Doctor at Hannover Medical School explores leukaemia and colorectal cancer
The 24-year-old physician Dr. Laura Hinze from Hannover Medical School receives the Paul Ehrlich and Ludwig Darmstaedter Prize for Young Researchers 2022, as announced today by the Scientific Council of the Paul Ehrlich Foundation. Laura Hinze is being honoured for her significant contribution to the understanding of signal transduction in cancer cells. She has discovered how leukaemia cells develop resistance to the chemotherapeutic agent asparaginase, thereby presenting a novel target for the treatment of acute lymphoblastic leukaemia (ALL), the most common cancer in children. Her discovery also derives a new approach for the treatment of colorectal cancer and other solid tumours.
FRANKFURT. Unlike normal body cells, leukaemia cells are not able to produce sufficient amounts of the amino acid asparagine. They have to import asparagine. Because the enzyme asparaginase catalyses the degradation of asparagine, its injection drastically reduces the extracellular supply of this amino acid. Consequently, leukaemia cells die from this depletion, while normal body cells are not harmed. However, leukaemia cells can learn to evade the effect of asparaginase.
To find out how this happens, Dr. Laura Hinze and her group used CRISPR/Cas9 gene scissors to systematically switch off around 19,000 genes in a culture of resistant ALL cells – only one in each cell – and observed what happened when they treated the cells with asparaginase. A culture to which only a buffer solution was added served as a control. In the culture treated with asparaginase, those cells in which one of the two genes NKD2 or LGR6 had been switched off, died particularly frequently. They had apparently lost their resistance. Conversely, this indicated that cells in which these genes function become resistant particularly frequently. Hinze and her team demonstrated that both genes code for inhibitors of the Wnt signalling pathway.
In the healthy organism, this signalling pathway is responsible for embryonic development and later for tissue repair and maintenance. Its untimely activation favours the development of cancer. This is mainly due to an excessive amount of the protein ß-catenin, which carries growth impulses into the cell nucleus. When the Wnt signalling pathway is inactive, the excess ß-catenin is marked for degradation with ubiquitin molecules. Central to this labelling work is the enzyme glycogen synthase kinase 3 (GSK3). It ensures that ß-catenin is fed to the proteasome, where it is broken down into small fragments and amino acids like all proteins that could harm the cell or that it does not need. It is from this source that the leukaemia cell fetches the asparagine of which it has been deprived of by treatment with asparaginase. Through a partial activation of the Wnt signalling pathway, which blocks the degradation of ß-catenin without spurring its potentially oncogenic signals, Hinze and colleagues succeeded in largely drying up this source of resistance. The same effect they achieved by selective GSK inhibition. Leukaemia mice that received both asparaginase and GSK3 inhibitors survived much longer than those treated with asparaginase alone.
Mutations in the Wnt signalling pathway that led to its overactivation are characteristic for many colorectal cancers. Hinze therefore examined to what extent her research results could be transferred to this second most common of all cancers. Her initial hypothesis: 15 percent of all Wnt signalling pathway mutations in colorectal cancer lie upstream of the enzyme GSK3. In patients with this genetic signature, the enzyme is thus endogenously inhibited. The proteasome no longer supplies asparagine. If one depletes asparagine additionally by administering asparaginase, one could starve the colon cancer cells. Laura Hinze and her group have now preclinically proven this hypothesis. It could also apply to other solid tumours that are characterised by a Wnt-induced endogenous inhibition of GSK3.
The prize will be awarded - together with
the main prize 2022 and the prizes of the year 2021 - on 14 March 2022 at 5
p.m. by the Chairman of the Scientific Council of the Paul Ehrlich Foundation
in Frankfurt's Paulskirche. Due to the pandemic, the number of available seats
is limited. The event will be broadcast via livestream. Please do not hesitate
to contact us if you have any questions.
Please find pictures of the award winner and a more comprehensive background information for download under: www.paul-ehrlich-stiftung.de
Moreover, COVID-19 drugs remain active against Omicron in cell culture study
A new study by researchers from the University of Kent and the Goethe-University Frankfurt shows that the SARS-CoV-2 Omicron variant is less effective than Delta at blocking a cellular defence mechanism against viruses, the so-called “interferon response". Moreover, cell culture findings indicate that eight important COVID-19 drugs and drug candidates remain effective against Omicron.
FRANKFURT/CANTERBURY. The SARS-CoV-2 Omicron variant causes less severe disease than Delta although it is better at escaping immune protection by vaccinations and previous infections. The reasons for this have so far remained elusive.
A new study by a research team with scientists from the University of Kent and the Goethe-University Frankfurt has now shown that Omicron variant viruses are particularly sensitive to inhibition by the so-called interferon response, an unspecific immune response that is present in all body cells. This provides the first explanation of why COVID-19 patients infected with the Omicron variant are less likely to experience severe disease.
The cell culture study also showed that Omicron viruses remain sensitive to eight of the most important antiviral drugs and drug candidates for the treatment of COVID-19. This included EIDD-1931 (active metabolite of molnupiravir), ribavirin, remdesivir, favipravir, PF-07321332 (nirmatrelvir, active ingredient of paxlovid), nafamostat, camostat, and aprotinin.
Prof Martin Michaelis, School of Bioscience, University of Kent, said: “Our study provides for the first time an explanation, why Omicron infections are less likely to cause severe disease. Obviously, Omicron can in contrast to Delta not effectively inhibit the host cell interferon immune response.“
Prof. Jindrich Cinatl, Institute of
Medical Virology at the Goethe-University, added: “Although cell culture
experiments do not exactly recapitulate the more complex situation in a
patient, our data provide encouraging evidence that the available antiviral
COVID-19 drugs are also effective against Omicron.“
Publication: Denisa Bojkova, Marek Widera, Sandra Ciesek, Mark N. Wass, Martin Michaelis, Jindrich Cinatl jr. Reduced interferon antagonism but similar drug sensitivity in Omicron variant compared to Delta variant SARS-CoV-2 isolates. In: Cell. Res. (2022) https://doi.org/10.1038/s41422-022-00619-9
information: The drug aprotinin inhibits entry of
SARS-CoV-2 in host cells (23rd Nov 2020)
Professor Jindrich Cinatl
Institute of MedicalVirology
Phone: +49 (0) 69 6301-6409
Archaeologists and archaeobotanists from Goethe University reconstruct the roots of West African cuisine.
Leafy vegetables accompany many West African dishes, such as pounded yam in the south of the region. In collaboration with chemists from the University of Bristol, researchers from Goethe University have now successfully shown that the origins of such dishes date back 3,500 years.
FRANKFURT. Over 450 prehistoric pots were examined, 66 of them contained traces of lipids, that is, substances insoluble in water. On behalf of the Nok research team at Goethe University, chemists from the University of Bristol extracted lipid profiles, with the aim of revealing which plants had been used. The results have now been published in “Archaeological and Anthropological Sciences": over a third of the 66 lipid profiles displayed very distinctive and complex distributions – indicating that different plant species and parts had been processed.
Today, leafy vegetables, for example the cooked leaves of trees such as the baobab (Adansonia digitata) or of the shrubby – nomen est omen – bitter leaf (Vernonia amygdalina), accompany many West African dishes. These leafy sauces are enhanced with spices and vegetables as well as fish or meat, and complement the starchy staples of the main dish, such as pounded yam in the southern part of West Africa or thick porridge made from pearl millet in the drier savannahs in the north. By combining their expertise, archaeology and archaeobotany researchers at Goethe University and chemical scientists from the University of Bristol have corroborated that the origins of such West African dishes date back 3,500 years.
The studies are part of a project funded by the German Research Foundation, which was headed by Professor Peter Breunig and Professor Katharina Neumann and ended in December 2021. For over twelve years, archaeologists and archaeobotanists from Goethe University studied the Nok culture of Central Nigeria, which is known for its large terracotta figures and early iron production in West Africa in the first millennium BC – although the roots of the Nok culture in fact stretch back to the middle of the second millennium. Research focused above all on the social context in which the sculptures were created, that is, including eating habits and economy. Using carbonised plant remains from Central Nigeria, it was possible to prove that the Nok people grew pearl millet. But whether they also used starchy plants, such as yam, and which dishes they prepared from the pearl millet had so far been a mystery.
“Carbonised plant remains such as seeds and nutshells preserved in archaeological sediments reflect only part of what people ate back then," explains Professor Katharina Neumann. They hoped, she says, that the chemical analyses would deliver additional insights into food preparation. And indeed, with the help of lipid biomarkers and analyses of stable isotopes, the researchers from Bristol were able to show, by examining over 450 prehistoric pots, that the Nok people included different plant species in their diet.
Dr Julie Dunne from the University of Bristol's Organic Geochemistry Unit says: “These unusual and highly complex plant lipid profiles are the most varied seen (globally) in archaeological pottery to date." There appear to be at least seven different lipid profiles in the vessels, which clearly indicates the processing of various plant species and plant organs in these vessels, possibly including underground storage organs (tubers) such as yam.
Since the beginning of the project, the archaeobotanists have sought evidence for the early use of yam. After all, the Nok region is situated in the “yam belt" of West Africa, that is, the area of the continent in which yam is nowadays grown. Carbonised remains are of no further help here because the soft flesh of the tubers is often poorly preserved and mostly non-specific as well. The chemical analyses indicate that – apart from leaves and other as yet unidentified vegetables – the Nok people also cooked plant tissue containing suberin. This substance is found in the periderm of both overground and underground plant organs – possibly a first indication that yam was used, if not the unequivocal proof hoped for.
Through the archaeobotanical study of carbonised remains, pearl millet (Cenchrus americanus) and cowpea (Vigna unguiculata), the oily fruits of the African elemi (Canarium schweinfurthii) and a fruit known as African peach (Nauclea latifolia), which due to its high number of seeds is reminiscent of a large fig, were already known. Molecular analysis now rounds off the picture of food preparation at the sites of the Nok culture. Archaeobotanist Dr Alexa Höhn from Goethe University explains: “The visible and invisible remains of food preparation in the archaeological sediment and the pottery give us a much more complete picture of past eating habits. This new evidence suggests a significant time depth in West African cuisine."
Publication: Julie Dunne, Alexa Höhn, Katharina Neumann, Gabriele Franke, Peter Breunig, Louis Champion, Toby Gillard, Caitlin Walton‑Doyle, Richard P. Evershed Making the invisible visible: tracing the origins of plants in West African cuisine through archaeobotanical and organic residue analysis. Archaeological and Anthropological Sciences https://doi.org/10.1007/s12520-021-01476-0
Picture download: https://www.uni-frankfurt.de/111577824
Caption: Excavation of a Nok vessel at the Ifana 3 site. (Photo: Peter Breunig)
Dr Alexa Höhn
African Archaeology and Archaeobotany
Telephone +49 (0)69-798-32089
Editor: Dr. Anke Sauter, Science Editor, PR & Communication Department, Tel.: +49 69 798-13066, Fax +49 69 798-763-12531, firstname.lastname@example.org
Instruct-ERIC has appointed Professor Harald Schwalbe as its new Director, succeeding Professor Sir David Stuart in the role.
OXFORD/FRANKFURT. Integrated structural biology has demonstrated its innovative power in a breath-taking manner in recent years, notably with impressive technological advances. As a European distributed research infrastructure, Instruct-ERIC has been at the forefront of this technological innovation, with centres across the continent providing access to advanced structural biology equipment and techniques.
The COVID-19 pandemic made it increasingly clear that coordinated research is required to utilise the power of structural biology to structurally understand the impact of new mutations in variants of concern. Such coordinated research has been conducted within Instruct-ERIC centres, providing a huge boost for vaccine development and drug discovery.
It is at this transition period that Prof. Harald Schwalbe from Goethe-University Frankfurt becomes the new Instruct-ERIC director as successor of Prof. David Stuart from Oxford University and Diamond Light Source.
David Stuart commented: “Instruct has been at the forefront of the transition of structural biology into a field that routinely provides deep insights from atomic structure to cellular function and disease. It has been a real privilege to have been involved in setting up the infrastructure and working with leading scientists across Europe and the fantastic staff at the Oxford hub, to realise a vision that, although now widely accepted, seemed far-fetched when it was laid out over ten years ago. The next ten years will see fundamental change across the experimental modalities with increasing integration of experiment with computation as AI and deep learning develop more predictive power to help make sense of the avalanche of experimental data. I look forward to seeing Harald lead Instruct as it responds to the exciting challenges and opportunities."
Harald Schwalbe: "It will be key to strengthen European research in Structural Biology. In NMR spectroscopy, new 1.2 GHz machines are available, pushing the boundaries for solid-state and liquid-state NMR spectroscopy. Technology advances for cryo-EM single particle and tomography analyses are impressive."
“The initiatives in structural biology have an impact not just on a continental scale, but also at a global level. Access needs to be provided to maximise the research impact. Given the pandemic - but also the requirements from global societal challenges - it will be important to link global research endeavours for the benefit of fundamental and applied research, and for fast reactions to immediate threats and challenges."
“I am taking over from Dave Stuart with huge gratitude. He has paved the way for coordinated European research in structural biology."
Professor Harald Schwalbe's career so far has led to him being well known both for development of NMR methods and pulse sequences, and their application to very challenging questions in Chemistry and Biology. His NMR contributions thus have tremendous impact to understand biological processes.
Instruct-ERIC is a pan-European distributed research infrastructure making high-end technologies and methods in structural biology available to users. ERIC stands for European Research Infrastructure Consortium, and refers to a specific legal form that facilitates the establishment and operation of Research Infrastructures with European interest, on a not-for-profit basis. ERICs are funded by subscription from member countries and governed by member country representatives. Instruct-ERIC is comprised of 15 Member Countries: Belgium, Czech Republic, EMBL, Finland, France, Israel, Italy, Latvia, Lithuania, Netherlands, Portugal, Slovakia, Spain and United Kingdom, and one Observer Country: Greece. Through its specialist research centres in Europe, Instruct-ERIC offers funded research visits, training, internships and R&D awards. By promoting integrative methods, Instruct-ERIC enables excellent science and technological development for the benefit of all life scientists. More on https://instruct-eric.org/
Caption: Prof. Dr. Harald Schwalbe, Goethe University Frankfurt (Photo: Jürgen Lecher, Goethe University)
Prof. Dr. Harald Schwalbe
Institute for Organic Chemistry and Chemical Biology
Center for Biomolecular Magnetic Resonance (BMRZ)
Goethe University Frankfurt
Phone: +49 69 798-29737
Cryo-electron microscopy and computer simulations of mitochondrial complex I
The respiratory chain plays a central role in energy metabolism of the cell. It is localized in mitochondria, the cell´s own power plants. In a new study, researchers from Goethe University, the Max Planck Institute of Biophysics and the University of Helsinki have determined the high-resolution structure of a central component of the respiratory chain, mitochondrial complex I, and simulated its dynamics on the computer. These findings both support basic research and enhance our understanding of certain neuromuscular and neurodegenerative diseases that are linked with mitochondrial dysfunction.
FRANKFURT. All vital processes require a constant supply of energy. In the cell, the chemically “charged" molecule ATP is the main provider of this energy. The ATP power packs are produced, among others, in specialised small organs (“organelles") of the cell, the mitochondria.
There, the protein complexes of the respiratory chain pump hydrogen ions (protons with a positive charge) from one side of the inner mitochondrial membrane to the other (“uphill"), creating a chemical concentration gradient and an electrical voltage. The protons “flow downhill" along this electrochemical gradient through a kind of turbine that generates useful energy for the cell in the form of ATP.
One of the proton pumps in the first step of the process is a large, L-shaped biomolecule, mitochondrial complex I (in short: complex I). Its horizontal arm is anchored in the membrane. The vertical arm binds the electron carrier molecule NADH, which is produced during metabolic breakdown of sugar and other nutrients. Complex I catalyses the transfer of electrons from NADH to ubiquinone (Q10), and the energy released in this reaction is used to drive the proton pump.
The research team from Goethe University and the Max Planck Institute of Biophysics in Frankfurt used cryo-electron microscopy to determine the 3D structure of complex I at high resolution. The researchers were able to show that water molecules in the protein structure play an important role for establishing proton translocation pathways.
The high-resolution structural data enabled colleagues at the University of Helsinki to conduct extensive computer simulations, which show the dynamics of the protein structure during its catalytic cycle.
Dr Janet Vonck from the Max Planck Institute of Biophysics explains: “Our study delivers new insights into how a molecular machine in biological energy conversion works." Professor Volker Zickermann from the Institute of Biochemistry II at Goethe University says: “This knowledge can contribute to a better understanding of certain mitochondrial diseases, such as loss of vision in Leber hereditary optic neuropathy."
Publication: Kristian Parey, Jonathan Lasham, Deryck J. Mills, Amina Djurabekova, Outi Haapanen, Etienne Galemou Yoga, Hao Xie, Werner Kühlbrandt, Vivek Sharma, Janet Vonck, Volker Zickermann: High-resolution structure and dynamics of mitochondrial complex I – Insights into the proton pumping mechanism. Sci Adv. 2021 Nov 12;7 (46) https://www.science.org/doi/10.1126/sciadv.abj3221
An image can be downloaded under: https://www.uni-frankfurt.de/109657054
Caption: A bit like a boot: The L-shaped structure of mitochondrial complex I at a resolution of 2.1 Ångström (0.00000021 millimetres), captured with a cryo-electron microscope. Image: Janet Vonck, MPI of Biophysics
Professor Volker Zickermann
Institute of Biochemistry II
Goethe University, Frankfurt am Main
Tel.: +49 (0)69 798-29575
Dr Janet Vonck
Max Planck Institute of Biophysics, Frankfurt am Main
Phone: +49 (0)69 6303-3004