Dancing RNA – understanding RNA dynamics for developing next-generation drugs – STIAS Public Lecture by Katja Petzold

22 November 2022

To some extent RNA (ribonucleic acid) has been the ugly stepsister to DNA (deoxyribonucleic acid) – in terms of understanding its roles, mechanisms and dynamics, but the COVID-19 pandemic has highlighted RNA resulting in increased interest in understanding exactly how RNA functions in health and disease, and for improving targets for drug and vaccine development.

STIAS Fellow Katja Petzold

“SARS-CoV-2 is an RNA virus and for the first time millions of people have taken mRNA (messenger RNA) vaccines. So the post-pandemic world is different – big pharma and funders are more involved, more students are interested in the field, we suddenly know and can do much more and the development of methodologies has accelerated. I believe there will be substantial progress in this area in the next five to ten years,” said Katja Petzold of the Department of Medical Biochemistry and Biophysics at the Karolinska Institute in Sweden. Petzold was presenting the sixth and last STIAS public webinar for 2022.

“The pandemic was bad for all but not for this area of science,” she said.

Petzold explained that mRNA vaccines didn’t come from nowhere – the development started with the discovery of mRNA in 1962, they were the first time synthesized in the laboratory in 1984 and used in mice studies from 1992, with trials in humans since 2010, but this is the first time they have been used on a large-scale in humans to fight a global RNA-based foe.

“Learn by doing and do what you love”

Petzold completed her Masters in Biochemistry/Biotechnology at the Martin-Luther University Halle, Germany and her PhD in Medical Biophysics at Umeå University, Sweden. She did postdoctoral fellowships at the University of KwaZulu-Natal and the University of Michigan where she studied RNA dynamics and the structure of RNA excited states – being among the first to describe these in the scientific literature. In 2014 she was appointed Assistant Professor of Biophysics at the Karolinska Institute. She is a Wallenberg Academy Fellow in Engineering and a Söderberg Fellow in Medicine, and has won numerous awards and grants including the Future Research Leader grant from the Foundation of Strategic Research and the Hugo Theorell Prize in Biophysics.

Her group’s research focuses on the study of RNA dynamics of disease-related systems, such as ribosomes or microRNA and viruses, and how RNA’s change their structures in order to function. They use Nuclear Magnetic Resonance (NMR) and other biophysical techniques to investigate the molecular mechanisms.

“Until recently, only snapshots of molecules could be observed,” she explained, “hiding their mode of operation but this has changed with the development of NMR making the function of these molecular machines more apparent and providing a variety of unique new drug targets.”

“NMR is basically a large magnet – with both liquid and solid-state imaging. Most people will be familiar with an MRI which has the nuclear part removed from its name for use in humans. It allows real-time tissue profiling to understand the structure,” explained Petzold. “Our laboratory develops methods in NMR and RNA biochemistry to try to understand viral, bacterial and eukaryotic regulatory RNAs.”

‘RNA world’ hypothesis

Although RNA and are both nucleic acids present in all living cells, traditional dogma has seen RNA’s principal role as acting as a messenger carrying instructions from DNA to control protein synthesis.

“Nowadays we have much more information,” said Petzold. “The ‘RNA world’ hypothesis is that RNA may have come first and that DNA evolved from RNA as a more stable storage molecule. In this theory, RNA had the potential to take over the functions of DNA including making proteins. This is not proven yet but is being worked on.”

“But studying RNA is difficult because it moves very fast and doesn’t like to stay still. Getting RNA into any kind of stabilised state is a challenge,” she said. “It wiggles or dances making very fast, big changes – for example six to 20 amino acids are added per second in a working ribosome, requiring immense structural rearrangements. So this cannot yet easily be observed. Many different steps need to be understood to explain the structure. So far we only know a few and it isn’t clear exactly what they mean and do.”

And capturing this is not easy. Petzold explained that the very expensive NMR is the only technology that can do it, currently. “In the beginning measuring one atom took four days, now it takes four hours, but it’s not fast enough yet.”

“RNA is unstable, it degrades easily – so studying it in cells via NMR is very blue sky research.”

Understanding the mechanisms of the dance is important in disease progression as well as in drug development.

Petzold explained that in HIV-genome dimerization studies it’s been possible to take a small piece of the HIV genome that is evolutionary conserved, make it more stable. “We are now trying to understand what happens if you inhibit the motion – it could mean that copies of the virus are not made.”

“We hope eventually to be able to develop better drugs for cancer and HIV, and novel antibiotics by understanding and manipulating RNA movements.”

One of the first microRNA-based drugs recently went into clinical trials in patients with end-stage liver cancer. MicroRNAs are small regulatory RNAs that act on mRNAs which are the blueprints for proteins. Unfortunately the trial experienced some severe events and it was clear that such drugs need even more specificity. “Probably about a third of the laboratory research underway now is about increasing specificity.”

When it comes to antibiotics, ribosomes are the main target and what Petzold describes as “the biggest RNA machine”.  Ribosomes are the structures within cells that make proteins based on instructions given to them by messenger RNA (mRNA). Learning how to manipulate the ribosomes is important for developing novel antibiotics. Petzold’s STIAS project is looking at tackling antibiotic resistance by finding alternative targets for antibiotics and increasing specificity. Antibiotic resistance in Tuberculosis is obviously highly relevant in South Africa. “This project will identify, by sequence alignments, potential target regions and perform structural predictions and dynamic algorithm searches for druggable invisible RNA pockets in the ribosome of Mycobacterium Tuberculosis as well as healthcare-associated infectious bacteria like Staphylococcus aureus (MRSA). This will be the basis for experimental testing and identification of future RNA-based small molecule antibiotics against multidrug-resistant pathogenic bacteria.”

“We can do much more than before but we need more people working in RNA, more funding and more collaboration,” said Petzold. “We recently joined a consortium, Covid19-NMR, which includes about 40 laboratories globally working to identify the structures of the COVID virus. This could be the future of science – shared data and samples, and an open, co-operative system.”


Michelle Galloway: Part-time media officer at STIAS
Photograph: Anton Jordaan

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