Category Archives: medical research

How a pregnancy test saved the lives of a family in Nazi times

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Susanne Krejsa MacManus explains how pregnancy testing saved the life of a refugee woman biochemist and her family in the run-up to World War II.

In the 1930s, the Institute of Animal Genetics at Edinburgh University was the only UK laboratory that ran pregnancy tests. Although the Aschheim-Zondek method invented in Berlin in the late 1920s had been seen as a great step forward, the result took more than 100 hours. It also required testing on female mice. No wonder that the scientific community was excited by a new method that took four hours.

Austrian biochemist Regina Kapeller-Adler had developed a method for detecting the amino acid histidine in the urine of pregnant women in 1933. As the Vienna Daily reported on 30 May 1933 under the heading “Eine neue Schwangerschafts-Reaktion” (a new pregnancy test): “The great advantage of this new chemical pregnancy test lies in the fact that it can be carried out in four hours, whereas the tool that has been most ideal for early diagnostics up until now […] requires a hundred hours until it can be read.”

The second advantage was that it employed a chemical instead of a biological reaction, and no mice had to be killed.

After Hitler occupied Austria (Anschluss) in March 1938, Regina, her medical doctor husband Ernst Adler and their young daughter Liselotte were in severe danger because they were Jewish. The Nazis persecuted Ernst Adler, and he escaped deportation to the Dachau concentration camp only at the very last moment. Regina lost her post at the Institute of Medical Chemistry at the University of Vienna; before that, she had also not been able to get her postdoctoral qualification – as a woman and a Jew.

When Francis Crew, Professor of Genetics at Edinburgh University, learned about the danger Regina and her family were in, he offered her a job in his laboratory, with support of The Society for the Protection of Science and Learning (formed in 1933 in help refugee scientists and other academics).

There was still a problem to be solved: Britain only permitted entry for foreigners if there was a mandatory “guarantor” to vouch for them. Fortunately, Napoleon and Henrietta Ryder deposited the considerable amount of £50 for the Adler family whom they did not know personally, and little is known about this couple. Regina together with husband and daughter could leave Austria, even taking their furniture and his medical equipment with them.

In Britain

In January 1939, they reached London and journeyed on to Edinburgh. Within two months of their arrival in Scotland, she was demonstrating her pregnancy test at the Eleventh British Congress of Obstetrics and Gynaecology. After the German invasion of Norway in 1940, most female foreign citizens were ordered to leave the east coast of Britain. Regina unusually received permission to remain in Edinburgh to continue her research since it was categorised as being of national importance. Ernst was interned on the Isle of Man from May to September 1940. After his release and re-qualification, he started a medical practice in Edinburgh in 1942.

In July 1941, Regina received her Doctor of Science degree from Edinburgh University. From the end of the war, she spent fruitful years in the Pharmacology Department of the university, and in 1952 she got her first university position as lecturer in the Department of Clinical Chemistry. From that time, she meticulously trained and encouraged a series of Ph.D. students, to whom she acted as mentor.

Regina gained recognition, grants and awards. She was internationally acclaimed as a major authority on histamine, which is made in the body and derived from histidine, and gallantly titled “The Histamine Queen” by her exclusively male colleagues in the field, an allusion to her forename. In June 1973, she was presented with the University of Vienna’s Golden Honorary Diploma. She died in Edinburgh on 31 July 1991 at the age of 91.

Kapeller-Adler’s method was an important step towards the modern pregnancy test, but it was not yet the final breakthrough. Not fully reliable on its own, it was used as an additional test or pre-test when standard tests did not give a clear yes-or-no answer.  Today, pregnancy tests detect the hormone human chorionic gonadotropin (hCG), which starts to be produced around 6 days after fertilisation. The results are available in a few minutes.

Acknowledgement and references

Information from this blog came direct from Liselotte Adler-Kastner, daughter of Regina Kappler-Adler and Ernst Adler. In addition, it refers to two articles that she wrote about her parents in “Visa to Freedom 1939 thanks to a Pregnancy Test”, Edinburgh Star 62, March 2009, 9-11, and “From personae non gratae in Vienna 1938 to respected citizens of Edinburgh: a vignette of my parents Dr Ernst Adler and Dr Regina Kapeller-Adler”, Wiener Klinische Wochenschrift (1998) 110/4-5: 174-180 (Viennese Clinical Weekly)

Further reading:

Interview with Liselotte Adler-Kastner at Refugee Voices.

Museum of Contraception and Abortion (MUVS)

Susanne Krejsa MacManus is an independent journalist, author and archivist in Vienna. She does research for the Museum of Contraception and Abortion (MUVS). Thanks go to Liselotte Adler-Kastner, Regina’s daughter.

 

 

Control and the therapeutic trial: the influence of insulin

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How do we decide whether a drug, or other treatment, actually works? Martin Edwards describes the rhetorical strategy adopted by the Medical Research Council to establish its authority.

Patients’ variations in response to disease and treatment can render it fiendishly difficult to know whether a therapy is benefitting a particular individual. For centuries, the gold standard was the assessment of a wise and experienced clinician but during the first half of the twentieth century, new methodologies arising from the laboratory, hospital and statistical theory challenged this traditional model.

The stakes were high, no less than the moral authority to adjudicate how the therapeutic efficacy should properly be ascertained. Between the wars, the debate in Britain was frequently vitriolic – particularly between the Royal College of Physicians, which prioritised clinical acumen, and the Medical Research Council (MRC) which advocated newer methodologies.

The University of Toronto in 1921 granted British patent rights over insulin to the MRC and thus offered the MRC control, not only over insulin manufacture and supply, but also how to assess its effects and proper usage.

In fact, the MRC’s approach to testing was, as with other drugs at that time, highly eclectic; it sent samples of insulin to trusted clinicians in prestigious hospitals without any protocol or scheme for investigation – the clinicians were simply asked to report their experiences with the drug.

An unanticipated consequence of the MRC’s control of insulin supply was that it was on the receiving end of public clamour for the drug. Heartrending letters to the MRC described young people, typically in their teens or early twenties, dying slowly and horribly from diabetes, and pleaded for supplies of life-saving insulin.

Patients even turned up at the MRC, supported by loved ones. Landsborough Thomson, MRC Council Secretary, recalled the MRC administration being swamped by these requests and unable to fulfil its normal functions.

Reserved for controlled studies

In response, the MRC under the direction of its chairman Walter Morley Fletcher adopted a standard response to such requests, stressing that insulin was a new drug which needed to be reserved for ‘controlled studies’. The meaning of ‘controlled’ was not defined nor did it refer to the presence of a comparison group – none of the MRC insulin trials used one – but rather vaguely implied proper conduct, regulation and scrutiny.

So successful was this rhetorical strategy that the MRC repeated it when restricting supplies of penicillin in the 1930s and streptomycin and influenza vaccine in the 1940s. In each case, it stated that the drug should be reserved for ‘controlled trials’.

Control is a powerful word with implications of authority, power, regulation and order. Without defining it, the MRC appended the word to their own studies in the interwar years, using it as a rhetorical device in the battle for authority to adjudicate therapeutic efficacy.

By the time the MRC’s trial of streptomycin in tuberculosis – reckoned by many trial historians to be the first randomised controlled trial – was published in 1948, the MRC had successfully co-opted the word as applying exclusively to its own studies. It offered the streptomycin trial as an exemplar of how therapeutic trials should be conducted, describing the methodology as ‘the controlled trial’. By then, ‘controlled’ referred technically to the presence of a control group, though the other powerful associations of the word continued to resonate.

We have depended on the ‘controlled trial’ ever since. The MRC’s adoption of the potent word ‘control’ arguably began with insulin. Had it not been for MRC control of British insulin supply, might we simply refer nowadays to a ‘randomised trial’?

This text is an abstract of a talk given to a session of the Apothecaries’ History of Medicine Fellows 8/12/2021 to commemorate the 100th anniversary of the discovery of insulin.

References/further reading:

  1. A Landsborough Thomson, Half a Century of Medical Research vol. 2: The Programme of the Medical Research Council (UK) (London: HMSO 1975) pp 40, 230
  2. Liebenau, ‘The MRC and the Pharmaceutical Industry: The Model of Insulin’, in J, Austoker and L. Bryder (eds), Historical Perspectives on the Role of the MRC (Oxford: Oxford University Press, 1989) 163-80
  3. Edwards, Control and the Therapeutic Trial: Rhetoric and Experimentation in Britain 1918-48 (Amsterdam: Rodopi Publishing, 2007)

Jenner, Fewster and Jesty

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Jenner vaccinating (Gillray) – Courtesy Wellcome Images

On the 14th May 1796 Edward Jenner carried out the first stage of his now famous vaccination experiment and inoculated a young boy named James Phipps with cowpox. To this day Jenner’s name is associated with the discovery of vaccination as a concept, and the worldwide eradication of smallpox. However, there were others who helped light the path to Jenner’s discovery, and even carried out that same experiment decades before Jenner.

Vaccination could not have happened without the development of variolation; the process of inoculating healthy individuals with smallpox matter in order to confer immunity against the disease. It was based on the observations that a primary attack of smallpox often provided a degree of immunity against contracting the disease again in the future. It was introduced to Britain in the early eighteenth century by Lady Mary Wortley-Montagu, who had come across the concept of ‘smallpox parties’ whilst living in Turkey. Following the successful variolation of her own son, she also had her daughter inoculated with smallpox matter in 1721 by the surgeon Charles Maitland. Others soon followed suit, including a royal variolation when George II had his two daughters inoculated with smallpox, at the request of his wife Caroline, Princess of Wales.

The concept gradually spread across the country, but it was not until it reached the county of Suffolk and the ears of a young surgeon named Robert Sutton, that it truly took off. Sutton advertised variolation as a service, including bed and board with the added incentive of ‘tea, wine, fish and fowl’ all for a monthly fee. Gradually inoculation houses started to appear across the country, inspired by the likes of Sutton and his business enterprise.

It was at one of these inoculation houses that in 1768 John Fewster, a Gloucestershire surgeon and apothecary, recognised that a great number of patients could not be infected with smallpox. On enquiry he discovered that they had all previously been infected with cowpox. He made note of this and communicated it to a small medical society of which he as a member at the time. It just so happened that Edward Jenner was also present at this society meeting, as a young apprentice to another local surgeon named Daniel Ludlow. Fewster was a strong supporter of the Suttonian method of variolation and he did not recognise the importance or see the need at the time for the development of inoculation with cowpox.

It would be wrong to talk about the history of vaccination without mentioning Benjamin Jesty (1736-1816), a dairy farmer from Yetminster, in Dorset. Not only did he recognise the protective effect that cowpox had over smallpox, but he also went so far as to vaccinate his wife and children with cowpox in 1774, at least twenty years prior to Jenner’s famous experiment. Furthermore he tested his vaccination trial in 1789 when his two sons were variolated by their local doctor and they did not go on to exhibit any signs of a reaction. Jesty unfortunately did not go on to publish his results, and perhaps due to the public outrage that ensued when the locals discovered that he had inoculated his family with animal matter, did not go out of his way to publicise them either. However, his experiment did not go unrecognised, and he was invited to attend George Pearson’s Original Vaccine Pock Institute in 1805. The physicians at that institute decided that Jesty’s experiment had pre-empted Jenner’s, and they awarded him with a testimonial scroll stating just this.

It is evident that the history of vaccination is more complex than the well-known story of Jenner, the milkmaid and the cow. The concept of cowpox being protective against smallpox was reportedly widely known throughout the dairy country in England and across the continent in Germany. However, it cannot be disputed that Jenner was the only one to make this fact publicly known and to recognise the importance that this discovery could have in the fight against smallpox. It was his determination and dedication to the subject which subsequently led to the World Health Organisation declaring the eradication of smallpox on 8th May 1980.

More can be discovered about this fascinating subject by paying a visit to Dr Jenner’s House, Museum and Garden in Berkeley, Gloucestershire. https://jennermuseum.com/

Roy Porter, ‘The Prevention of Smallpox’, in The Greatest Benefit to Mankind. A Medical History from Antiquity to the Present.(London: HarperCollins, 1999) 275-6

S.L. Kotar and J.E. Gessler, Smallpox: A History (North Carolina: McFarland & Company, 2013),18

Robert Jesty and Gareth Williams, ‘Who invented vaccination’, Malta Medical Journal, 23, 2 (2011) 29-32

Lydia Thurston and Gareth Williams, ‘An examination of John Fewster’s role in the discovery of smallpox vaccination’, J R Coll Physicians Edinb,45 (2015) 173-179

Lydia Thurston

Finding the “missing link”

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Historians will be familiar with the challenges of researching an archive: sifting through a pile of dusty records, drawing a blank in a confusing catalogue, or scoring hundreds of hits searching an electronic database. With the help of an archive expert, however, the rewards outweigh the effort required.

When preparing for my presentation on English medical researcher Dr Annie Homer at the recent BSHM Congress in Edinburgh, I wanted to find out more about her time in Canada at the start of the First World War. In particular, she had served as the Assistant Director of the University of Toronto’s Antitoxin Laboratory, the forerunner of the Connaught Laboratories.

Extract from Antitoxin Laboratory Record of Diphtheria Antitoxin Refining, dated Sept 28th, 1914 [SPC Archives 83-006-01]

I contacted Dr Christopher Rutty, professional medical and public health historian, and consultant to Sanofi Pasteur Canada’s Connaught Campus in Toronto, where the original buildings and archive documents are preserved as part of the country’s medical heritage. By return e-mail, Chris sent me a copy of a lab notebook, which contained several pages written in Homer’s distinctive hand, revealing her work at the start of the war. The preservation of this “missing link” was a stroke of good fortune.

The Connaught Laboratories, University of Toronto, officially opened on Oct 25th, 1917 [SPC Archives 0591]

The Connaught Laboratories were established in 1917 to make up a shortfall of tetanus antitoxin needed by the Canadian Expeditionary Force, and became the site of pioneering advances in the production of vaccines, heparin and insulin. More information is available via The Legacy Project which can be viewed online at www.thelegacyproject.ca

Edward J Wawrzynczak