Tag Archives: molecular genetics

Professor George Gow Brownlee’s lab notebooks now available

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George Gow Brownlee (photograph from the Royal Society)

George Gow Brownlee (photograph from the Royal Society)

The archive of Professor George Gow Brownlee, FMedSci, FRS, is now available online. Professor Brownlee was born in 1942 and took his degree and then a PhD at Emmanuel College, Cambridge, studying under double Nobel Laureate Fred Sanger at the Laboratory of Molecular Biology (in 2014 he published a biography of Sanger). He worked for the Medical Research Council in Cambridge from 1966 until 1980 and then came to Oxford as a Fellow of Lincoln College and the first E.P. Abraham Professor of Chemical Pathology at the Sir William Dunn School of Pathology, a chair he held until retirement in 2008.

Professor Brownlee’s research interests were in molecular biology and he and his group made significant discoveries in sequencing RNA and DNA during the early days of that field of research. In 1977, his group discovered the existence of pseudogenes – abnormal, mutated genes – which are now known to be ubiquitous in the genome of all organisms. After 1980, Brownlee became more involved in applied medical problems, and managed to isolate the clotting factor IX gene (also known as Christmas factor), which is present in people with haemophilia B. This led to improved treatment for people with the disease. He went on to work on gene regulation in influenza. In 1999 he and Ervin Fodor, whose contributions feature heavily in this archive, were able to isolate recombinant influenza virus, which led to improved vaccines for children.

These lab notebooks, which span most of Professor Brownlee’s career, form a rich scientific record that interestingly covers failed experiments as well as the experiments that led to major discoveries. And as a bonus, the catalogue is based on Professor Brownlee’s own descriptions of the notebooks, so it offers a level of detail that couldn’t be replicated by anybody else. The archive is likely to be of interest to scientists in the field as well as medical historians.

‘A True Geneticist’s Geneticist’

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The papers of Sir Walter Bodmer have been intriguing, not only in terms of what they reveal about the history of science and genetics, but also for providing snapshots into the networks of co-operation, collaboration and relationships formed between prolific scientists. The large correspondence series of Sir Walter’s papers offer insight into how geneticists were continually learning from each other throughout their careers (and often disagreed), and through these exchanges of knowledge and ideas, lasting friendships were formed. The professional and personal correspondence between Walter Bodmer and Guido Pontecorvo (1907-1999) are one example of such a relationship.

As a young graduate student, Walter Bodmer travelled to Glasgow with his wife Julia and two young children, to spend time in the laboratory of Italian geneticist Guido Pontecorvo at Glasgow University. Pontecorvo was head of the new Department of Genetics in Glasgow, which he helped to establish (like Bodmer, who would later be instrumental in initiating the Department of Genetics in Oxford), and Professor of Genetics from 1955 to 1968.

Shortly after Bodmer completed his PhD in 1959, he became increasingly interested in the idea that quantitative genetics could be carried out properly on biochemical characters. Having learned about Pontecorvo’s work on Aspergillus, he hoped to travel to Glasgow and stay for a day or two to learn about this work and broaden his own outlook. In a report, Sir Walter wrote, ‘my reason for learning these techniques is a belief that they provide opportunities for a fundamental approach to the study of continuous quantitative genetics”. However, Pontecorvo firmly believed that basic biochemical and molecular genetics should be undertaken without the quantitative genetics. In addition, Pontecorvo was quite insistent that Bodmer would require several months (not days) to become acquainted with the techniques of biochemical genetics.

Dr. George Owen to Guido Pontecorvo, 28 November 1958

In 1987, Sir Walter looked back to 1959 when he first met Pontecorvo:

My first contact with him was nearly 30 years ago when, under the influence of my Professor, Sir Ronald Fisher, I had developed an interest in quantitative genetics but felt the need for biochemical analysis. It seemed that the Aspergillus system would be a marvellous basis for this, so I asked my formal supervisor, Dr. Owen, to write a letter, which I drafted, to Professor Pontecorvo about this. Perhaps I could visit for a day or so in the first instance and explore the applications of the Aspergillus system. In those days it would have been unusual for a graduate student to write directly to the Professor. I still have his reply. In it he said, “I strongly dislike the subject of quantitative genetics in general, and in particular in micro-organisms, which are so much better suited for the study of variations in fine genetic structure and its correlation with fine differences in proteins”. He was, of course, right.

Sir Walter has noted, “this was my first lesson in the value of persistence and calmness in relationships with others who may be much more senior than you are”.  It was this experience with Pontecorvo that gave Bodmer his first exposure to microbial genetics and modern genetics studies using the Aspergillus system (in addition to ideas on somatic cell genetics, perhaps the most significant influence on Sir Walter career and a major stimulus for the Human Genome Project).  According to Sir Walter, “Ponte’s pioneering insight that the asexual system of genetic analysis which he had developed for a fungus could be applied to human and animal cells in culture and laboratory” provided the fundamental background for later laboratory advances and applications at the molecular level. Indeed, the Bodmer archive contains a range of lab notebooks and papers from experiments using fusions to produce hybrids based on Pontecorvo’s method.

Sir Walter has written, “though my time in Glasgow was short, I count myself as one of Ponte’s students”. In fact, Guido Pontecorvo and Walter Bodmer became very good friends; they would have a lot of contact during Pontecorvo’s later career after he moved from Glasgow to the ICRF in London at the invitation of Michael Stoker (Bodmer’s predecessor as Director of Research at the ICRF). In 1987 Sir Walter initiated and organised a symposium and special edition of Cancer Surveys in honour of Pontecorvo on the occasion of his 80th birthday.

Francis Crick to Walter Bodmer, 18 May 1987 (Pontecorvo was known as ‘Ponte’ to his friends and colleagues).

Guido Pontecorvo has remained an important influence on the career of many geneticists, with Sir Walter referring to him as “a true geneticist’s geneticist”.

Preserving Science in the Archives (Part 1)

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Sir Walter and Lady Julia Bodmer’s archive covers nearly all aspects of their research careers as geneticists. While it is often the case that scientists discard research papers (or delete digital files) such as laboratory notes and datasets once the scientific conclusion results in published output, Sir Walter has been careful to retain every step of the research process leading up to publication. The archive includes sequencing and other experimental data sets, punch cards, lab notes and log books, multiple drafts of scientific papers and grant applications. Importantly, the more informal aspects of the research process have also been kept, adding a real human dimension to the archive. The correspondence, casual memos, jottings and annotations on reprints and lab notes encapsulate the ideas and observations, not to mention the frustrations endured throughout the research process, and ultimately, the thrill of scientific discovery.

stripey-walter-2
Sir Walter Bodmer c.1977

For this post I thought it would be useful to share some examples of the experimental materials enclosed in many of the lab notebooks. The archive comprises an impressive amount of lab work making up around a third of the full archive, which totals over 2000 boxes. This also includes the notebooks of collaborators and junior research staff working in various labs headed by the Bodmer’s in Oxford, Stanford and the Imperial Cancer Research Fund (now Cancer Research UK) in London.

The collection’s research sequences include Sir Walter’s early genetics work on Aspergillus and Neurospora, which he carried out as a postgraduate student at Cambridge University during the 1950s and until he went to Stanford in the 1960s. This covers molecular genetics experiments on DNA transformation in Bacillus subtilis, and work on human lymphocyte antigens. From the Genetics Laboratory at Oxford University research notebooks cover a variety of experiments throughout the 1970s, including those relating to HLA determinants on somatic cell hybrids. There are nearly 200 boxes alone containing lab notes from Julia Bodmer’s ICRF Tissue Antigen Laboratory including work on the production of monoclonal antibodies, in particular, DR antigens. There are also a similar number of boxes relating to colorectal cancer research carried out in Sir Walter’s Director’s Laboratory at the ICRF. Many of these papers offer a window into the development of techniques and methodologies used for work on extracting proteins and DNA.

strips
Lab work relating to polyclonal screening of colorectal cancer cell lines
 isolation
These images represent a small selection of lab techniques such as Western and Southern blotting, and gel electrophoresis. The technique of Southern blotting was developed by Sir Edwin Southern in 1973, and uses gel electrophoresis for the detection of a specific DNA sequence in a sample of DNA. Western blotting is similar but is used to detect and separate proteins, thereby allowing for the identification of specific antibodies (while Northern blotting detects RNA). Blotting by gel electrophoresis enables the transfer of membranes and involves hybridisation to a probe.
gel 2
gel 3
Western blot gel
Gel electrophoresis
dot blot 1
 There are also a number of dot blots, which is a method of applying proteins directly onto a membrane. Unlike Western blotting, it does not use electrophoresis to separate proteins. Sample proteins are applied directly on a membrane as a dot and hybridized with an antibody that acts as a probe.
gel
From an archivist’s perspective, the laboratory materials are both fascinating and unusual, and have also posed many preservation challenges concerning long-term protection of the archive. The generous support from the Wellcome Trust has enabled us to safeguard these important materials in order to ensure their long-term physical survival and make them accessible to future researchers. As such, we have worked with the Libraries’ preventative conservator and health and safety representatives to find the most suitable enclosures for these materials.Thankfully the majority of lab material is in an excellent and stable condition with no degradation, and we have been taking protective steps to ensure future degradation is minimal and avoids crosslink and damage with other materials. Preservation measures have included the use of acid absorbers and archival quality non-acidic repackaging material.
Western wet transfer
Immunodetection using Amersham ECL Western blotting kit (immunodetection uses antibodies to detect the presence of specific antigens)

Importantly, the majority of the collection has been retained (by the Bodmers and now archivist) within its original order and context. For a non-scientist archivist, the abundance of explanatory documentation that exists with the laboratory papers has proved invaluable for contextualisation, and will also add to the collection’s historical value.