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08 March 2019

How Embryologists See: Anne McLaren’s Mouse Models

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This post forms part of a series on our Science blog highlighting some of the British Library’s science collections as part of British Science Week 2019.

What does an embryo look like? You’ve probably seen pictures –photos of clumps of tiny little cells, most likely taken of a petri dish in a lab. But embryologists face many barriers when bringing these miniscule cells into vision. The developmental biologist Dr Anne McLaren found ways around some of these problems starting with her work in the 1950s.   

In 1952, the mammalian developmental biologist Dr Anne McLaren moved to UCL to begin conducting a series of experiments intended to transplant mouse embryos from the uterus of one mother to the uterus of another, foster, mother – a technique called embryo transfer. There were several reasons for her wanting to do this, but the central one was a problem of vision. She wanted to make the embryos visible. As she explained in 1960,

Experimental embryology in mammals starts with a grave and obvious disadvantage compared to experimental embryology in, say, frogs or sea-urchins - namely the relative inaccessibility of the mammalian embryo. On the other hand it is a subject of particular interest, not only because man himself, and most of his domesticated animals, are mammals, but also because the mammalian embryo goes through almost all the critical stages of development in the most intimate contact with a genetically different organism, its mother.

This intimate relationship between the embryo and its mother in the very early stages of implantation, and the potential applicability of these insights to other mammals, like humans, made this an important area of study. This relationship also represented a prime example of McLaren’s central research interest, namely how the gene and environment interact in development. In the mammal, the maternal uterus crucially provides the environment in which the genes have to exert their effects. This is why maternal effects on inherited characters are of particular interest to McLaren.


At school we are often taught that development looks something like this,

Image-1-1
Illustration: human fertilization and embryogenesis. With kind permission of Gaurab Karki, at www.onlinebiologynotes.com


McLaren saw things differently. Although the embryo could indeed develop into a foetus and a baby, this was only under particular circumstances, in a given environment. McLaren wanted to better understand what was required of this environment for the embryo to develop into a healthy mouse. Development could also go wrong, and it was certainly not as simple as the expression of a set of genes against a neutral backdrop. In fact, she believed that the whole concept of a gene meant fairly little without an adequate account of the environment through which they were expressed. 

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‘The Bucket Model and When Causes Interact,’ are from The Mirage of a Space Between Nature and Nurture, Evelyn Keller Fox, pp. 8-9, Copyright, 2010, Duke University Press. All rights reserved. Republished by permission of the copyright holder. www.dukeupress.edu



But the problem of being able to see this environment remained. Although she could not look directly inside the womb, McLaren realised that instead she could make the interactions taking place between the embryo and the uterus visible. This was made possible by a phenomenon that had been noticed with the number of lumbar vertebrae, the vertebra starting after the last rib attachment and running down to the last vertebra not sacralised, in the offspring of reciprocal crosses between two strains of mouse. In Problems of Egg Transfer in Mice (1955), she explained,

We suspect the existence of a maternal effect whenever reciprocal crosses are made between two genetically differing strains or varieties, if the progeny differs according to which strain was taken as the maternal parent, and which the paternal. …In species hybrids between the horse and the donkey, the mule, which has a horse mother and a donkey father, differs in a number of respects from the hinny, which has the donkey mother and the horse father. One difference lies in the number of lumbar vertebrae that the animals have. Most mules have 6 lumbar vertebrae, like their mothers; while most hinnies have 5 lumbar vertebrae, again like their mothers.

Another example of this effect observed in mules by John Hammond and Arthur Walton in 1938, was the case of lumbar vertebrae in mice. E. L. Green and W. L. Russel, working at Bar Harbor in New York in 1943, noticed such a phenomenon, a suspected maternal effect on lumbar vertebrae in mice, but their experiments had been stopped short by a fire in their laboratory. The effect presented McLaren with an observable trait that was definitely not just due to chromosomal sex linkage, because the difference also appeared in female progeny of the crossed strains, who of course carry two of the same X chromosome. Even through the trait was not sex-linked, it could still be determined either by the cytoplasm of the egg or the uterine environment that the mother provides. The case thus provided a specific instance of the question of the respective roles of gene and environment in the inheritance of an observable trait. The best way of distinguishing between these contributions, she decided, would be by transferring eggs between females of the two strains, “since such eggs would have the cytoplasm of one strain but the uterine environment of the other” (Research Talk, 1953). If the influence was exerted through the cytoplasm, the young would be unaltered in phenotype by the transfer; but if it was exerted through the uterine environment, the reciprocal difference would be reversed.

Image-1-4
Image: Is it the uterus or the egg affecting the number of vertebrae of the mice? Copyright estate of Anne McLaren MS89202/12


Embryo transfer techniques had been around for a while – in fact, the pioneer of the technique, Walter Heape had used the technique as early as 1890, to show the exact opposite of what McLaren suspected was the case with lumbar vertebrae – namely that the uterus had absolutely no effect on the developing embryo. As their experiments progressed, McLaren and her then husband and collaborator Donald Michie showed that the uterus, in the case of lumbar vertebrae, did exert an effect on the embryo. The mice in the surrogate uterus expressed the trait of the surrogate, not the genetic mother.  There was something in the maternal uterus, not the cytoplasm, that effected the number of lumbar vertebrae. By the end of the experiment she was not able to determine exactly how  this effect was exerted but, she reflected in 1985, the message of the experiment was clear,

As to how this influence is exerted, from the physiological point of view, we are so far in complete ignorance. But the general moral for the geneticist, I think, is clear: that is, when we are dealing with mammals we must be prepared to extend our picture of the genetic control of morphogenetic processes, to envisage their regulation not only by the action of the embryo's genes, but also by the action of the genes of the maternal organism in which the embryo is gestated

Turning cauliflowers into mice: mouse model growing pains 

As might be expected with such a new technique, it took a while to perfect it, to be able to produce standardised results. In the process, McLaren began to see some unusual things. Indeed, during the early days of the experiments, McLaren and Michie were worried about the appearance of some the fertilised ova being produced by the donor female after they’d administered the hormones to induce ovulation. In a research talk from 1953, McLaren recounts,

During the Summer of last year, we were using two-day eggs only; and one day, actually the day we were rejoicing because for the first time we’d got transferred eggs to develop into mice, our 2-day eggs, instead of looking like normal mouse eggs with 4 or 8 distinct spherical blastomeres, suddenly began to look like cauliflowers. The blastomeres coalesced, and the eggs looked awful.

She goes on,

From that day onward, all their eggs looked like that, and as it seemed obvious that something looking like a cauliflower couldn’t develop into a mouse, we didn’t even bother to transplant many of them, but spent much fruitless effort trying to find the cause of the trouble. However, we’ve now got over this difficulty, partly because by using 3-day eggs, which look quite normal, as well as 2-day eggs; partly because this Summer only some of our 2-day eggs looked like cauliflowers; and partly because we’ve got some evidence that cauliflowers can in fact develop into mice.

These pages from McLaren’s lab notebooks show how she tested different variables, like the PH of the medium in the dish before transfer to the foster mother, or the daylight to which embryos were being exposed. She obtained some strange shapes in the process.

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Strange cauliflower shapes. Detail from Anne McLaren’s ‘UCL Embryo Transfer’ laboratory notebook, 1953-1956. Copyright estate of Anne McLaren (Add MS 83843).
 
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‘Ghosts’, or disappearing, eggs. Detail from Anne McLaren’s ‘UCL Embryo Transfer’ laboratory notebook, 1953-1956. Copyright estate of Anne McLaren (Add MS 83843).
 
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A healthy blastocyst (Cells differentiated into cell layers, preceding the embryo stage) –‘hooray’! Detail from Anne McLaren’s ‘UCL Embryo Transfer’ laboratory notebook, 1953-1956. Copyright estate of Anne McLaren (Add MS 83843).

McLaren was discovering new things about the ways in which embryos could develop, and she didn’t always understand what was going on. The appearance of these cauliflowers in development point to the limited view she was getting. It remained difficult to visualise what was going on at these early stages inside the maternal uterus, and the best the embryologist could do was to set up an limited model of the process, to bring to the fore some of the phenomena she was interested in. But biological models, unlike the ones we draw or build out of inanimate material, don’t always comply. Moreover, the view was always partial, and in this case especially limited because all she could do was move her embryos between uteri –about which she knew very little. The only way of knowing more about the uterus would be by intervening in this environment, changing it in some ways and observing the effects this had on the developing embryo which was impossible while the womb remained inaccessible.  As we shall see, McLaren soon went on to develop another window that would allow her to visualise more directly the forces acting on the embryo during development. 

From wombs to dishes

As far as her interest in making the interactions between uterus and embryo visible was concerned, McLaren had definitely succeeded. She had done this by intervening in the biological process of gestation, by moving an embryo from one mother to another and observing the effects it had on the developing embryo. As we have just seen, this technique threw up obstacles and limitations. The cauliflower effect was just one example of a malformation that McLaren was unable to explain because she had little idea about what the uterine environment was made of. She could not figure out the exact mechanisms by which the uterus acted on the embryo because, in order to do this, she would have to play around with them like she had with the medium in the dish prior to transfer, to isolate different variables until she could figure out what factors were at work. She would have to manipulate to be able to see. At the same time, however, McLaren was developing a very promising technique that could provide the solution – the technique of embryo culture. Writing in 1958, she mentioned a method by which egg transfer enables the experiment to influence the environment of the early mouse embryo directly, instead of through the medium of the mother or the other embryos. In collaboration with Dr. Biggers, I have been culturing 8-16 cell mouse embryos according to the technique of Whitten, on Krebs bicarbonate with glucose and bovine plasma albumen added. In two days at 37 [symbol: degrees], nearly 100% of such embryos reach the blastocyst stage, a development which in vivo takes only one day. I then transferred these blastocysts to the uteri of pregnant female recipients, and found that their viability relative to that of control blastocysts had been in no way impaired by the culture treatment….So far we have done no more than demonstrate the feasibility of the technique; but it seems to me that a study of the effects upon subsequent development of variation in the conditions of culture and the constitution of the culture medium, might provide yet another means to overcome the inaccessibility of the mammalian embryo…

Embryos in dishes would allow McLaren to figure out the conditions needed for normal embryonic development. When she and John Biggers (1958) later showed that a mouse embryo after being cultured outside the womb for over 24 hours, could be replaced in the uterus of a mouse mother and develop into a normal healthy mouse, they had pathed the way for In Vitro Fertilisation in humans that would become a reality 20 years later. IVF, a technique that changed the field of embryology as well as society at large, was just one of the offshoots of McLaren’s explorations of gene-environment interactions.

Marieke Bigg
Ph.D candidate, University of Cambridge

Further reading:

McLaren, Anne, and J. D. Biggers. 1958. ‘Successful Development and Birth of Mice Cultivated in Vitro as Early Embryos.’ Nature 182 (September): 877.
McLaren, Anne. 1958, 1960. Experimental studies on the effect of the prenatal environment. 
McLaren, Anne. 1985. An effect of the uterine environment. 

Marieke Bigg is a Ph.D candidate at the University of Cambridge. After completing a B.A. Honors in comparative literature at the University of Amsterdam, she obtained an M.Phil in sociology from the University of Cambridge. In her current PhD research, which she conducts under the supervision of Professor Sarah Franklin, she draws on the biography of Anne McLaren to map the debates on human embryo research in Britain in the 1980s, and proposes new models for policy-making in the area of human fertilisation and embryology today. She is funded by the Wellcome Trust.

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28 February 2019

A visit to the Joint Library of Ophthalmology at Moorfields Eye Hospital

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Conjunctiva
Eye painting by an unknown artist from the Moorfields collection, digitised by UCL. Used under a CC-BY Creative Commons license.


Yesterday Philip went on a CILIP-sponsored visit to the Joint Library of Ophthalmology at Moorfields Eye Hospital.

The library is joint between the NHS trust responsible for Moorfields and the UCL Institute for Ophthalmology. The hospital was opened in 1805 in Charterhouse Square as the Dispensary for Curing Diseases of the Eye and Ear. The driving reason for this was the number of soldiers who were returning from the Napoleonic wars in North Africa with what was known as “Egyptian Ophthalmia”, now recognised as trachoma. The founders were John Cunningham Saunders and Dr. John Richard Farre. In 1810 a medical school was opened and alumni were responsible for opening ophthalmic hospitals in other parts of the world. In 1821 the hospital was moved to Lower Moorfields near what is now the Broadgate office complex and renamed the London Ophthalmic Infirmary, although it quickly became popularly known as “Moorfields”. In 1837 it achieved royal patronage and became known as the Royal London Ophthalmic Hospital. In 1897 the hospital moved to its current site in City Road after the Moorfields site became overcrowded. In 1947 the hospital merged with the Royal Westminster Ophthalmic Hospital and Central London Ophthalmic Hospital, and the name officially became Moorfields. A green line is painted on the pavement from Old Street tube station to the hospital main entrance, to help partially-sighted people find their way.

The Institute of Ophthalmology was founded in 1948, initially on the site of the former Central London Ophthalmic Hospital in Judd Street. It became part of UCL in 1995.

The library now includes items from all the predecessor organisations, and as it is considered a national subject collection no material is disposed of. Much of the journal collection was donated in exchange for the content being indexed in either the British Journal of Ophthalmology or Ophthalmic Literature. There are 7000 books, 63 currently subscribed journals, and 250 journals which are no longer published. There are over 280 CDs or DVDs. The library currently keeps paper subscriptions when possible due to concerns about loss of access due to subscription cancellation or technical obsolescence – many of the CDs or DVDs cannot be used due to outdated software requirements. Most of the material is on open shelf apart from the rarer collections. The rarer material consists of 1500 books and pamphlets, many of which have been digitised by the Wellcome Institute and are included in the Wellcome online digital library. There is also a unique collection of 1700 painted images of healthy and pathological eyes. Many of the earlier eye paintings were by the sisters Mary and Alicia Boole, who were daughters of George Boole of Boolean logic fame. They were mathematicians in their own right and many of their siblings and the following generation had notable achievements in science and art. Later twentieth century paintings were created by the talented medical artist Terry Tarrant. The paintings have been digitised by UCL .The rare books include copies of John Dalrymple’s 1834 “Anatomy of the Human Eye”, the first ophthalmic textbook in English, and the “Atlas of Ophthalmoscopy” by Richard Liebreich, inventor of the ophthalmoscope.

There is a photographic collection of patients and their conditions, often “before and after” treatment. This includes an interesting dimension in terms of Victorian attitudes to privacy and personal identification – many poorer patients had their full names given, while more middle or upper-class patients are identified only by given names or initials. There is also a collection of bound notes on patients back to 1877.

Finally, there is a “museum” collection of artifacts. Many of them are originally from the Institute of Ophthalmology. They include eye testing equipment, ophthalmoscopes, surgical instruments and microscopes. Particularly unusual exhibits include an ivory leech holder used to apply leeches to the area around the eye to treat glaucoma, and a pair of prism spectacles that redirect the vision downwards through ninety degrees, to allow patients forced to lie flat on their backs to read more easily.

The library still serves an audience of predominantly medical students and practitioners. They do a lot of training on databases and library inductions. They lend the majority of the material and there are self-service lending/returning terminals. They also do inter-library loan.

Other activities include doing systematic reviews and helping people with basic IT skills.

There are 32 satellite sites with electronic resources only.

Last year the library achieves Platinum status in the Green Impact scheme for environmentalism in libraries, based around recycling and saving energy.

The whole institution is intended to move in a few years time to a new site in the St Pancras area.

23 January 2019

Lab notebooks - handwriting at the core of science

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McLaren notebook
Page from Anne McLaren's notebook (shelfmark Add MS 83844) covering embryo transfer experiments in mice, 1950s. (Copyright estate of Anne McLaren)


Today is World Handwriting Day, and we thought we’d pay our respects to the most important role handwriting plays in science, one which you might not have heard of if you aren’t a practicing scientist. This is the “lab notebook”, a scientist’s daily diary of all their experiments, thoughts, and other scientific activities. Until relatively recently, these were always handwritten, as they were meant to record what, in detail, someone was doing as they did it. Waiting to create them until work was finished caused too much risk of forgetting or distorting something.


Lab notebooks grew out of the personal diaries and notebooks of individual researchers. Some notebooks by well-known scientists have become Library treasures in their own right. One of the most famous works in our Treasures of the British Library exhibition is the Codex Arundel, a collection of notes written by Leonardo da Vinci (although probably not in the order they were bound) in the sixteenth century. At the other extreme of history, the Treasures Gallery currently displays the biologist Anne McLaren's lab book on embryo transfer in mice. Outside the BL, most of the lifelong field and theoretical notebook collections of Charles Darwin are digitised and available online, as are some of Albert Einstein's most significant theoretical notebooks. At the other end of accessibility, some of the lab notebooks of Marie and Pierre Curie, held by the National Library of France, are reported to still be so radioactive that they are not safe to handle without protective clothing.


Laboratory notebooks later became an even more important record of exactly what was done, as lone researchers were replaced by academic and private-sector research groups, science and technology became ever-more important to society, and scientists were expected to describe their methods in detail so that they could be replicated and turned into innovative technologies, materials and treatments. Additionally, until quite recently, American patent law worked on a “first to invent” basis whereby the person who could prove that they had the idea for an invention first, or their employer, had the right to a patent. Laboratory notebooks were the main source of evidence for this. In recent years, scientific misconduct has become a higher-profile issue, as scientists worry about a “replicability crisis” where too many uncertain or exaggerated results have been published. Lab books help prove that the work was done as the researchers claim, or the detail expected in them make discrepancies easier to recognise. And the notebooks of eminent scientists are a rich source for scientific historians.


By the latter part of the twentieth century, some organisations had very detailed instructions for how laboratory notebooks should be completed and stored. Lab books had to be written exactly as the work was carried out, or as soon as possible – no jotting notes on scraps of paper and writing them up at the end of the day. Notebooks were considered the property of the employer or the university, and could not be removed from the lab. And they had to be clearly paginated with no chance of pages being removed or replaced.


Many laboratories still use paper notebooks, due to the ease of simply writing notes down as you go. In many types of science, electronic devices are at risk of being exposed to spillages or damaging electromagnetic conditions, or are simply unwieldy. Some researchers also like to keep their detailed records to themselves instead of sharing them with a group. Some research groups and organisations are now moving to electronic recording, but the lifetime of electronic data can be questionable due to failure to back up and the lifespan of media. Specifically-designed electronic laboratory data systems are more secure. They are more common in industry than academia, as academics are more independent and less likely to respond to top-down orders, and academic institutions can be less able to afford the necessary software and hardware. The advantages of electronic research notes systems are that you can save large amounts of original data directly into the system without retyping or printing it, clone records from earlier experiments to save time, search your records more easily, share data within the group easily, and track the history of records. Now data is often electronically recorded and can be directly copied into a laboratory system without a transcription stage. It is possible to use general project and collaboration software packages such as Evernote, SharePoint, or GoogleDrive but specifically-designed software is now available. 


In 2011, Gregory Lang and David Botstein published a scanned copy of the entire lab notebook covering the research leading to a paper on yeast genetics, as an attachment to their e-journal article.


Modern lab books rarely find their way into the British Library collection, but our most famous example is the collection of Alexander Fleming, the discoverer of penicillin (also including records of earlier experiments by his mentor Sir Almroth Wright). As well as the material by Anne McLaren mentioned earlier, we also have some material from the photography pioneer Henry Fox Talbot, electrical inventor David Edward Hughes, and biologist Marilyn Monk.

Sources and further reading:
Barker, K, At the bench: a laboratory navigator, Cold Spring Harbor: Cold Spring Harbor Press, 2005. pp. 89-99. Shelfmark YK.2005.b.1888
Baykoucheva, S. Managing scientific information and research data, Oxford: Chandos Publishing, 2015. Available electronically in British Library reading rooms.
Bird, CL, Willoughby, C and Frey JG, "Laboratory notebooks in the digital era: the role of ELNs in record keeping for chemistry and other sciences", Chemical Society reviews, 2013, 42(20), pp. 8157-8175. Shelfmark (P) JB 00-E(105) or 3151.550000.
Elliott, CA, "Experimental data as a source for the history of science", The American archivist, 1974, 37(1), pp. 27-35. Shelfmark Ac. 1668 or 0810.390000, also available electronically in British Library reading rooms.
Holmes, FL, "Laboratory notebooks: can the daily record illuminate the broader picture", Proceedings of the American Philosophical Society, 1990, 134(4), pp.349-366. Shelfmark Ac. 1830 or 6630.500000, also available electronically in British Library reading rooms.
Stanley, JT and Lewandowski, HJ, "Lab notebooks as scientific communication: investigating development from undergraduate courses to graduate research", Physical review: physics education research, 2016, 12, 020129, freely available online at https://journals.aps.org/prper/pdf/10.1103/PhysRevPhysEducRes.12.020129.
Williams, M, Bozyczko-Coyne, D, Dorsey, B and Larsen, S, "Appendix 2: Laboratory notebooks and data storage", in Gallager, SR and Wiley, EA, Eds. Current protocols essential laboratory techniques, Hoboken: John Wiley & Sons, 2008. Shelfmark YK.2008.b.6299 or m09/.30081

18 December 2018

Arabic science manuscripts from the British Library

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Kitab al sirah
The beginning of Kitāb al-sīrah al-falsafīyah, an autobiographical treatise by the physician and philosopher Abū Bakr Muḥammad ibn Zakarīyā al-Rāzī (Add MS 7473, f. 1v)


Today is World Arabic Language Day, so here's a reminder of the scientific content in our Qatar Digital Library digitisation project. Our friends on the Asian and African Studies blog created two lists of major scientific works digitised in the collection, including Arabic versions of classical scientific texts, some of which were lost from Western European culture until the Renaissance, and original works by great early scientists of the Arabic-speaking world, such as Quṭb al-Dīn al-Shīrāzī, Ibn Sīnā (Avicenna), Ibn Haytham (Alhazen), and Abū Bakr Muḥammad ibn Zakarīyā al-Rāzī (Rhazes).

27 November 2018

Cats in science

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Cat image
At the end of last week, our free exhibition "Cats on the Page" opened, covering cats in all their roles in fiction and art. Here are a few examples of the roles that cats have played in science.

The most famous cat in science, of course, is the notorious Schrödinger's Cat thought experiment, put forward by the physicist Erwin Schrödinger in 1935 to express what he thought were the truly bizarre implications of the Copenhagen Interpretation of quantum physics. In this morally questionable experiment, a cat is sealed in a box with an apparatus that has a predictable probability, within a set time, of releasing cyanide gas and killing it, analogous to a subatomic particle which, until it interacts with another object, may be in one of a number of states with known probabilities. According to Schrödinger, when the probability of the cat being dead reaches 50%, it can be considered, so long as the box is not opened, to be simultaneously alive and dead. Schrödinger actually put this forward as a self-evidently ludicrous demonstation of how silly he thought that the Copenhagen interpretation was, but many physicists since have taken it entirely seriously, and single atoms or subatomic particles have been demonstrated in real-world experiments to behave as if they are in two states simultaneously.

There has been at least one recorded case of a cat being credited writer on a peer-reviewed scientific paper. In 1975, the physicist and mathematician Jack H Hethrington was irritated when a peer reviewer for Physical Review Letters pointed out that he had used "we" consistently in a manuscript on which he was the only credited author, and that the journal style guide would require this to be corrected to "I" throughout. Rather than rewrite the paper, Hethrington credited his cat, Chester, as the second author "F D C Willard", the "FD" coming from Felis domesticus and Willard from the name of Chester's father. In 1980 he published a popular science article under the name of Willard alone. In this case, it was reportedly motivated by disagreements between him and some co-authors, leading to them not wanting to credit it to any real person.

That example was not motivated by hostility, but stings based on exposing questionable degrees or dubious professional organisations by having animals "earn" qualifications have a long history. The first case seems to have taken place in 1967 when a Television Wales team investigating a bogus "English Association of Estate Agents and Valuers" successfully got them to appoint a cat named "Oliver Greenhalgh" as a fellow. British science writer Ben Goldacre has exposed the dubious nature of certain "nutritionist" qualifications by getting his cat a professional certification. To rub salt in, the cat had been dead for some time.

And finally, cats may some day have a role in protecting post-apocalyptic humans from our darker legacies if our technological civilisation collapses. A serious proposal has been made to genetically engineer cats to change colour or glow if they encounter radioactivity, and create a legend that they can detect evil, in order to prevent far-future peoples from unknowingly digging up still-hazardous nuclear waste dumps.

Posted by Philip Eagle (Subject Librarian - STM)

13 November 2018

The centenary of the 1918 flu pandemic

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2 Nov Contagion
A dancer in "Contagion", a piece memorialising the pandemic presented at the British Library earlier in November


This November sees not just the centenary of the end of the First World War, but the centenary of the peak of the influenza epidemic that came at its end. The 1918 flu epidemic may have killed fifty million people or more worldwide, over three times the number of people killed in the war. It is thought to have been the third worst disease epidemic ever in Europe, after the fourteenth-century Black Death and the sixth-century Plague of Justinian. 228,000 people died in the UK, with as many as a third of the population infected, although the death rate among those who fell ill was around 2.5%. 1918 was the first year since official records began that deaths in Britain outnumbered births. Epidemiological studies have shown that children whose mothers suffered flu during pregnancy suffered lifelong negative effects on their health and employment histories.

 The flu is still sometimes known as the Spanish Flu, although this is a misnomer that, even at the time, seriously upset the Spaniards. It was associated with Spain because Spain, being neutral in the war, had less media censorship than other European countries, so that the epidemic was more honestly reported. The first unambiguous cases of the pandemic broke out at a US Army base in Kansas in March 1918. The first worldwide wave continued through the spring and summer, but appeared to be no more problematic than ordinary flu. The second, far more lethal wave, occurred in September to December 1918, while a third, less serious wave took place in the first half of 1919.

However, some people have suggested that earlier outbreaks of disease may have been unrecognised early stages of the flu pandemic. Particular suspicion has been cast on an outbreak of a lung disease called at the time "purulent bronchities" which struck the Allied Powers' huge military camp at Etaples in France in early 1917, and a lethal epidemic of lung infection which hit the region of Shansi in China in the winter of 1917-8, although that was believed by local authorities at the time, and many scientists to this day, to have been pneumonic plague.

A major question, especially given the possibility of further flu pandemics in the future, is what made the 1918 virus so lethal. As well as the sheer number of fatalities, it was unusual in killing young and healthy people in large numbers, rather than those who were elderly or frail. Some people have blamed the physical and psychological stresses of the war, and in particular the long-term effects of chemical warfare, for this, but young people also died in countries which were barely affected by the war. It has been suggested that healthy people died because of a phenomenon known as "cytokine storm", where the influenza infection causes the immune system to go into such a state of extreme activity that it itself causes fatal damage to the lungs. This is more likely to happen in people with healthier immune systems, although recent work has suggested that it might be more likely in people with a specific genetic condition in which the first stage of immune response, involving the production of interferon, is unusually weak.

In 2005, the genetic code of the 1918 virus was sequenced from samples taken from the body of a woman buried in Alaska, which had been partly preserved by the cold climate. This indicated that the 1918 virus was a member of the "H1" type of flue virii. That gave rise to a new theory about the higher death rate among young people - for the previous thirty years the majority of influenza circulating worldwide had been of the "H3" type, so older people may have been more likely to have encountered H1 influenza before and had more immunity to it.

Another mystery is why the 1918 pandemic had so little apparent cultural impact at the time. The most famous deaths from the virus were the poet Guillaume Apollinaire, the artist Egon Schiele (along with his wife Edith, who was pregnant with their first child), and John McCrae, author of one of the most famous poems of WWI remembrance, "In Flanders Fields". It also had a wider historical impact. Some military historians argue that the last major German offensive in 1918 failed only because of flu among the soldiers. The British prime minister David Lloyd George nearly died, although this was covered up at the time. The Versailles Treaty might potentially have been less harsh on Germany, reducing the chances of WWII, if the US President, Woodrow Wilson, had not been incapacitated with the flu during the later part of the negotiations. And the death of the leading USSR politician and administrator Yakov Sverdlov has been said to have opened up an opportunity for Josef Stalin to begin his rise to power. Some suggest that the influenza was not seen by people in general as a separate catastrophe from the war, while others have argued that, despite the death toll, it was seen as "just the flu" in an era when death from infectious disease was still much more common than it is today.

Further reading:

Honigsbaum, M. Living with Enza. London: Macmillan: 2009. Shelfmark YC.2009.a.3229 or m08/.36952
Johnson, N. Britain and the 1918-19 influenza pandemic (Routledge studies in the social history of medicine no. 23). Abingdon: Routledge, 2006. Shelfmark YC.2007.a.11206 or 8026.519925 no. 23
Ministry of Health. Report of the pandemic of influenza 1918-19, Reports on public health and medical subjects, 1920, No. 4. Shelfmarks B.S. 17/1, (P) HF 00-E(18), or 7665.590000
Spinney, L. Pale rider. London: Jonathan Cape, 2017. Shelfmark YC.2018.a.7038, or available in British Library Reading Rooms as Legal Deposit e-Book.

Posted by Philip Eagle

10 October 2018

Andreas Vesalius - The most famous Belgian you have never heard of

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This week, the episode of Sky Arts’ Treasures of the British Library featuring the actor Jim Carter, who you might remember as Mr. Carson in Downton Abbey or, if you are a bit older, Philip Marlow’s father in The Singing Detective, was broadcast. One section covered Jim’s interest in anatomy, and among the items we showed him was one of our copies of Andreas Vesalius’s paradigm-shifting anatomy textbook, Atlas of the Human Body, the first truly scientific anatomical work. The copy shown in the programme is our copy of the book's first edition, which was owned by Hans Sloane, a famous eighteenth-century doctor and collector whose collections of books, antiques and curiosities formed the original core of both the British Museum and the British Library. I showed the book to Jim in the programme, and here is some more information on Vesalius.

It is a standing joke, much to the annoyance of Belgians, that it is difficult to name great descendants of their proud kingdom in Western Europe. Mentions of Tintin and Poirot (fictional characters) or Jean Claude Van Damme (The muscles from Brussels) may just accentuate their irritancy. However, one of their greatest sons, one Andreas Van Wiesel, who would adopt the more impressive Latinised name of Vesalius, changed anatomy and medicine forever and he really did know about muscles. His magnum opus De Humani Corporis Fabrica, published in 1543, was both a paradigm shift for the study of human anatomy and also a work of the finest aesthetic beauty.

Vesalius compressed
Andreas Vesalius, a portrait included in "De Humani Corporis Fabrica"

 Vesalius chooses his parents well and is born into a family of physicians in 1514 in Brussels, then part of the Holy Roman Empire. Initially studying at the University of Louvain, he completes his doctorate in Padua in 1537 and becomes the chair of anatomy and surgery at the tender age of 23; however, this was not considered an especially important branch of medicine compared to the more exciting emerging areas of lotions and potions.

His big break comes when a local judge, impressed with his work, permits use of corpses of executed criminals thus enabling him to perform comparative dissection of the human form. Such opportunity was denied to the great Galen of the second century who despite being physician to the stars such as the gladiators and emperors, only ever worked on animals due to the religious dogma of the time.

Vesalius quickly realised that Galen had simply extrapolated his findings to humans and consequently had made a huge number of glaringly embarrassing assumptions and errors.

Most notably Galen thought that blood was made in the liver and then used for fuelling muscles, and he also thought there were holes in the septum, allowing blood flow from one side of the heart to the other. Galen incorrectly described the human jawbone as being made of two bones, like that of a canine and he was completely wrong about the shape of the human liver. Vesalius was also able to demonstrate that males and females have identical numbers of ribs, the biblical orthodoxy was that men had one less because God made Eve from Adam’s rib.

VesaliusFront
The frontispiece of the book, showing Vesalius dissecting a body in allegorical surroundings

 

Vesalius then pulls another masterstroke as he goes about publishing this great work, which is essentially the human anatomy in seven books. He employs an artist out of the school of Titian to do the illustrations. These stunningly beautiful drawings of figures striking theatrical poses in classical landscapes grab the limelight, and they will be for ever be known as the muscle men. Vesalius stock rises and he becomes physician at the imperial court of Charles V and later to his son Philip II of Spain. Vesalius is aged 29 and at the height of his powers, 1543 is his annus mirabilis.

Muscle Man 1
One of the "muscle man" images from the book

The frontispiece of De Fabrica shows Vesalius performing a dissection, centre stage playing to a packed house; it is literally standing room only and an entirely allegorical scene. Three large robed figures loom imposingly at the front, surely a nod to the ancient wisdom of Galen, Socrates and Hippocrates. Right at the epicentre stands Vesalius one hand on the corpse and the other pointing towards the heavens, a good move to be acknowledging God is on his team also.

Then in 1564, he has his annus horribilis and for the man with the surgical Midas touch, it all appears to go wrong. One story suggests he dissected a corpse who wasn’t quite as dead as he might have been and possibly as a form of penance he was advised to do a tour of the Holy Land; a journey from which he would never return. A second possibility is that he fell foul of the Inquisition, causing this empirical man of science to find making the pilgrimage a good idea.

He dies in the same year aged 50 in mysterious circumstances on the Greek island of Zakynthos, his burial site and grave remain unknown. Unlike his working life, which is referenced with earth shattering evidence based medicine; his final year is shrouded in mystery. No monument or memorial depicts his final resting place. Perhaps the only epitaph needed is de humani corporis fabrica. Anatomy and medicine changed forever, his legacy lives even if his name and accomplishments have been lost to most.

By Matt Hunt, Head of Research User Services

25 September 2018

New Scientist Live

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New Sci logo
I visited New Scientist Live at Excel on Friday, which is an annual event aimed at popularising science, promoted by the weekly popular science magazine. There were a wide range of exhibitors, a mixture of learned societies, universities, technology companies, commercial and charitable organisations offering science "experiences", and makers of scientific ornaments and clothing.

There were also forty-minute talk slots throughout the day by different speakers on current science. The celebrity names were on a VIP stage offered only to those who bought more expensive tickets, but the other talks I attended were all very interesting.

Lee Cronin from Glasgow University described his work on creating a chemical computer, using the two states of a reversible Belousov-Zhabotinsky reaction as the equivalents of the binary 0 and 1. At the moment, the system is at proof of concept stage, but it holds the potential to produce computers more powerful than anything achievable using traditional solid-state electronics.

Paul Bernal gave a somewhat depressing but convincing talk on the difficulties of preventing online "fake news" and bullying. "Fake news" arguably dates back to the early modern era or even earlier, with the circulation of slanderous woodcut broadsheets and songs about peoples' political enemies, while online bullying essentially transfers eternal human social dynamics onto social media, with the novelty lying in the speed and scale with which such behaviour can occur. Bernal pointed out that "fake news" on Facebook and bullying on Twitter are negative versions of precisely what the platforms have been designed to do in terms of, respectively, acting as a powerful advertising medium and providing a means of large scale conversation which anyone can join. Bernal told the cautionary and morally ambiguous story of Brenda Leyland, a woman who bombarded the parents of the missing child Madeleine McCann with online allegations that they had killed their daughter... and was then driven to suicide by the hounding she received from the traditional news media.

James Wong discussed the argument (commonly made by organic-farming campaigners) that nutrient levels in plant foods have been declining due to industrialised food production. His arguments were that this has been observed, and is probably due to faster-growing varieties failing to absorb minerals as efficiently, but that the effect is probably not significant compared to other causes of variation in crop nutrient content such as weather and storage conditions, and is outweighed by the sheer increase in food quantity and variety that modern agriculture and international trade have achieved.

Patricia Vargas's talk was billed somewhat misleadingly as a discussion of whether AIs deserve human rights, but instead dealt more with characteristics that robots might be designed with, that would make humans more likely to accept them in their daily lives and form emotional attachments to them. She mentioned in particular robot pets, such as PLEO, based on a baby dinosaur, and Paro, based on a baby seal.

Fianlly, Mark Miodownik gave an entertaining talk, with demonstrations, on the nature and history of kerosene as a fuel.

17 August 2018

The 150th anniversary of the first observation of helium

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Saturday is the 150th anniversary of a total eclipse of the Sun that was seen across a wide band of Asia on 18th August 1868. Any total eclipse is interesting, but this one is particularly historic for chemists, as it was during this eclipse that observations were made that, with hindsight, led to the discovery of helium, the first element to be discovered in space before it was found on Earth.

NASA eclipse
Image of total solar eclipse in 2017, photographed by Carla Thomas. Copyright NASA

However, the story often told in encyclopaedias, that Pierre Janssen and Norman Lockyer discovered helium by observing the 1868 eclipse, is far too simple. In fact, Janssen, who was in India and is often credited with the discovery, was interested in completely different things, and never claimed any credit during his lifetime, Norman Pogson, who was in India and was the first person to speculate that something unusual might be happening, was forgotten, and Norman Lockyer, who is often credited as the co-discoverer and made the biggest contribution, wasn’t in India and made his discoveries without needing the eclipse.

Helium is the second-most-common element in the universe after hydrogen, but is very rare on Earth, and odd in other ways. It is one of the so-called “noble gases”, that, because they have a particular number of electrons, are uniquely happy to exist as single atoms and reluctant to react with other elements. Helium only exists on Earth because it is given off when many radioactive elements naturally decay. Once produced, because it is so light and so non-reactive, it usually flies straight out of the atmosphere and vanishes into space. It only stays on Earth if it is produced deep underground and trapped within rocks. However, helium is very common in stars, including our Sun, because the energy of most stars comes from hydrogen atoms being fused into helium, and stars’ greater gravity than the Earth keeps it in.

So how was it possible to find helium in the Sun by looking at eclipse light?

For reasons too complicated to explain here, electrons in atoms and molecules can only have certain precise amounts of energy. They can climb from one amount to a higher one by absorbing a photon of light, or drop to a lower one by emitting a photon of light. The amount of energy contained in a photon varies according to the wavelength of the light, and so this means that atoms or molecules can only absorb or emit light of very specific wavelengths. As a result, if you shine a light through a particular substance, the light that comes out will have certain wavelengths and colours of light reduced or missing (an absorption spectrum), and if you heat up a substance to the point that it starts glowing, the light produced will be mainly or only of the same specific wavelengths and colours (an emission spectrum). By studying the light absorbed or emitted by a substance, we can derive a lot of information about what it is and what its structure might be.

The first step in the story of the discovery of helium happened in 1814, when the lens-maker turned physicist Joseph Fraunhofer split sunlight using a telescope, prism, and diffraction slit to create a spectrum broad enough to notice that there were dark lines, so-called "Fraunhofer" lines, where particular wavelengths of light were simply not present. In 1834, David Brewster suggested that the Fraunhofer lines were due to light of specific wavelength being absorbed by gas either within the Sun or in the Earth's atmosphere. James D Forbes suggested that the dark lines could be proved to originate from the Sun rather than the Earth's atmosphere by observing light from the edge of the Sun's disc during an eclipse - as this passes through more of the Sun's atmosphere on its path to the observer, the lines will be stronger if they are produced by the solar atmosphere.

Physicists and chemists began studying the absorption and emission spectra of known substances and found that their characteristic lines were constant. In 1857 William Swan showed that particularly strong dark lines in the yellow region of the Sun's spectrum, known as the D lines, corresponded to the emission spectrum of sodium - something we are all familiar with now given the yellow tinge of sodium-vapour streetlights.

In 1859, Gustav Kirchhoff and Robert Bunsen (of gas burner fame), at the University of Heidelberg, were among the scientists who were making systematic studies of the spectra of different elements. When a major fire broke out in the city of Mannheim, across the valley, they playfully turned their spectroscope on the light from the flames, and were able to identify the characteristic emission spectra of strontium and barium. This experience made them realise that, if they could discover trace elements in a burning building, the Fraunhofer lines might be the key to discovering the elements present in the Sun.

The following year, the two were studying the spectrum of mineral water from a major local spa, Bad Dürkheim. They spotted two blue lines that were found in the spectrum of no known substance, and guided by this managed to prepare and purify compounds of a previously unknown element, caesium. This was the first new element to be discovered using spectroscopic methods. Within the next few years, Kirchhoff and Bunsen would discover rubidium by a similar route, and William Crookes would discover thallium.

In 1868, a total eclipse of the Sun was predicted to occur in India. The eclipse ws expected to have six minutes of totality, an extremely long time by the usual standards in which to perform observations. Spectroscopists were particularly interested in the eclipse, as with the main part of the Sun obscured from the Earth it would be possible to study the light from the Sun's outer atmosphere, potentially helping to investigate both the Sun's chemical composition and its internal structure.

The French astronomer Pierre Janssen had already made his name in the field of the solar spectrum. He had invented a much-improved astronomical spectroscope with the instrument maker Ignazio Hofmann, although the two men quickly fell out bitterly about whose contribution was greatest. In 1866 he had captured the absorption spectrum of water vapour, by a logistically challenging experiment in which he viewed the light given off by sixteen gas burners through long iron pipes filled with high-pressure steam, and verified which of the Fraunhofer lines were produced by it as sunlight passed through the Earth's atmosphere. He was selected by the French Bureau of Longitude to make a government-funded trip to India.

Science Museum spectroscope
1880 automatic spectroscope by John Browning. Image by Science Museum, released under a CC-BY-NC-SA licence

Meanwhile, the government of the British Empire, rulers of India at the time, were making their own plans for scientific observations of the eclipse. The main expedition, led by Major James F Tennant, headed for the town of Guntur in Andhra Pradesh, in Southeastern India. Meanwhile, Norman Pogson, director of the Madras Observatory, headed to Machilipatnam (then known to English-speakers as Masulipatam), closer to the coast. When Janssen arrived in India, he also considered Machilipatnam, but decided that on the coast there was too much risk of fog and cloud. He decided to go to Guntur as well, possibly because it had at one time been ruled by the French and there were still some wealthy French merchants living there. Tennant's team moved into the British government compound, while Janssen set up at the home of one Jules Lefaucheur. Janssen generously helped Tennant to set up his spectroscope and telescope.

When the eclipse occurred, all the investigators paid attention to the spectrum. Janssen did not mention anything unexpected. Tennant saw an orange line which he thought was the normal sodium D line. Only Pogson saw something unusual - a third line close to the sodium D line, but not identical with it.

Pogson report
Pogson's eclipse observations, from his printed report.

It was not until the following days that Janssen made the realisation that would be his real breakthrough of the event, and the one that popular history would later confuse with the discovery of helium. He realised that the emission spectrum of the solar atmosphere and prominences was so strong that, if one could focus the spectroscope on the precise edge of the Sun, they might be visible even without an eclipse. He experimented and found that it was entirely possible, but was easiest if you moved the spectroscope to try to find the spectrum, rather than trying to focus visually on the edge of the Sun. He excitedly wrote to his wife in a letter, "They sent me to observe the eclipse for five minutes, and I am bringing back a perpetual eclipse from India." Finally, he sent a letter to the Academy of Sciences, announcing his discoveries for the first time.

Back in London, Norman Lockyer, a civil servant and prominent amateur astronomer, with a great interest in studying the Sun, was independently realising that the spectrum of the outer atmosphere of the Sun could be viewed by accurately focussing a spectroscope, without any need for an eclipse. He also seems to have somehow got a copy of Pogson's report with its reference to a previously unidentified line in the spectrum. In October, he received a new spectroscope and managed to focus on the solar atmosphere and obtain its emission spectrum. He also noticed a new line near the D line. Among the organisations he sent preliminary reports to was the French Academy of Sciences, his letter arriving within a few days of Janssen's report from India, both being read out at the same meeting on 26th October. In 1872, to avoid a potentially ugly interpersonal and international row, the French government issued a medal featuring both Janssen and Lockyer to commemorate their solar discoveries.

By the end of the year, both Janssen and Lockyer were convinced that the yellow line near the sodium D line was new. Lockyer and the chemist Edward Frankland spent some time experimenting with the spectrum of hydrogen under different conditions, and by the end of it were convinced that the Sun consisted mostly of hydrogen, but the the yellow line could not be produced by that element. By 1871 Lockyer was convinced that the yellow line was produced by a new element never found on Earth which he named "helium", but did not make such an extreme speculation in public, only in private communications with other scientists. The first public statement of it is believed to have been in Sir William Thompson's presidential address to the British Association for the Advancement of Science in 1871. This concluded the series of events that led, in later years, to Janssen and Lockyer wrongly being jointly credited with the discovery of helium in 1868.

Why was Pogson forgotten, even though Lockyer credited him in his own brief memoir of the discovery of helium, in Nature in 1896? Although he is now remembered for his development, earlier in his career, of a scale for the apparent magnitude, or brightness of astronomical objects, his career in India was not a success. He seems to have suffered from social snobbery due to his middle-class background and lack of a university degree, but he was also a somewhat abrasive personality, as can be seen from the negative comments in his report on the "needless and lavish expenditure" on the various expeditions to view the eclipse, and the even more offensive remarks about the local Indian people in general, which I will not quote in detail here. Another item in the India Office records shows his conflict with the government and the Dutch astronomer Jean Oudemans over longitude measurements that he did not consider particularly important and delayed in analysing. Pogson's report on the eclipse was not published in a peer-reviewed journal, but in a low-profile government publication - Pogson himself complained in a letter in 1882 that it had been treated as "waste paper".

Helium was subsequently shown not just to exist in the Sun, when in 1876 the French astronmer Alfred Cornu observed it in the spectrum of a star in the Cygnus constellation. In the meantime, however, speculation on new elements in the stars had become somewhat wild and uncontrolled, developing a bad name due to multiple announcements of "new elements" that proved too frequent to be credible. (One of the most notorious was "coronium", assigned to a spectral line from sunlight at 5303 angstroms wavelength, which was eventually discovered to come from very highly-ionised iron atoms.)

In 1887, William Hillebrand discovered a mysterious gas while treating uranium ore with acid, that he suspected to be nitrogen. He noticed that its spectrum did not match that known for nitrogen, but did not realise that it was a new element, as at the time it was known that the spectrum of nitrogen could vary considerably with the conditions. In 1895, Baron Rayleigh found that nitrogen extracted from the atmosphere had a different molecular weight to chemically-produced pure nitrogen, and suspected that another element was present. He investigated further, and managed to purify a completely new element, which he named argon. William Ramsey, who was working with Rayleigh on argon, was shown Hillebrand's paper by another colleague who thought Hillebrand's gas might have been argon as well. He repeated Hillebrand's experiment with a different type of uranium ore, and discovered that the gas he produced was much lighter than argon, and had a spectrum that included the D3 line of the mysterious solar element helium. Helium had finally been discovered on Earth.

But scientific research on the Sun continues - this week NASA launched its Parker Solar Probe, to become the first human-created object to enter the Sun's outer atmosphere and observe it.

Sources and further reading:

Janssen, P J, The total solar eclipse of August 1868. Part I, Astronomical Register, 1869, 7(77), pp. 107–110. Shelfmark PP.1556 or 1755.800000
Janssen, P J, The total solar eclipse of August 1868. Part II, Astronomical Register, 1869, 7(78), pp. 131-133 Shelfmark PP.1556 or 1755.800000
Lockyer, J. N. The story of helium, Nature, 1896, 53(1371), pp.319-22. Shelfmark P.P.2011c or (P) BX 80-E(3). Also available online in BL Reading Rooms
Nath, B B. The story of helium and the birth of astrophysics. New York City: Springer, 2013. Available online in British Library Reading Rooms.
Pogson, N R. Report of the Government Astronomer upon the proceedings of the Observatory in connexion with the total eclipse of the Sun on August 18th, 1868, as observed at Masulipatam, Vunpurthy, Madras and other stations in Southern India. Madras: Madras Observatory, 1875. Shelfmark IOR/V/27/430/8.
Pogson, N. R. Letter to Captain Awdry, 10th June 1882, in Grant Duff Collection, Miscellaneous English Correspondence, pp. 96-98. Shelfmark Mss Eur F/234/67
Ramsay, W. Helium, a gaseous constituent of certain minerals, Part I Proceedings of the Royal Society, 1895, 58 pp. 80-89. Shelfmark Ac.3025/21 or (P) JA 00-E(12). Also available free online at https://www.jstor.org/stable/115763
Reddy, V., Snedegar, K.. Balasubramanian, R. K. Scaling the magnitude: the fall and rise of N. R. Pogson, Journal of the British Astronomical Association, 2007, 117(5), pp. 237-245. Shelfmark Ac.4176, (P) OT 00-E(34), or 4713.000000

Posted by Philip Eagle. Thanks to Margaret Makepeace for help in researching India Office records.

07 June 2018

The sixtieth birthday of obstetric ultrasound

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Ultrasound image
Ultrasound image by mylissa, CC-BY-SA

Today is the sixtieth anniversary of the publication in The Lancet of the first scholarly article on medical ultrasound by the obstetricians Ian Donald and John MacVicar, and the engineer Tom Brown. While earlier groups had experimented with ultrasound, it was Donald and Brown who achieved real diagnostic success with it, and popularised it in the medical profession. They initially applied it to distinguish uterine cysts from solid tumours such as fibroids, and later developed it for other important tasks, such as diagnosing placenta praevia (a potentially lethal condition during pregnancy in which the placenta attaches too low down in the womb) and directly observing foetuses. It is thanks to their work that ultrasound has become routine in pregnancy and many peoples' first view of their children. 

Donald had become interested in the potential of ultrasound for medicine thanks to his experience with both radar and sonar while serving in the RAF during World War II. Much of his success was because he happened to work for the University of Glasgow, in a city with a large-scale shipbuilding industry which used ultrasonic techniques to test for flaws in metal parts. It was also the home of Kelvin and Hughes, one of the main manufacturers of ultrasonic testing equipment, for which company Brown worked.

There was also a particular perceived need at the time for a safer method of examining foetuses in the womb, as epidemiological studies had discovered that X-ray examinations during pregnancy led to a higher risk of leukaemia and other cancers in the early lives of the children.

Donald subsequently became a celebrity not just for his scientific and medical skills, but as a prominent medical campaigner against abortion. He frequently stated that his observations of foetuses in the womb had confirmed him in his belief that they qualified as human beings from conception, although unlike some religious pro-life campaigners he morally accepted abortion when the foetus was clearly unlikely to survive childbirth or where the child would be very severely disabled. Brown's career effectively ended with the failure of an attempt to start a business producing medical ultrasound equipment, and he felt later in life that much of the media neglected his vital technological contributions to the development of the idea, although Donald always acknowledged them in public.

Further reading:

Brown, T G. Personal recollections. 1999. Available free online at http://www.ob-ultrasound.net/brown-on-ultrasound.html
Craig, M. Craig's Essentials of Sonography and patient care, Baltimore: Saunders, 2018. Available as an ebook in the British Library reading rooms.
Donald, I, MacVicar, J, and Brown, T G. Investigation of abdominal masses by pulsed ultrasound, The Lancet, 1958, 271(7032), pp. 1188-1195. Available at (P) GP 00 - E(14) and also electronically in the British Library reading rooms.
Nicholson, M and Fleming, J E E. Imaging and imagining the foetus. Baltimore: Johns Hopkins University Press, 2014. Available at YK.2014.a.7586.
Norton, M E. Callen's Ultrasonography in obstetrics and gynecology, Elsevier, 2016. Available as an ebook in the British Library reading rooms.