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Microbial Genomics: Standing on the Shoulders of Giants

Professor Everitt George Dunne Murray (1890–1964)
Professor Murray was a microbiologist and clinician who qualified at the beginning of the 20th century. During World War I he was involved in developing some of the first serotyping schemes, for Cerebro-Spinal Fever-causing meningococci, as well as dysentery. He later described the pathogen Listeria monocytogenes and its disease manifestation before moving to McGill University in Canada where he was responsible for building the Department of Bacteriology and Immunology while remaining active in bacterial taxonomy and research. Over his career he amassed hundreds of clinical isolates of enteric bacteria, most of which were collected before the widespread clinical use of antimicrobials. This collection of 'pre-antibiotic' bacteria was passed on to his son when Murray died in 1964 and was formally preserved in the National Collection of Type Cultures in the 1980s, where it is now publically available as a research resource.
[Picture credit: Wellcome images]
 

Murray, microbes, and me - Kate Baker

"If I have seen further it is by standing on the shoulders of giants." That famous, but arguably sarcastic, remark from Isaac Newton to Robert Hooke, is quoted in the dedication page of my doctoral thesis, so it seems appropriate that I honour this sentiment through a specific example. We all rely on the incremental advances of those who came before us to shape our own hypotheses, as well as the support and guidance of our supervisors and mentors, but every now and then we come across an additional scientific 'giant' whose work is particularly formative for ourselves and our career trajectory. And this can happen even when they died nearly two decades before we were born.

Like myself, Everitt George Dunne Murray journeyed across the equator to take up his studies in Cambridge. Born in Johannesburg in 1890, he completed his B.A between the University of Cambridge and St Bartholomew’s Hospital in London in 1912 and shot to early responsibility at the outset of World War I, when he was sent to the Pasteur Institute to work on meningococcus serum, developing the first serological subtyping of a bacterial species (Gordon and Murray, 1915). Murray was fascinated by bacterial diversity and he later turned his attention to my own bug-love, Shigella, the causative agent of bacillary dysentery that was the most prevalent diarrhoeal disease during WWI (Linton, 2010) and for which Murray also developed a serological subtyping scheme (Murray, 1918). The recognition that the war had brought together a hitherto unforeseen diversity of dysentery, and the importance of preserving this diversity for future study, was what prompted the formation of the National Collection of Type Cultures (NCTC) in 1920, a resource that operates and grows to this day, housing over 3,000 reference isolates of pathogenic organisms (Andrewes and Inman, 1919).

The foresight of these early microbiologists facilitated our 2014 study of the evolution of Shigella flexneri in the 100 years since WWI. We sequenced the genome of NCTC1, a Shigella bacterium isolated from the Western Front during WWI, and the first isolate accessioned into the NCTC. By comparing it with three other Shigella genomes from the same lineage collected at different time points, we revealed that the functions acquired over time related almost entirely to increasing pathogen virulence, antimicrobial resistance and serotype switching, presumably for immune evasion (Baker et al., 2014). This highlighted to me how exquisitely-targeted the evolution of Enterobacteriacae through lateral gene transfer can be over longer time scales. This targeted evolution over time, along with the immediate epidemiological impact this evolutionary capacity can have on modern-day Shigella concerns (which I have seen through my work on emerging multidrug-resistant genetic lineages of Shigella in community-associated risk groups (Baker et al, 2015b, Baker et al., 2016)) made it obvious why we are now amid a global crisis of antimicrobial resistance, and cemented my interest in the area. However, conclusions drawn from such a small number of isolates are perhaps better-treated as robust hypotheses, and further work examining pathogen evolution spanning the antibiotic era is necessary.

It is fortunate then that E.G.D. Murray continued to amass a private collection of Enterobacteriaceae alongside the growing NCTC, including a dysentery strain with which he was infected while working in Mesopotamia (Wilson, 1966). His enthusiasm and persistence for amassing the collection is clear in his communiques from supplying scientists, and between 1917 and 1954 he had collected over 600 strains. In addition to providing the important observation that approximately 70%–90% of the bacteria survived long-term (up to 60 years) storage on agar slopes (Murray, 1985), The Murray Collection of Enterobacteriaceae remains to this day one of the largest collections of live bacterial isolates collected prior to the widespread clinical use of antimicrobials, making it an invaluable resource for studying the evolution of antimicrobial resistance.

To this end, in 1980 under the impetus of Professor Naomi Datta, The Murray Collection was sub-cultured and brought over to the United Kingdom from Canada, where E.G.D. Murray had played out the remainder of his days building up the Department of Bacteriology at McGill University and remaining active in bacterial classification and taxonomy (Wilson, 1966, Collip, 1965). The transfer of The Collection was facilitated by R.G.E. Murray, E.G.D. Murray’s microbiologist son who had inherited the collection on his father’s death in 1964. At the time, his son reflected that the resuscitation of The Collection was "Good to contemplate after some years of feeling guilty about not making the best use of them" [Quote from a latter from Professor R.G.R. Murray to Dr. R.L. Hill at the NCTC, dated May 9, 1980, held at NCTC.] Together, Professors Datta, R.G.E. Murray and Dr Laurence Rowland Hill, coordinated the transfer of the strains to the NCTC (curated at the time by Hill). This paved the way for Datta and research assistant Victoria Hughes’ seminal work on the collection, demonstrating the common occurrence of plasmid groups known to carry antimicrobial resistance in the pre-antibiotic era isolates (Datta and Hughes, 1983, Hughes and Datta, 1983). Subsequent uses of the Murray collection have studied phenotype variation, including virulence; and resistances to mercury, disinfectants and antimicrobials; and, for my own pet-bug, Murray Collection strains were recently instrumental in reconstructing the evolution and accumulated antimicrobial resistance in Shigella dysenteriae (Njamkepo et al., 2016, Baker et al., 2015a).

To accelerate the capitalisation on Murray's foresight in preserving the bacteria, access to The Murray Collection was recently improved by a collaborative initiative between the Wellcome Trust Sanger Institute and Public Health England. Nearly 400 of the strains from The Collection were whole genome sequenced and the entire collection was made publicly available through the NCTC (Baker et al., 2015a), creating a unique research resource that is timely given the growing number of individuals and groups working on antimicrobial resistance whose studies might be further illuminated by Murray’s collection. I was humbled to be involved in this initiative, and hope that in doing so we honoured his son’s intentions that The Collection might be used to its full potential when it was released from his guardianship. Together, we as a community will no doubt continue to utilise The Collection to quantitate and qualify the impact of the use of antimicrobials and other agents on shaping bacterial populations over the antibiotic era, which threatens to come to a close.

The affinity I feel for E.G.D. Murray goes beyond his being another enthusiastic antipodean that moved to the United Kingdom for study and beyond his carrying his mother's maiden name "Dunne" through another generation, which was an inspirational discovery for this early career, female researcher. It even transcends the scientific parallel of his pioneering subtyping techniques for Shigella which I, and colleagues, work to improve using microbial genomics (Connor et al., 2015, Holt et al., 2012, Njamkepo et al., 2016). The affinity I have for Murray arises from the rare and great honour it was to pick up on threads of investigation intentionally left behind by another scientist, sadly departed, and I am proud to have contributed in some way to realising his hopes for the future of microbiology. In 1954, 10 years before his death, Murray commented that "Until quite recently, the difficulties and the seemingly merely academic importance of the minute structure of bacteria have induced most of us to be content with little more than the shape of their cells and their arrangement" (Murray, 1954). Since then the landscape of microbiology has been completely transformed, and I feel confident that he would have been excited to see his strains set into the context of the current revolution in microbiology and bacterial classification brought about by microbial genomics, as well as the promise that his strains may contribute to combatting antimicrobial resistance – surely one of the greatest global public health challenges we will face in the 21st century.

An excerpt from a copy of E.G.D. Murray's "Dysentery notebook" noting the 'Cable' strain that was later accessioned by Andrewes and Inman as NCTC1 (scanned from NCTC archives and reproduced with permission for the purposes of non-commercial research).

References:

  1. ANDREWES, F. W. & INMAN, A. C. 1919. A study of the serological races of the Flexner group of dysntery bacilli. Medical Research Committee, Special Report Series His Majesty's Stationery Office.
  2. BAKER, K. S., BURNETT, E., MCGREGOR, H., DEHEER-GRAHAM, A., BOINETT, C., LANGRIDGE, G. C., WAILAN, A. M., CAIN, A. K., THOMSON, N. R., RUSSELL, J. E. & PARKHILL, J. 2015a. The Murray collection of pre-antibiotic era Enterobacteriacae: a unique research resource. Genome Med, 7, 97.
  3. BAKER, K. S., DALLMAN, T. J., ASHTON, P. M., DAY, M., HUGHES, G., CROOK, P. D., GILBART, V. L., ZITTERMANN, S., ALLEN, V. G., HOWDEN, B. P., TOMITA, T., VALCANIS, M., HARRIS, S. R., CONNOR, T. R., SINTCHENKO, V., HOWARD, P., BROWN, J. D., PETTY, N. K., GOUALI, M., THANH, D. P., KEDDY, K. H., SMITH, A. M., TALUKDER, K. A., FARUQUE, S. M., PARKHILL, J., BAKER, S., WEILL, F. X., JENKINS, C. & THOMSON, N. R. 2015b. Intercontinental dissemination of azithromycin-resistant shigellosis through sexual transmission: a cross-sectional study. Lancet Infect Dis, 15, 913–21.
  4. BAKER, K. S., DALLMAN, T. J., BEHAR, A., WEILL, F. X., GOUALI, M., SOBEL, J., FOOKES, M., VALINSKY, L., GAL-MOR, O., CONNOR, T. R., NISSAN, I., BERTRAND, S., PARKHILL, J., JENKINS, C., COHEN, D. & THOMSON, N. R. 2016. Travel- and Community-Based Transmission of Multidrug-Resistant Shigella sonnei Lineage among International Orthodox Jewish Communities. Emerg Infect Dis, 22, 1545–53.
  5. BAKER, K. S., MATHER, A. E., MCGREGOR, H., COUPLAND, P., LANGRIDGE, G. C., DAY, M., DEHEER-GRAHAM, A., PARKHILL, J., RUSSELL, J. E. & THOMSON, N. R. 2014. The extant World War 1 dysentery bacillus NCTC1: a genomic analysis. Lancet, 384, 1691–7.
  6. COLLIP, J. B. 1965. Proffessor Egd Murray. An Appreciation. Can Med Assoc J, 92, 95–7.
  7. CONNOR, T. R., BARKER, C. R., BAKER, K. S., WEILL, F. X., TALUKDER, K. A., SMITH, A. M., BAKER, S., GOUALI, M., PHAM THANH, D., JAHAN AZMI, I., DIAS DA SILVEIRA, W., SEMMLER, T., WIELER, L. H., JENKINS, C., CRAVIOTO, A., FARUQUE, S. M., PARKHILL, J., WOOK KIM, D., KEDDY, K. H. & THOMSON, N. R. 2015. Species-wide whole genome sequencing reveals historical global spread and recent local persistence in Shigella flexneri. eLife, 4, e07335.
  8. DATTA, N. & HUGHES, V. M. 1983. Plasmids of the same Inc groups in Enterobacteria before and after the medical use of antibiotics. Nature, 306, 616-7.
  9. GORDON, M. H. & MURRAY, E. G. D. 1915. Identification of the meningococcus. Journal of the Royal Army Medical Corps., 25, 411–423.
  10. HOLT, K. E., BAKER, S., WEILL, F. X., HOLMES, E. C., KITCHEN, A., YU, J., SANGAL, V., BROWN, D. J., COIA, J. E., KIM, D. W., CHOI, S. Y., KIM, S. H., DA SILVEIRA, W. D., PICKARD, D. J., FARRAR, J. J., PARKHILL, J., DOUGAN, G. & THOMSON, N. R. 2012. Shigella sonnei genome sequencing and phylogenetic analysis indicate recent global dissemination from Europe. Nat Genet, 44, 1056–9.
  11. HUGHES, V. M. & DATTA, N. 1983. Conjugative plasmids in bacteria of the 'pre-antibiotic' era. Nature, 302, 725–6.
  12. LINTON, D. S. 2010. "War dysentery" and the limitations of German military hygiene during World War I. Bulletin of the History of Medicine, 84, 607–639.
  13. MURRAY, E. G. D. 1918. An attempt at classification of Bacillus dysenteriae, based upon an examination of the agglutinating properties of fifty-three strains. Journal of the Royal Army Medical Corps., 31, 257–271
  14. MURRAY, E. G. D. 1954. A Surmise on Some Trends in Bacteriology. Lancet, 1, 221–224.
  15. MURRAY, R. G. E. 1985. More on bacterial longevity: The Murray Collection. American Society for Microbiology News, 51, 261–262.
  16. NJAMKEPO, E., FAWAL, N., TRAN-DIEN, A., HAWKEY, J., STROCKBINE, N., JENKINS, C., TALUKDER, K. A., BERCION, R., KULESHOV, K., KOLINSKA, R., RUSSELL, J. E., KAFTYREVA, L., ACCOU-DEMARTIN, M., KARAS, A., VANDENBERG, O., MATHER, A. E., MASON, C. J., PAGE, A. J., RAMAMURTHY, T., BIZET, C., GAMIAN, A., CARLE, I., SOW, A. G., BOUCHIER, C., WESTER, A. L., LEJAY-COLLIN, M., FONKOUA, M. C., HELLO, S. L., BLASER, M. J., JERNBERG, C., RUCKLY, C., MERENS, A., PAGE, A. L., ASLETT, M., ROGGENTIN, P., FRUTH, A., DENAMUR, E., VENKATESAN, M., BERCOVIER, H., BODHIDATTA, L., CHIOU, C. S., CLERMONT, D., COLONNA, B., EGOROVA, S., PAZHANI, G. P., EZERNITCHI, A. V., GUIGON, G., HARRIS, S. R., IZUMIYA, H., KORZENIOWSKA-KOWAL, A., LUTYNSKA, A., GOUALI, M., GRIMONT, F., LANGENDORF, C., MAREJKOVA, M., PETERSON, L. A., PEREZ-PEREZ, G., NGANDJIO, A., PODKOLZIN, A., SOUCHE, E., MAKAROVA, M., SHIPULIN, G. A., YE, C., ZEMLICKOVA, H., HERPAY, M., GRIMONT, P. A., PARKHILL, J., SANSONETTI, P., HOLT, K. E., BRISSE, S., THOMSON, N. R. & WEILL, F. X. 2016. Global phylogeography and evolutionary history of Shigella dysenteriae type 1. Nat Microbiol, 1, 16027.
  17. WILSON, G. S. 1966. Everitt George Dunne Murray, 21 July 1890-6 July 1964. J Pathol Bacteriol, 91, 641–56.


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