AAGGCTC: What genes reveal
The population geneticist Ulrich Nübel can detect potentially new active substances hidden in bacterial strains.
For the population geneticist Ulrich Nübel almost everything revolves around gene sequences of bacterial strains. The scientist obtains a lot of information through analysing them: The course of infectious disease outbreaks and epidemics, as well as the spread of resistance. He can also detect potentially new active substances hidden in bacterial strains. Since 1 June 2014, Prof Ulrich Nübel has been bringing this expertise to the DZIF with his professorship “Microbial Genome Research”, established together with the TU Braunschweig and also located in Braunschweig at the German Collection of Microorganisms and Cell Cultures (DSMZ).
“Here, in the DSMZ basement, we probably have the coolest sequencer currently available,” Nübel explains. The usually rather reserved scientist is animated when he talks about “PacBio RSII”. It is a rather inconspicuous box from the outside, but with a very active interior. The process taking place inside is called Next Generation Sequencing and is able to decode entire genomes overnight, meaning that it determines the sequence of their building blocks, i.e. their nucleotides. The genetic code is encoded in the sequence of the base pairs adenine, guanine, thymine, and cytosine –abbreviated as A, G, T and C. “This new sequencing method is great for population geneticists,” Nübel explains. He is especially interested in organism diversity, particularly in bacteria, which, with the necessary expertise in bioinformatics, can be read from the gene sequences. “Point mutations in the bacterial genome occur with great regularity,” the researcher explains. “If you make these mutations visible in different strains through sequencing, then the genealogical tree and information about their spread can be reconstructed.”
Genetic sequencing methods were at a very early stage of development when Nübel started his studies in biotechnology in Braunschweig in 1989. However, he dared to venture into investigating bacterial genes. In his dissertation at the Max Planck Institute for Marine Microbiology in Bremen, he investigated the diversity of cyanobacteria, and in his subsequent research period in Montana he investigated phototrophic bacteria and archaebacteria in thermal springs and in hypersaline environments. Back in Germany, he lead a young research group at the DSMZ in Braunschweig for two years, working on themes in population genetics and biogeography of marine bacteria.
He quickly came to realise: In order to conduct successful population genetics, he would need appropriate strain banks, which at the time were only available in medicine. He had a Staphylococcus aureus collection at his disposal at the Robert Koch Institute in Berlin and in Wernigerode. Nowadays, these bacteria are known as dreaded multidrug-resistant hospital superbugs. They are resistant against methicillin (MRSA) and many other antibiotics through which they have become dangerous for ill and immunocompromised people. Ulrich Nübel requested the British Sanger Institute in Cambridge carry out genome sequencing of the different strains. Among other things, the analyses revealed that these multidrug-resistant bacteria had developed in England; in fact at the hospital in which the antibiotic had first been tested. They spread out into the world from there.
Nübel will be continuing these interesting investigations in a large EU project together with international partners. They are planning to develop an information bank in which the routes of spread and genealogical trees of the most different pathogens are recorded. “A kind of epidemiological weather chart which could, of course, also help to pre-detect outbreaks,” Nübel explains.
At the DZIF, Nübel is also working on bacteria, but more from a positive perspective – not as pathogens but as producers of active substances. A large number of antibiotics that have been discovered up to now stem from actinomycetes, and Nübel is certain that genome analyses of other strains, or of strains as yet unknown, could help detect a lot of new substances. The unusual collection of microorganisms at the DSMZ, the existing bioinformatics research group and the “Natural Compound Library”, a collection of active substances at the DZIF, were all reasons for taking up his professorship position. He then comes to speak about “PacBio” again, explaining why this highly modern sequencing method is so valuable for this purpose in particular. The initial stage is creating DNA snippets, as is also done in the conventional method, which have to be put together like a jigsaw puzzle after the sequencing. The larger these snippets are, the easier it is to subsequently combine them. While earlier methods produced “reads” of about 100 base pairs, methods nowadays produce reads with an average length of 10,000 base pairs. This is a big advantage for investigations into completely unknown genomes.
Nübel has sequenced the first six myxobacteria genomes together with DZIF colleagues at the Helmholtz Center for Infection. “We are optimistic about finding interesting substances. And under the roof of the DZIF we have the opportunity to successfully screen candidates for active substances and develop them further,” he says. He quickly felt at home in his new place of work at the DSMZ, not least because he had previously worked there, years ago. And for the father of two children, Braunschweig is already home ground. He has been living here with his family for ten years, and used to drive past the DSMZ in Stöckheim on an almost daily basis on his way to the Robert Koch Institute in Wernigerode. So now he is saving on fuel and time, which also benefits the DZIF.
