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Defect in gene regulation is responsible for high leukaemia risk in children with Down syndrome – biochemical analysis creates basis for therapy development
People with a third copy of chromosome 21, known as trisomy 21, are at high risk of developing Acute Myeloid Leukaemia (AML), an aggressive form of blood cancer. Scientists led by the Department of Paediatrics at University Hospital Frankfurt have now identified the cause: although the additional chromosome 21 leads to increased gene dosage of many genes, it is above all the perturbation of the RUNX1 gene – a gene that regulates many other genes – that seems to be responsible for AML pathogenesis. Targeting the perturbed regulator could pave the way for new therapies.
Leukaemia (blood cancer) is a group of malignant and aggressive diseases of the blood-forming cells in the bone marrow. Very intensive chemotherapy and in some cases a bone marrow transplant are the only cure. Like all cancers, leukaemia is caused by changes in the DNA, the heredity material present in human cells in the form of 46 chromosomes. In many forms of leukaemia, large parts of these chromosomes are altered. People with Down syndrome, who have three copies of chromosome 21 (trisomy 21), are highly vulnerable: the risk of developing aggressive Acute Myeloid Leukaemia (AML) in the first four years of their life is more than 100 times greater for children with Down syndrome. Down syndrome is the most common congenital genetic disorder, affecting about one in 700 newborn babies.
RUNX1 transcription factor is responsible
The research group led by Professor Jan-Henning Klusmann, Director of the Department of Paediatric and Adolescent Medicine at University Hospital Frankfurt, has now discovered how the additional chromosome 21 can promote AML. With the help of genetic scissors (CRISPR-Cas9), they examined each of the 218 genes on chromosome 21 for its carcinogenic effect. It emerged that the RUNX1 gene is responsible for the chromosome's specific carcinogenic properties. In further analyses, the researchers were able to corroborate that only one particular variant – or isoform – of the gene promotes the development of leukaemia. Klusmann explains: “Other RUNX1 isoforms were even able to prevent the cells from degenerating. This explains why RUNX1 has so far not stood out – in several decades of extensive cancer research."
The RUNX1 gene encodes a “transcription factor" – a protein responsible for regulating the activity of other genes. RUNX1 regulates many processes, including embryonic development and early and late haematopoiesis, or blood formation. Disruption of this important regulator is therefore a key event in the development of AML. “Thanks to our research results, we now have a better understanding of what happens in leukemogenesis," explains Klusmann, an expert in paediatric cancer. “The study underlines how important it is to examine all gene variants in carcinogenesis. In many cases, certain mutations in cancer cells alter how these variants form," he says.
Development of more sophisticated therapeutic approaches
These insights are important for a better understanding of the complex mechanisms of carcinogenesis, as Klusmann explains: “In this way, we have laid the groundwork for developing more sophisticated therapeutic approaches. Through our biochemical analyses, we now know exactly how the gene variant alters the blood cells. From there, we were able to use specific substances that block the disease mechanism." The intention now is to further explore the effect of these substances for use in medical care. Klusmann: “On the basis of our expertise, we now want to develop therapies to correct this malfunction. Applying them in clinical practice will certainly take a few more years, but hopefully they will lead in the future to sparing our young patients from intensive chemotherapy."
Publication: Gialesaki S, Bräuer-Hartmann D, Issa H, Bhayadia R, Alejo-Valle O, Verboon L, Schmell AL, Laszig S, Regenyi EM, Schuschel K, Labuhn M, Ng M, Winkler R, Ihling C, Sinz A, Glaß M, Hüttelmaier S, Matzk S, Schmid L, Strüwe FJ, Kadel SK, Reinhardt D, Yaspo ML, Heckl D, Klusmann JH. RUNX1 isoform disequilibrium promotes the development of trisomy 21 associated myeloid leukemia. Blood (2023)
Caption 1: Professor Jan Klusmann, MD, University Hospital Frankfurt. Photo credit: Klaus Waeldele, University Hospital Frankfurt
Caption 2: Bone marrow smear from a child with Down syndrome who suffers from leukemia. The purple-coloured leukemic blasts displace normal blood formation. Photo credit: Jan Klusmann, University Hospital Frankfurt
Professor Jan-Henning Klusmann
Department of Paediatric and Adolescent Medicine
University Hospital Frankfurt
Tel.: +49 69 6301-5094
Twitter: @UK_Frankfurt @goetheuni
Editor: Dr. Markus Bernards, Science Editor, PR & Communication Office, Tel: +49 (0) 69 798-12498, firstname.lastname@example.org
Goethe University’s Archaeology Department participates in a new German Research Foundation (Deutsche Forschungsgemeinschaft, DFG)-funded project: Cooperation with the State Service for Heritage Protection and Management Hesse and the Universities of Mainz and Kiel.
The Landgraben, the body of water between the German cities of Groß-Gerau and Trebur, flows into the Rhine northwest of Astheim. Its name goes back to Count Georg I (1547-1596) of Hesse-Darmstadt, to whom the origin of this artificial watercourse has been attributed until now. Archaeologists, however, suspect the waterway had a different genesis. A team from the State Service for Heritage Protection and Management Hesse and the universities of Frankfurt, Mainz and Kiel can now use the DFG's funding to research the Roman past.
Following archaeological investigations in the Hessian Ried, initial indications show the canal may have been dug much earlier than previously estimated: It is thought the Roman military created the artificial body of water during the conquest and development of the Ried, located on the right bank of the Rhine, in the 1st century AD. The land ditch, which merged into today's Schwarzbach stream near Trebur, probably served to supply materials and goods to the Roman fort and its nearby civilian settlement in Groß-Gerau. With the new funds in hand, further research is now getting underway.
The German Research Foundation has made 370,000 euros available to continue the explorations. The money will go towards geophysical investigations, drillings and smaller archaeological excavations aimed at finding the canal's original course and taking a closer look at the Roman settlement sites in Berkach, Groß-Gerau, Wallerstädten, Trebur and Astheim, located along its course, as well as their relationship to the body of water. The resulting findings will form the basis for two dissertations in the subjects of archaeology and geography at the universities of Frankfurt and Mainz.
The search for the course of the Roman land ditch currently is being conducted in the area of Groß-Gerau – Wallerstädten. As part of the practical field course at the University of Mainz, a group of students is surveying the area, taking measurements of the electrical resistance in the subsoil and drilling at selected points to clarify the soil structure and obtain dating evidence for the site's original appearance. At the same time, Kiel University is carrying out large-scale geophysical measurements to clarify the relationship between the Roman settlement site and the artificial watercourse in this area.
Both written records and corresponding findings such as the so-called canal of Corbulo in the Netherlands constitute proof of the fact that the Romans already had the technical skills to steer and manipulate water bodies or even to create artificial canals. If the upcoming investigations confirm the hypothesis of the Landgraben's Roman origins, this would be the first evidence of such a structure from the Roman period in Germany. The fact that the artificial watercourse exists as a body of water to this day would illustrate just how massive and lasting an impact the Romans' intervention in the landscape has had.
The Roman fort "Biebelslache", near Wallerstädten, was of decisive importance for the initial dating of the Landgraben, explains Prof. Markus Scholz, archaeologist at Goethe University. The fort bordered directly on the canal or – this is something the current research has set out to verify – was actually intersected by it. In the first case, Scholz says, the canal would be at least as old as the camp. In the second case, the camp, which existed from about 40 to 70 AD, would likely have served as a terminus post quem for the canal's construction. "Our Institute held several teaching excavations at fort 'Biebelslache' between 2008 and 2012," Scholz explains, adding that there now is a new opportunity to evaluate the excavations with the latest hypothesis in mind. As such, doctoral student Henrik Leif Schäfer will date and analyze other Roman sites along the trench in his dissertation. At the same time, doctoral student Elena Appel will study the geo-archaeological aspects of the project, which also gives students the opportunity to conduct fieldwork.
Images for download: https://www.uni-frankfurt.de/132990291
Image 1: At a site visit in the Hessian Ried (from left): Prof. Andreas Vött, University of Mainz, Prof. Markus Scholz, Goethe University, Dr. Thomas Becker and Prof. Udo Recker, both State Service for Heritage Protection and Management Hesse. (Photo: Lars Görze, State Service for Heritage Protection and Management Hesse)
Image 2: The investigation of the Landgraben's history will include the use of geophysical surveys, drillings and smaller archaeological excavations. (Photo: Lars Görze, State Service for Heritage Protection and Management Hesse)
Image 3: The explorations at the Landgraben will take several years. From left: Dr. Thomas Becker, State Service for Heritage Protection and Management Hesse, Prof. Markus Scholz, Goethe University. (Photo: Lars Görze, Hessian State Office for the Preservation of Historical Monuments).
Prof. Markus Scholz
Archaeology and History of the Roman Provinces
Institute for Archaeological Sciences, Department II
Tel. +49 (0)69 798 32265
Fax +49 (0)69 798 32268
Marketing gag of the “Domaine du Météore” winery turns out to be a real impact crater – Researchers at Goethe University Frankfurt led by Frank Brenker and Andreas Junge disprove science’s decades-old mistake
With the aim of creating an appealing brand, the name of the “Domaine du Météore" winery near the town of Béziers in Southern France points to a local peculiarity: one of its vineyards lies in a round, 200-meter-wide depression that resembles an impact crater. By means of rock and soil analyses, scientists led by cosmochemist Professor Frank Brenker from Goethe University Frankfurt have now established that the crater was indeed once formed by the impact of an iron-nickel meteorite. In doing so, they have disproved a scientific opinion almost 60 years old, because of which the crater was never examined more closely from a geological perspective.
FRANKFURT. Countless meteorites have struck Earth in the past and shaped the history of our planet. It is assumed, for example, that meteorites brought with them a large part of its water. The extinction of the dinosaurs might also have been triggered by the impact of a very large meteorite.
Meteorite craters that are still visible today are rare because most traces of the celestial bodies have long since disappeared again. This is due to erosion and shifting processes in the Earth's crust, known as plate tectonics. The “Earth Impact Database" lists just 190 such craters worldwide. In the whole of Western Europe, only three were previously known: Rochechouart in Aquitaine, France, the Nördlinger Ries between the Swabian Alb and the Franconian Jura, and the Steinheim Basin near Heidenheim in Baden-Württemberg (both in Germany). Thanks to millions of years of erosion, however, for laypersons the three impact craters are hardly recognizable as such.
Geologist and cosmochemist Professor Frank Brenker from Goethe University Frankfurt is convinced: the new meteorite crater will now extend the list. While on holiday, the “Domaine du Météore" winery caught his attention. One of its vineyards lies in a round depression about 220 metres in diameter and 30 meters deep, and the proprietors use the scientific hypothesis that it is the impact crater of a meteorite – seemingly long disproved – as a marketing gag for their wine. Although this hypothesis was proposed by several geologists in the 1950s, it was dismissed by acclaimed colleagues a few years later.
Frank Brenker explains: “Craters can form in many ways, and meteorite craters are indeed very rare. However, I found the various other interpretations of how this depression could have formed unconvincing from a geological perspective." That is why he and his wife collected rock samples for analysis in the labs at Goethe University – and indeed found the first signs of an impact crater. Brenker: “The microanalysis showed that dark-colored layers in one of the shists, which usually simply comprise a larger percentage of mica, might be shock veins produced by the grinding and fracturing of the rock, which in turn could have been caused by an impact." He also found evidence of breccia, angular rock debris held together by a kind of “cement", which can also occur during a meteorite impact.
The following year, Brenker took his colleague Andreas Junge, Professor of Applied Geophysics at Goethe University, and a group of students with him to Southern France to examine the crater in detail. They discovered that Earth's magnetic field is slightly weaker in the crater than in the surrounding area. This is typical for impact craters because the impact shatters or even melts the rock, which can thus contribute less to Earth's magnetic field.
With the help of strong magnets attached to a plate, the researchers also found tiny iron oxide spherules of up to one millimeter in diameter. Such spherules had already been found in other impact craters. Later laboratory analysis showed that the ones here also contained nickel-bearing iron and encased a core of minerals typical for the crater environment. In addition, the researchers discovered numerous shock microdiamonds produced through the high pressure during the meteorite's impact.
Frank Brenker explains: “Such microspheres form either through abrasion of the meteorite in the atmosphere or only upon impact, when a large part of the iron meteorite melts and then reacts with the oxygen in the air. On impact, material shattered at the point of impact might then also be encased. This, together with the lower magnetic field and the other geological and mineralogical finds, allows us to draw hardly any other conclusion: a meteorite did indeed strike here." This makes the crater very exciting for geological laypeople too, says Brenker, because “every visitor can experience here the immense energies released upon such an impact."
Publication/Abstract: Frank E. Brenker, Andreas Junge. Impact origin of the “Domaine du Meteore"-crater, France. Compelling mineralogical and geophysical evidence for an unrecognized destructive event in the heart of Europe. LPSC Houston, #1910 (2023) https://www.hou.usra.edu/meetings/lpsc2023/pdf/1910.pdf
Picture download: https://www.uni-frankfurt.de/132616835
1. The “Trou du Météore": The crater at the “Domaine du Météore" winery really was caused by a meteorite impact. Photo: Frank Brenker, Goethe University Frankfurt
2. Microsphere from the meteorite: The iron oxide spherule found in the “Domaine du Météore" crater has a core composed of minerals typical for the crater environment and also contains a large number of microdiamonds. Photo: Frank Brenker, Goethe University Frankfurt
Professor Frank E. Brenker
NanoGeoscience / Cosmochemistry
Institute for Geosciences
Goethe University Frankfurt
Tel.: +49 151 68109472
Editor: Dr. Markus Bernards, Science Editor, PR & Communication Office, Tel: -49 (0) 69 798-12498, email@example.com
Goethe University’s Provincial Roman Archaeology department disproves previous assumptions during teaching excavation in Bad Ems
In their search for silver ore, the Romans established two military camps in the Bad Ems area near Koblenz in the 1st century AD. This is the result of research carried out as part of a teaching excavation that spanned several years and was carried out by Goethe University's Department of Archaeology and History of the Roman Provinces in cooperation with the federal state of Rhineland-Palatinate. Several surprising findings were made during the process. For one, the exciting research story earned young archaeologist Frederic Auth first place at the Wiesbaden Science Slam.
FRANKFURT: When Prof. Markus Scholz, who teaches archaeology and the history of Roman provinces at Goethe University, returned to Bad Ems toward the end of the excavation work, he was astonished: After all, all the photos sent by his colleague Frederic Auth showed but a few pieces of wood. Not surprisingly, Scholz was ill-prepared for what he saw next: a wooden defense construction consisting of sharpened wooden stakes, designed to prevent the enemy's approach. The martial-looking structure was intended to deter enemies from attacking the camp. Such installations – comparable, if you will, to modern barbed wire – are referenced to in literature from the time. Caesar, for instance, mentioned them. But to date, none had been found. The damp soil of the Blöskopf area obviously provided the ideal conditions: The wooden spikes, which probably extended throughout the entire downward tapering ditch around the camp, were found to be well preserved.
Two previously undiscovered Roman military camps
The work of the Frankfurt archaeologists and Dr. Peter Henrich of the General Directorate for Cultural Heritage of the German federal state of Rhineland-Palatinate, uncovered two previously unknown military camps in the vicinity of Bad Ems, situated on both sides of the Emsbach valley. The excavations were triggered by observations made by a hunter in 2016, who, from his raised hide, spotted color differences in the grain field, indicating the existence of sub-surface structures. A drone photo of the elevation, which bears the beautiful name "Ehrlich" (the German word for “honest"), confirmed the thesis: the field was crisscrossed by a track that could have originated from a huge tractor. In reality, however, it was a double ditch that framed a Roman camp. Geomagnetic prospecting later revealed an eight-hectare military camp with about 40 wooden towers. The archaeological excavations, carried out in two campaigns under the local direction of Dr. Daniel Burger-Völlmecke, revealed further details: the camp, apparently once intended as a solid build, was never completed. Only one permanent building, consisting of a warehouse and storeroom, was located there. The 3,000 soldiers estimated to have been stationed here probably had to sleep in tents. Burn marks show that the camp was burned down after a few years. But why?
It was the student team, led by Frederic Auth, that identified the second, much smaller camp, located some two kilometers away as the crow flies, on the other side of the Emsbach valley. The "Blöskopf" is no blank slate when it comes to archaeology: Exploratory excavations carried out in 1897 uncovered processed silver ore, raising the assumption that a Roman smelting works was once located there. The thesis was further supported by the discovery of wall foundations, fire remains and metal slag. For a long time it was assumed that the smelting works were connected to the Limes, built some 800 meters to the east at around 110 AD. These assumptions, considered valid for decades, have now been disproved: The supposed furnace in fact turned out to be a watchtower of a small military camp holding about 40 men. It was probably deliberately set on fire before the garrison left the camp. The spectacular wooden defense structure was discovered on literally the penultimate day of the excavations – along with a coin minted in 43 AD, proof that the structure could not have been built in connection with the Limes.
Roman tunnels located above the silver deposit
But why did the Romans fail to complete the large camp, instead choosing to abandon both areas after a few years? What were the facilities used for? Archaeologists have found a possible clue in the writings of historian Tacitus: He describes how, under Roman governor Curtius Rufus, attempts to mine silver ore in the area failed in 47 AD. The yield had simply been too low. In fact, the team of Frankfurt archaeologists was able to identify a shaft-tunnel system suggesting Roman origins. The tunnel is located a few meters above the Bad Ems passageway, which would have enabled the Romans to mine silver for up to 200 years – that is, if only they had known about it. In the end, the silver was mined in later centuries only. The Romans' hope for a lucrative precious metal mining operation also explains the military camp's presence: They wanted to be able to defend themselves against sudden raids – not an unlikely scenario given the value of the raw material. "To verify this assumption, however, further research is necessary," says Prof. Scholz. It would be interesting to know, for example, whether the large camp was also surrounded by obstacles meant to hinder an enemy approach. So far, no wooden spikes have been found there, but traces could perhaps end up being discovered in the much drier soil.
Silver mining reserved for later centuries
The fact that the Romans abruptly abandoned an extensive undertaking is not without precedent. Had they known that centuries later, in modern times, 200 tons of silver would be extracted from the ground near Bad Ems, they might not have given up so quickly. The soldiers who were ordered to dig the tunnels obviously had not been too enthusiastic about the hard work: Tacitus reports that they wrote to Emperor Claudius in Rome, asking him to award the triumphal insignia to the commanders in advance so they would not have to make their soldiers slave away unnecessarily.
All considered, an exciting research story, which Frederic Auth, who has led the excavations in Bad Ems since 2019, also knows how to recount in an exciting way. His account won first prize in an interdisciplinary field of applicants at the 21st Wiesbaden Science Slam in early February. The young archaeologist is already booked for further appearances: Auth will perform in Heidelberg on March 2, in Bonn on March 7, and in Mannheim on March 19. More information about the events can be found at: https://www.science-slam.com/ (in German).
The research in Bad Ems was carried out jointly with the Directorate of State Archaeology in the General Directorate for Cultural Heritage of Rhineland-Palatinate, the Institute of Prehistory and Early History at the University of Erlangen-Nuremberg, and the Berlin University of Applied Sciences. Also involved were the hunter and honorary monument conservator Jürgen Eigenbrod and his colleague Hans-Joachim du Roi, as well as several metal detectorists with the necessary permits from the historical monument authorities. The project was financed with support from the Gerhard Jacobi Stiftung, the Society for Archaeology on the Middle Rhine and Moselle, and the German Research Foundation (Deutsche Forschungsgemeinschaft, DFG). The wooden spikes have meanwhile been preserved at the Römisch-Germanisches Zentralmuseum in Mainz.
Publication: A monograph on the archaeological excavations in Bad Ems is currently being prepared.
Images for download: https://www.uni-frankfurt.de/132551146
Image 1: "Tractor Tracks". The excavations in Bad Ems were initiated by J. Eigenbrod, who spotted suspicious traces in the field from his high seat. The traces constitute changes in the vegetation, indicating ground interventions, in this case the ditches of the Roman camp on the "Ehrlich" (Photo: H.-J. du Roi)
Image 2: The geomagnetic prospection confirms the assumption that traces of the former usage of the “Ehrlich" hill would be found under the fields in the soil. (Photo: C. Mischka, FAU Erlangen-Nuremberg).
Image 3: The big surprise for the archaeologists unfolded during the last days of the excavation campaign: A construction of wooden spikes had been preserved in the damp soil of the "Blöskopf" hill, meant to deter potential attackers. (Photo: Auth)
Image 4: Although Caesar had told of comparable obstacles meant to deter the enemy's approach, so far no physical evidence of their existence had been found. For the most part, the wooden defensive constructions did not survive the test of the centuries. (Photo: Auth)
Image 5: Winner among the interdisciplinary field of applicants at the 21st Wiesbaden Science Slam: Goethe University's archaeologist Frederic Auth (3rd from left) with moderator Rainer Holl (from left) and science slammers Maria Bruhnke, Christopher Synatschke, Nina Lanzer and Uwe Gaitzsch. (Photo: science-slam.com)
Prof. Markus Scholz
Archaeology and History of the Roman Provinces
Institute for Archaeological Sciences, Department II
Tel. +49 (0)69 798 32265
Fax +49 (0)69 798 32268
Frankfurt microbiologist honored as "Class of 2023 Fellow"
Prof. Volker Müller, a microbiologist at Goethe University Frankfurt, is one of three Germans and a total of 65 scientists from around the world who have now been inducted as fellows into the American Society for Microbiology's (ASM) Academy, the professional society announced. With some 30,000 members, the ASM is one of the world's largest scientific associations in the life sciences. The Academy is ASM's think tank and honorary governing body, and each year appoints 65 excellent microbiologists as fellows.
FRANKFURT Outstanding achievements in their field and a strong commitment to teaching and mentoring – these are the criteria employed by the jury of senior scientists from the American Society for Microbiology to select 65 fellows from among the 148 high-caliber nominations from basic and applied research, teaching, public health, and industry.
Goethe University President Prof. Enrico Schleiff congratulated the new fellow, saying: "In the past year alone, Volker Müller has attracted the scientific community's attention with his high-profile work on the fixation of the greenhouse gas CO2 using bacteria, and with the concept of a hydrogen battery driven by bacterial enzymes. I congratulate him on this great honor. His induction into the Academy is a testimony to the international visibility Goethe University enjoys thanks to outstanding scientists like Volker Müller."
Prof. Volker Müller, Head of the Department of Molecular Microbiology and Bioenergetics at Goethe University, was delighted about the accolade: "The distinction is both a pleasure and an honor. Throughout my career, I have had and continue to have the great fortune and privilege of working with excellent students on exciting questions, ranging from the beginnings of biochemistry and bioenergetics in ancient bacteria on early Earth to the development of these bacteria as production platforms in a CO2-based bio-economy or as catalysts in hydrogen technology. These acetogenic bacteria have been and continue to be a veritable goldmine."
The ASM promotes microbial sciences through conferences, publications, certifications, and educational opportunities. Its goal is to improve laboratory capabilities around the world. The ASM provides a network for scientists from academia, industry, and clinical settings. Its Academy's “Class of 2023 Fellows" is made up of researchers from 11 different countries: Argentina, China, Germany, France, India, Israel, Canada, Austria, Singapore, the United Kingdom, and the United States.
How bacteria gain energy through CO2 fixation
Researchers from Goethe University Frankfurt develop new biobattery for hydrogen storage:
Image for download: https://www.uni-frankfurt.de/128212374
Caption: Prof. Volker Müller of Goethe University Frankfurt (Photo: Uwe Dettmar for Goethe University)
Professor Volker Mueller
Department of Molecular Microbiology & Bioenergetics
Institute for Molecular Biosciences
Tel: 49 (0)69 798-29507
Twitter-Handle: @goetheuni @ASMicrobiology
Editor: Dr. Markus Bernards, Science Editor, PR & Communication Office, Tel: +49 (0) 69 798-12498, Fax: +49 (0) 69 798-763 12531, firstname.lastname@example.org