Although one disease-causing virus is dominating the headlines at the moment (SARS-CoV-2, which is responsible for the Covid-19 pandemic) viruses are not the only pathogen to cause human disease.
Some bacteria are pathogenic and harmful to humans. They are responsible for causing serious, and sometimes deadly, conditions like tuberculosis, meningitis and pneumonia, and are particularly threatening, even in the 21st century, because of their impressive ability to evolve and develop resistance to antibiotic drugs designed to combat them.
As a result of work by German microbiologist Robert Koch in the late 1800s, bacterial cultures are the gold standard for infectious disease research. Microbiological cultures are used to determine the cause of an infectious disease, as well as allowing clinical studies into the susceptibility of bacteria to certain antibiotics.
This year marks the centenary of the world’s oldest repository of bacterial cultures, the UK’s National Collection of Type Cultures (NCTC).
Today, the NCTC, which is operated by Public Health England, houses more than 5,000 bacterial culture samples that represent almost 1,000 different species of bacteria; this discrepancy is because the collection contains various strains of different bacteria, as well as the type strain on which the description of the bacteria is based.
The collection’s samples date as far back as the late 19th century, with between 50 and 200 samples donated every year from around the world, according to the New York Times.
To honour this amazing resource, which supports crucial medical and scientific research to better human health, we look back at the NCTC’s 100-year history and its promise for the future.
1920: NCTC founded
In 1920, the NCTC was set up with funding from the Medical Research Committee (now known as the Medical Research Council) under the directorship of Sir John Ledingham, the chief bacteriologist of the Lister Institute of Preventative Medicine in Chelsea, London. The NCTC was initially also based at the Lister Institute.
The first specimens to be deposited in the NCTC came from a collection amassed by Sir Frederick William Andrewes during WW1. This included 200 strains of Shigella flexneri bacteria, which causes dysentery.
The very first strain to be added to the collection, known as NCTC 1, has a fascinating history. It was sent to Dr Andrewes by Lieutenant William Broughton-Alcock, a military bacteriologist, who took the sample of S. flexneri from Private Ernest Cable after he died. Cable is believed by the NCTC to be the first British soldier in WW1 to die of dysentery.
In its first year of existence, the NCTC distributed nearly 2,000 cultures free of charge to researchers across the UK.
1930s: NCTC refines it practices and moves out of London
During its first decade, the NCTC distributed its cultures in Dorset egg agar sealed with paraffin wax. However, as a result of experiments in the 1930s, by 1934 all samples in the collection were freeze-dried in glass ampoules to better preserve them.
The same freeze-drying techniques are still used today to distribute the cultures to researchers globally. Records show that in 1938 more than 6,000 cultures were distributed to scientists; 46 of those were posted outside the UK.
In 1939, the entire collection and associated records were transferred from London to the Lister Institute’s Farm Laboratories in Elstree, Hertfordshire. This turned out to be an excellent decision as the Lister Institute’s London base was bombed during WW2.
1930s – 1940s: Discovery of penicillin, the first antibiotic
Penicillin, the first antibiotic, was discovered by a team at Oxford University led by Sir Howard Florey, which famously included Alexander Fleming. Their work included studying the newly cultivated penicillin on bacteria cultures.
One such culture they used was of Staphylococcus aureus, and categorised as NCTC 6571, which Alexander Fleming himself had donated to the NCTC in 1943. According to the NCTC, this became its second-most distributed culture in the 1944 and became known as the ‘Oxford Staph’ because of the university’s extensive use of it in studies.
NCTC 6571 was only one of 16 cultures that Fleming donated to the NCTC between 1928 and 1948, one of which, NCTC 4842 of the Haemophilus influenzae bacteria, he sourced from his own nose.
The NCTC was therefore instrumental in the development of penicillin, but also in continuing future work on new and improved antibiotics. The repository’s cultures, and particularly those in the Murray Collection, have also helped to support research into understanding how some bacteria can develop resistance to these drugs over time.
1947: Focus on bacteria of medical interest and referencing
In 1947, the second curator of the NCTC, Ralph St John-Brooks, who had taken over from Ledingham in 1930, was himself replaced by Samuel Tertius Cowan.
Cowan oversaw many changes at the NCTC. One major addition was the introduction of nominal distribution charges – one shilling per culture. A more concrete payment system was created in the 1970s to cover NCTC’s operating costs.
Additionally, Cowan shifted the strategic priorities of the NCTC so it focused only on bacteria of medical interest. Non-medical cultures were transferred to different institutes with more appropriate expertise.
This move led to a mass characterisation project of the remaining collection of 3,000 cultures and, a decade later, the establishment of the first international code for referencing medical specimens. This in turn was linked to a manual that Cowan co-wrote to improve identification of bacterial species in the mid-1960s.
In 1949, after WW2 had ended, the NCTC moved back to London. It was housed in the central laboratory of the Public Health Laboratory Service (PHLS), which was part of the newly created National Health Service. Its administration was transferred from the MRC to the PHLS in 1960.
1960s: Pioneering cutting-edge technology
In the 1960s, building on its work on bacterial identification, the NCTC pioneered the use of numerical and computerised taxonomy to improve on biochemical tests to determine the similarities between different bacteria. This work was carried out using a research grant from the Department of Health and Social Security in 1965.
The next three decades saw the NCTC embrace new technology for analysis of bacterial cultures – starting with gas liquid chromatography to compare different species, then moving to gel electrophoresis for molecular identification and finally, 16S ribosomal RNA sequencing.
2013 – 2018: NCTC launches 3,000 whole genome project
A proud moment in the history of the NCTC is the five-year collaboration it signed with the Wellcome Trust’s Sanger Institute (WTSI) in 2013. The project involved producing an electronic record of whole-genome sequence data from 3,000 NCTC bacteria strains. Bioscience’s proprietary technology was leveraged and all data from the project is publicly available free of charge through the European Bioinformatics Institute.
The genome of Fleming’s nose isolate and Private Cable’s NCTC1 strain of S. flexneri were both part of the NCTC 3,000 Project. Although dysentery is often thought of as an old-fashioned disease, it still kills hundreds of thousands of children every year in developing countries and is a particular threat as it is resistant to two antibiotics – penicillin and erythromycin.
Researchers at WTSI led by Dr Kate Marker compared the genome of NCTC 1 with other NCTC S. flexneri strains isolated in 1954, 1984 and 2002 and found an evolutionary pattern that explains its virulence and the development of antimicrobial resistance. Their findings were published in The Lancet in 2014.
The 3,000 Project similarly enabled NCTC scientists to employ proteomic analysis techniques on Neisseria gonorrhoeae, the bacteria that causes gonorrhoea, another disease affected by AMR. The NCTC has provided the World Health Organization with 14 cultures of N. gonorrhoeae to support an international project to track the drug resistance patterns of these bacteria.
2018: PHE’s next-generation sequencing supported by NCTC
Another foray into whole-genome sequencing for NCTC came in 2018 when it became involved in Public Health England’s next-generation sequencing (NGS) service. This launched alongside the UK Government’s 2012 100,000 Genomes Project and focused on genomes for infectious diseases. It aims to improve management and control of infectious diseases both nationally and internationally and is now part of the National Infection Service.
To support this initiative, NCTC made a range of its DNA products derived from cell lines in its catalogue available to the NGS labs. One of these was NCTC 10538, E.coli K 12 genomic DNA, which became the control material for PHE’s entire service. The freeze-dried format of the NCTC’s E.coli product was central to its success as a suitable control.
PHLS – the NCTC’s administrative body – became part of Public Health England in 2013, and as a result the NCTC was relocated to PHE’s headquarters at Porton Down, Wiltshire.
2020: NCTC at 100 – resistance and mollicutes
Despite the Covid-19 pandemic disrupting its ability to distribute cultures to research laboratories at the moment, the NCTC has continued to accept donations of cultures.
Most notably, this year the US Food and Drug Administration deposited 17 novel strains of bacteria isolated from animals into the NCTC, including novel species of the genus Mycoplasma, Acholeplasma and Ureaplasma, which are types of mollicutes.
Mollicutes are a class of bacteria that do not have a cell wall around their cell membranes, making them very likely to be naturally resistant to any antibiotics that target cell wall synthesis, such as penicillin and vancomycin.
Having novel strains of this type of bacteria significantly adds to the NCTC’s existing repository of 126 strains of mollicutes and supports research into the consequences of these drug-resistant bacteria for human health.