March 14, 2022

Sights set on resistant bacteria and pandemic viruses – Double award ceremony at St. Paul’s Church in Frankfurt

The award of the Paul Ehrlich and Ludwig Darmstaedter Prizes for 2021 and 2022.

For the first time in its history, the Paul Ehrlich and Ludwig Darmstaedter Prize was awarded for two consecutive years at the same time. The 2021 prize honours Bonnie Bassler and Michael Silverman, whose discovery of how bacteria communicate with each other paves the way for a whole new class of antibiotics. Three laureates share the 2022 prize: Katalin Karikó, Uğur Şahin and Özlem Türeci, whose research work on messenger RNA culminated in the spectacularly fast development of a highly effective vaccine against COVID-19 and also offers promising prospects for the battle against cancer.
FRANKFURT. Last year, the award ceremony for the Paul Ehrlich and Ludwig Darmstaedter Prize had to be cancelled due to the pandemic. “This year, now that we've regained the possibility to attend in person, we're honouring laureates who have made a significant contribution to overcoming the pandemic," says Thomas Boehm, Chairman of the Scientific Council of the Paul Ehrlich Foundation and Director at the Max Planck Institute of Immunobiology and Epigenetics in Freiburg. “At the same time, we're commending a discovery that offers a new approach to the global problem of antibiotic resistance."

Bacteria that render antibiotics useless are gaining ground worldwide. This constitutes a deadly threat, which according to the World Health Organization has assumed alarming proportions and makes new antibiotics necessary. However, most of the new substances developed follow the old principle. They stop the bacteria from growing or kill them off. That microorganisms use mutations to counter this attack lies in their nature. This is followed by the selection of more resistant strains, and it is then only a question of time until these too become resistant to new antibiotics. The Paul Ehrlich and Ludwig Darmstaedter laureates of 2021 have laid the groundwork for a new principle of antibiotic action. Michael Silverman and Bonnie Bassler have discovered and deciphered the language that bacteria use to communicate with each other. By exchanging certain signal molecules, the bacteria agree on when they have reached a quorum sufficient to be able to act against a host organism with a high probability of success. Interrupting this microbial chit-chat pharmacologically through “quorum quenching" makes the bacteria “shut up" without killing them off. They do not experience any selection pressure to create resistance. Researchers throughout the world are now working on the development of such new antibiotics. They have already achieved remarkable progress in combating multi-resistant pathogens such as Pseudomonas aeruginosa.
Viruses that appear as if from nowhere are capable of abruptly throwing the lives of all humankind into disarray – something we have all learnt since the outbreak of the COVID-19 pandemic. That it has nonetheless been possible to contain this pandemic is largely thanks to the achievements of the Paul Ehrlich and Ludwig Darmstaedter laureates of 2022. Through their quick-witted reaction to the sudden emergence of the SARS-CoV-2 coronavirus, they succeeded in developing a vaccine in record time that has saved the lives of millions of people worldwide. The basis for this success was their research work over decades on the messenger mRNA molecule and its optimisation for medical purposes. Unperturbed by many obstacles along the way, Katalin Karikó has been searching since the beginning of her career for methods to stimulate intracellular protein production by introducing mRNA. In the process, she made the ground-breaking discovery of how the body's immune defence against externally applied mRNA can be switched off. Uğur Şahin and Özlem Türeci primarily concentrated on developing cancer vaccines that present a patient's immune system with the antigens of their own tumour so that it can destroy it. In the process, they discovered how mRNA can be stabilised and significantly increased in its messages' efficiency. In 2008, they founded their own company – BioNTech, where they have already developed several mRNA-based therapeutic cancer vaccines up to the point of clinical trials.

Apart from the main prizes, the Paul Ehrlich and Ludwig Darmstaedter Prize for Young Researchers will also be awarded for two consecutive years at the same time. Biologist Elvira Mass will receive the prize for 2021. Through the skilful use of genetic marking methods, she has discovered that an organism's healthy development is already controlled from a very early stage by specialised immune cells originating from the yolk sac of the embryo. The 2022 prize for young researchers goes to physician Laura Hinze. With the help of genome-wide screening, she has discovered how leukaemia cells' resistance to a certain chemotherapeutic agent can be overcome. From this she has derived a new potential strategy for treating solid tumours such as colorectal cancer.

January 25, 2022 - 10am

Outstanding research on cancer resistance: Laura Hinze receives Paul Ehrlich and Ludwig Darmstaedter Prize for Young Researchers

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.

September 21, 2021 – 10am

The Paul Ehrlich and Ludwig Darmstaedter Prize 2022 will be awarded to Katalin Karikó, Özlem Türeci and Uğur Şahin

Frankfurt am Main. The biochemist Katalin Karikó (66), the physician Özlem Türeci (54) and the physician Uğur Şahin (56) are the recipients of the Paul Ehrlich and Ludwig Darmstaedter Prize 2022. Today, this was announced by the Scientific Council of the Paul Ehrlich Foundation. The three award winners are being honoured for their achievements in the development of messenger RNA (mRNA) for preventive and therapeutic purposes. They have established a technology platform that is likely to initiate a paradigm shift in some areas of medicine - away from the external application of immunising antigens or therapeutically effective proteins to their internal production within the cells of patients. The spectacularly rapid development of a highly effective vaccine against the coronavirus disease COVID-19, which has proven to play a decisive role in the worldwide containment of the SARS-CoV2 pandemic, has been an outstanding success.

mRNAs are messenger molecules that carry genetic information from the DNA in the cell nucleus to the ribosomes in the cytoplasm, where they instruct protein synthesis. In this way, genetic information is translated into biological function. In contrast to DNA, mRNAs are very unstable molecules and insufficient protein production has been considered their main weakness. In addition, our immune system normally regards externally applied mRNA as an unwanted intruder and in response releases inflammatory signal molecules. This signal cascade serves to eventually inhibit the translation of the externally derived mRNA. While great (and to date largely unfulfilled) hopes were placed in gene therapies with DNA, mRNA seemed to have little to offer for medical purposes.

Undeterred by the dominance of DNA research in the 1990s, however, Katalin Karikó remained true to her goal of stimulating the production of proteins by introducing mRNA into living cells, in order to provide missing or replace faulty proteins in patients suffering from hereditary disorders, such as cystic fibrosis. She was convinced of the potential of such protein replacement therapies. Unlike DNA therapeutics, mRNA does not have to enter the cell´s nucleus to exert its effect. Unlike DNA therapeutics, which carry a risk of mutagenicity, RNA does not integrate into the genome of its target cell; moreover, because it is rapidly degraded, its temporal effects can be well controlled. Despite many obstacles, Karikó, who conducts research at the University of Pennsylvania, finally achieved a decisive breakthrough: she discovered how to blunt the body's own defence response against synthetic mRNA, and consequently, how to significantly increase intracellular protein production.

Uğur Şahin and Özlem Türeci have a background in cancer research. Working at the medical schools of Homburg/Saar and Mainz since the mid-1990s, they have focused on developing cancer vaccines, including truly individualized ones, to present a patient's immune system with the antigens of his or her own tumour to stimulate target-specific destruction. In the late 1990s, they began a systematic discovery process to solve the basic mRNA-associated problem of short-lived protein production. They developed a series of optimized designs for various structural components of mRNA, thereby significantly increasing both its intracellular stability and its translational efficiency. In 2006, the results of this work won them the first Go.Bio award of the Federal Ministry of Education and Research, which motivated them to found BioNTech in 2008.

In the years to follow, they further improved vaccine efficacy by strategies to deliver RNA into dendritic cells (DCs) located in lymphoid tissues. This particular DC species are the "high-performance trainers" of the immune system. With a lipid nanoparticle formulation, the two doctors and their team achieved body-wide targetting of mRNA into DCs, thereby generating a large number of immune cells that precisely recognized only the cancer cells. These breakthrough improvements formed the basis for the successful use of mRNA for various human applications. To successfully realize their original vision of an individualized vaccine technology, Uğur Şahin and Özlem Türeci developed a breakthrough approach in which each mRNA vaccine is tailored according to the genetic profile of the patient´s tumor that can be universally applied to different types of cancer.

During the last years, BioNTech has made significant progress in the clinical application of cancer vaccines. Several of the company's cancer vaccines have successfully passed the first phase of clinical trials. The principle of targeting DCs in lymphoid tissues and the knowledge and knowhow gained in the development of cancer vaccines later decisively contributed to the rapid availability of the COVID19 mRNA vaccine. Moreover, BioNTech's COVID19 vaccine greatly benefited from the incorporation of the optimized designs for various structural components of mRNAs originally developed by Uğur Şahin and Özlem Türeci for their cancer vaccines

Katalin Karikó joined BioNTech in 2013. The non-immunogenic mRNA modifications she discovered are essential for the development of protein replacement therapies. They are not essential for the development of cancer vaccines, where cellular immunity is most important. After all, a certain immune stimulation (an adjuvant effect) is mandatory for every successful vaccination. Non-immunogenic mRNA, however, offers substantial advantages in case of infectious disease vaccines, where humoral immunity is the main goal. With immunogenic mRNA it would have been much more difficult to develop a highly effective COVID-19 vaccine in a comparably short time. Thus, both mRNA vaccines that have been successful in the fight against the Corona pandemic to date incorporate Katalin Karikó's discovery of non-immunogenic mRNA alongside other optimized mRNA components. Their adjuvant effect is ensured by their lipid formulations.

The prizes will be awarded together with the prizes of the year 2021 - on 14 March 2022 at 5 pm CET by the Chairman of the Scientific Council of the Paul Ehrlich Foundation in the Paulskirche in Frankfurt. We kindly ask you to consider this date in your schedule. Please do not hesitate to contact us if you have any questions.






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Joachim Pietzsch
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