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14 March 2019

From Cauliflowers to Chimaeras: A New Window onto Development

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

 In my previous blog  we saw how, as she conducted her embryo transfer experiments, Dr Anne McLaren was already looking for ways of more directly influencing the environment of the embryo, in order to test what effect this would have on the embryo itself. This was part of her project to illuminate the interactions between genes and their environment in the development of the embryo. She found her answer in the in vitro dish:

In my laboratory we culture… very early mouse embryos in little plastic dishes, under a layer of liquid paraffin. Drops of culture medium are added, just a simple salt solution, with some glucose and some protein, and some antibiotics to stop bacteria growing; the mouse embryos, which are just too small to be seen with the naked eye at this stage, are then added, several to each drop, and the dish is put in an incubator, in the right temperature and gas conditions.

Now McLaren no longer had to influence embryos and cells in the earliest stages of development through the environment but could directly manipulate them, change the conditions under which they were put, and see what effect this had on subsequent development. One way in which she changed the environment of the embryo was by making what she called ‘Chimaeras’. In Homeric legend, the chimaera described a strange hybrid animal that had “the body of a she-goat, the head of a lion, and the tail of a serpent”, and throughout the literature of antiquity many other strange combinations are found. McLaren picked up on this, as she explained in Mammalian Chimaeras (1976):

…the six-limbed centaur, half man, half horse; the harpy, a bird of prey with the head and breasts of a woman; the griffon, with eagle’s head and legs, and the body of a lion; the beats of the Apocalypse, like a seven-headed leopard with the mouths of a lion and the feet of a bear; the Apocalyptic locusts, horse-shaped with men’s faces, women’s hair, lion’s teeth and scorpions’ tails. All bear witness to the ambition of Man to combine outstanding qualities of different animals into a single creature of surpassing power.

IMAGE 2-1 : Etruscan Chimaera, 4th Century BC, National Archaeological Museum, Florence, Italy. With kind permission from Steven Zucker CC BY-NC-SA 2.0

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Sexual reproduction is also a way of forming a composite, of selecting traits from two different animals, two parents, and recombining them in a given environment to form an organism that carries forth the traits of both into a next generation. The method is anything but certain. McLaren’s transfer experiments showed that a lot can go wrong, the results are unpredictable, and the method can only be used within a species or it will produce infertile offspring. Nonetheless,

Biology as well as mythology provides examples of strange and often intimate associations between different species. Alga and fungus form a partnership so close we refer to it by a single name, ‘lichen’; the hermit crab collects stinging sea anemones to guard its shell; the sea slug (Aeolis pilata) accumulates nematocysts from the hybroid that it eats, and positions them in its epidermis as a defence. Even some subcellular organelles, like chloroplasts and mitochondria, are now thought to have originated as independent organisms existing in symbiotic relationship to a host cell.

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IMAGE 2-2:  Lichen, a composite of alga and fungus. Photo courtesy of Hans Braxmeier. Pixabay License

There are thus lots of examples in nature of chimaeras. In experimental embryology, the term has a slightly more specific meaning, and is used to refer to a “composite animal or plant in which the different cell populations are derived from more than one fertilized egg, or the union of more than two gametes”. McLaren showed with her collaborator Dr John Biggers in 1958 that if you take two 8-cell mouse eggs and push them together, they’ll stick, and the total 16 cells will develop as a normal embryo and that, when transferred to another female mouse, the cells will grow up into “a muddled but otherwise normal mouse”. This mouse would thus be described as a chimaera.

So why would McLaren want to interfere with mouse embryo development in this way? What would this tell her about gene-environment interactions? After all, she wasn’t so much changing the culture environment in the dish which had replaced the maternal uterus, as the cells of the embryo themselves. In Chimaeras in Mouse and Man (1970), she explains,

How do genes link up with chimaeras? Well, one of the subjects that has always fascinated me as a geneticist is the interaction of genes and environment, the old Nature-Nurture dichotomy. A gene on its own cannot determine a single feature of an organism. It's only a meaningful concept in interaction with a particular environment, and the same gene in different environments may produce quite different effects. In mammals, an important part of the environment may experienced by the developing embryo is provided by the mother, before birth. Some years ago my colleague Donald Michie and myself studied how mice of the same genotype reacted differently in different uterine environments, that is in different mothers. In a chimaera one is studying a still more intimate interaction between genotype and environment, because each of the two cell populations is developing in an environment largely made up not only of its own type, as would be the case in any normal animal, but in the most intimate interaction with cells of the other type…this can produce unexpected effects.

So what kind of experiments did this new research technique lead to? One of the problems this method allowed her to investigate was the development of sex. What happens when you create a chimaera that is half male and half female? What is the effect of this altered cellular environment on the phenotypic [the traits expressed] sex of the mouse? If two male embryos are fused, or two females, McLaren showed, their sexual development presents no problems, or no special problems at least. When, however, male and female cells are fused, you would expect them to develop into hermaphrodites with special combinations of male and female organs.

What she found, however, was that in a sample of randomly aggregated male-female chimaeras, the proportion of hermaphrodites was nowhere near 50%, which is what you would statistically expect when mixing half male and half females. The proportion was closer to 10%. The reason turned out to be that the mice which are made up of both male and female cells develop as perfectly normal males. The proportion of male and female cells in the body of these chimaeras also varies even though half of each were used initially to form the chimaeras. This is because, when the eggs are fused and the two types of cells get mixed together, sometimes more female cells will get into the outer layer of the embryo, which is the layer that goes on to develop into extraembryonic structures, such as the placenta and membranes, and sometimes more will get into the inner part, in which case female dells will predominate in the baby mouse itself.

The experiments eventually showed, in combination with work done by Dr Chris Tarkowski who was working in Poland, that normal female development only occurs if virtually all the cells in the body are female. If there are a small proportion of male cells present, then the mouse develops abnormally, as a hermaphrodite. However, if the proportion of male cells approaches 50% or more, the animal develops as a normal male, and the fact that it has a lot of female cells scattered throughout the body does not seem to upset the overall phenotype or make it less male.

These experiments thus showed that sex is not only or directly determined by the XX or XY chromosome, that the overall phenotype results from regulation at the level of the whole animal, and that means that the interaction between cells determines what sex the embryo has. In this sense, the mouse chimera is not like the mythological chimera at all, because, even when composed of different parts it will still function as a coherent whole. There is often nothing outwardly ‘unusual’ about a chimera, in fact we are always composed of two distinct genotypes coming together, although this isn’t included in the biological definition of the chimera, it proposes the same biological conundrum. The interesting question in biology is how different parts come to function as a unity. No monsters here, only lots of composite individuals.

Marieke Bigg

Ph.D candidate, University of Cambridge

Further reading:

McLaren, Anne. 1968. The Developing Egg.

McLaren, Anne. 1970. Chimaeras in Mouse and Man.

McLaren, Anne. 1976. Mammalian Chimaeras. Cambridge, London, New York and Melbourne: Cambridge University Press.

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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The Flight of the Hoverfly

“According to classical aerodynamics, it is impossible for a bumblebee to fly!” said the Doctor once, around 1971, standing in the Wiltshire countryside. (Doctor who? THE Doctor. The Third one.)

But years earlier, in the 1950s, John Maynard Smith – not a doctor then or ever, except when people misaddressed him – had in fact glued one to a pin and showed why and how they could.

Well, to be honest, he had glued a hoverfly to a pin, not a bumblebee. Although he and M.J. Davies, fellow undergrad at University College London, had tried bees. But the bees were unwilling to fly when tethered, so hoverflies had to serve as stand-ins.

Their reason was so nicely summed up by the Doctor: science could not only not explain how bumblebees managed to fly, according to science – aerodynamics to be precise – they shouldn’t be able to fly at all. This idea had got hold of people’s minds because they took aerodynamics as applied to helicopters and rotating disks and then applied it to the wings of bees and large flies. Thinking like that, they concluded that these insects shouldn’t be able to get enough lift to fly.

So Maynard Smith and Davies etherised flies and glued them onto a pin before they surrounded them with, essentially, fluff (metaldehyde particles, to be exact) and flash photographed them, timing the length of exposure. ‘The resulting photographs,’ Maynard Smith remembered in 1990, ‘were fairly awful by modern standards, but were good enough to show that the velocity of the air in the jet was about one-third of the theoretical values, and the area of the jet correspondingly greater.’ Below is a surviving photograph from the experiments, numbered 11. The large white shape roughly in the centre is the fly, the white smudges around it the traces left by the fluff, indicating the air movement created by the beating wings.

6a00d8341c464853ef0240a445c629200c-800wiIMAGE 1: Photograph: Insect Flight, c 1950. Copyright estate of John Maynard Smith. (Add MS 86626)

To put the results differently, insects like bumblebees, bees and hoverflies can fly because of the air’s viscosity. Viscosity is the resistance to a change in shape, or the movement of neighbouring portions relative to one another. This means that when a large insect beats its wings, the wings drag along more air than just the air directly affected by the wing. This additional volume of air - ‘about ten times more air than you’d think’ - is large enough to provide lift for the insect; the downward jet of air supports its weight: it flies.

Why? Scale proved to be important: helicopters and bees operate on rather different ones. ‘It’s a very small scale, and the viscosity of the air means that not only the air that’s actually gone past the wings is going into a jet below the bee but a great mass of the air from all around is being sucked in by viscosity. […] We tried to publish that and never could. I was [...] cross about that.’

While they didn’t manage to publish in a scientific journal (the Journal of Experimental Biology rejected it around 1950), Maynard Smith did present his and Davies’ findings at a meeting on insect flight at the Zoological Laboratory in Cambridge during the summer of 1953. The meetings were the result of ‘attempts to bring together a group of persons with a special interest in the flight of insects.’ The meeting notes stress that the experiment had been developed independently by Maynard Smith and Davies. This was important because it was similar to one described by F.S.J. Hollick, who had, for example, published on the flight of the fly Muscina stabulans in 1940.

IMAGE 2: F. S. J. Hollick. (1940). The flight of the dipterous fly Muscina stabulans fallén. Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences 230(572), 357-390. Reproduced by kind permission of the Royal Society.

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(The report also gives us the exact formula used by Maynard Smith and Davies: ‘The mass of air passing through the wings per second (m) was then calculated by using the expression W = mv, where W is the weight of the insect, and v the velocity of the air. Power was then calculated from the expression P = 1/2m.v2, and the average value determined for several species was 0.009 h.p. per lb. of flight muscle. Using Wigglesworth’s figures for the rate of sugar consumption in Drosophila, the efficiency was estimated at between 1 and 2 per cent.’)

The experiment and ‘fairly awful’ photograph saved in Maynard Smith’s archive are fascinating not only as an example of 1950s research tools. It also illustrates Maynard Smith's transition from aircraft engineer to biologist. He had a first degree from Cambridge, then worked as an aircraft engineer during the Second World War, and only in the late 1940s switched careers by going back to university to study biology. In studying the mechanics and efficiency of flight, both in insects and in birds, his engineering background and knowledge of aerodynamics, mathematics and equations proved invaluable.

Second, it is an example of Maynard Smith’s early trouble in getting papers published. His research and results were from hard to impossible to get past mathematically ignorant biologist reviewers. A comment on one of his papers on the evolution of flight even claimed that the author had no knowledge of aerodynamics!

‘Now this did slightly annoy me,’ Maynard Smith commented. ‘If they had rejected it on the grounds that I didn’t know anything about animals I wouldn’t have minded so much, ‘cause it was probably true. But, you know, test pilots had been trusting their lives to the fact that I knew some aerodynamics for a number of years; I felt a bit cross.’

IMAGE 3: Maynard Smith, J. (1953). Birds as aeroplanes. New Biology 14, 64-81. Copyright Penguin Random House UK.

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Maynard Smith did manage to publish that particular paper eventually, in 1952, but his work with Davies on hoverflies proved impossible to publish in a scientific journal. His contacts at Oxford saved him. David Lack, author of The Life of the Robin and Darwin’s Finches, introduced Maynard Smith to Michael Abercrombie and M.L. Johnson, a husband-and-wife team of biologists at the University of Birmingham. They were editing the popular biology journal New Biology, published by Penguin. The journal aimed to reach the educated layman and schools, explaining and presenting biological research. Maynard Smith published “Birds as Aeroplanes” with them in 1953. All the things he had trouble getting into professional journals, he included: his research with Davies and mathematics. The above figure from that article translates the photograph into a more easily interpretable illustration. This article marks the start of Maynard Smith’s successful third “career” as a science communicator, which he continued to do next to his research for almost half a century.

Lastly, the photograph shows Maynard Smith in the role of the experimental biologist, a role that he later abandoned for theoretical biology. As a postgraduate he worked in the laboratory on the genetics of the European fruit fly Drosophila subobscura and largely ignored theoretical problems. This wasn’t due to theoretical incompetence but rather due to the fact that J.B.S. Haldane, one of the founding fathers of population genetics, was working down the hallway. Maynard Smith later commented that their was no point in doing theory because Haldane would find the solutions before anyone else. The switch to theory happened around the time Maynard Smith accepted a deanship at the University of Sussex in 1965. Not only had Haldane left the UK for India previously, but Maynard Smith's new duties didn’t leave much time for fruit fly farming and experiments.

It remains to clear the Doctor of any possible misapprehension that he was ignorant of insect flight. He likely knew exactly how and why bumblebees fly. He’s the Doctor. But he needed to make a point to a rather incredulous sergeant who was about to build an instrument with the Doctor’s instructions.

OSGOOD: What’s the principle, sir?

DOCTOR: Negative diathermy, Sergeant. Buffer the molecular movement of the air with the reverse phase short waves. It’s quite simple.

OSGOOD: Simple? It’s impossible.

DOCTOR: Yes, well, according to classical aerodynamics, it is impossible for a bumblebee to fly!

This blog was written for British Science Week. As part of this ten-day celebration of science, the John Maynard Smith Archive will also feature in an event on 15 March 2019: ‘Dear John: The Kin Selection Controversy’.

Helen Piel
Collaborative Doctoral Partnership (CDP) PhD student, University of Leeds and the British Library

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08 March 2019

How Embryologists See: Anne McLaren’s Mouse Models

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,

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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.

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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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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

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

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

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)

24 November 2018

Psychology Resources and Research Methods Workshop for Scholars

Drawing-of-the-new-British-Library-building-from-Ossulston-Street-by-Colin-St-John-Wilson-c1991

Image source: British Library Press Images

London is blessed with a rich seam of psychology research collections represented by the British Library and the London Psychology Librarians’ Group institutions.

Together curators, reference subject specialists and psychology librarians support students, researchers and professionals in advancing our understanding the the mind, brain and behavior.

You are warmly welcome to a free workshop on Monday 3 rd December at the British Library in the afternoon, focusing on psychology research resources in London.

Monday 3 December (14.00-17.00)

This workshop, for registered Readers (and those who would find it useful to register as readers for their research needs) takes place in the Eliot Training Room in the Library’s Knowledge Centre. The workshop programme is:

Part 1: Welcome to the Library and introduction to the London Psychology Librarians Group:

  • Qualitative methods in psychology research; Christine Ozolins, Neuroscience researcher, Birkbeck College
  • Psychology collections: the London Landscape; Mura Ghosh, Research Librarian, Senate House Library

14.50-15.30 Tea break (Tea provided)

Part 2 British Library Psychology Resources and Information Literacy:

  • Information literacy for psychology research; James Soderman/Paula Funnell, Liaison Librarians, Queen Mary College
  • The post graduate psychology student voice; Holly Walton, Psychology post graduate representative
  • Psychology resources in the British Library; Paul Allchin, British Library, Reference specialist,

16.30-17.00: Question & answer session.

To find out more or to book a place, please email us at: ReferenceServicesTraining@bl.uk or speak to a member of staff at the Science Reference Desk.

The speakers will share their expertise on the what, where, and how of psychology research in London based libraries and the research needs of students and researchers generally.

BL flickr 11004937825

Image source: https://www.flickr.com/photos/britishlibrary/11004937825/

Posted by Paul Allchin - Reference Specialist, Science.

14 November 2018

Light in the Dark Ages: Anglo-Saxon Medicine

The Anglo-Saxons and medicine (in the modern scientific sense of the word) do at first glance seem to be separated by a huge chasm of science and reason. No doctor today would recommend the use of cow dung in any circumstances! Yet, when one looks more closely, we can see that the Anglo-Saxons idea of medicine (or perhaps “healing” would be a more appropriate term) is based not just on superstition but classical teachings, folklore and practical observation. In particular, the Anglo-Saxon’s were no different from other people of the distant past in that they held on to an ancient desire to harness the healing power of plants and the world around them.

Early managed plant life, and later gardens, were for culinary and healing purposes, rather than leisure or aesthetic reasons. This is evidence from the long history of Herbals, or, in effect, botanical encyclopaedias. One of the oldest extant examples of an Herbal and healing / medical book is Bald’s Leechbook (shelfmark Royal MS 12 D XVII). One recipe from Bald’s Leechbook involves mixing wine, leek and garlic to vanquish an infected eyelash follicle, more commonly known as styes. Freya Harrison, a microbiologist, and Christina Lee, an Anglo-Saxon scholar, decided to test this Anglo-Saxon potion in laboratory conditions. The potion was tested on skin samples infected with Staphycloccus aureus which is a version of the bacteria that causes styes and the MRSA superbug. Amazingly, the potion killed 90% of the bacteria of this antibiotic-resistant superbug (C. Wilson. New Scientist, 2015). This demonstrates the Anglo-Saxons were not just blindly throwing around different ingredients in the hope of finding a cure, but were applying various potions and then noting the effects. In this case, they would have noticed what we know today as the antibacterial qualities of garlic and leek.

A page from a handwritten manuscript, Bald's Leechbook, in Early English

Text page from BL Royal 12 D XVII, f. 7v, Bald's Leechbook

Bald’s Leechbook also suggests that the Anglo-Saxons were aware of a longer medical tradition going back to antiquity. This can be glimpsed from a linguistic study of the text. The vernacular material provides insightful readings of Latin technical vocabulary, and also shows a knowledge of technical terms of Greek origin. However, this limited knowledge of the ancient world does create what Cayton describes as “an uneasy fusion of Classical doctrines such as the four humours, and pagan Teutonic ideas such as the worm and elfshot as carriers of disease.” (Cayton, 1977)

As the exhibition Anglo-Saxon Kingdoms: Art, Word, War makes clear, the Anglo-Saxons were much more than just a bunch of inward looking Dark Age warriors who had no knowledge of the wider world, and whose only medical experimentation involved using leeches and cow dung to solve their ailments. We can see from Bald’s Leechbook alone, that the Anglo-Saxons were involved in rudimentary observational science and had a knowledge of Latin and Greek texts.

To add a light hearted note, I should also say that the Anglo-Saxons believed in the Doctrine of Signature. This is the belief that herbs and plants that resembled parts of the body could be used to treat ailments for the corresponding body parts. I think there could be plenty of material here for a new Carry On film about the Anglo-Saxons!

 

Selected Bibliography

Wilson. C, (2015). ‘Anglo-Saxon remedy kills hospital superbug MRSA’. New Scientist https://www.newscientist.com/article/dn27263-anglo-saxon-remedy-kills-hospital-superbug-mrsa/

Cayton. H. M, (1977). Anglo-Saxon Medicine within its Social Context (University of Durham). Link to ETHOS https://ethos.bl.uk/OrderDetails.do;jsessionid=728405D3CDE4BC17210EE440A7856171?uin=uk.bl.ethos.450980

Meaney. A. L, (1992). ‘The Anglo-Saxon View of the Causes of Illness.’ Health and Disease and Healing in Medieval Culture. Ed. Campbell. S et al (Macmillan). British Library shelf mark YK.1992.a.2007

 

 

By Ian Moore - Science Reference Team

13 November 2018

The centenary of the 1918 flu pandemic

A blonde woman in a white leotard contorts herself in apparent pain on a hospital bed, on a background of microscope images of cells.
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