On some neglected diseases

Sven F. F. Britton

In memory of Elias Bengtsson

Parasitological research in the North is like the prevalence of parasites in the area - scarce. Otherwise, it has the feature of Scandinavian research in general. It is methodological in nature, thereby reflecting the mind of its inhabitants.

On the other hand, it has a different origin than parasitological research in Europe and North America at large. Whilst the latter is tightly linked to military medicine and colonization, parasitological research in this northern part of Europe comes from missionary medicine and foreign aid, activities that may be coined spiritual colonization by some. The scientist to whom this chapter is dedicated exemplifies this. Elias Bengtsson who died in 1998 was the second professor of infectious diseases at the Karolinska Institute, Stockholm where this discipline was not academically recognized as an entity of its own until 1956 up until which time it was comprised within paediatric medicine.

Elias Bengtsson's interest in parasitology and tropical medicine came both from his close links with returning missionaries from the warm continents carrying exotic diseases and also from his service as a physician in Swedish peace keeping missions under the UN in the then Congo and in Gaza in the Middle East. Through these experiences he was confronted with parasitologic infections of exotic origin and this came to be his research interest and that of his many disciples for several decades. He tried, and was very close to succeed in creating a special professorship of Tropical Medicine and Parasitology at the Karolinska Institute. However, a chair in pure Parasitology (without clinical affiliation) was not finally installed at the Karolinska Institute until 1993 and its first holder is a pupil of Elias Bengtsson. This is the first and so far only professorship of human parasitology in the Nordic countries. However, parasitological research has an older date than this century. The most famous natural scientist until now in this part of the world (and here I believe my fellow neighbours in Denmark, Finland, and Norway agree with me) is the Swedish scientist Carl Linnaeus. He was later knighted and got the more German sounding name von Linné. He made a short, but as always with him, important contribution to parasitology. He was primarily a botanist, although professor of practical medicine at Uppsala University. Medicine was more permissive at the time. Linnaeus was a taxonomist in good Scandinavian tradition but he had that extra gift which is rare among us, to link methodological examination to function in its widest sense. In his 24 pages long doctoral thesis that he defended in Holland 1736, he discusses the relation between the marshland biotope and the appearance of a febrile disease then endemic even in northern Europe, that is, what we understand now as malaria (Linnaeus 1736). (He later had 180 PhD students of his own). It is not wrong to characterize

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Linnaeus as one of the first ecologists and in this regard he studied plants, parasites, insects, and mammals including man. Another of his observations was to describe and characterize a cestode Diphyllobotrium latum not reported of before (Plater et al. 1978). His main contributions though are, of course, the systematization of plants and animals (including Homo sapiens) and the introduction of the binomial nomenclature.

Perhaps, the most famous Nordic research linked to a parasitological disease, although admittedly taxonomically outside of classical parasites, is the one conducted by Gerhard Armauer Hansen in the late nineteenth century in Bergen, Norway. It concerns leprosy, the causative agent of which, Mycobacteria leprae, parasitizes the host macrophage. Leprosy is a bacterial disease that is coined by WHO as one of the six neglected diseases. The other diseases (malaria, schistosomiasis, leishmaniasis, filariasis, and trypanosomiasis) are strictly parasitological in nature. Hansen, through careful observation of transmission chains refuted the then dogma that leprosy was an inherited disease. It has to be acknowledged that transmission studies up until today are very difficult to perform. The route of transmission of M. leprae is still not known, where disease penetrance is very low (~1% of exposed individuals) and where the incubation time, from time of infection to occurrence of disease, is on average 10 years. Hansen managed to show in the microscope M. leprae bacilli from the skin of lepromatous leprosy patients without knowing the Ziehl-Neelsen method for staining of acid-fast bacilli, simply because of the extraordinary abundance of bacilli in the affected organs of lepromatous leprosy cases. Through this observation, Hansen, who was an auto-didact scientist working as a country doctor, was one of the first scientist to link a disease to a microbial pathogen (Hansen 1874). This was a couple of years before Koch linked M. tuberculosis to the clinical entity of tuberculosis (Koch 1882). This is by far the most important single scientific contributions by Nordic scientists to parasitological research and it also serves to demonstrate that many of the so-called tropical diseases for which a better term is 'diseases of poverty'- were present in Scandinavia up until and within the twentieth century. This includes not only leprosy where the last domestic case died in the 1950s, but also malaria where the last (latest) indigenous cases of Plasmodium vivax malaria occurred in Finland in the 1950s. Although some parasitological infections clearly are latitude confined, the main denomination for their spread appears to be poverty, a state of affairs that Nordic countries on the Scandinavian peninsula have successfully conquered as some of the first nations of the world. Hence, the relatively low prevalence of parasite driven infections in this part of the world today.

The discovery of 'Hansen bacilli' or M. leprae and the studies of Linnaeus have had profound influence of host parasite research in general and of such research in Scandinavia as well. A direct spin-off is the foundation of a research institute for the study of leprosy and leishmaniasis in Addis Ababa, Ethiopia. This Institute called The Armauer Hansen Research Institute came to be through initiative from Norwegian and Swedish scientists of which Elias Bengtsson was one. The idea was to conduct research on diseases of poverty at the site where these diseases appeared and at the same time provide scientific training of local science students. Thus, this Institute was erected 30 years ago with support from the Norwegian and Swedish governments in direct association with a large leprosy hospital founded by the Swedish and Norwegian Save the Children organizations in the mid-1930s. The Institute was started in the mid-1960s when modern immunology had its most blooming period and hence its emphasis has been biomedical research on leprosy and leishmaniasis with an immunological angle to it. Its first director was Morten Harboe, who has remained an international nester of leprosy research ever since. He has used counter electrophoresis-methodology for characterizing the humoral immune response to M. leprae

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bacilli (Harboe et al. 1978) thus applying the original method of protein separation, through electrophoresis of Arne Tiselius (Tiselius et al. 1965) and its application to antibody mediated precipitation by Orjan Ouchterlony (Navalkar et al. 1965), to leprosy research. Harboe, who retired as professor of immunology at Oslo University in 1998, was succeeded by the Director of AHRI, Tore Godal, a Norwegian MD with interest in disorders of immunohaematological origin. At AHRI he made some fundamental discoveries in collaboration with local scientists, on the nature of the specific immunological unresponsiveness in lepromatous leprosy (Godal et al. 1971) and its putative correction through immunological interventions. Godal, later on came to be a very important figure in modern parasitological research in general. In collaboration with, among others, Kenneth Warren and Barry Bloom, he alerted WHO on the need for research on the six great neglected diseases which resulted in the creation of a new department within WHO in 1984, coined Tropical Diseases Research (TDR) of which Tore Godal became the second director. Through the initiative of Ken Warren, a famous American scientist, on the immunopathology of Schistosoma haematobium resources were generated from the Rockefeller Foundation for research in parasitology which resulted in a world wide upsurge of such research with participation of scientists from developing countries. This development is still ongoing albeit the initial enthusiasm and resource generation may have subsided somewhat, to which the premature death of Ken Warren in 1996 may have contributed. Nordic scientists at AHRI have continued to contribute to the progress in understanding and treatment of leprosy, notably through work of the Norwegian Gunnar Bjune on the immunopathological origin of reversal nerve reactions in leprosy and their suppression by high doses of steroids (Bjune et al. 1976). The findings of one of the later AHRI directors, Rolf Kiessling described the cellular nature and specificity of cytotoxic reactions in leprosy (Kaleab et al. 1990). Hannah Akuffo described through work at AHRI the putative differences in parasite strains causing diffuse versus local cutaneous leishmaniasis. She, later on in Sweden, described an innate responsiveness to Leishmania antigens even in a fraction of non-exposed Swedes (Akuffo and Britton 1992), perhaps the cellular basis for susceptibility versus resistance to this infection.

Danish parasitological research had a flashing start when Jens Fibiger in 1927 was awarded the Nobel prize in medicine for his demonstration of the minute nematode Spiroptera neoplastica and its role as a causative agent in gastric cancers of rats. However, these findings could never be repeated outside the laboratory of Fibiger and much to the disgrace of Fibiger himself, but even more so to the Nobel committee. It turned out that what Fiber saw in his microscope most probably were artefacts or contaminating impurities and the cancers were most likely induced by bad breeding conditions of the rats (vitamin deficiencies). However, after this debacle Danish parasitological research proved itself of good international standard when J. C. Siim, later on director of the Statens Serum Institut, described an acquired lymphoglandular disease caused by Toxoplasma gondii. This protozoa with world-wide distribution, had first been demonstrated by the discoverer of the malaria Plasmodium, namely the Frenchman, Laveran. Twenty years after his major finding (malaria), he described the Toxoplasma gondii in Java sparrows in 1900. Whereas congenital toxoplasmosis had been described already in the 1930s by Wolf, Cohen Siim was the first to identify the acquired febrile lymphoglandular form of this normally asymptotic infection, a very elegant and clinically important achievement (Siim 1961) first presented in 1950. Two decades later, the biologist Mandahl-Barth, disclosed parts of the intermediate snail-worm-relations in Schistosoma hematobium infection. He later on established the Danish Bilharzia laboratory (DBL) which has been a training and research institute for waterborne parasitological

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disease ever since, although lately it has been engaged in general nutritional health problems as well. Finnish parasitology has shown fidelity to the parasites of the North, reflecting their more insulated character and Sporing 1747 published the first paper on the occurrence of D. latum in Finland. J. W. Runeberg already 1886 described the clinical entity of anaemia and weight loss resulting from consumption of raw fish infected with D. latum larvae. The habit of eating raw fish was quite common in Finland explaining the high incidence of this infection, reflecting the similarity of both the lake districts and eating habits in Finland and the former Soviet Karelia. The D. latum prevalence in Finland was estimated to be as high as 20% in the late 1940ies. A rapid decline was seen as the result of intense chemotherapy and information campaigns. Parasite prevalence figures in Finland have been different from those of the other Nordic countries and malaria was seasonal there, many years after it was eradicated in the rest of Scandinavia. Finnish clinical parasitology research has centered around the pathogenesis of tapeworm anaemia by B. von Bonsdorff and his tapeworm team, whereas active research on fish parasites and parasites of veterinary importance has been performed at the Parasitological institute at the Academy of Abo (Abo Akademi) established 1963 by the Societas Scientarum Fennica. B-J. Wikgren was the head of the Institute, followed by his student G. Bylund. In recent years E. Linder has contributed to the development of improved diagnostic methods, notably in Schistosoma and Pneumocystis carinii infections in Sweden.

Parasitological research in Scandinavia today has centres in the Swedish Institute of Infectious Disease Control, Karolinska Institutet and Department of Immunology, University of Stockholm and in the Panum Institute of Copenhagen University with its connections with Statens Serum Institut and the Danish Bilharzia Institute. In Norway, it is Department of Infectious Diseases, Oslo University, and the Center for International Health, University of Bergen.

At the Karolinska Institutet, the first professor of human parasitology in Scandinavia, Mats Wahlgren is heading an internationally composed group exploring a phenomenon first described by Wahlgren in 1989 (Udomsangpetch et al. 1989), that is, red cell rosetting in cerebral malaria. Wahlgren observed that Plasmodium falciparum infected red cells formed rosetting agglutinates with uninfected red cells and through epidemiological field studies in West Africa, his group described that P. falciparum isolated from patients with cerebral malaria had significantly higher tendency to create rosettes than strains from patients without cerebral malaria. His group is now working on which receptors that are involved in this process and this interaction can be interfered with as a mode of treating or preventing cerebral malaria rather than the infection as such.

The other group in Stockholm working on malaria is from Stockholm University where Peter Perlmann, who some 20 years ago started a new career as a malaria immunologist from having been a very reputed cellular immunologist with particular interest in tumour immunology and auto-immunity. His group has mainly focused on assessing P. falciparum specific blood stage antigens that give protective immunity and can be used as components in a merozoite antigen-based vaccine (Berzins and Perlmann 1996). His group has also studied the immunity to P. falciparum and lately found that a Th2 driven IgE response can be linked to severe, for example, cerebral forms of malaria (Perlmann et al. 1997). At the Karolinska Institute Anders Bjorkman, yet another pupil of Elias Bengtsson has followed up the early malaria epidemiological studies from Liberia where they restored proguanil as an efficient plasmodiestatic drug when used in combination with Chloroquine. His later work with Ingegerd Rooth in Tanzania is based on a very close observation of a small village regarding malaria, measles, and HIV. An interesting observation from this work was the finding of a positive interaction between measles and malaria where parasitemia is considerably reduced for rather long time period in relation to measles similar in duration to the eliminated Purified Protein Derivative (PPD) skin reactivity (Rooth and Bjorkman 1992) following measles. In Gothenburg, parasitological research was initiated in the 1970s when Gunnel Huldt and Inger Ljungstrom from the National Bacteriological Laboratory wanted to test the immuno-suppressive effects of Toxoplasma gondii and Trichnella spiralis respectively on mucosal immunity. Gothenburg and the departments under Jan Holmgren and Lars Ake Hansson of Medical Microbiology have become the Mecca of mucosal immunity reseach. Indeed such immuno-suppression did occur. Earlier on, in 1970, a famous infectious disease professor of Sweden, Ragnar Norrby had made his PhD thesis in Gothenburg on sub-cellular interactions between Toxoplasma and its target cell (Norrby 1970). Presently, studies from Gothenburg focus on schistosomiasis. These studies are both from a diagnostic point of view, where Orjan Ouchterlony's methodological skills are still used, and also through epidemiological studies. One study on the island of Kome in lake Victoria in Tanzania where different methods of intervention are tried and ensuing infections are measured with the immunologically based techniques that have been developed by the group together with the group of Deelder in Leiden, Holland ( Jamaly et al. 1997).

Danish malaria research today is focused around Ib Bybjerg at the parasitological unit of the Rigshospitalet. He was recently appointed the first Danish professor of International Health. Their work concerns the epidemiology of chloroquin and mefloquin resistant malaria particularly through studies in East Africa (Bygbjerg et al. 1983). Another unique contribution comes from Harald Fugelsang who during 10 years in West Africa studied the natural course of blinding Oncocerca volvolus infection (Fuglsang et al. 1979). At the Pannun Institute the group around Thor Teander and Lars Hviid study visceral leishmaniasis in Sudan with particular reference to the immunological response profiles. The long-term aim is to produce a vaccine and also, like the groups of Perlmann and Wahlgren in Sweden to understand the immunology of severe malaria and how it can be interfered with. A similar intervention study is done by Sven Gunnar Gundersen (Gundersen 1992) from the Center for International Health in Oslo using the local natural product Endod developed in Ethiopia by the late Prof. Aklilu Lemma. Endod is the product of the berry of the Endod plant, which grows along the riverbanks in Ethiopia, as well as the rest of Africa. It has been used as a washing powder since long in Ethiopia and the original observation was that the Schistosome transmitting snails died in the wash water downstream. A major study under Sven Gundersen using three different rivers where one received a calibrated regular dosage of Endod powder, one just Endod for river water washing and one without Endod treatment will be the study areas. The appearance of Schistosoma infection along these three different rivers will be followed and they all appear in a similar biotope with ethnically similar populations. This major study of interfering with schistosomiasis with a natural plant is soon to be completed and it is done in good Linnaeus tradition.

At the Center for International Health in Bergen, its first director and the first professor of International Health in the North, Prof. Bjarne Bjorvatn, was the first to establish an animal model for the study of immunity to Leishmania major. This model was later used to reveal the relevance of Th1/Th2 immunity in an infectious disease (Bjorvatn and Neva 1979). At that centre a broad activity of research pertaining to international health goes on and in the parasitological field can be mentioned studies on treatment and serological diagnosis of Entamoeba histolytica infections and the genetics of P. falciparum.

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I hope that the reader has now appreciated that parasitological research in Scandinavia is considerably richer than the parasitic infections of the area. Parasite in Greek means sharing the food of another's table and scientists of the North have gone overseas to share the rich parasitological table of, above all, the African continent. They have made fairly substantial contributions in this field besides creating contacts with scientists of that continent of whom one is an editor of this book.

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