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nucleic acids

New Cluster for Nucleic Acid-based Therapeutics in Munich

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The winners of the second round of the Clusters4Future competition in Germany have been announced by the German Federal Ministry of Education and Research (BMBF). Among them is C-NATM, a cluster focused on the development of innovative therapies using nucleic acids. C-NATM is led by Prof. Thomas Carell, Director of the Institute of Chemical Epigenetics at LMU Munich and Supervisor of two ESRs in NATURE-ETN. The cluster involves the two universities in Munich, the Helmholtz Center for Health Research, and various international and biotech companies based in the Munich area.

The main objective of C-NATM is to create ground-breaking therapeutics using DNA, RNA, and smaller nucleic acids. An example of this is the development of RNA-based vaccines for combating COVID-19, although the potential of these technologies extends far beyond that, potentially opening up a new era in drug therapy.

The Cluster will receive five million euros funding annually from the German government, the Free State of Bavaria, and participating companies.

Crystal clear insight: ESRs explore the world of crystallography and structural biology

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The Early-Stage Researchers (ESRs) were thrilled to participate in the 5th training week about nucleic acids and crystallography. The first two days were spent attending the Oligo 2023 conference in Oxford. They listened to experts talk about nucleic acid, base modification, aptamers, and more. They were fascinated by the new developments and ideas in this field.

After the conference, the ESRs visited the Oxford Nanopore Technologies research facilities. They gained a deep understanding of how the research industry works and how scientists turn their ideas into reality. The ESRs were impressed by the state-of-the-art facilities and the advanced equipment used for research.

The next two days were spent at the University of Reading, where the ESRs attended engaging talks about crystallography and data processing. They had the opportunity to participate in hands-on activities such as crystallisation, plate preparation, high throughput robot, and learning to recognise and collect good crystals. Finally, they collected data from the X-ray, which was an exciting experience for them.

After a free afternoon spent in London, the ESRs were welcomed at Diamond Light Source. They were given an intense tour of the different facilities and beam lines available at the synchrotron. They gained an understanding of the Cryo-EM and laser technology used in the field of structural biology for protein and nucleic acids. It was an eye-opening experience for them, and they had a lot of fun learning about this exciting field. Overall, the ESRs found the 5th training week about nucleic acids and crystallography to be an enlightening experience. They were exposed to the latest developments in the field, and the hands-on experience provided them with a deeper understanding of the processes involved. They were inspired to continue their research with renewed enthusiasm and curiosity.

By Ahmad Abdullrahman (ESR4)

Webinar on oligonucleotide synthesis

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Professor Tom Brown (University of Oxford) will be a speaker at the webinar “Traditional and Emerging Methods of Oligonucleotide Synthesis”, organised by Biotage and taking place on the 5th of April at 11am CEST.

Prof. Brown will review the history of oligonucleotide synthesis, examine how they are made currently and highlight emerging synthesis methods, including enzymatic approaches. He will also discuss the various applications of synthetic oligonucleotides, from diagnostics to therapeutics and more.

You can register here: https://go.technologynetworks.com/oligonucleotide-synthesis

The 4th training week – In the core of NATURE-ETN

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Early-stage researchers (ESRs) and principal investigators have been invited to attend the 4th training week at Dublin City University where this EU-funded research consortium was born.

Prof. Andrew Kellett first gave an update on the project before introducing Prof. Nicholas Farrell from Virginia Commonwealth University (US), who is one of the scientific advisors of NATURE-ETN and is interested in Glycosaminoglycans as signalling molecules. He talked about his latest results and joked about how retiring is difficult when you can’t stop looking for more results.

Each ESR presented their results obtained so far followed by questions, comments, and discussions for future ideas. On Thursday, a team from the German biophysical instrument manufacturer NanoTemper delivered training on the Monolith technologies in Andrew Kellett’s lab to ESRs who had the opportunity to prepare the samples, learn how to read the results, and think about how this technology can be applied to their projects.

Finally, on the last day of the training week, ESRs were hosted by Prof. Niall Barron at the National Institute for Bioprocessing Research and Training (NIBRT). Prof. Barron explained the advanced therapy medicinal products, emphasizing the need to keep in mind the patient delivery process while obtaining basic research results. ESRs conducted a complete tour guided by Dr Adam Pritchard who showed and explained the technologies behind the bioproduction of recombinant proteins, vaccines, and cell and gene therapies.

Before saying goodbye, the ESRs decided to go for a walk together. This time down to the lighthouse at Dún Laoghaire, a small town outside the busy Dublin. Prof. Barron mentioned Emerson who said, “Science does not know its debt to imagination”, and isn’t the sea the best place to clear the mind and fire the imagination?

In this training week, new collaborations were created between ESRs, wrapping up before departing to their different locations in Europe, where they will bring home new ideas to apply in their labs and Irish souvenirs!

By Ahmad Abdullrahman (ESR4)

Jamie’s secondment at the MRC Laboratory of Molecular Biology completed

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Our ESR Chun Yin (Jamie) Chan from the Carell group at LMU had the opportunity to go on secondment at the MRC Laboratory of Molecular Biology (LMB) in Cambridge, UK, from July to October 2022.

The MRC LMB is one of the world’s leading research institutes in molecular biology. Jamie joined the group led by Dr. Philipp Holliger, which focuses on chemical biology, synthetic biology and in vitro evolution. The Holliger lab investigates fundamental questions of the chemical logic and constraints of molecular information encoding and the encoded synthesis; replication and evolution of novel sequence-defined biopolymers for applications in biotechnology and medicine; and the emergence of genetic function in chemical systems.

During his stay, Jamie explored the capacity of a recently discovered RNA polymerase ribozyme utilising trinucleotide triphosphates (triplets) as substrates to incorporate chemically modified triplets, for example, for the template-directed and sequence-specific positioning of chemical groups in nucleic acid polymers, and investigated how could these modifications possibly impact the ribozyme’s polymerisation in terms of fidelity, activity and chemical space for evolution in a prebiotic scenario.

New publication examines the multi-modal activity of copper(II) and silver (I)-phendione complexes on DNA scission within P. aeruginosa

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Recent collaborative work from NATURE-ETN has been published in the Journal of Biological Inorganic Chemistry by researchers in the Kellett lab at DCU. Co-authors include NATURE-ETN coordinator Dr. Andrew Kellett, co-supervisor Dr. Georgia Menounou, and ESR Conor Bain. The paper investigated the multi-modal activity of copper(II) and silver(I) complexes with the N,N-coordinating ligand, 1,10-phenanthroline-5,6-dione, with particular focus on DNA damage within Pseudomonas aeruginosa.

The emergence of microbial drug-resistance in recent decades has given rise to the need for novel antimicrobial therapeutics. The metal-based complexes [Ag(1,10-phenanthroline-5,6- dione)2]ClO4 (Ag-phendione) and [Cu(1,10-phenanthroline-5,6-dione)3](ClO4)2.4H2O (Cu-phendione) have previously demonstrated efficient antimicrobial action against multidrug-resistant species. The focus of the study was to understand the binding potential of these complexes with double-stranded DNA using a combination of in silico and in vitro approaches. Promising results arising from this work revealed a potentially new class of antimicrobial drug candidate with a distinct therapeutic mechanism against the multidrug-resistant pathogen P. aeruginosa.

Molecular docking studies showed both complexes elicit a multi-mechanistic approach to DNA-binding via hydrogen bonding, hydrophobic and electrostatic interactions, with both complexes favouring minor groove binding. Of the two complexes, Cu-phendione achieved the highest binding affinity for both major and minor grooves with nearly 10x greater affinity to DNA than Ag-phendione and nearly 20x greater affinity than the phendione ligand alone. Cu-phendione achieved DNA scission through free radical oxidative damage, as well as DNA-nicking and relaxation of supercoiled plasmid DNA. It was concluded that both complexes elicit a dose-dependent effect, with successful DNA fragmentation within multi-drug resistant pathogen P. aeruginosa when treated with a single dose of Cu-phendione. This work proposes a novel dose-regulated class of metal-based antimicrobial therapeutics.

Reference:

Galdino, A.C.M., Viganor, L., Pereira, M.M., Devereux, M., McCann, M., Branquinha, M.H., Molphy, Z., O’Carroll, S., Bain, C., Menounou, G., Kellett, A., Dos Santos, A.L.S. Copper(II) and silver(I)-1,10-phenanthroline-5,6-dione complexes interact with double-stranded DNA: further evidence of their apparent multi-modal activity towards Pseudomonas aeruginosa. J Biol Inorg Chem (2022). https://doi.org/10.1007/s00775-021-01922-3

Second training week – Entrepreneurship, IP and ESR updates

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From the 13th to the 15th of September 2021, the ESRs took part in the second online NATURE-ETN training week.

In the first two days, the ESRs updated each other on their progress and receive valuable feedback from their peers and PIs. Potential opportunities for collaboration and secondments were also explored.

On the third day, Dr. Thomas Frischmuth, CEO of baseclick GmbH, provided two training sessions on entrepreneurship and Intellectual Property (IP). Using the leading biotechnological company and NATURE-ETN beneficiary baseclick as a basis, Dr. Frischmuth shared his experience and perspectives in terms of business models and company growth. During the IP session, the ESRs were introduced to internal vs. external IP, patent filing strategies, and examples of European and national patenting processes.

First training week – combining soft and technical skills

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From the 18th to the 22nd of June 2021, the ESRs took part in the first NATURE-ETN training week, which covered a mix between soft and technical skills. The training was held virtually due to the COVID-19 pandemic and subsequent travel limitations.

During the first day, the ESRs were introduced to Hugh Kearns’ (ThinkWell) Seven Secrets of Highly Successful Research Students.

In this workshop, Kearns described key habits that help PhD students complete their research project efficiently, ensuring appropriate work-life balance and overcoming issues such as writer’s block and imposter syndrome.  
 
The second day started with a training session on Research Project Management from the partner organisation accelopment Switzerland Ltd.
 
The training covered aspects such as project planning, project monitoring, reporting, risk management, and project communication.

The scientific training consisted of both live and pre-recorded (asynchronous) lectures and the materials will remain available to the ESRs for future references.

Prof Tom Brown from the University of Oxford gave introductory and advanced lectures on the Synthesis of Biomolecules. This training notably covered nucleic acid structures, as well as oligonucleotide synthesis and their use as drugs in genetic and forensic analyses.
 
Dr Tom Brown Jnr from the oligonucleotide synthesis company ATDBio provided additional insights from more applied and commercial perspectives, and an introduction to ATDBio’s activities.
 
On the third and last day, Prof Andrew Kellett, Coordinator of NATURE-ETN, and his team at the Dublin City University (DCU) introduced the ESRs to artificial gene editing systems and molecular methods.

Prof Andrew Kellett discussed in detail metallodrug-DNA interactions, chemical nucleases, and advanced hybrid biomaterials for gene editing using click chemistry. Pre-recorded lectures with the principles of novel methodologies, techniques, and biophysical assays developed within the Kellett group were followed by high-quality virtual laboratory sessions recorded at the exceptionally well-equipped facilities at DCU.

This was the first of a series of training events that will be held both online and in-person throughout the project duration.