     14, 15virus has been isolated from humans.

     6

    There have been no large controlled of general pathology. Thus, morphological prevalence studies but methods for data supported the viral etiology of some diagnosis of human infection were reliable cardiovascular diseases (arteritides,

    21suggesting an association between BDV and the role of chlamydia, myocarditides)and neuropsychiatric disorders, including rickettsia and some herpesviruses in the unipolar depression, bipolar disorder or etiopathogenesis of some congenital schizophrenia. BDV has also been linked malformations and spontaneous

    22 to chronic fatigue syndrome, abortions.

     An innovative concept developed I shall detail my remarks to by Levaditi and Nicolau was viral Nicolau’ papers on the relations between oncolysis in studies where the viruses and cancer, published in the period

     neurovaccinal virus was inoculated into from 1960 to 1967, which I personally

    16grafted tumours. Sinkovics J.C., and consider highly significant. The author

    17Horwath J. (Viruses and cancer. Medical summarises the general properties of Hypotheses 1995, 44, 359-368.) quoted human tumour viruses, reviews the from the paper of Romanian scientists: development of causal thinking in Tumours are more susceptible to viruses microbiology and proposes guidelines that than normal cells and tumours act as a might help to determine the role of viruses sponge attracting viral replication". This in human cancer. The work on the role of hypothesis is now in the centre of interest viruses in the pathogenesis of human for many biotechnology companies who cancer was hampered by the fact that enlarge cancer virotherapy models. virus-associated cancer develops only in a

     Stefan S. Nicolau made obvious small minority of infected subjects, which the theory of viral etiology of some implies that, if the virus does play a role in cancers. With a remarkable intuition the pathogenesis of the malignancy, other Nicolau promoted the hypothesis of the factors must be also involved. Naturally oncogenic potential of the viral nucleic oncolytic viruses are replication-acids. He developed the infravirus model competent viruses that have an innate the autonomized form of viral nucleic ability to selectively infect and kill tumour acids which, after its integration in the cells. Despite being used in the original host cell genome, contribute to the viral attempts to treat cancer with live viruses transformation and the occurrence of five decades ago, interest in naturally various morbid states. oncolytic viruses has lagged behind the

     The school of professor Nicolau support for engineered adenoviruses and provided significant arguments for the herpesviruses as cancer therapeutics. involvement of viruses in the other fields Recently, however, there has been

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    renewed interest in the high potency and carcinoma); and animal T-cell Leukemia selectivity of these naturally occurring Viruses (bovine, murine T-cell

    19, 20agents. The criteria most often leukemias).

    used in determining causality were

     Levaditi and Nicolau were the first consistency of the association, either to study the action of a neurotropic strain epidemiologic or on the molecular level, of vaccinia virus on tumours of mice and and oncogenicity of the agent in animal rats. They found epitheliomas of these 21, 22models or cell cultures. Whereas for

    animals to provide an excellent culture most of the tumour viruses the viral medium for the virus in contrast to genome persists in an integrated or sarcoma. These findings were in accord episomal form with a subset of viral genes with their previous investigations where expressed in the tumour cells, some agents neurovaccinia was shown to have (Hepatitis B virus) are not inherently ectodermal rather than mesodermal oncogenic, but infection leads to tropism. transformation of cells by indirect

     Studying tumours infected with 23, 24means. For some malignancies the neurovaccinia in immune animals Levaditi viral agent appears to serve as a cofactor and Nicolau showed that virus did not (Burkitt's lymphoma-EBV; mesothelioma survive in the immune host. If a portion of - SV(40)). For others the association is the tumour were transplanted into non-inconsistent (Hodgkin's Disease, breast immune animal, it would support growth cancer - EBV) and may either define of the infectious agent. The proliferative subsets of these malignancies, or the virus power of the transplantable tumour was may act to modify phenotype of an also interfered and is not always possible established tumour, contributing to tumour to make successful transplants from progression rather than causing the tumour. tumours carrying the vaccinia virus. In many other cases the association with

     Nicolau and his co workers malignancy is less consistent or still developed investigations among many emerging. For example, despite the potent animal and human viruses that contribute oncogenic properties of some strains of 18to a variety of malignancies. Between human adenovirus in tissue culture and most studied viruses linked to cancers animals the virus has not been linked with were human papillomaviruses (cervical any human cancers. Finally it is likely that carcinoma); human polyomaviruses more agents, most likely viruses, both (mesotheliomas, brain tumours); Epstein-known and unidentified, have yet to be Barr virus (B-cell lymphoproliferative implicated in human cancer. In the diseases and nasopharyngeal carcinoma); meantime study of tumourigenic infectious hepatitis viruses (hepatocellular

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    agents will continue to elucidate molecular 5. Levaditi C., and Nicolau S., Vaccine et oncogenic processes. neoplasmes. Ann. Inst. Pasteur, 1923, 37,

    443-447.

    6. Levaditi C., Nicolau S., Sur le culture du Viruses have been used for cancer

    virus vaccinal dans les neoplasmes treatment for over a century. From the

    epitheliaux. Compt. Rend. Soc. Biol. early clinical studies with various wild-(Paris), 1929, 101, 334. type viruses, to the modern trials with 7. Nicolau S. S. & Kopciowska L A new

    stain method. Compt. Rend. Soc. Biol. engineered viruses, virotherapy has

    (Paris) 1929, 101, 655-7 emerged as a promising therapeutic

    8. Nicolau S.S. & Kopciowska L. 19strategy. In a recent review, which also Persistence of rabies virus in vaccinated mentions Levaditi and Nicolau priority, animals. Compt. Rend. Soc. Biol. (Paris),

    1932, 110, 348-351. japanese authors discuss the progress and

    9. Nicolau S.S., and Galloway I. Preliminary challenges associated with oncolytic

    note on the experimental study of enzootic virotherapeutic agents, summarizing the encephalo-myelitis (Borna disease) Br. J. data from clinical reports, and the Exp. Pathol. 1927, 8, 336-341. implications of this data for future 10. Levaditi C. and, Nicolau S. S., Virus et

    25tumeurs. Ann Inst Pasteur 1923, 37, 1-3. virotherapy development. Beyond

    11. Nicolau S., Kopciowska L., Balmus G. historical perspective on the development Inclusions cytoplasmiques simulant les of oncolytic virus the reviewers present corps de Negri dans le cerveau de la the encouraging results of recent clinical souris normale. . Compt. Rend. Soc. Biol.

    (Paris) 1933, 113, 851-855. trials (e.g., an modified herpesvirus has

    12. Nicolau S.S., Galloway I.A., Dimancesco-been tested in clinical trial of nearly 250 Nicolau O. ? Étude sur les septinévrites à patients and approved for human use by ultravirus neurotropes ? Masson, Paris, the Chinese FDA). 1929.

    13. Nicolau S.S., and Galloway I. Borna

    disease and enzootic encephalomyelitis of REFERENCES

    sheep and cattle. Spec. Rep. Ser. Med. Res. 1. Landsteiner, K., and Levaditi C. La

    Council 1928, 121, 7-90. transmission de la paralysie infantile aux

    14. Bode L., Dürrwald R., Rantam F.A., singes. Compt. Rend. Soc. Biol. (Paris).

    Ferszt R. and Ludwig H. First isolates of 1909:592-594.

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    from patients with mood disorders. ? Les ultravirus des maladies humaines ?.

    Molecular Psychiatry 1996, 1, 200212. Librairie Maloine Paris, France, 1938.

    15. Dittrich W., Bode L., Ludwig H., Kao M. 3. Levaditi C., and Nicolau S., Affinite du

    and Schneider K. Learning deficiencies in virus herpetique pour les neoplasmes

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    healthy rats. Biological Psychiatry 1989, (Paris), 1922, 87, 498-500.

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    16. St. S. Nicolau “Cancer and viruses”, Rend Soc Biol (Paris) 1922, 86, 563.

    1955, Editura Academiei, Bucharest

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    17. Sinkovics J.C., and Horwath J., Viruses into an immunogenic virus under the

    and cancer. Medical Hypotheses 1995, 44, action of copper. Acta Biol Med Ger.

    359-368. 1962, 8, 219-29.

    22. Nicolau S. S. et al. Study on the rickettsial 18. Nicolau S.S., Cajal N., Schächter A., S

    etiology of various angiopathies. Rev Sci rþeanu D., Cepleanu M., Sorodoc Y.

    Med. 1963, 8, 69-73. Les relations entre l'ornithose et la

    23. St. S. Nicolau Viral hepatitis 1960, maladie de Hodgkin. Archives of

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    24. Nicolau S.S. Inframicrobial epidemic 19. Nicolau S.S., The oncolytic action of

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    Med Rev. 1961, 5, 19-23. Inframicrobiol. 1960, 11, 529-48.

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    7, 123-125. Editura Medicalã, Bucharest.

     21. Nicolau S. S. et al. Experimental

     investigations on the antirabies vaccine

    prepared under the action of copper ions.

    Contributions concerning the mechanism

     of transformation of the pathogenic virus

     („Virus infections of the liver”)- Şt. S.

    Nicolau, Ed. Academiei R.P.R., Bucharest, Books 1957. 1. Şt. S. Nicolau HEPATITE 8. Şt. S. Nicolau, Al. Rădulescu, N. M.

    INFRAMICROBIENE (Viral hepatitis) Constantinescu, N. Cajal, G. Marinescu,

    - Ed. Academiei R.P.R., Bucharest, 1954. POLIOMIELITA („Poliomyelitis”), Ed.

    2. V. BABEŞ (OPERE ALESE) (Selected Academiei R.P.R., Bucharest, 1961.

    works of Victor Babeº”) Vol. I (Şt. S. 9. Şt. S. Nicolau, N. M. Constantinescu, N.

    Nicolau, M. Babeş, Fl. Horodniceanu, Cajal. TURBAREA („Rabies”) - Ed.

    eds), Ed. Academiei R.P.R., Bucharest, Academiei R.P.R., Bucharest, 1962.

    1954. 10. Şt. S. Nicolau (ed) ELEMENTE DE 3. V. BABEŞ (OPERE ALESE) (Selected INFRAMICROBIOLOGIE SPECIALĂ

    works of Victor Babeº”) Vol. II - Şt. S. („Infections of inframicrobial etiology”) –

    Nicolau, M. Babeş, Fl. Horodniceanu, Ed. Medicală, Bucharest, 1962.

    eds), Ed. Academiei R.P.R., Bucharest, 11. Şt. S. Nicolau, N. Constantinescu

    1959. RICKETTSII ŞI RICKETTSIOZE 4. Şt. S. Nicolau CANCER ŞI VIRUSURI. („Infections of rickttsial etiology”-, Ed.

    CÎTEVA CONSIDERAŢII Academiei R.S.R., Bucharest, 1965.

    PRIVITOARE LA IPOTEZA VIROTICĂ 12. Şt. S. Nicolau, Elisabeta Nastac,

    A CANCERULUI („Cancer and Viruses – VIRUSURI ŞI TUMORI („Viruses and

    remarks on the cancer viral etiology”), Ed. tumours”) - Ed. Academiei R.S.R.,

    Academiei R.P.R., Bucharest, 1955. Bucharest, 1968. 5. Şt. S. Nicolau ELEMENTE DE 13. Şt. S. Nicolau, N. Drăgănescu

    INFRAMICROBIOLOGIE GENERALĂ HERPESUL („Hepres viruses”) - Ed.

    (Basic inframicrobiology), Ed. Academiei R.S.R., Bucharest, 1968.

    Academiei R.P.R., Bucharest, 1956.

    6. Şt. S. Nicolau (editor) PROBLEME DE

    INFRAMICROBIOLOGIE (Progress in

    inframicrobiology)- coautori: Şt. S.

    Nicolau, N. Cajal, A. Derevici, C. Iacob,

    G. Marinescu, S. Mateescu, R. Portocală,

    D. Sărăţeanu, J. Schwartz, Ed. Medicală,

    Bucharest, 1956.

    7. Şt. S. Nicolau HEPATITELE

    INFECŢIOASE INFRAMICROBIENE

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