Researchers decode mechanism for diversifying bioactive phenazines
FRANKFURT. Bacteria produce a cocktail of various bioactive natural products in order to survive in hostile environments with competing (micro)organisms. In the current issue of Nature Chemical Biology, researchers at Goethe University demonstrate that they do so by modifying basic structures, similar to the approach taken in pharmaceutical research.
Phenazines are widespread and chemically diverse bacterial natural products that can fulfil various biological functions. Like antibiotics, some derivatives kill bacteria; others are toxic to fungi and/or cancer cells. There are also derivatives that allow the bacteria to survive in an environment that is hostile to them, such as the human body. These virulence factors are often crucial for the bacteria to become pathogenic.
Biochemically, all phenazines are derived from simple basic structures, such as the phenazine-1,6-dicarboxylic acid or phenazine-1-carboxylic acid, whose biosynthesis is well understood. However, these initial structures can be drastically modified in the periphery so that a large number of phenazine derivatives are possible, several of which can indeed be found in different bacteria. The Molecular Biotechnology research group led by Professor Helge Bode has now succeeded in identifying new mechanisms that allow the bacteria to modify these simple basic structures, resulting in derivatives that act on both Gram-positive and Gram-negative bacteria, as well as on cells of higher organisms.
“Bacteria are able to determine which derivatives should be created using a central new aldehyde intermediate as well as the activation of a second biosynthetic gene cluster," explains Dr. Yi-Ming Shi, who investigated this system during a Humboldt scholarship. This means that bacteria use mechanisms for drug development similar to those used in pharmaceutical research, where new derivatives are produced using the same basic structures. Most likely the bacteria use the phenazines to kill other bacteria and fungi that are food competitors in their particular ecosystem. Using a strategy of creating many different kinds of derivatives, the bacteria are well equipped to counteract unknown competitors, as the cocktail of derivatives exhibits a wide range of biological activity.
“It would now be fascinating to find out how bacteria actually recognise which derivatives are required at a given time," states Helge Bode. “Either they produce only those derivatives that are actually required, or the bacteria keep an arsenal of derivatives so that they are prepared for any situation."
The group will therefore continue their research in this area. First results on the underlying regulation mechanisms that could also be used for biotechnical applications appear promising.
Publication: Yi-Ming Shi, Alexander O. Brachmann, Margaretha Westphalen, Nick Neubacher, Nicholas J. Tobias, Helge B. Bode, Dual phenazine gene clusters enable diversification during biosynthesis. Nature Chemical Biology, 2019, 10.1038/s41589-019-0246-1.
A picture may be downloaded at: http://www.uni-frankfurt.de/76883939
Caption: Examples of the phenazine cocktail produced by Xenorhabdus szentirmaii bacteria. Phenazines are not only bioactive, but also exhibit the colours depicted here. Credit: Dr. Yi-Ming Shi
Further information: Professor Helge B. Bode, Molecular Biotechnology, Faculty 15, Riedberg Campus, Tel.: +49 69 798-29557, email@example.com.
Innovative methods lead to foundation of start-up Vivlion GmbH
FRANKFURT. CRISPR/Cas enables the targeted deactivation of genes by cutting DNA at pre-determined sites. This is accomplished by providing the Cas enzyme with a genetic zip code. Using an entire library of zip codes, it is then possible to simultaneously probe multiple sites within the genome, for example to determine which genes are essential for cancer cell survival. This could revolutionize drug discovery.
Unfortunately, however, creation of libraries containing high numbers of zip codes covering the entire genome proved to be difficult. Researchers at Goethe University now succeeded in solving this problem. As Dr Manual Kaulich reports in the scientific journal “eLife", he and colleagues found a reliable method for creating libraries of any magnitude. “Using our newly developed 3Cs technology, we for the first time came up with a library that allows us to investigate the entire genome simultaneously – including non-coding regions outside of genes. In total, our library contains 16.5 million unique zip codes," explains Kaulich, who leads an independent research group at the Institute of Biochemistry II.
The non-coding regions which represent 98% of our genome are of particular interest as they are suspected to hold the key to numerous regulatory mechanisms. CRISPR/Cas reagents produced by the novel method can for example help to better understand mechanisms underlying chemotherapy resistance.
The flash of inspiration hit Manuel Kaulich together with colleague Dr Andreas Ernst, who at that time was also heading a research group at Institute of Biochemistry II. “We were chatting about our different areas of expertise and suddenly there was this compelling idea on how to elegantly combine the two," state Kaulich and Ernst.
Since then, Manuel Kaulich has established numerous additional collaborations, like the one with Dr Anja Bremm, also a group leader at the Institute of Biochemistry II, on the biological relevance of a certain protein class. Together with Institute Director Professor Ivan Dikic, he set up the “Frankfurt CRISPR/Cas Screening Center" (FCSC), which aims at making the technology broadly accessible for studying unknown cellular functions. Ivan Dikic comments: “This exciting discovery is also attributed to the unique culture of our Institute, which inspires creativity, new ideas, and teamwork."
Through its technology transfer subsidiary Innovectis, Goethe University has meanwhile applied for a patent to protect the innovative idea. The patent also forms the basis for the start-up company Vivlion GmbH, which was recently founded by three employees of the Institute of Biochemistry II together with Goethe University. Vice President Professor Manfred Schubert-Zsilavecz comments: “This is a milestone for the Goethe University: Vivlion is the first start-up that was founded with the participation of Goethe University employees."
Innovectis prepared the grounds for the start-up to take off. As Innovectis CEO Martin Raditsch states, “I am very happy about successfully starting Vivlion GmbH from out of Goethe University, because we have here a very promising technology coming together with an excellent working group and a perfectly assembled founding team." The company will introduce the first 3Cs reagents to the market in the upcoming months.
Publication: Wegner M, Diehl V, Bittl V, de Bruyn R, Wiechmann S, Matthes Y, Hebel M, Hayes MG, Schaubeck S, Benner C, Heinz S, Bremm A, Dikic I, Ernst A, Kaulich M. Circular synthesized CRISPR/Cas gRNAs for functional interrogations in the coding and noncoding genome. Elife. 2019 8: e42549. doi: 10.7554/eLife.42549. https://elifesciences.org/articles/42549
A picture may be downloaded here: http://www.uni-frankfurt.de/76899967
Caption: The team of Manuel Kaulich (2nd from right) in the laboratory. Credit: Uwe Dettmar
Further information: Dr. Kerstin Koch, Institut für Biochemie II, Universitätsklinikum, Tel.: +49 69 6301 84250, firstname.lastname@example.org
An experiment at GSI simulates how heavy elements capture protons
FRANKFURT. Heavy elements are produced during stellar explosion or on the surfaces of neutron stars through the capture of hydrogen nuclei (protons). This occurs at extremely high temperatures, but at relatively low energies. An international research team headed by Goethe University has now succeeded in investigating the capture of protons at the storage ring of the GSI Helmholtzzentrum für Schwerionenforschung.
As the scientists report in the current issue of Physical Review Letters, their goal was to determine more precisely the probability for a proton capture in astrophysical scenarios. As Dr. Jan Glorius from the GSI atomic physics research department explains, they were faced with two challenges in this endeavour: “The reactions are most probable under astrophysical circumstances in an energy range called the Gamow window. In this range, nuclei tend to be somewhat slow, making them difficult to obtain in the required intensity. In addition, the cross section – the probability of proton capture – decreases rapidly with energy. Until now, it has been almost impossible to create the right conditions in a laboratory for these kinds of reactions."
René Reifarth, Professor for experimental astrophysics at Goethe University suggested a solution as early as ten years ago: The low energies within the Gamow window range can be reached more precisely when the heavy reaction partner circulates in an accelerator in which it interact with an stationary proton gas. He achieved first successes in September 2015 with a group of Heimholtz early career researchers. Since then, his team has gained excellent support from Professor Yuri Litvinov, who leads the EU-funded research project ASTRUm at GSI.
In the experiment, the international team first produced xenon ions. They were decelerated in the experimental storage ring ESR and caused to interact with protons. This resulted in reactions in which the xenon nuclei captured a proton and were transformed into heavier caesium – a process like that which occurs in astrophysical scenarios.
“The experiment makes a decisive contribution to advancing our understanding of nucleosynthesis in the cosmos," says René Reifarth. “Thanks to the high-performance accelerator facility at GSI, we were able to improve the experimental technique for decelerating the heavy reaction partner. We now have more exact knowledge of the area in which the reaction rates occur, which until now had only been theoretically predicted. This allows us to more precisely model the production of elements in the universe."
The experiment took place as part of the research collaboration SPARC (Stored Particles Atomic Physics Research Collaboration), which is part of the FAIR research programme. Equipment funded by the Verbundforschung (collaborative research) of the Federal Ministry for Education and Research was used in this experiment.
A picture can be downloaded here: http://www.uni-frankfurt.de/76756294
Caption: For the first time, it was possible to investigate the fusion of hydrogen and xenon using an ion storage ring at the same temperatures as during stellar explosions. Credit: Mario Weigand, Goethe-Universität
Publication: J. Glorius et al: Approaching the Gamow window with stored ions: Direct measurement of 124Xe(p,γ) in the ESR storage ring, in PRL, DOI:10.1103/PhysRevLett.122.092701
Further information: Professor René Reifarth, Institute for Applied Physics at Goethe University, Riedberg Campus, Tel.: +49 69 798-47442, Reifarth@physik.uni-frankfurt.de.
Laser light determines chirality of molecules
FRANKFURT. Seven of the ten most frequent medications contain chiral agents. These are molecules that occur in right- or left-handed forms. During chemical synthesis both forms usually occur in equal parts and have to be separated afterward, because chirality determines the agent's effect in the body. Physicists at Goethe University have now succeeded in using laser light for the purpose of creating either right- or left-handed molecules.
“In pharmaceutics, being able to transition a molecule from one chirality to the other using light instead of wet chemistry would be a dream," says Professor Reinhard Dörner from the Institute of Atomic Physics at Goethe University. His doctoral student Kilian Fehre has now brought this dream one step closer to coming true. His observation: the formation of the right- or left-handed version depends on the direction from which laser light hits the initiator.
For his experiment, Kilian Fehre used the planar formic acid molecule. He activated it with an intense, circularly polarized laser pulse to transition it to a chiral form. At the same time, the radiation caused the molecule to break into its atomic components. It was necessary to destroy the molecule for the experiment so that it could be determined whether a duplicate or mirror version was created.
Fehre used the “reaction microscope" (COLTRIMS method) that was developed at the Institute for Atomic Physics for the analysis. It allows the investigation of individual molecules in a molecular beam. After the molecule's explosive breakdown, the data provided by the detector can be used to precisely calculate the direction and speed of the fragments' paths. This makes it possible to reconstruct the molecule's spatial structure.
In order to create chiral molecules with the desired chirality in the future, it has to be ensured that the molecules are oriented the same way with regard to the circularly polarized laser pulse. This could be achieved by orienting them beforehand using a long-wave laser light.
This discovery could also play a critical role in generating larger quantities of molecules with uniform chirality. However, the researchers believe that in such cases, liquids would probably be radiated rather than gases. “There is a lot of work to be done before we get that far," Kilian Fehre believes.
The detection and manipulation of chiral molecules using light is the focus of a priority programme which goes by the memorable name “ELCH" and which has been funded by the German Research Council since 2018. Scientists from Kassel, Marburg, Hamburg and Frankfurt have joined forces in this programme. “The long-term funding and the close collaboration with the priority programme provide us with the necessary resources to learn to control chirality in a large class of molecules in the future," concludes Markus Schöffler, one of the Frankfurt project managers of the priority programme.
Publication: K. Fehre, S. Eckart, M. Kunitski, M. Pitzer, S. Zeller, C. Janke, D. Trabert, J. Rist, M. Weller, A. Hartung, L. Ph. H. Schmidt, T. Jahnke, R. Berger, R. Dörner und M. S. Schöffler: Enantioselective fragmentation of an achiral molecule in a strong laser field, in: Science Advances, doi: 10.1126/sciadv.aau7923
An image can be downloaded here: www.uni-frankfurt.de/76731281
Caption: The formic acid model is in the centre. The color code of the surrounding sphere shows the direct chirality of the formic acid for every direction from which the laser comes. If the laser is directed from the right side (right arrow), it results in right-handed formic acid; if from the left, in left-handed formic acid. Both chiral formic acids reflect the common structure of the molecule.
Further information: Kilian Fehre, Tel: +49 69 798-47004, email@example.com; Prof. Reinhard Dörner, Tel: +49 69 798-47003, firstname.lastname@example.org; Dr. Markus Schöffler, Tel: +49 69 798-47022, email@example.com. Institute for Atomic Physics, Faculty of Physics, Riedberg Campus.
Goethe University’s Institute for Law and Finance (ILF) makes the top ten in worldwide ranking
FRANKFURT/BRÜSSEL. The Institute for Law and Finance (ILF) at Goethe University has a strong international profile. It has now been named one of the top ten LL.M programmes in the field of law for banking, finance and securities for the year 2019 by the online portal “LL.M. Guide."
“LL.M." stands for “Master of Laws". It is a postgraduate law degree which can be obtained by law graduates as well as graduates of business, finance and other equivalent disciplines. The degree is especially widespread in the English-speaking parts of the globe. The Institute for Law and Finance at Goethe University offers two degrees programmes, namely LL.M. Finance and LL.M. International Finance. The institute is relatively young: it was established as a non-profit foundation in 2002 by Goethe University with the support of supervisory authorities, banks, and law firms for the purpose of conducting research and education in law and finance.
The “LL.M. Guide" portal is a leading web portal for master of laws programmes. Prospective students can find extensive information on LL.M. master programmes offered worldwide, a discussion forum, and editorial articles about law degree programmes. Applicants from all over the world desiring an LL.M. use the portal to acquire information and prepare their applications for acceptance to a programme.
The “LL.M. Guide" compared and evaluated the ILF's two degree programmes with the LL.M. master of laws programmes at globally renowned international universities (e.g, Harvard, Columbia, Boston, London School of Economics, National University of Singapore). Outside of the Anglo-American parts of the globe, the ILF is the best institute of its kind in the world.
Further information: Prof. Dr. Andreas Cahn, Institute for Law and Finance, House of Finance, Westend Campus, Tel: +49 69/798-33753, E-Mail: mailto:Cahn@ilf.uni-frankfurt.de; Homepage Institute for Law and Finance: https://www.ilf-frankfurt.de