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An epidemiologist's journey from typhus to thalidomide, and from the to Seveso Marcus Klingberg J R Soc Med 2010 103: 418 DOI: 10.1258/jrsm.2010.10k037

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Downloaded from jrs.sagepub.com at The Royal Society of Medicine Library on October 14, 2014 FROM THE JAMES LIND LIBRARY An epidemiologist’s journey from typhus to thalidomide, and from the Soviet Union to Seveso

Marcus Klingberg 12 rue Vavin, 75006 , E-mail: [email protected]

DECLARATIONS Extraordinary circumstances led me to become We moved on, and eventually arranged for each of an epidemiologist.1,2 I was a 21-year-old medical the children to be returned to their parents, leaving Competing interests student in in September 1939 when my me free to search for a medical school where I None declared father urged me and the rest of our family to ‘go could complete my undergraduate medical train-

Funding east’ to escape the Nazi occupation of . My ing. The medical school at Lvov was already full, mother objected, convinced that the British and partly because of the influx of Polish students who None French would come to our rescue. Although my had also fled from the Nazis. However, some Ethical approval father could not dissuade her, and was not pre- friends of mine in that part of Soviet-occupied Not applicable pared to leave her, he insisted that one of us ‘had to Poland had highly-placed contacts in , capi- survive’, so ordered me to leave for the Soviet tal of Soviet Byelorussia. They arranged for me to Guarantor Union. My parents and my brother remained in be admitted to the medical school there, and I MK Poland until they were deported to the Treblinka qualified in June 1941. It was a special committee extermination camp, where they perished in of the Ministry of Health which then decided that I Contributorship 1942. was to become an epidemiologist. I had never con- MK is the sole The medical school in Warsaw had been closed sidered this option (I had wanted to study internal contributor by the Nazis, and I was working in a home for medicine), partly because were ineligible for Acknowledgements Jewish children with severe learning disabilities, government jobs in pre-war Poland. I am grateful to my mainly Down’s syndrome. The director of the On the day the Germans launched their offen- sive against the USSR on the 22 June 1941, I volun- friend, Iain home was a communist, and he came up with a plan. The mother of one of the children came from teered for the Red Army and was made a captain in Chalmers, who the area of Poland which had been occupied by the the Medical Corps. After being wounded in my encouraged me to Soviet Union. She obtained a permit for herself, her right leg on the Byelorussian front, I was sent to prepare this text; to own child and three other children to return there. Molotov – now renamed Perm – in the Urals, my daughter, Sylvia The director of the home suggested that I should where I was appointed head of an anti-epidemic Klingberg, for travel with them to help her look after four men- unit. The unit consisted of physicians, paramedics helping me to record tally disabled children during the journey. After (feldschers), nurses and disinfection personnel, these reminiscences; tutoring by my mother in how to recite for the and we had a small mobile laboratory for serologi- to Eva Alberman, German authorities the words written on the cal tests. Jan Chalmers, Judit Russian travel document, but fictitiously adding Druks and Richard my name, the six of us were authorized to leave Typhus in the Soviet Union Horton for German-occupied Poland and to remove our ‘Star commenting on of David’ armbands. In Perm, although we had to deal with outbreaks earlier drafts; and to A train conveyed us as far as the railhead at of typhoid fever, bacillary dysentery, scarlet fever, Bengt Källén for Małkinia. From there we had to walk for a few rubella and measles, our main concern was to pre- kilometres through a forest, crossing no man’s land vent or contain outbreaks of epidemic typhus. allowing me to make into Soviet territory at Zaremby Kos´cielne. It was a For example, in 1942 we were confronted with an available his Friday evening, and when we spotted candles outbreak in a kolkhoz (collective farm). We went reflections on the alight within a house, we asked the Jewish family from house to house, looking for typhus-stricken work of there for something to drink; but we were refused. people, grouped them together in a temporary

418 J R Soc Med 2010: 103: 418–423. DOI 10.1258/jrsm.2010.10k037 Downloaded from jrs.sagepub.com at The Royal Society of Medicine Library on October 14, 2014 An epidemiologist’s journey from typhus to thalidomide, and from the Soviet Union to Seveso

the International hospital set up in a requisitioned school, and The next step was to meet the director general of Clearinghouse. disinfected their clothes and home belongings, and the new coalmine, a high-ranking man in his late Additional material the garments of those who had been in contact forties. He listened politely as I described the epi- for this article is with sick people, whom we kept under obser- demiological situation and asked him why he had available from the vation. Prevention of typhus was very important not prepared accommodation and other facilities James Lind Library because, in those pre-antibiotic days, only sympto- before the arrival of tens of thousands of workers. website (www. matic treatments were available for people who Did he not understand that without adequate contracted the disease. living facilities and basic sanitary arrangements, jameslindlibrary.org), In our attempts to trace the source of the epi- outbreaks of communicable diseases were to be where it was demic, we looked for information everywhere: expected? originally published among the relatives and neighbours of infected The director general said he agreed with me, but people, teachers, local authority officials, party asked whether I realized that the Soviet Union activists and police officers. Since we lacked note- would be unable to fight the fascists without coal paper, we used the wallpaper in our office to draw for the country’s industry in general, and for mili- a map of the farm, and to get a picture of the tary industry in particular. ‘Before I left Moscow,’ disease’s evolution: the location of the index case, he said, ‘I was summoned to the Kremlin and in- and the dates of the first symptoms for the subse- structed personally by comrade Stalin to produce quent cases. We traced the outbreak of the epi- coal in very great quantities and to start the enter- demic to the house in which a recently released prise immediately. This was an order! And for your prisoner had first stayed. We then identified other information, I am obliged to report daily to com- households where he had stayed, and had infected rade Molotov how much coal we have produced. other families. As the man had already left the Now, please tell me what I can do. If I do not kolkhoz, we had to discover his whereabouts. The achieve the production target I shall be tried and local militia made clear that searching for him on face a death sentence. I may choose to be sent to foot was completely unrealistic, so, although I had one of the punitive battalions on the front line. If never previously ridden a horse, I was persuaded I survive there I shall be a hero; but as you may to accompany them horseback. We eventually know, the chances of survival there are almost found him and burned his clothes. zero. And by the way, if the outbreak of epidemic Another example illustrates the problems that typhus spreads and there are many fatal cases, I confronted us. One day, a coded telegram arrived will be blamed for that as well.’ After this very sad notifying us of an outbreak of epidemic typhus conversation, the director general invited me for a in one of the new coalmining locations. By 1942 dinner of caviar, different kinds of sausages and the huge coal fields in the Ukraine were under meats and vodka. We were alone apart from a German occupation, and the Soviet government young woman who served us. He did not pressure had started to explore new coal fields in the east of me to write a dishonest report. the country, including the Urals. After our anti- I stayed at the coalmine with my unit for some epidemic unit’s arrival there, I went first to meet weeks. We tried our best to prevent further spread the local chief medical officer. The outbreak was of the outbreak, but our efforts were only partly putting at risk tens of thousand of workers who successful. After returning to Perm, I prepared a had been brought there from the Caucasian Soviet report, and, as far as I know, the regional authori- Republics to create new coal mines. ties and the Regional Party Executive sent it to Very unsatisfactory provision had been made the Regional Prosecutor. I do not know what the for this influx of workers; the housing, lavatories, outcome was. showers, facilities for washing clothing, and so In June 1943, I was sent to Moscow for post- on were hopelessly inadequate. After visiting the graduate training by the best epidemiologists in the provisional hospital and the arrangements for country, including Professor Lev Gromashevski, quarantining typhus contacts I sent an urgent the master of Soviet epidemiology. By the end of coded telegram to the Regional Department of 1943, some parts of eastern Byelorussia had been Health, asking for an immediate supply of medi- liberated from the Nazis and I was appointed chief cines, soap, beds, mattresses, clothing and special epidemiologist of the Byelorussian Republic. The facilities for washing and disinfection. masses of refugees, the hundreds of thousands of

J R Soc Med 2010: 103: 418–423. DOI 10.1258/jrsm.2010.10k037 419 Downloaded from jrs.sagepub.com at The Royal Society of Medicine Library on October 14, 2014 Journal of the Royal Society of Medicine

wounded, the hunger, cold and poor sanitary con- contact were not affected. Our investigation re- ditions, all created a fertile ground for epidemics. vealed that wheat stocks of the affected families Epidemic typhus remained our main concern, but, had run out during the winter. Harvest had been as in Perm, we also had to deal with epidemics of difficult because the men and many of the young typhoid fever, bacillary dysentery, scarlet fever, women of the village were serving in the Red rubella and measles. In addition, there was an out- Army, or were working in factories. Those remain- break of malaria in one district, and scabies was ing in the kolkhoz were old people, children and everywhere. invalids. As a result, it had only been possible for Towards the end of the war, I witnessed how the them to harvest some of the wheat. When the retreating German army used epidemic typhus spring sun melted the snow, those who had run out as a weapon. In 1944, in the Mozyr region of of wheat reserves had gone to the fields to collect Byelorussia, the Nazi troops put tens of thousands the unharvested wheat, which had rotted in the of unaffected Soviet citizens in a detention camp meantime. After we had ordered the villagers to they were evacuating where epidemic typhus was stop eating it, the epidemic came to an abrupt end. raging. The Germans knew that the Red Army This was another example of many in history of the would try to rescue these people, and this was a way that effective public health action can be taken way of targeting it. We were charged with the task without a complete understanding of aetiology. I of isolating the sick and quarantining those who learned after the war that the disease was alimen- had had contact with affected individuals. In this tary toxic aleukia, or septic angina, which is a form way, we succeeded in preventing contamination of of mycotoxicosis associated with the ingestion the Red Army. of grain contaminated with fungi containing tri- Today, sociologists and social anthropologists chothecenes. urge medical scientists in general and epidemiolo- gists in particular to acknowledge the potential : from infectious disease contribution of the social sciences to epidemiologi- epidemiology to epidemiological cal research. Although I was unfamiliar with the teratology term ‘social anthropology’ at the time, I recognize in retrospect that my epidemiological work during After the war, I returned to Poland for about the war by necessity had to encompass sociological two years as a deputy high commissioner in the investigations. I remember an outbreak of typhoid Ministry of Health, doing anti-epidemic work. fever in a Muslim village in the Perm region. I However, in 1948, because (apart from me) one knew nothing about Islam or Muslim culture, but cousin was the only member of my family who had on inquiry, we found that the outbreak was con- survived the Nazis, I decided to emigrate to Israel. nected somehow to the funeral of the community In Israel, I worked in increasingly senior positions leader, the mullah. Since people were unwilling to in the Division of Preventive Medicine in the Office talk to us about their traditional practices, we of the Surgeon General of Israel Defence Forces. In remained in the dark until the village teacher, who the 1950s, we encountered outbreaks of another was a party member, told us about the local purifi- disease of unknown origin, which came to be cation funerary rites, which included manual known as West Nile Fever. We were the first to cleaning of the rectum. This explained how the describe its natural history, epidemiological distri- disease had spread after the mullah’s death. bution, clinical presentation and laboratory find- Another case illustrating the importance of ings, which we reported in a series of papers familiarity with the community’s social practices published in the American Journal of Hygiene (now concerned an unknown disease which caused the American Journal of Epidemiology) and else- vomiting, diarrhoea and haemorrhages, and had a where.3,4 I left my position as director and chief high fatality rate. Initially it was suspected that it epidemiologist in the Israel Defence Forces in 1953, was an infectious disease, but local doctors had after being appointed to direct the military Medi- never previously witnessed a similar epidemic. cal Research Laboratories, and in 1957, I finally left Nor did the pattern fit an infectious disease epi- the army to become the deputy scientific director demic: whole families were sick, yet their neigh- of the Israel Institute for Biological Research, at bours and other people with whom they had .

420 J R Soc Med 2010: 103: 418–423. DOI 10.1258/jrsm.2010.10k037 Downloaded from jrs.sagepub.com at The Royal Society of Medicine Library on October 14, 2014 An epidemiologist’s journey from typhus to thalidomide, and from the Soviet Union to Seveso

As I have explained, I was confronted during congenital malformations detected at birth.8,9 In- the war with outbreaks of non-infectious diseases, deed, we discovered that the only case of thalido- as in the case of the mycotoxin, but my work as an mide embryopathy encountered in epidemiologist in the Soviet Union had mainly between 1961 and 1963 had been so designated on been on infectious diseases. In 1951, however, I the birth certificate: under the heading ‘Complica- was introduced by John Gordon, then head of the tions of Pregnancy’, an astute physician had noted Department of Epidemiology at the Harvard ‘thalidomide ingestion in first trimester’. School of Public Health, to the use of epidemiology for problems other than infections. He was study- ing the epidemiology of traffic accidents; and he The International Clearinghouse also mentioned Donald Reid’s studies of the epi- for Birth Defects Monitoring 5 demiology of hearing loss in the UK. Not only Systems were these examples outside the traditional uses of epidemiology, but the former had nothing to do During the 15 years following the identification of with what I then conceived as medical questions. thalidomide as a teratogen, researchers working in In 1962, I went on a two-year sabbatical to the various congenital malformation monitoring pro- Henry Phipps Institute in Philadelphia, and I came grammes communicated informally, but all of us to realize there that infectious disease epidemiol- felt the need for more systematic collaboration. ogy had become a peripheral discipline within the The original idea behind the Clearinghouse was to developed world. It was at the Institute that Pro- make monitoring of congenital malformations fessor Theodor Ingalls persuaded me not to pursue more sensitive by collecting data from a large my interest in infectious diseases and urged me population from different parts of the world. One instead to collaborate with him in epidemiological wanted to detect a new thalidomide situation as investigations of congenital malformations. Al- quickly as possible even if the infants with a rare though reluctant at first, it did not take long for me malformation or a combination of malformations, to swallow the bait and to start working enthusias- caused by the new teratogen, were born in differ- tically on the subject. My interest was aroused ent areas.11 particularly by McBride’s 1961 Lancet letter about In 1974, at a meeting in Helsinki, the March of thalidomide,6 as well as the protracted subsequent Dimes Birth Defects Foundation sponsored the correspondence between him and Ingalls. With the organization of the International Clearinghouse information gathered after the tragic consequences for Birth Defects Monitoring Systems. In addi- on the equivocal effects of thalidomide on chick, tion to the involvement of the World Health mouse, rat, guinea pig and rabbit embryos, it Organization (WHO), the meeting was attended would have hardly been possible to arrive at the by representatives of monitoring systems in nine conclusion that thalidomide was a threat to the countries: Canada (Philip Banister), England–Wales human embryo. At that time, only very high doses (Josephine Weatherall), Finland (A Härö), France given to pregnant New Zealand rabbits produced (Madeleine Dessemond), Hungary (Andrew limb reduction deformities,7 and we were dubious Czeizel), Israel (me), (Tor Bjerkedal), about applying findings in animals to humans. To (Bengt Källén), and the United States support our insistence on the need for monitoring (William Flint). Many other countries subse- human populations, Ingalls and I8,9 quoted JG quently joined the Clearinghouse. Wilson’s view stated a decade earlier that society There were several schools of thought about must ‘depend upon an actual human experiment how to build up the International Clearinghouse. to detect teratogenic effects of new agents in The main division of opinion was between those women’.10 We and others concluded that surveil- who wanted the responsibility for collecting, pool- lance and registration of congenital malformations ing and analysing raw data to be with a central in newborn human populations were essential. body, such as WHO, and others who conceived the We started working using certificates of births, Clearinghouse as a communication tool, to pro- stillbirths and infant deaths. This was possible mote the sharing of data collected using agreed because in Philadelphia, as in many other commu- standard methods and formats. The majority sup- nities, certificates had a specific space for recording ported the latter point of view.

J R Soc Med 2010: 103: 418–423. DOI 10.1258/jrsm.2010.10k037 421 Downloaded from jrs.sagepub.com at The Royal Society of Medicine Library on October 14, 2014 Journal of the Royal Society of Medicine

In 1977, those involved in establishing the programs routinely collected interview information Clearinghouse decided to try to achieve Non- on maternal use of drugs, with or without controls. Governmental Organization (NGO) status for it My idea was that one should compare the reported with WHO (it was not until 1986 that it succeeded). maternal drug associated with different malforma- By 1980, after analysing monitoring activities in tions, adjusting for reporting programme and, for the various individual programmes, 11 specific instance, maternal age, in order to identify associ- malformations were selected by consensus for use ations between specific drug use and specific in the regular exchange of incidence data: anen- “common” malformations. Again only some of the cephaly; spina bifida; hydrocephaly; cleft palate; Clearinghouse programs participated. The system total cleft lip; tracheo-oesophageal fistula; oeso- was called MADRE and some publications from it phageal atresia and stenosis; rectal and anal stresia have appeared. The basic idea was to get a signal and stenosis; hypospadias; reduction deformity of system, not to use this material for epidemiological limbs; and omphalocoele. Down’s syndrome was research. If a signal appeared, one would have to also included. look more carefully into it.’ While I was preparing this account, Bengt ‘However, none of our efforts identified a new Källén kindly sent me some observations on the teratogenic drug. Indeed, the identification of val- work of the Clearinghouse (personal communi- proic acid as a teratogen was the result not of the cation). He noted in these that: monitoring activity, but rather of the observations of an alert clinician (Elisabeth Robert) who found ‘In order to have everyone to look at his/her data the association during her routine interviews with regularly, we wanted quarterly reporting of the women who had infants with spina bifida.’13–15 agreed “standard” malformations but also a list of unusual conditions which we had not seen so often before. Most members could produce the former Seveso tables but many were reluctant to report the latter, It was because of my work with the International because “there is no suitable code for them”.’ Clearinghouse for Birth Defects Monitoring Sys- ‘In order to keep up the interest, we tried to use tems that I was contacted in the summer of 1976 the routinely collected material for various epi- by Professor Gaetano Maria Fara, from Milan. On demiological analyses. Although the material as a Saturday 10 July 1976, there had been an explo- whole could usually not be used, a group of inter- sion in a factory in Meda operated by Industrie ested people got together to analyse not only the Chimiche Meda Società Azionaria, a subsidiary of common malformations like hypospadias, but also Givaudan, which in turn was a subsidiary of 11,12 extremely unusual conditions.’ Hoffmann-La Roche. As a result, the population in ‘Quite early in the history of the Clearinghouse, Meda and neighbouring towns, the largest among we stressed the importance of an analysis of infants which was Seveso, had been exposed to dioxin with multiple malformations and we tried to get (2,3,7,8-tetrachlorodibenzo-p-dioxin – TCDD). people to report these with verbal descriptions. Professor Fara wanted me to chair a symposium Most of the recognized human teratogens caused two months later (on the first day of the 5th Con- multiple damage so it seemed logical to concentrate ference of the European Teratology Society, in on multi-malformed infants. After some discussion, Gargnano, ) to assess the possible teratogenic we decided how to analyse this material to look for risks resulting from dioxin exposure. I agreed to do patterns of similar malformations . We decided to so, and, as I was totally ignorant about dioxin, I test our proposed method by describing three (ficti- asked him to send me all the papers available on tious) infants with similar – but not identical – the topic. In addition, I asked some chemists in the malformations, and then submitted these descrip- Ness Ziona Institute to provide me with infor- tions to our colleagues for assessment. One of them mation about the chemical. detected the “cluster”, and was very excited until Soon after the symposium, the Lombardy Re- we told him that it had been faked.’ gional government asked me to serve as a consult- ‘Another idea we tried was to increase the power ant epidemiologist to investigate the health effects of monitoring by combining outcome (malforma- of the dioxin exposure and assess whether it had tions) with exposures (maternal drug use). Many any impact on either mortality or birth defects in

422 J R Soc Med 2010: 103: 418–423. DOI 10.1258/jrsm.2010.10k037 Downloaded from jrs.sagepub.com at The Royal Society of Medicine Library on October 14, 2014 An epidemiologist’s journey from typhus to thalidomide, and from the Soviet Union to Seveso

the population of the Seveso area. Later, the Italian high security prison, under a false name and a government appointed an International Scientific fabricated profession. In spite of my suffering dur- Steering Committee for the Seveso incident ing this long imprisonment, I have never regretted (Comitato dei garanti), members of which in- my modest attempt during the Cold War to under- cluded Irving Selikoff, Nathan Mantel, Donald mine what I believed to be the dangers associated Young and Robert Miller (I was elected chairman). with imbalances in scientific knowledge. My feel- We established an epidemiological monitoring ings about this remain with me despite the fall of system for the total population of 220,000 inhabit- the Soviet Union – a country to which not only I ants. Apart from 193 cases of chloracne, some very owe my life, as well as my career in epidemiology serious, we did not detect other adverse effects and my most useful work; but, above all, the during the first few years following the Seveso opportunity to fight fascism. incident. To avoid political pressure, we held our meetings in camera, and only after finalizing our References recommendations did we disclose them to the 1 Morabia A. “East Side Story”: on being an epidemiologist Uficio Speciale of the incident, in the presence of the in the former USSR. An interview with Marcus Klingberg. media. The Seveso incident resulted in standard- Epidemiology 2006;17:115–19 2 Klingberg MA, Sfard M. Hameragel ha’aharon (The Last ized industrial safety regulations in the European Spy). : Maariv Books; 2007 Union, which are known as the Seveso II Directive 3 Marberg K, Goldblum N, Sterk VV, Jasinska-Klingberg W, (http://ec.europa.eu/environment/seveso/index. Klingberg MA. Natural history of West Nile fever. Clinical observations during an epidemic in Israel. Am J Hyg htm). 1956;64:259–69 4 Klingberg MA, Jasinska-Klingberg W, Goldblum N. Certain aspects of the epidemiology and distribution of Reflections immunity of West Nile Virus in Israel. Proceedings of the 6th International Congress of Tropical Medicine and Malaria After my return from the United States most of 1959;5:132–40 my epidemiological research was on congenital 5 Reid CM. Donald Darnley Reid (1914–1977). The James Lind Library 2008. See http://www.jameslindlibrary.org malformations, but I did not abandon my initial 6 McBride WG. Thalidomide and congenital abnormalities. ‘epidemiological love’ for studies of infectious dis- Lancet 1961;2:1358 eases. In 1965, I received a five-year contract from 7 Somers GS. Thalidomide and congenital abnormalities. Lancet 1962;1:912–13 the USA Army Medical Corps to study recrudes- 8 Ingalls TH, Klingberg MA. Implications of epidemic cent typhus, and this was followed by a further embryopathy for public health. Am J Public Health Nations five-year contract to research spotted fever. Ironi- Health 1965;55:200–8 9 Ingalls TH, Klingberg MA. Congenital malformations. cally, I was the first scientist at the Ness Ziona Clinical and community considerations. Am J Med Sci Institute to be awarded a grant by the US military. I 1965;249:316–44 also contributed to studies of influenza surveil- 10 Wilson JG. Is there specificity of action in experimental teratogenesis? Pediatrics 1957;19:755–63 lance and immunization, and rubella vaccination. 11 Källén B, Castsilla EE, Lancaster PA, et al. The cyclops and With these research interests, and as head of the the mermaid – an epidemiological study of two types of department of Preventive and Social Medicine at rare malformations. J Med Genet 1982;29:30–5 12 Mastroiacovo P, Källén B, Knudsen LB, et al. Absence of , my professional life was very limbs and gross body wall defects: an epidemiological full – until 19 January 1983, the day my scientific study of related rare malformation conditions. Teratology career ended abruptly.2 On that day I was secretly 1982;46:455–64 13 Robert E, Guibaud P. Maternal valproic acid and arrested, interrogated harshly, tried in camera, and congenital neural tube defects. Lancet 1982;2:937 sentenced to a 20-year prison term, because I had 14 Bjerkedal T, Czeizel A, Goujard J, et al. Valproic acid and provided highly secret scientific information to the spina bifida. Lancet 1982;2:1096 15 Källén B. Methodological issues study in the Soviet Union. For the first 10 years of my 20-year epidemiological study of the teratogenicity of drugs. sentence I was held in solitary confinement, in a Congenit Anom (Kyoto) 2005;45:44–51

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