THE BRITISH LIBRARY

Science blog

Discover Science at the British Library

Introduction

We are the British Library Science Team; we provide access to world-leading scientific information resources, manage UK DataCite and run science events and exhibitions. This blog highlights a variety of the activities we are involved with. Follow us on Twitter: @ScienceBL. Read more

21 June 2019

Influencing Environments: Material, Socio-political, and Ethical Environments in Anne McLaren’s Work

Anne McLaren (1927-2007) was a leading mammalian developmental biologist who worked primarily with mice and contributed to many fields, including most famously the development of in vitro fertilization (IVF). As McLaren often put it, she was interested in ‘everything involved in getting from one generation to the next’, and in particular, she emphasized the ways in which an individual is always connected to, and a part of, its many environments. Taking a cue from McLaren, then, this post considers how environments—understood materially, socially, and ethically—shaped McLaren’s work.

Scientific Environments

For McLaren, environmental effects are never incidental—not for cells, not for science, and not for the scientist in society—and even her earliest experiments probed deeply into the effects of various environments. Some of the environmental effects she studied are more familiar, like the effect of ambient temperature on population variance, and others are more surprising, like the genetic effect that a mother’s uterus, and not just the material contained within the egg, has on the development of an embryo.

Fig-1
Figure 1. Slide from McLaren’s thumbnail sheet (Add MS 89202/2/20). Copyright © Estate of Anne McLaren.

While McLaren’s research showed how interconnected our very cells are with our environments, she showed an acute awareness for how this interconnectivity proves equally true for science itself. For example, McLaren knew that science needed diverse perspectives to grow, and so she actively fostered collaborative working environments. She was also highly attuned to socio-political issues, including the changing interests of funding bodies; structural gaps, like the lack of accessible childcare, that limit the participation of women in science; and the rise of new social concerns, including those surrounding ‘designer babies’ as embryonic research progressed. She knew that each of these issues materially shaped what scientific questions got asked and by whom (McLaren).
But McLaren did not stop with simply acknowledging the ways in which science was affected by its environment. She also held the reciprocal to be true: scientists affect their own physical, socio-political, and ethical environments. She therefore worked throughout her life to uphold what she saw as the duty of scientists, namely, to share research widely and to work with the public in ensuring that science progresses ethically and in the best interests of society.

Working Environments

But how did McLaren’s own research environments affect her actual work? The path that led to her 1958 breakthrough with John Biggers (1924-2001) on successfully transplanting fertilized mouse embryos cultured in vitro (in glass) to surrogate mothers proves an illuminating example.
From 1952-1959, McLaren and her then-husband Donald Michie (1923-2007) worked together on embryo transfer experiments. They first worked at University College London, but when they ran out of space for their mice in 1955, they undertook what proved to be a fortuitous move into the larger facilities at the Royal Veterinary College, London. There, they had room to grow and, as an added bonus, enjoyed relative autonomy from a specific department while doing their work (McLaren).

Fig-2
Figure 2. Note recording the move to the Royal Veterinary College. (Add MS 83844) Copyright © Estate of Anne McLaren

.
McLaren and Michie’s experiments went through more than just a change of scenery though. Across their work, they tested a variety of processes for ovary transplants, specimen preservation methods, and embryo transfers from a donor mouse to a surrogate mother. They also experimented with superovulation and superpregnancy, or hormonally triggered ovulation cycles and artificially increased litter sizes respectively, in order to consider, for example, what factors might hinder an embryo’s chance of survival, such as uterine crowding. They asked as many questions as they could and perfected a method of transferring embryos in vivo (directly from the donor to the surrogate), while also proving that the surrogate mother’s uterus passed on genetic effects to the transplanted offspring, tracked in the case of their experiments through the number of lumbar vertebrae (McLaren and Michie).

Fig-3comp
Figure 3. Pages from McLaren's Embryo Transfer Experiments Notebook, 1955-1959 (Add MS 83844). Copyright © Estate of Anne McLaren.


In the midst of this flurry of work, McLaren and Michie met Biggers. Their research interests overlapped, and, with him, McLaren and Michie undertook even more parallel experiments. One such experiment considered the effect of temperature on population variance, mentioned above, which was inspired in part because they had access to three different temperature rooms at the Vet Collage. Biggers, McLaren, and Michie also briefly considered the relationship between the length of a mouse’s tail—a major site of heat loss—and its ability to regulate temperature, although Biggers reports that they never fully explored that project (Biggers).

Fig-4
Figure 4. Charles Darwin's On the Origin of Species diagram, public domain

This rich, collaborative, and multi-tasked environment can be likened to a Darwinian tree of research ideas with many offshoots. As a product of this environment, a seemingly small experiment took place over about two months in the summer of 1958. Using the techniques McLaren had perfected with Michie, she and Biggers cultured 249 fertilized embryos for 48 hours in vitro before transplanting them into eight female mice (McLaren and Biggers). Nineteen days later, these transplants resulted in the live birth of two mice, or as McLaren called them, ‘bottled babies’, which were the first mammals ever cultured outside of a uterine environment pre-implantation (Biggers).

Fig-5
Figure 5. Anthony Smith, ‘Brave New Mice.’ Daily Telegraph, 6 October 1958, p. 11.

This experiment, dubbed by the press as producing ‘Brave New Mice’, justifiably received much scientific and public attention, while also laying the ground work for IVF in humans only 20 years later. Yet, as we see, the experiment itself was but a single offshoot in a much larger web of experiments, in which IVF as such was not specifically McLaren’s focus. This incredible range of McLaren’s impact is due in no small part to the efficient way in which she used the environments, people, and resources around her to their fullest potential, asking as much as she could from and through them in order to learn and give back.


Bridget Moynihan
PhD student, University of Edinburgh

As a PhD student at the University of Edinburgh, Bridget Moynihan’s research focuses on archival ephemera and digital humanities. These same interests led Bridget to undertake a British Library internship, researching the notebooks of Anne McLaren.

Further reading in the British Library

    1. For more on the temperature experiments, consult Add MS 83846, Add MS 83847, and Add MS 83848 for laboratory notebooks documenting these experiments, and Add MS 83972, which contains some of McLaren’s relevant published papers, such as 'The growth and development of mice in three climatic environments'. See also Add MS 89202/6/26, which includes tail length data.
    2. For more on the uterine effect experiments, consult Add MS 83843, Add MS 83844, and Add MS 83845 for laboratory notebooks documenting these experiments, Add MS 83830 for conference papers presented by McLaren, including ‘An Effect of the Uterine Environment upon an Inherited Skeletal Character in the Mouse’, and Add MS 83972 for some of McLaren’s relevant published papers, such as ‘Factors Affecting Vertebral Variation in Mice. 4: Experimental Proof of the Uterine Basis of a Maternal Effect’.
    3. For more on the in vitro mice, consult Add MS 89202/2/10 for McLaren and Biggers’ article ‘‘Test-Tube’ Animals. The Culture and Transfer of Early Mammalian Embryos’.

References

Biggers, JD. ‘Research in the canine block.’ Int J Dev Biol. 2001; 45:469–76.
McLaren, A. and Michie, D. ‘Factors affecting vertebral variation in mice. 4: Experimental proof of the uterine basis of a maternal effect.’ JEEM 6, 1958: 645-659.
McLaren, A. and Biggers, JD. ‘Successful Development and Birth of Mice Cultivated in vitro as Early Embryos.’ Nature 182, 1958: 877-878.
McLaren, A. ‘Professor Dame Anne McLaren interviewed by Martin Johnson and Sarah Franklin.’ 2007, oral history recording at the British Library.

09 May 2019

Perfecting the Writing Machine: Blind and Visible Writing Typewriters

Remington advert_LOU.LD21_13Jan1883new
From Lloyd's List 13th January 1883, shelfmark LOU.LD21

Among the exhibits in our Writing: Making Your Mark exhibition is this advertisement for a "Remington Perfected Typewriter". Guest blogger James Inglis, from the University of St Andrews and the National Museum of Scotland, wrote this guest post for us on how far it was from "perfected".

In 1878, American sewing machine and gun manufacturers E. Remington and Sons released the Remington Standard No. 2. Often regarded as the first commercially successful writing machine, the No. 2 Typewriter incorporated many features of typewriters that we are familiar with today. The No. 2 was the first machine to use a shift mechanism; based on patents by Lucian S. Crandall and Byron Brooks in 1875, this allowed the user to change between upper and lower-case letters. The No. 2 also showcased a QWERTYUIOP keyboard, which was first introduced on Remington’s Sholes and Glidden Type-Writer released in 1874. Today the QWERTY keyboard is ubiquitous across computers and smart devices.

The No. 2 Typewriter was followed by the Perfected No. 2 Typewriter in 1879, which ironed out some of the technical bugs with the original design. Adverts for the Remington Perfected Typewriter proudly stated that “it is to the pen what the sewing machine is to the needle”, reinforcing Remington’s role in the development of sewing machines and typewriters. The No. 2 Typewriter was so successful that Remington continued manufacture for 16 years. By the time the No. 2 typewriter was withdrawn in 1894 almost 100,000 machines had been sold: it was easily the most successful typewriter up to that point. 

Yet for all its success, there was one glaring problem with the Remington Perfected Typewriter. This was a drawback that beset all Remington typewriters in the late 19th and early 20th centuries. The No. 2 was a blind writing typewriter. In other words, the writing was not visible as you were typing it!
To understand the blind writing typewriter design, the images below show a No. 2 Typewriter from the National Museum of Scotland’s collection. The carriage of the No. 2 Typewriter is raised to reveal the circular arrangement of typebars known as the typebasket. At the end of each typebar are letters, numbers or symbols cast in relief. Each typebar carries two characters which are selected by using the shift key. Upon pressing a particular key, a system of wires pulls the corresponding typebar upwards, out of the typebasket so that it comes into contact with the inked ribbon directly beneath the underside of the platen (the roller around which the paper is wrapped). The pressure of the typebar through the ribbon leaves an imprint on the paper and the character is formed!

1Remington No. 2comp
Remington No. 2 Typewriter manufactured c. 1887. Held at National Museum of Scotland’s Collection Centre. Object reference T.1960.34.

The problem is that when the carriage is lowered the typebars are concealed. The characters are formed on the underside of the platen, out of the operator’s sight. The typist can only see what is written three or four lines later, once the platen has rotated around enough to reveal their previous work.

2Remington No. 2comp
Remington No. 2 with carriage raised revealing the inked ribbon and type-bar basket. Object reference, T.1960.34
3Remington No. 2comp
View from above showing how the typebars strike the ribbon from below

The video below show how pressing the keys lifts the typebars out of the typebasket and brings them into contact with the ribbon.

For inexperienced typists the amusing results of this drawback were illustrated in the article ‘The Type-Writer and Type-Writing’ published in The Girl’s Own Paper on August 18th, 1888. The article describes how, “During the first week or two the learner’s attempts will probably be something like the following”:  

5 Bad Typing
Type sample of an inexperienced typist, from an article in The Girl’s Own Paper, Saturday, August 18, 1888, BL shelfmark P.P.5993.w.

The fourth line is particularly bemusing and is caused by the operator typing straight over the previous sentence. Clearly, the typist did not return the carriage correctly in order to start a new line. These kinds of mistakes went unnoticed because the text was completely out of sight.
Yet the common argument was that a properly trained typist shouldn’t need to be able to see their work. A contemporary account of typewriters from Encyclopedia Britannica insisted:


Doubtless the novice who is learning the keyboard finds a natural satisfaction in being able to see at a glance that he has struck the key he was aiming at, but to the practical operator it is not a matter of great moment whether the writing is always in view or whether it is only to be seen by moving the carriage, for he should little need to test the accuracy of his performance by constant inspection as the piano player needs to look at the notes to discover whether he has struck the right one.


The reality of course was somewhat different, and typists of all levels found ways of getting around the problems with blind writing typewriters. The most popular solution was to stop and check on the progress of writing. Typewriters like the No. 2 came with carriages that could be raised and lowered on a hinge for basic operations such as loading the paper and changing the ribbon.
 
The film below, courtesy of British Pathé, shows a typing pool from around 1905. The typists regularly lift the carriage on the typewriters to check on their work.

Raising and lowering the carriage to check what was typed became a routine part of a typist’s work. While this got around the problem of writing visibility this technique was highly inefficient. As typewriter chronicler and inventor Henry Charles Jenkins commented in a paper to the Society of Arts in 1894:  


The Remington, Caligraph, Smith-Premier, Densmore, and Yost machines all have means by which the paper carrier or holder can be turned over upon some kind of hinge, and the writing, which has been performed under and out of sight, is brought into view. Operators get used to this, that they scarcely know how often they do it, but it must consume much time.


Unsurprisingly, rival typewriter manufacturers developed machines where the writing was always visible. The first visible writing typewriter was the Horton released in 1883. A circular introducing the Horton announced: “In the Horton Typewriter has been fully attained
 the invaluable object of having all the writing, to the last word, visible to the eye of the operator”. Of the many individuals this will benefit the advert claimed:

It will especially commend itself to those, such as clergymen, journalists and writers generally, who use writing machines in original composition. In the use of machines in which the writing is out of sight much time is necessarily lost in turning up the printing cylinder to get at the run of a sentence construction of which has escaped from the memory; and then, when this has been ascertained and the printing cylinder turned down again, the last word is perhaps forgotten before the rest of the sentence has been formed in the mind, so that the printing cylinder has to be turned up a second time before the writer is able to make any further progress.

6The Horton Typewriter
Preliminary circular for the Horton typewriter c. 1885

Despite these benefits, the Horton achieved very little success and it was not until the 1890s that visible writing typewriters gained much popularity. One particularly successful machine was the Oliver. The Oliver used U-shaped typebars that struck down on the paper from the right and the left. The video below shows an Oliver Visible No. 3 manufactured in 1904.

 

The machine that changed the state of the play more than any other was the Underwood. Invented by Franz Xavier Wagner in 1892, and manufactured by the Wagner Typewriter Company, this machine has been described as “the first truly modern typewriter”. In 1895, the patent rights were bought by John T. Underwood, marking the birth of the Underwood Typewriter Company. The Underwood was a front-strike typewriter. That is, the typebars hit the front of the platen leaving the text in full view of the operator.

8Underwood typewritercomp
Underwood Typewriter manufactured c. 1905. Held at the National Museum of Scotland’s Collection Centre. Object reference, T.1934.212

Finally, in 1908 Remington brought out its own front-strike, fully visible typewriter: the Remington Model 10.  The perfected, Perfected Typewriter you might say.

In an advertising pamphlet titled ‘Miss Remington Explains the New Model No. 10’, Miss Remington assures readers: “Yes, I am using one of the new No. 10 Remington Models, and I never supposed that it would be possible to combine so many good things in one machine.”

9 Miss Remington Explainscomp
‘Miss Remington explains the New Model No. 10 Typewriter’ c. 1908. An advertising pamphlet held at the National Museum of Scotland’s Collection Centre.

Yet Miss Remington makes no mention of the move from the blind writing, up-strike design of the Remington no. 9; to the front-strike visible writing set-up of the Model 10, which was arguably the biggest change in design since the introduction of the shift key 30 years earlier. Instead, Miss Remington makes vague comments such as “It has all the splendid points that my old Remington had and a dozen others that no writing machine has ever had.”

By 1908, the Remington Typewriter Company had been supporting their blind writing typewriter design for over a quarter of a century. While market pressures forced the company to change to the new and more popular visible writing system, it was too much of a climb down for Remington to admit that the old blind writing typewriters they had promoted and sold for so long, were far from perfect!

Sources
Michael H. Adler, The Writing Machine. London: Allen & Unwin, 1973. BL shelfmark X.620/7108
https://www.antikeychop.com/

James Inglis, The University of St Andrews and the National Museum of Scotland

Posted by Philip Eagle, Subject Librarian STM

Copyright James Inglis, posted by the British Library under a Creative Commons CC-BY-NC license. All illustrations are copyright James Inglis or public domain.

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

Image-2-1

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.

Image-2-2

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. 

BSW_RGB_POS_HI