News

Research / 02.07.2020
B-cell protectors

The protein Pdap1 (red) is located in the cytoplasm of B cells (Foto: Di Virgilio Lab, MDC)
The protein Pdap1 (red) is located in the cytoplasm of B cells (Foto: Di Virgilio Lab, MDC)

A research group at the MDC has discovered a protein that protects mature B lymphocytes from stress-induced cell death. It also helps immune cells produce effective antibodies, which can stop the pathogen at different points in the infection.

Whenever a germ gets into the human body, the immune system usually responds immediately to fight off the enemy attacker. One of our defense system’s most important strategies involves B lymphocytes, also known as B cells, which produce antibodies that target and neutralize pathogens. B cells play a central role in adaptive immunity and, together with T cells and components of the innate system, they protect the body against foreign pathogens, allergens and toxins.

Many Berlin researchers involved in the study

A team led by Dr. Michela Di Virgilio, head of the Genome Diversification & Integrity Lab at the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), has now identified a protein called Pdap1 that supports B cells in this important task while simultaneously protecting them from stress-induced cell death.

The lead authors of the study, which was published in the Journal of Experimental Medicine, are the two doctoral students Verónica Delgado-Benito and Maria Berruezo-Llacuna – both members of Di Virgilio’s lab. Researchers from the MDC’s Berlin Institute of Medical Systems Biology (BIMSB) and the Experimental and Clinical Research Center (ECRC ) were also involved. The ECRC is a joint institution of the MDC and Charité – Universitätsmedizin Berlin.

B cells must continuously adapt

“A successful humoral immune response, which is mediated by antibodies, is dependent on several factors,” explains Di Virgilio. Mature B cells have to modify their genes (i.e., building instructions) in order to create antibodies that better match the distinguishing features on the surface of the invading pathogen. This is known as the lock-and-key principle and is achieved by somatic hypermutation, which mutates the pathogen-recognizing portion of the antibody molecule after the encounter and B cell activation.

Over the course of the humoral immune response, another part of the antibodies is transformed in a process known as class-switch recombination (CSR). Here, B cells change the isotype of the antibodies they produce. Instead of immunoglobulins of the isotype IgM, which are predominantly produced at the start of an infection, they may produce, for example, IgG antibodies, which have a different effector function. This process potentiates the ability of antibodies to effectively dispose of the pathogen.

The protein was found with the help of “gene scissors”

“In the beginning, we primarily wanted to understand how class switching works,” says Delgado-Benito. “So we genetically modified a mouse B cell line using the CRISPR-Cas9 gene scissors to prevent them from producing certain proteins.” In this way, she and the team discovered that without PDGFA associated protein 1 (Pdap1), less class switching occurs.

“In the next step, we generated mice where the gene for Pdap1 was switched off specifically in B cells,” reports Berruezo-Llacuna. “This showed us that the protein is also crucial for somatic hypermutation.” Without the protein, fewer such mutations occurred in the pathogen-recognizing part of the antibody, thus reducing the possibility to generate highly-specific variants.

B cells die more easily without Pdap1

“A particularly surprising finding to come out of our in vivo experiments, however, was that mouse B cells that are unable to produce Pdap1 die far more easily than is normally the case,” adds Di Virgilio. Her team discovered that the protein protects B lymphocytes from stress-induced cell death. “Mature B cells experience cellular stressors particularly when they begin to grow and proliferate rapidly after contact with the pathogen,” explains the researcher.

It seems that in unmodified animals, Pdap1 helps B cells to cope with this stress. Without the protein, however, a program is started that ultimately leads to cell death. “So Pdap1 not only helps the B lymphocytes to consistently produce the effective antibodies,” says Di Virgilio. “It can also be seen as their protector.”

Text: Anke Brodmerkel

www.mdc-berlin.de

Research / 30.06.2020
Osmotic stress identified as stimulator of cellular waste disposal

Image of mouse astrocytes showing the actin cytoskeleton (red) and lysosomes (green). (Image: Tania Lopez-Hernandez)
Image of mouse astrocytes showing the actin cytoskeleton (red) and lysosomes (green). (Image: Tania Lopez-Hernandez)

Cellular waste disposal, where autophagy and lysosomes interact, performs elementary functions, such as degrading damaged protein molecules, which impair cellular function, and reintroducing the resulting building blocks such as amino acids into the metabolic system. This recycling process is known to keep cells young and, for instance, protects against protein aggregation, which occurs in neurodegenerative diseases. But what, apart from starvation, actually gets this important system going? Researchers from the Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP) in Berlin have now discovered a previously unknown mechanism: osmotic stress, i.e. a change in water and ionic balance, triggers a response within hours, resulting in the increased formation and activity of autophagosomes and lysosomes. The work, now published in “Nature Cell Biology”, describes the new signaling pathway in detail, and provides a crucial basis for improving our understanding of the impact environmental influences have on our cellular recycling and degradation system, and how this knowledge can be used for therapeutic purposes.

 

Image of mouse astrocytes showing the actin cytoskeleton (red) and lysosomes (green). (Image: Tania Lopez-Hernandez)

Our cells are occasionally in need of a “spring clean” so that incorrectly folded protein molecules or damaged cell organelles can be removed, preventing the aggregation of protein molecules. The mechanisms responsible for this removal are so-called “autophagy” and the closely related lysosomal system, the discovery of which earned the Nobel Prize for Medicine in 2016.
Quite a number of studies suggest that autophagy and lysosomes play a central role in aging and in neurodegenerative diseases. It is also generally agreed that fasting or food deprivation can kickstart this cellular degradation and recycling process. Other than that, little is known about how cells and organs control the quality of their protein molecules, and which environmental influences give the decisive signal to start cleaning up.

Water loss induces the formation of lysosomes and autophagy
A new trigger has now been identified by scientists from the Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP) in Berlin: it is osmotic stress, i.e. the state in which cells lose water, that starts the system of autophagy and of lysosomal degradation. The study has just been published in the prestigious journal “Nature Cell Biology”.
“When dehydration occurs, we suddenly see more lysosomes in the cells, i.e. more organelles where aggregated protein molecules are degraded,” explained co-last author PD Dr. Tanja Maritzen. “It’s a clever adaptation because cellular water loss simultaneously fosters the aggregation of proteins. These aggregates must be removed quickly to ensure the continued function of cells, and this works better when cells have more lysosomes.”

Ion transporter NHE7 switches on newly discovered pathway
The researchers were able to observe what happens at the molecular level in dehydrated cells using astrocytes, star-shaped cells in the brain that assist the work of our nerve cells: in the event of dehydration, the ion transporter NHE7 translocates from the cell’s interior, where it is normally positioned, to the cell's limiting plasma membrane that shields the cell from the outside. This leads to an influx of sodium ions into the cell, indirectly increasing the level of calcium – a key messenger – in the cytosol. The elevated level of calcium in turn activates a transcription factor called TFEB, which finally switches on autophagy and lysosomal genes. In other words, the system is initiated by the ion transporter NHE7, triggered by osmotic stress.
“This pathway was completely unknown,” stated group leader and last author of the study, Professor Dr. Volker Haucke. “It is a new mechanism that responds to a completely different type of physiological challenge to those previously known.”


Discovery of aggregated proteins in brain cells
Counter experiments revealed the importance of this pathway for human health: when the researchers removed a component of the signaling pathway, such as the transporter NHE7 or the transcription factor TFEB, aggregated protein molecules accumulated in astrocytes under osmotic stress conditions; they could not be broken down. In the study, this phenomenon was demonstrated for components such as synuclein – a protein that plays a role in Parkinson’s disease.
“Neurodegenerative diseases in particular are a possible consequence of this pathway being switched on incorrectly,” stated Tania López-Hernández, post-doc in Professor Haucke’s and Dr. Maritzen’s respective groups, and lead author of the study. “In addition, NHE7 is a so-called Alzheimer’s risk gene. We now have new insights into why this gene could play such a critical role.”
Another interesting point is that an intellectual disability in boys, passed on via the X chromosome, is due to a mutation in the NHE7 gene. The researchers suspect that the disease mechanism is linked to the degradation mechanism that has now been described. If only the switch, i.e. the NHE7 protein, were defective, an attempt could be made to turn on the pathway in another way. “It is very difficult in practice, and extremely expensive, to repair a genetic defect, but it would be conceivable to pharmacologically influence the NHE7 protein or to use other stimuli such as spermidine as a food supplement to switch on the autophagy system in these patients,” explained cell biologist and neurocure researcher Volker Haucke.

Medical relevance of basic research
In order to carry out such interventions, however, the foundations need to be researched more thoroughly. For example, it is not yet clear how osmotic stress affects the translocation of NHE7 to the cell surface. It is also not known whether the entire degradation system is initiated or whether just individual genes are switched on, or which specific responses to osmotic stress are needed to activate the lysosomal system. Nor is it known which other stimuli may be triggered by this physiological process. The researchers now seek to answer all these questions in subsequent projects.
“Our work has shown us the fundamental impact that our water and ionic balance has on the capability of our cells and tissue to break down defective protein molecules,” remarked Volker Haucke. “Now we want to gain a better understanding of this mechanism – also because it plays a major role in aging, neurodegeneration and the prevention of several other diseases.”

Text: Beatrice Hamberger
Translation: Teresa Gehrs

Source:
Lopez-Hernandez, T., Puchkov, D., Krause, E., Maritzen, T., Haucke, V. Endocytic regulation of cellular ion homeostasis controls lysosome biogenesis. In: Nature Cell Biology July 2020 issue. DOI10.1038/s41556-020-0535-7

 

www.leibniz-fmp.de

Research / 18.06.2020
Jan Philipp Junker receives Helmholtz AI grant

Junker with Zebrafish. (Photo: Pablo Castagnola/MDC)
Junker with Zebrafish. (Photo: Pablo Castagnola/MDC)

MDC researcher Jan Philipp Junker and his collaborator Maria Colomé-Tatché at Helmholtz Center Munich have received a €200,000 grant to improve big data processing to better understand how gene networks are wired together during development and disease.

Scientists generally understand how stem cells transform into a specialized heart, brain or muscle cell. But now they want more specifics: the precise, step-by-step instructions that drive cell fate and function. Understanding the exact flow of genes turning on or off other genes, called “gene regulatory networks,” throughout the normal cell differentiation process could also help clarify what goes wrong in diseases such as cancer and heart disease.

Researchers at the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC) and Helmholtz Center Munich will use a Helmholtz Artificial Intelligence Grant to try to decode these complex networks by combining advanced experimental, sequencing and machine learning tools. “Suddenly, with recent technological developments, this goal that seemed to be almost unreachable, is within reach,” says Dr. Jan Philipp Junker, who heads the Quantitative Developmental Biology Lab at MDC’s Berlin Institute for Medical Systems Biology.

Ambitious collaboration

The Helmholtz AI Grant program supports “high-risk, high-reward” research over a relatively short timeframe of three years, encouraging investigators to try out novel ideas and “fail fast” if need be and continue innovating. “This doesn’t mean this should be completely reckless research and that we are ready to burn the money entirely,” Junker says. “It’s a calculated risk.”

The €200,000 grant will be shared equally by Junker and his collaborator, Dr. Maria Colomé-Tatché, a group leader at the Institute of Computational Biology at Helmholtz Center Munich, to support a post doc and a Ph.D. student conducting experiments, developing computational tools and analyzing data. The two centers are required to provide matching funds.

Really big data

With the recent advent of single-cell sequencing, scientists are able to see which genes are active in individual cells as they progress from undifferentiated cells into specific cell types, such as a muscle cell or brain cell. But so far, computational tools have not successfully pieced together how genes specifically influence each other.

“In principle, we can see what happens, what genes go on and what genes go off as a cell differentiates, but understanding which gene turns on which other genes, how these activation networks work in different cell types, that is still basically an open question,” Junker explains. Attacking this question requires colossal amounts of data – sequencing tens of thousands of active genes, in tens of thousands of individual cells. One data set includes at least 20,000 dimensions. That’s where AI and machine learning can help, sifting through all that data and finding meaningful patterns, which in this case, are the gene regulatory networks.

It also requires aligning the time scales of multiple data streams so they can be effectively analyzed and yield accurate insights. The team is working to improve this alignment. Notably, they have adapted a method called SLAM-seq to label freshly transcribed RNA molecules, which indicate newly activated genes. Identifying old RNA present in a cell versus new RNA will help clarify the order of gene activations. Combining this information with data on DNA accessibility should help make network reconstructions more accurate. 

Future applications

Junker and his team will initially seek to reconstruct gene networks in normal embryonic development of zebrafish, a model organism for vertebrates, including humans. Once the computational approach is verified, they can use it to study disease development in humans, which can open doors to new treatments.

“In the more distant future,” Junker says, “when we have a complete network for cell differentiation for an organ, then we could go to the drawing board and decide which arrow or node we want to attack with a therapy.”

Text: Laura Petersen

https://www.mdc-berlin.de/news/press/junker_helmholtz-ai-grant

Research / 11.06.2020
Overactive enzyme causes hereditary hypertension

Narrowed mesenteric arteries in rats with a mutated PDE3A gene (right) cause increased resistance to blood flow.  (Photo: Dr. Q. Fatimunnisa, Bader Lab, MDC)
Narrowed mesenteric arteries in rats with a mutated PDE3A gene (right) cause increased resistance to blood flow. (Photo: Dr. Q. Fatimunnisa, Bader Lab, MDC)

After more than 40 years, several teams at the MDC and ECRC have now made a breakthrough discovery with the help of two animal models: they have proven that an altered gene encoding the enzyme PDE3A causes an inherited form of high blood pressure. This could lead to new concepts for the treatment of hypertension.

A Turkish family from a village near the Black Sea first caught the attention of medical researchers in the early 1970s. A physician discovered that many members of this large family had both unusually short fingers and astronomically high blood pressure, sometimes twice as high as that of healthy people. Those affected die around the age of 50, usually due to a stroke.

Some twenty years later a group of researchers at the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), led by Professor Friedrich Luft and Dr. Sylvia Bähring, began to study this mysterious phenomenon. It proved to be no easy task. Not until May 2015 were the researchers able to report in the journal Nature Genetics that they had found an altered gene in all patients who were affected by the hypertension and brachydactyly (HTNB) syndrome – i.e., high blood pressure and abnormally short digits. The genetic disorder is also known as Bilginturan syndrome, after its Turkish discoverer.

The genetic makeup encodes an enzyme called phosphodiesterase 3A, or PDE3A for short, that regulates both blood pressure and bone growth. The gene mutation that Luft and his team had discovered causes the enzyme to be more active than usual.

Researchers provide the missing evidence

Yet so far there has been no evidence that definitely shows that the mutated PDE3A causes Bilginturan syndrome, which has since been discovered in other families around the world. An international group of 40 researchers from Berlin, Bochum, Limburg, Toronto (Canada) and Auckland (New Zealand) has now supplied this evidence in the journal Circulation. Participating in the study were research groups from the MDC and Charité – Universitätsmedizin Berlin, including teams led by Professors Luft, Michael Bader, Maik Gollasch and Dominik N. Müller as well as Dr. Arndt Heuser and Dr. Sofia Forslund. The last author of the paper is Dr. Enno Klußmann, head of the MDC’s Anchored Signaling Lab.

“We mainly worked with two animal models,” reports Dr. Lajos Markó, the paper’s co-lead author along with Maria Ercu. One of the models consisted of genetically modified mice in which the human enzyme PDE3A in the smooth muscle cells of the vessel walls was overactive due to the gene alteration. “These animals exhibited extremely high blood pressure as compared to the control animals,” Markó says.

Genetically modified rats recapitulate the genetic disorder

But what proved more interesting to the scientists was a rat model created by the Bader Lab using CRISPR-Cas9 technology. With the help of the gene-editing tool, the team had altered nine base pairs in a region of the PDE3A gene that is mutated in the syndrome, a so-called mutation hot spot. The resulting enzyme differed from the normal variants with respect to three amino acids. “And just as in the patients, this tiny change increased the activity of the enzyme,” Ercu says.

“The rats resembled human patients to a truly extraordinary degree,” Ercu adds. “They not only suffered from high blood pressure, but the toes on their forefeet were significantly shortened – similar to the fingers of people with the syndrome.” And using micro-computed tomography, the researchers discovered a prominent loop in the brain vessels of the rats that is also found in people with the syndrome. “Our rat model provides, in my view, definitive proof that the syndrome is caused by a mutation in the PDE3A gene,” Klußmann says.

The goal is to treat hypertension more effectively

The researchers have even developed an approach for treating this inherited form of high blood pressure. “There is a drug called riociguat that is already approved as a therapeutic for pulmonary hypertension,” Klußmann says. We know, he says, that it activates an enzyme that produces a signaling molecule, which in turn dampens down an overactive PDE3A. “The blood pressure of rats to which we administered a derivative of riociguat dropped to a normal level,” Klußmann reports. There are already other PDE3A inhibitors on the market, according to him, but they are not suitable for long-term therapy due to their side effects.

Klußmann now wants to take a closer look at how the mutated PDE3A interacts with other protein molecules. Stronger interaction with certain adaptor proteins, he says, could cause cells of the vessel walls to replicate at an increased rate.

In fact, Klußmann has a big goal in his sights: “By learning more about the effects of the PDE3A’s interactions with other proteins and understanding how they are involved in the regulation of blood pressure, we will hopefully find new and more effective therapeutic approaches for one of the most widespread diseases of all, hypertension.”

Text: Anke Brodmerkel

www.mdc-berlin.de

05.06.2020
Discovery of important molecular mechanism of Charcot-Marie-Tooth disease

Sciatic nerves from 3-month-old mice in cross section (Image: Alessandra Bolino, IRCCS Ospedale San Raffaele)
Sciatic nerves from 3-month-old mice in cross section (Image: Alessandra Bolino, IRCCS Ospedale San Raffaele)

Charcot-Marie-Tooth (CMT) disease is the most common form of inherited neuropathies. A genetic mutation causes the insulating myelin layer of peripheral nerves to become progressively damaged, resulting in severe disabilities in the case of CMT type 4B, for instance. Since the molecular basis is largely unknown, this type of CMT is untreatable and incurable to this day. Now researchers from the Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP) in Berlin, in collaboration with colleagues from Milan, Paris and Mexico, have been able to highlight a new molecular mechanism: According to their discovery, the protein Rab35 and the mTOR signaling pathway it regulates play a central role in the formation of myelin sheaths in the peripheral nervous system. First in-vivo experiments show that new therapies can be derived from the findings. The work has now been published in the prestigious journal “Nature Communications”.

Many of our nerve cords (axons) are enveloped by a myelin sheath, which ensures that signals can be sent near instantaneously from the brain to muscles and organs. However, genetically programmed defects in myelination occur among the broad group of inherited neuropathies, disrupting this signaling process. This results in the onset of a variety of neurological deficits occurring in peripheral nerves and the degeneration of the nerve cords. This is the case with Charcot-Marie-Tooth disease (CMT), the most common inherited neuropathy. CMT type 4B is characterized by a very early onset of the disease; sufferers are often already confined to a wheelchair in their teens. In the worst case, neurodegeneration spreads to the respiratory tract, which can lead to death by respiratory failure. At present, there is no prospect of a cure.

Unexpected interaction partners
It is therefore all the more important to explore the largely unknown molecular mechanisms of the disease. This is exactly what scientists from the Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP) in Berlin have done, in collaboration with teams of researchers led by Professor Alessandra Bolino (IRCCS Ospedale San Raffaele University, Milan), Professor Arnaud Echard (Sorbonne Université / Institut Pasteur, Paris) and Professor Genaro Patiño-López (Hospital Infantil, Mexico).
Researching the protein Rab35, the Berlin team led by Linda Sawade and Professor Volker Haucke discovered more or less by chance that this small GTPase, which is involved in the regulation of intracellular membrane transport, interacts with three proteins associated with CMT 4B: Owing to a gene mutation, MTMR2, MTMR5 and MTMR13 do not function properly in CMT 4B patients, or they are completely lacking.
These three critical proteins belong to the group of myotubularin-related (MTMR) phosphatidylinositol (PI) phosphatases that specifically hydrolyze the endosomal signaling lipids PI(3)P and PI(3,5)P2 at the 3’-phosphate group, i.e. they remove phosphates from lipids.

Rab35 regulates myelin sheath formation
“Our study revealed that the protein Rab35 regulates the longitudinal growth of the myelin sheath by binding and recruiting the two pseudophosphatases MTMR13 and MTMR5, and hence, also the active phosphatase MTMR2 bound to it in a complex,” reported Linda Sawade, lead author of the study.
The new finding was that Rab35 binds this lipid phosphatase complex, and therefore plays a key role in regulating myelin sheath formation. The detection was confirmed in knock-out micethat specifically lack the Rab35 protein in Schwann cells – the cells in the peripheral nervous system that form myelin sheaths. Loss of the Rab35 protein led to the abnormalities and, eventually, the degenerative destruction (demyelination) of myelin sheaths in the sciatic nerve.

Inhibition of mTORC1 proves effective
Coincidentally, the researchers observed an abnormally elevated activity of the mTORC1 signaling pathway– one of the central signaling complexes for regulating myelin sheath formation in nerve tissue. Pharmacological inhibition of the hyperactive mTORC1 signaling complex using the drug Rapamycin partially rescued nerve damage in knock-out mice. Further experiments on cultured cells in which Rab35 expression had been suppressed confirmed the positive effects of mTORC1 inhibition on defective myelin sheaths.
The researchers were also able to draw an important conclusion from the absence of the Rab35 protein: mTORC1 is hyperactive because PI 3-phosphates are no longer regulated, causing the accumulation of PI(3)P and PI(3,5)P2 lipids. “We assume that this pathological process results from an impaired recruitment of MTMR complexes,” explained biochemist and cell biologist Linda Sawade. “Conversely, this would mean that Rab35 normally suppresses the activity of mTORC1 by recruiting MTMR phosphatases to lysosomes.”

Findings have an impact beyond basic research
In a nutshell, the results have a great impact for basic research: Rab35 is a previously unidentified regulator of myelin sheath formation in the peripheral nervous system and a repressor of mTORC1.
The results also offer a glimmer of hope to CMT4B patients: Therapeutic treatment using mTORC1-inhibiting drugs such as Rapamycin could improve disease progression. It would be the first treatment option for this serious condition.
Group leader Professor Dr. Volker Haucke: “Our work has led to the discovery of a new molecular mechanism in a particularly severe form of inherited neuropathy that is highly clinically relevant and that we now want to explore in greater depth with the Milan team led by Alessandra Bolino.

Publication
Linda Sawade, Federica Grandi, Marianna Mignanelli, Genaro Patiño-López , Kerstin Klinkert, Francina Langa Vives, Roberta Di Guardo, Arnaud Echard, Alessandra Bolino, Volker Haucke. Rab35-regulated lipid turnover by myotubularins represses mTORC1 activity and controls myelin. Nature communications. June 2020; https://doi.org/10.1038/s41467-020-16696-6

Text: Beatrice Hamberger, Translation: Theresa Gehrs

Image: Sciatic nerves from 3-month-old mice in cross section: In contrast to control animals (on the far left), animals with loss of the Rab35 protein in Schwann cells exhibit demyelination of nerve fibers: myelin outfoldings (yellow arrow); myelin degeneration (green arrow); ‘tomacula’ – focal thickening of the myelin sheath (red star). (Image: Alessandra Bolino, IRCCS Ospedale San Raffaele)

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Research / 28.05.2020
Clarifying a culprit in inflammatory bowel disease

f.l.t.r.: Inge Krahn, Marina Kolesnichenko, Uta Höpken, Eva Kärgel, Jana Wolf (Photo: Felix Petermann, MDC)
f.l.t.r.: Inge Krahn, Marina Kolesnichenko, Uta Höpken, Eva Kärgel, Jana Wolf (Photo: Felix Petermann, MDC)

 It’s been a bit of a mystery: is a particular family of proteins responsible for cell survival or cell death in the intestinal lining? A new mouse model developed at the Max Delbrück Centre for Molecular Medicine (MDC) provides clear evidence and a potential treatment target for inflammatory bowel disease.

A common protein found throughout the body, NF-kB, promotes harmful inflammation, cell proliferation and cell death in the intestinal lining, the key features of inflammatory bowel disease (IBD), according to research recently published in The Journal of Pathology.

“This was surprising because usually NF-kB helps protect cells from death,” says Dr. Marina Kolesnichenko. The scientist from the Signal Transduction in Tumour Cells Lab spearheaded the research at Max Delbrück Centre for Molecular Medicine in the Helmholtz Association (MDC).
Good or bad?

NF-kB is a family of transcription factor proteins, which transcribe parts of DNA inside cells to carry out various cellular processes, from cell replication and survival, to inflammation and cell death, which is called apoptosis.

NF-kB’s role in apoptosis in the intestine has been up for debate, with some studies suggesting it plays a protective or “anti-apoptotic” role, while others found hints it might be “pro-apoptotic,” contributing to cell death. One reason for the lack of clarity: previous studies mostly disrupted the signaling pathway several steps “upstream”, this means before NF-kB gets activated, rather than targeting NF-kB directly.

A specific target

Normally, NF-kB can’t begin its work until it is released by an inhibiting molecule. Kolesnichenko and her collaborators developed a mouse model that blocks the inhibitor specifically in the epithelium, which are the cells lining the gut. This unleashed persistent NF-kB activation only in that tissue. Extended activation in the intestinal lining was distinctly harmful, leading to increased inflammation in both the intestine and colon, as well as dangerous stem cell hyperproliferation and cell death in the intestine.

“The study demonstrates that activation of NF-kB alone, without any contribution of upstream components, is sufficient to trigger an IBD-like pathology,” says Prof. Claus Scheidereit, who heads the Signal Transduction in Tumour Cells Lab.

Cancer connection

The team further investigated the results in epithelial organoids, which are miniature guts cultured from the intestinal linings of the modified mice. The researchers found that without immune cells present, activated NF-kB boosted abnormal signaling of the Wnt pathway. Aberrant Wnt signaling is detected in the majority of cases of colorectal cancer.

Given that IBD patients are at higher risk of developing colorectal cancer later in life, Kolesnichenko is curious to investigate if NF-kB is a key driver of that transition towards cancer. Further investigations might reveal that blocking NF-kB in the intestinal lining could help treat IBD or colorectal cancer.

A unique position

Kolesnichenko initiated and led the study, collaborating with several women from other units at MDC and at Charité – Universitätsmedizin Berlin. Notably, she published the results as the senior paper author, which is unusual for MDC post docs. Kolesnichenko notes it is important for post docs to be able to show independence and initiative, particularly when seeking funding from agencies that consider the number of “last author” papers they have published.

“The most rewarding part was working together with truly inspiring scientists, each of whom contributed something unique and essential to the story,” Kolesnichenko says.

https://www.mdc-berlin.de/news/news/clarifying-culprit-inflammatory-bowel-disease

www.mdc-berlin.de

Research / 19.05.2020
Cells sound the alarm on chlamydia

© Audrey Xavier, MDC
© Audrey Xavier, MDC

A chlamydia infection triggers an inflammatory response at the cellular level. MDC researchers conducted experiments in cell cultures to examine the role that the enzyme GBP1 plays in this response. They have now published their findings in Cell Reports.

Chlamydia is one of the most common sexually transmitted diseases in Germany. Chlamydia bacteria need host cells to survive and reproduce. They often use mucous membrane cells in the human reproductive and urinary organs for this purpose, effectively “hijacking” the host’s cellular metabolism. These intruders either go undetected or signaling molecules alert the innate immune system of their presence. In the latter case, the body’s own defense system recognizes the bacteria as foreign and provokes an inflammatory response to destroy the bacteria.

The human guanylate-binding protein 1 (GBP1) plays a key role in the defense mechanisms against chlamydia or other pathogens. Researchers already know that this enzyme is not only capable of slowing down the reproduction of the chlamydia bacteria, but can also set off an inflammatory response by turning on certain signaling pathways. Yet exactly how these processes work is still a mystery. Now, a team led by Professor Oliver Daumke at the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC) has learned more about the role of specific metabolites of the enzyme in question. Working with the Max Planck Institute for Infection Biology, the researchers discovered which signaling pathways and protein complexes are activated by the metabolites.

GMP is important for the immune defense

The enzyme being studied – GBP1 – can act as a catalyst to speed up the cleavage of bioactive compounds. “It converts GTP to GMP in two steps through a reaction with water,” Daumke says. “GTP is a widely distributed cellular molecule that serves as a building block of RNA and is required for signaling processes.”

To understand what effect this cleavage has on the cell, Audrey Xavier, a PhD student in Daumke’s lab and the lead author of the study, modified the catalyzing enzyme. The enzyme either no longer functioned or it could only carry out the first step of the cleavage. She then introduced the different variants of the enzyme into human immune cells and infected them with chlamydia. The researcher was only able to measure typical inflammatory responses in those cells where the cleavage was fully possible. “That shows that GMP is crucial for this process,” Xavier says. But GMP does not appear to be responsible for slowing the growth of chlamydia. “Unfortunately, we still don’t exactly know how GBP1 inhibits the growth of the bacteria,” she says.

Blocking the signaling pathway

Xavier was even able to determine which signaling pathway GMP turns on in infected cells. According to the researcher, there are various protein complexes that can provoke an inflammatory response in cells, and the most well-known of these – the NLRP3 inflammasome – is activated when GMP is broken down to uric acid.

She managed to shut down this uric acid signaling pathway with an already approved drug that is normally used to treat gout. This disease is characterized by especially severe inflammatory responses. The research team observed that the agent allopurinol attenuates the inflammatory symptoms in cells infected with chlamydia. “Allopurinol helps reduce inflammation – and possibly also in people who have chlamydia,” Xavier says, adding: “But first clinical trials will need to test whether this might have potential as a supplemental therapy in combination with an antibiotic.”

Source: https://www.mdc-berlin.de/news/news/chlamydia-cells-enzyme-GBP1-allopurinol

Research / 14.05.2020
Support for SARS-CoV-2 diagnostics

The LabHive digital platform aims to provide necessary resources to diagnostic centres to enable more tests for SARS-CoV-2. Tobias Opialla from the MDC is one of 15 volunteers who has been involved in the project since the #WirvsVirus Hackathon organized by the German government.

An interdisciplinary team of 15 scientists, physicians, web developers, and security experts will use the digital platform LabHive to bundle testing capacities for SARS-CoV-2 and to compensate for bottlenecks in diagnostic centers. On LabHive qualified volunteers can provide their manpower, and research laboratories can offer reagents and equipment. Diagnostic centres have access to these services and can call on support if needed.

"In many university or non-university research labs, the corona crisis has restricted scientific operations," says Dr. Tobias Opialla from the Berlin Institute for Medical Systems Biology (BIMSB), an institution of the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC). "LabHive provides resources such as personnel, reagents or equipment that might otherwise remain unused." Like all participants, Opialla works voluntarily on the development and implementation of the platform.

The idea for this project was born during the #WirVsVirus-Hackathon of the German government and the project is currently funded by the German Federal Ministry of Education and Research. Their partner is the Björn Steiger Foundation.

Further Information

Press Contacts

Dr. Tobias Opialla
Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC)
Berlin Institute for Medical Systems Biology (BIMSB)
Scientist at the Proteomics and Metabolomics Platform
+49 30 9406 1330
Tobias.Opialla@mdc-berlin.de

Christina Anders
Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC)
Editor, Communication Department
+49-30 9406 2118
christina.anders@mdc-berlin.de or presse@mdc-berlin.de

www.mdc-berlin.de

Innovation / 12.05.2020
Q1 Performance Stable despite Oil Price Slump and Corona Expenses. Strong Growth in Radiopharmaceutical Products

Despite heavy burdens from corona and the drop in oil prices, Eckert & Ziegler Strahlen- und Medizintechnik AG (ISIN DE0005659700, TecDAX), a specialist for isotope applications in medicine, science and industry, completed the first quarter of 2020 roughly at the same level as last year. While sales increased by around 2% to 44 mm EUR million, net income came in at 0.98 EUR per share, some 14% or 16 Cent down from previous year’s quarter.

The main reason for the relatively steady performance was the continued strong growth, compared to the previous year, in sales and earnings from radiopharmaceutical products and services in the Medical segment. While sales revenues here increased by 26% or EUR 4.2 million to just under EUR 21 million, the segment's net profit even rose by 28% to EUR 3.5 million or EUR 0.62 per share.

In contrast, sales and earnings in the industrial components business retrenched as expected. While in the previous year the Isotope Products segment was able to contribute EUR 0.59 per share to earnings, it only achieved a net income of EUR 1.3 million or EUR 0.26 per share in the first quarter of 2020. The most significant factor for the decrease were currency losses of about EUR 1 million or minus EUR 0.19 per share, which had to be posted at the end of March due to the devaluation of the Brazilian real. In February, the exchange rate of the Latin American country had collapsed by around 20% against the euro in the course of the Corona pandemic. The quarterly result of the Isotope Products segment was also negatively impacted by a 12% year-on-year decline in sales to EUR 24 million, reflecting the recent drop in oil prices and, as expected, a related slump in demand for measurement technology components.

The Executive Board expects the results of the first quarter to mark a bottom, which should roughly characterize the second quarter. It therefore confirms its earnings forecast of EUR 3.50 per share for the full year 2020 and the dividend recommendation of EUR 1.70 per share, which will be submitted to the Annual General Meeting on June 10, 2020.

The complete financial statements can be viewed here:
http://www.ezag.com/fileadmin/user_upload/ezag/investors-financial-reports/englisch/euz120e.pdf

About Eckert & Ziegler.
Eckert & Ziegler Eckert & Ziegler Strahlen- und Medizintechnik AG with more than 800 employees, is one of the world's largest providers of isotope-related components for radiation therapy and nuclear medicine. Eckert & Ziegler shares (ISIN DE0005659700) are listed in the TecDAX index of Deutsche Börse.

www.ezag.com

Innovation / 11.05.2020
US health authorities to provide USD 6 million in funding for MYELO radiation protection pill

Berlin-based MYELO Therapeutics, an affiliated company of Eckert & Ziegler Strahlen- und Medizintechnik AG, will receive USD 6 million from the National Institutes of Health (NIH) over the next three years for the further development of its radiation protection pill MYELO001. The company is one of the few European applicants to successfully compete for funds from the relatively generous US catastrophe prevention program.

The money will be used to finance further tests and proof of concept and to investigate the functional mechanism of the new orally applicable drug. If the multi-year trials are successful, MYELO has the opportunity to win valuable contracts from civil protection agencies in America and elsewhere to build up emergency stocks.

"MYELO Therapeutics is one of a series of strategic investments that Eckert & Ziegler is using to push its growth into new dimensions in the mid term," explained Dr. Andreas Eckert, CEO of the TecDAX company Eckert & Ziegler. "The Executive Board has been able to continuously increase the financial resources for this purpose over the past few years. Although it would still be years too early to make concrete statements on sales or earnings potential, the award of the contract by the American health authorities shows that Eckert & Ziegler is on the right track when it comes to selecting its financing projects".

For details of the radiation protection pill and the funding commitment of the American health authorities, see the detailed press release of MYELO Therapeutics: http://www.myelotherapeutics.com/news.html

About Eckert & Ziegler.
Eckert & Ziegler Eckert & Ziegler Strahlen- und Medizintechnik AG with more 800 employees, is one of the world's largest providers of isotope-related components for radiation therapy and nuclear medicine. Eckert & Ziegler shares (ISIN DE0005659700) are listed in the TecDAX index of Deutsche Börse.

Innovation / 07.05.2020
Eckert & Ziegler Enters TecDAX

The Berlin-based Eckert & Ziegler Strahlen- und Medizintechnik AG (ISIN DE0005659700, S-DAX) a specialist in isotope-related applications in medicine, science and industry, will enter the TecDAX effective as of 8 May 2020.

This index, which is measured in terms of market capitalisation of the free float and trading volume in the shares, comprises the 30 largest technology stocks in Germany.

"We are pleased about the admission to the TecDAX and expect that this will give our company and our share additional attention on the international capital market. Thanks to its strong growth, Eckert & Ziegler is now officially one of the largest listed technology companies in Germany," said Dr. Andreas Eckert, Chief Executive Officer of Eckert & Ziegler AG.

About Eckert & Ziegler.
Eckert & Ziegler Eckert & Ziegler Strahlen- und Medizintechnik AG with around 800 employees, is one of the world's largest providers of isotope-related components for radiation therapy and nuclear medicine.

www.ezag.de

Research / 06.05.2020
Phage capsid against influenza: perfectly fitting inhibitor prevents viral infection

Phage shell docks on and inhibits the influenza virus (visualization Barth van Rossum)
Phage shell docks on and inhibits the influenza virus (visualization Barth van Rossum)

A new approach brings the hope of new therapeutic options for suppressing seasonal influenza and avian flu: On the basis of an empty – and therefore non-infectious – shell of a phage virus, researchers from Berlin have developed a chemically modified phage capsid that “stifles” influenza viruses. Perfectly fitting binding sites cause influenza viruses to be enveloped by the phage capsids in such a way that it is practically impossible for them to infect lung cells any longer. This phenomenon has been proven in pre-clinical trials, also involving human lung tissue. Researchers from the Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP), Freie Universität Berlin, Technische Universität Berlin (TU), Humboldt-Universität (HU), the Robert Koch Institute (RKI) and Charité-Universitätsmedizin Berlin were involved in this groundbreaking work. The results are also being used for the immediate investigation of the coronavirus. The findings have now been published in Nature Nanotechnology.

Influenza viruses are still highly dangerous: The World Health Organization (WHO) estimates that flu is responsible for up to 650,000 deaths per year worldwide. Current antiviral drugs are only partially effective because they attack the influenza virus after lung cells have been infected. It would be desirable – and much more effective – to prevent infection in the first place.
This is exactly what the new approach from Berlin promises. The phage capsid, developed by a multidisciplinary team of researchers, envelops flu viruses so perfectly that they can no longer infect cells. “Pre-clinical trials show that we are able to render harmless both seasonal influenza viruses and avian flu viruses with our chemically modified phage shell,” explained Professor Dr. Christian Hackenberger, Head of the Department Chemical Biology at the Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP) and Leibniz-Humboldt Professor for Chemical Biology at HU Berlin. “It is a major success that offers entirely new perspectives for the development of innovative antiviral drugs.”

Multiple bonds fit like hook-and-loop tape
The new inhibitor makes use of a feature that all influenza viruses have: There are trivalent receptors on the surface of the virus, referred to as hemagglutinin protein, that attach to sugar molecules (sialic acids) on the cell surface of lung tissue. In the case of infection, viruses hook into their victim – in this case, lung cells – like a hook-and-loop fastener. The core principle is that these interactions occur due to multiple bonds, rather than single bonds.
It was the surface structure of flu viruses that inspired the researchers to ask the following initial question more than six years ago: Would it not be possible to develop an inhibitor that binds to trivalent receptors with a perfect fit, simulating the surface of lung tissue cells?

We now know that this is indeed possible – with the help of a harmless intestinal inhabitant: The Q-beta phage has the ideal surface properties and is excellently suited to equip it with ligands – in this case sugar molecules – as “bait”. An empty phage shell does the job perfectly. “Our multivalent scaffold molecule is not infectious, and comprises 180 identical proteins that are spaced out exactly as the trivalent receptors of the hemagglutinin on the surface of the virus,” explained Dr. Daniel Lauster, a former PhD student in the Group of Molecular Biophysics (HU) and now a postdoc at Freie Universität Berlin. “It therefore has the ideal starting conditions to deceive the influenza virus – or, to be more precise, to attach to it with a perfect spatial fit. In other words, we use a phage virus to disable the influenza virus!”
To enable the Q-beta scaffold to fulfill the desired function, it must first be chemically modified. Produced from E. coli bacteria at TU Berlin, Professor Hackenberger’s research group at FMP and HU Berlin use synthetic chemistry to attach sugar molecules to the defined positions of the virus shell.

Virus is deceived and enveloped
Several studies using animal models and cell cultures have proven that the suitably modified spherical structure possesses considerable bond strength and inhibiting potential. The study also enabled the Robert Koch Institute to examine the antiviral potential of phage capsids against many current influenza virus strains, and even against avian flu viruses. Its therapeutic potential has even been proven on human lung tissue, as fellow researchers from the Medical Department, Division of Infectiology and Pneumology, of Charité were able to show: When tissue infected with flu viruses was treated with the phage capsid, the influenza viruses were practically no longer able to reproduce.

The results are supported by structural proof furnished by scientists at Freie Universität Berlin from the Research Center of Electron Microscopy (FZEM): High-resolution cryo-electron microscopy and cryo-electron microscopy show directly and, above all, spatially, that the inhibitor completely encapsulates the virus. In addition, mathematical-physical models were used to simulate the interaction between influenza viruses and the phage capsid on the computer. “Our computer-assisted calculations show that the rationally designed inhibitor does indeed attach to the hemagglutinin, and completely envelops the influenza virus,” confirmed Dr. Susanne Liese from the AG Netz of Freie Universität Berlin. “It was therefore also possible to describe and explain the high bond strength mathematically.”

Therapeutic potential requires further research
These findings must now be followed up by more preclinical studies. It is not yet known, for example, whether the phage capsid provokes an immune response in mammals. Ideally, this response could even enhance the effect of the inhibitor. However, it could also be the case that an immune response reduces the efficacy of phage capsids in the case of repeated-dose exposure, or that flu viruses develop resistances. And, of course, it has yet to be proven that the inhibitor is also effective in humans.
Nonetheless, the alliance of Berlin researchers is certain that the approach has great potential. “Our rationally developed, three-dimensional, multivalent inhibitor points to a new direction in the development of structurally adaptable influenza virus binders. This is the first achievement of its kind in multivalency research,” emphasized Professor Hackenberger. The chemist believes that this approach, which is biodegradable, non-toxic and non-immunogenic in cell culture studies, can in principle also be applied to other viruses, and possibly also to bacteria. It is evident that the authors regard the application of their approach to the current coronavirus as one of their new challenges. The idea is to develop a drug that prevents coronaviruses from binding to host cells located in the throat and subsequent airways, thus preventing infection.

Berlin university alliance at its best
Cooperation between scientists from different disciplines played a major role in the discovery of the new influenza inhibitor. Biologists, chemists, physicists, virologists, medical scientists and imaging specialists from three Berlin universities HU, Freie Universität Berlin and TU, the Robert Koch Institute, Charité and, last but not least, FMP were all involved in the project. “In my opinion, such a complex project could only have been undertaken in Berlin, where there truly are experts for every issue,” stated Professor Dr. Andreas Herrmann, Head of Molecular Biophysics at HU Berlin. “It was the Berlin university alliance at its best,” he added, “and I hope that the follow-up studies will be equally successful.”

The project was funded within Collaborative Research Center 765 (Speaker Professor Dr. Rainer Haag, Freie Universität Berlin) of the German Research Foundation (DFG).


Publication

Daniel Lauster, Simon Klenk, Kai Ludwig, Saba Nojoumi, Sandra Behren, Lutz Adam, Marlena Stadtmüller, Sandra Saenger, Stephanie Franz, Katja Hönzke, Ling Yao, Ute Hoffmann, Markus Bardua, Alf Hamann, Martin Witzenrath, Leif E. Sander, Thorsten Wolff, Andreas C. Hocke, Stefan Hippenstiel, Sacha De Carlo, Jens Neudecker, Klaus Osterrieder, Nediljko Budisa, Roland R. Netz, Christoph Böttcher, Susanne Liese, Andreas Herrmann, Christian P. R. Hackenberger. Phage capsid nanoparticles with defined ligand arrangement block influenza virus entry. Nature Nanotechnology DOI 10.1038/s41565-020-0660-2

 

www.leibniz-fmp.de

Research / 04.05.2020
MDC cautiously begins basic operations

Photo: Peter Himsel
Photo: Peter Himsel

After nearly seven weeks of minimal operations, the scientists at the Max Delbrück Center will return to their laboratories on May 4, 2020. During basic operations, stringent safety measures will be in place due to the pandemic.

Biomedical research does not only take place in the laboratory. While the pandemic caused research operations to be put in emergency mode, the scientists at the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC) published numerous studies, analyzed test data and designed new experiments. Many research groups at the MDC have also taken on a new scientific challenge: to study and better understand Sars-CoV-2. They are participating in global efforts to prevent and combat the virus.

Starting Monday, May 4, scientists who are not involved in coronavirus research can resume work in the laboratories. Staff who are critically needed so as to not jeopardize the success of a study or an experiment or to not delay research projects any longer will be allowed to return to the MDC. The vast majority of staff – those whose presence is not absolutely required – will continue to work remotely from home.

During basis operations, the MDC will implement stringent safety rules and a strict hygiene concept that comply with federal and state regulations. Safe physical distancing of ideally 2 meters, but at least 1.5 meters is mandatory in MDC buildings. Masks must be worn outside of offices and laboratories. New shift and signage systems will reduce density of staff using research facilities and help prevent close contact between employees. There are limits on the number of persons that can be present in the laboratories and offices. Special rules apply to employees who belong to at-risk groups.

Public lectures, on-site seminars and meetings will continue to be prohibited. Such events can only take place digitally. Business trips are also not permitted.

Source: https://www.mdc-berlin.de/news/news/mdc-cautiously-begins-basic-operations

www.mdc-berlin.de

Research / 30.04.2020
The networker

Dr. James Poulet (Photo: David Ausserhofer/ Copyright: MDC)
Dr. James Poulet (Photo: David Ausserhofer/ Copyright: MDC)

The neuroscientist Dr. James Poulet has been appointed to the W3 professorship for Systems Neuroscience at Charité – Universitätsmedizin Berlin in cooperation with the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC). Professor Poulet took up the post on April 1, 2020.

When someone runs their hand over an icy surface, they simultaneously feel how cool and smooth it is. “We take it completely for granted that many sensory stimuli are perceived as one sensation, but we don’t know how they are combined,” James Poulet explains. The British neuroscientist has since 2009 led the Neural Circuits and Behavior Lab at the Max Delbrück Center for Molecular Medicine and has been working at the NeuroCure Cluster of Excellence. He and his team investigate how the brain integrates touch and temperature. The 44-year-old Poulet has now been appointed to the W3 professorship for Systems Neuroscience at Charité – Universitätsmedizin Berlin in cooperation with the MDC.

“James Poulet is one of Europe’s leading researchers in the field of systems neuroscience. We warmly congratulate him on his appointment,” says Professor Thomas Sommer, interim Scientific Director of the MDC. Systems neuroscientists study how the activities of individual neurons are processed in neural circuits and how this in turn leads to very specific and measurable behavior. “To conduct his research, Poulet has combined a series of very sophisticated and innovative techniques that include optical methods,” Sommer says. “He also collaborates very successfully with researchers in Germany and abroad; in Berlin this includes the MDC labs of Professors Gary Lewin, Carmen Birchmeier and Helmut Kettenmann as well as the NeuroCure groups of Professors Benjamin Judkewitz and Dietmar Schmitz.”

It started with a video conference – thanks to the coronavirus

“I am naturally extremely pleased and honoured to receive the professorship,” Poulet says. Even if things didn’t start out quite like he had expected due to the corona crisis. “I met with the dean of Charité, Professor Axel Radlach Pries, on March 30 to sign the final contract,” Poulet recounts. “We didn’t shake hands and we kept a two-meter distance between ourselves during our brief talk.” His first day as professor began with a lab group meeting held via video conference, and afterwards he helped his three kids with their schoolwork. “My days have since followed a similar routine of video conferencing, writing and helping with schoolwork,” he says.

Poulet studied biology at the University of Bristol and received his PhD from the University of Cambridge. He then held postdoc positions in Cambridge and at the Swiss Federal Institute of Technology (EPFL) in Lausanne. Poulet joined the MDC as a junior research group leader in 2009. He and his team have since conducted their research as part of the NeuroCure Cluster of Excellence at Charité. Poulet has already received two awards from the European Research Council (ERC) for his fundamental research. In 2010 he received a €1.5 million ERC Starting Grant for early-career researchers. And in 2017 he was awarded an ERC Consolidator Grant of €2 million to support his groundbreaking research.

A surprising finding on warm perception

“Our long-term goal is to identify neural mechanisms of sensory processing and perception. We have a special interest in the function of the thalamus and neocortex, two areas that are thought to be at the center of sensory perception” Poulet says. His studies are conducted on mice, whose forepaws function much like human hands. They are used not only for locomotion, but also to reach and sense objects. The skin of the forepaws contains nerve endings, very similar to those found in in humans, that convey sensory stimuli like touch, temperature and pain to the brain. Poulet and his team closely observe individual neurons embedded in their intact networks as mice perform sensory tasks. In addition, they often use genetically altered types of neurons to help understand how the brain generates a sensory percept.

In his most recent paper, published in late March, Poulet collaborated with Gary Lewin (MDC) to show that warm perception in mice functions differently than previously believed. As he and his team reported in the journal Neuron, perceiving warmth requires input from a surprising source: cool receptors. The researchers’ finding challenged the widely held theory that dedicated and separate neurons relay either warm or cool sensations to the brain.

Source: https://www.mdc-berlin.de/news/news/networker

www.mdc-berlin.de

Research / 28.04.2020
A potential agent for treating preeclampsia

Histological image of a rat placenta: This image helps researchers analyze, among other things, the spiral arteries in order to gain insights into fetal nutrition. © Nadine Haase, MDC
Histological image of a rat placenta: This image helps researchers analyze, among other things, the spiral arteries in order to gain insights into fetal nutrition. © Nadine Haase, MDC

Researchers at the ECRC have successfully used RNA molecules to treat a dangerous pregnancy disorder called preeclampsia. They were able to alleviate common symptoms of the disorder, like maternal high blood pressure and fetal undernutrition, with virtually no side effects.

It usually begins after the 20th week of pregnancy: The affected women suddenly develop high blood pressure. They excrete increased amounts of protein in their urine (called proteinuria) – a sign that the small blood vessels in the kidneys are damaged. It can also cause life-threatening damage to the liver and bone marrow. Moreover, the unborn baby is not adequately nourished, which can interfere with the baby’s growth and development. About five percent of all pregnant women in Western countries suffer from some form of preeclampsia.

“Preeclampsia is the most common pregnancy-related disease that today in Germany still causes a significant number of deaths among women, and it is also the leading cause of premature births, with some births occurring between the 24th and 30th weeks of pregnancy,” says Dr. Nadine Haase from the Experimental and Clinical Research Center (ECRC ), a joint institution of the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC) and Charité – Universitätsmedizin Berlin. Haase is the lead author of a study on preeclampsia that is now being published in the Journal of Clinical Investigation. She is a member of the Hypertension-Mediated End-Organ Damage Lab, led by Professors Dominik Müller and Ralf Dechend, the latter of whom is the senior author of the paper.

The disease has previously been untreatable
There are not yet any medications for treating preeclampsia. “We know that the endogenous renin-angiotensin-aldosterone system (RAAS), which regulates blood pressure as well as water and electrolyte balance, is disrupted in women with the disease,” Haase says. “However, those agents already known to intervene in the RAAS system cannot be administered to pregnant women, because they could harm the unborn baby, especially impairing kidney development.” And other antihypertension drugs, such as methyldopa, have only a minimal effect on preeclampsia. “Often the only option is preterm delivery, and many of these premature babies don’t survive or have disabilities,” Haase says.

So, together with colleagues from Berlin, Essen, Hamburg, and Jackson, Mississippi, as well as a team from the Cambridge, Massachusetts-based medical research firm Alnylam Pharmaceuticals, Haase began to search for more effective drugs to treat preeclampsia. The researchers wanted to find out if the small interfering RNA (siRNA) molecules developed by Alnylam could alleviate the symptoms of preeclampsia without harming the fetus. “The siRNA we are using slows the production of the hormone angiotensinogen (AGT) in the liver,” Haase explains. “AGT is a precursor of angiotensin. As a result, the siRNA acts on the RAAS system in regulatory manner.” Alnylam has already successfully employed this mechanism of action to treat other diseases in humans.

Two animal models of preeclampsia
Haase and her colleagues tested the siRNA on two animal models. In the first model, the team of researchers used female rats that had been genetically altered so that they produced human AGT. They crossed these animals with male rats that produce human renin. Such a procedure leads to hyperactivity of the RAAS system with corresponding symptoms of preeclampsia during the gestation of the female rats.

In the other model, which was developed in the United States and goes by the name of reduced uteroplacental perfusion (RUPP), clips that reduce blood flow in the placenta were applied to the gestating rats. This caused the rat fetuses to be undernourished. In addition, the maternal rats treated with the clip developed – as did the genetically altered animals – high blood pressure and proteinuria, albeit at a lower level. Two clinical biomarkers – PlGF and sFlt-1 – that are used in the diagnosis of preeclampsia were also altered in the rats.

Lower blood pressure, larger fetuses
For the therapeutic experiment, the researchers injected siRNA under the skin of the rats. They had chemically altered the molecules so that they would only act on the liver – i.e., where the hormone AGT is produced. “As hoped, we observed a decrease in the symptoms of preeclampsia in the treated rats, and this was true for both models,” Haase says. “Their blood pressure fell and the proteinuria disappeared.” Moreover, the biomarker ratio, PlGF/sFlt-1, returned to normal. Consequently, the offspring in the womb were also better nourished.

In addition, Haase reports that it was possible to show that the siRNA molecules only blocked the production of the hormone AGT in the liver of the rats. The siRNA was not detectable in the placenta. The researchers also studied whether the treatment administered to maternal rats affected organ development (e.g., brain, lung, heart, kidney) in the offspring. “We did not find any negative effects in the rat fetuses nor in the fetuses that were delivered,” Haase says. “The siRNA therapy thus appears to be safe, at least in animals.”

First clinical trial with pregnant women
“Our study provided the data required to take the next step toward a clinical trial,” Haase says. But further basic research is also needed. “Developing an RAAS blocker that does not cross the placental barrier and cause harm to the child is one of the greatest challenges in prenatal medicine,” says Ralf Dechend, the senior author of the study. He reports that the US company Alnylam is now planning to conduct its first therapeutic trial with pregnant women in which he will be involved in a medical advisory role. Haase, on the other hand, is already contemplating her next research project: a preclinical study in which she wants to test how a peptide (a small protein molecule) affects the treatment of preeclampsia.

Text: Anke Brodmerkel

Source: https://www.mdc-berlin.de/news/press/potential-agent-treating-preeclampsia

www.mdc-berlin.de

Research / 23.04.2020
Likely Entrypoints for SARS-CoV-2

Copyright: Sars-CoV-2 (gelb), NIAID-RML
Copyright: Sars-CoV-2 (gelb), NIAID-RML


Two specific cell types in the nose have been identified as likely initial infection points for the novel coronavirus that causes COVID-19. Using data from the Human Cell Atlas, scientists discovered that goblet and ciliated cells in the nose have high levels of the entry proteins that SARS-CoV-2 uses to get into our cells.

The identification of these cells by researchers from the Wellcome Sanger Institute, University Medical Centre Groningen, University Cote d’Azur and CNRS, Nice and their collaborators, as part of the Human Cell Atlas Lung Biological Network, could help explain the high transmission rate of SARS-CoV-2.

Reported today (April 23rd) in Nature Medicine, this first publication with the Lung Biological Network is part of an ongoing international effort to use Human Cell Atlas data to understand infection and disease. It further shows that cells in the eye and some other organs such as the heart also contain the viral-entry proteins. The study also predicts how a key entry protein is regulated with other immune system genes and reveals potential targets for the development of treatments to reduce transmission.

Novel coronavirus disease - COVID-19 – primarily affects the lungs and airways. Patient’s symptoms can be flu-like, including fever, coughing and sore throat, while some people may not experience symptoms but still have transmissible virus. In the worst cases, the virus causes pneumonia that can ultimately lead to death. The virus is thought to be spread through respiratory droplets produced when an infected person coughs or sneezes, and appears to be easily transmitted within affected areas. So far the virus has cost more than 176,000 lives.

Pinpointing the cell types involved in the infection

Scientists around the world are trying to understand exactly how the virus works, to help prevent transmission and develop a vaccine. While it is known that the virus that causes COVID-19 disease, known as SARS-CoV-2, uses a similar mechanism to infect our cells as a related coronavirus that caused the 2003 SARS epidemic, the exact cell types involved in the nose had not previously been pinpointed.

To discover which cells could be involved in COVID-19, researchers analysed multiple Human Cell Atlas (HCA) consortium datasets of single cell RNA sequencing, from more than 20 different tissues of non-infected people. These included cells from the lung, nasal cavity, eye, gut, heart, kidney and liver. The researchers looked for which individual cells expressed both of two key entry proteins that are used by the virus to infect our cells.

Dr Waradon Sungnak, the first author on the paper from Wellcome Sanger Institute, said: “We found that the receptor protein - ACE2 - and the TMPRSS2 protease that can activate SARS-CoV-2 entry are expressed in cells in different organs, including the cells on the inner lining of the nose.  We then revealed that mucus-producing goblet cells and ciliated cells in the nose had the highest levels of both these virus proteins, of all cells in the airways. This makes these cells the most likely initial infection route for the virus.”

Cells in the nose are highly accessible to the virus

Dr Martijn Nawijn, from the University Medical Center Groningen in the Netherlands, said, on behalf of the HCA Lung Biological Network: “This is the first time these particular cells in the nose have been associated with COVID-19. While there are many factors that contribute to virus transmissibility, our findings are consistent with the rapid infection rates of the virus seen so far. The location of these cells on the surface of the inside of the nose make them highly accessible to the virus, and also may assist with transmission to other people.”

The two key entry proteins ACE2 and TMPRSS2 were also found in cells in the cornea of the eye and in the lining of the intestine. This suggests another possible route of infection via the eye and tear glands, and also revealed a potential for fecal-oral transmission.

When cells are damaged or fighting an infection, various immune genes are activated. The study showed that ACE2 receptor production in the nose cells is probably switched on at the same time as these other immune genes.

ACE2 can also be found in the heart

Up to 20 per cent of COVID-19 patients also suffer myocardial damage and consequent cardiac decompensation. Thus, it was crucial to map SARS-CoV-2 receptor and enabling proteases gene expression in the heart as well. “We analysed ~500,000 single cells from 14 human hearts and identified three cellular compartments expressing the entry receptor: pericytes, cells of the heart fine capillary network; cardiac muscle cells; and fibroblasts, the cells contributing to maintain the heart structure”, said Dr Michela Noseda from the National Heart & Lung Institute at Imperial College, London. “Knowing the exact target cells of the virus in the heart provides the basis to understand the mechanisms of damage and guide treatment choices.”

“We have an exceptional set of single cell data”, said Professor Norbert Hübner, head of the Genetics and Genomics of Cardiovascular Diseases group at the Max Delbrück Center for Molecular Medicine (MDC) who also heads projects at the Berlin Institute of Health (BIH ) and German Center for Cardiovascular Diseases (DZHK ). Together with Dr Jonathan Seidman, the Bugher Professor of Cardiovascular Genetics at Harvard Medical School, he coordinates a team of 13 scientists from Germany, the United Kingdom, and the United States dedicated to probing and understanding the human heart, cell by cell. Michela Noseda and Sarah Teichmann are part of this team. “We found the ACE2 receptor in particular in the pericytes. This receptor probably has a fundamental role in maintaining blood flow in the body. However, its role in cardiac problems of COVID-19 patients is another matter. We still don’t know whether the cardiac damage is caused by the virus itself or whether it is a secondary effect.”

Using the Human Cell Atlas to understand COVID-19

The work was carried out as part of the global Human Cell Atlas consortium which aims to create reference maps of all human cells to understand health and disease. More than 1,600 people across 70 countries are involved in the HCA community, and the data is openly available to scientists worldwide.

Dr Sarah Teichmann, a senior author from the Wellcome Sanger Institute and co-chair of the HCA Organising Committee, said: “As we’re building the Human Cell Atlas it is already being used to understand COVID-19 and identify which of our cells are critical for initial infection and transmission. This information can be used to better understand how coronavirus spreads. Knowing which exact cell types are important for virus transmission also provides a basis for developing potential treatments to reduce the spread of the virus.”

The global HCA Lung Biological Network continues to analyse the data in order to provide further insights into the cells and targets likely to be involved in COVID-19, and to relate them to patient characteristics.

Professor Sir Jeremy Farrar, Director of Wellcome, said: “By pinpointing the exact characteristics of every single cell type, the Human Cell Atlas is helping scientists to diagnose, monitor and treat diseases including COVID-19 in a completely new way. Researchers around the world are working at an unprecedented pace to deepen our understanding of COVID-19, and this new research is testament to this. Collaborating across borders and openly sharing research is crucial to developing effective diagnostics, treatments and vaccines quickly, ensuring no country is left behind.”

This work was supported by Wellcome, the Chan Zuckerberg Initiative, the European Union Commission and other funders. Please see the paper for the full list of funders.
 

Further information

The Human Cell Atlas

The Human Cell Atlas (HCA) is an international collaborative consortium, which aims to create comprehensive reference maps of all human cells—the fundamental units of life—as a basis for both understanding human health and diagnosing, monitoring, and treating disease. The HCA is steered and governed by an Organising Committee, which is co-chaired by Dr Sarah Teichmann of the Wellcome Sanger Institute (UK), and Dr Aviv Regev of the Broad Institute of MIT and Harvard (USA).  www.humancellatlas.org

The Human Cell Atlas Lung Biological Network is a consortium of 71 scientists who collaborate on mapping the airway cells in our body. This group is coordinated by Drs Martijn Nawijn, Pascal Barbry, Alexander Misharin and Jayaraj Rajagopal.

Source: https://www.mdc-berlin.de/news/press/likely-entrypoints-sars-cov-2

 

www.mdc-berlin.de

Research / 21.04.2020
New therapeutic options for multiple sclerosis in sight

For the subsequent transcriptome analysis Alexander Mildner controls sorted monocytes under the microscope. (Photo: Alexander Mildner, MDC)
For the subsequent transcriptome analysis Alexander Mildner controls sorted monocytes under the microscope. (Photo: Alexander Mildner, MDC)

Strategies for treating multiple sclerosis have so far focused primarily on T and B cells. A group of MDC researchers has now unveiled a new approach in Nature Immunology – one that seeks to increase treatment effectiveness by selectively targeting another type of immune cell called monocytes.

Multiple sclerosis (MS) is known as “the disease with a thousand faces” because symptoms and progression can vary dramatically from patient to patient. But every MS patient has one thing in common: Cells of their body’s own immune system migrate to the brain, where they destroy the myelin sheath – the protective outer layer of the nerve fibers. As a result, an electrical short circuit occurs, which prevents the nerve signals from being transmitted properly.

Many MS medications impair immune memory

Researchers don’t yet know exactly which immune cells are involved in stripping away the myelin sheath. Autoreactive T and B cells, which wrongly identify the myelin sheath as a foreign body, travel to the brain and initiate the disease. “Up until now, MS drugs have essentially targeted these T and B cells, both of which are part of the acquired immune system,” says Dr. Alexander Mildner, a scientist at the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC) and the senior author of the paper now published in Nature Immunology.

Mildner is currently conducting externally funded research as a DFG Heisenberg fellow in Professor Achim Leutz’s lab at the MDC, which focuses on cell differentiation and tumorigenesis. “But by attacking the acquired immune system, the MS drugs adversely affect the body’s immune memory, thus making patients more susceptible to infections in the long run,” the scientist says.

MS symptoms improved in mice by reducing monocytes

As a result, Mildner has been pursuing a different strategy for a couple of years now. He wants to find out what role immune cells – particularly those that are part of innate immunity – play in the development of MS and whether they represent a promising target structure for therapy of MS patients. “In an earlier study with a mouse model of MS, we were able to show that disease symptoms in the mice declined significantly within a few days after their monocytes were selectively destroyed by antibodies,” the researcher reports. This result came as a big surprise to him and to many of his colleagues. “Apparently, it is not only T and B cells that are involved in causing tissue damage in MS,” Mildner says.

The monocytes he studied are a special type of white blood cells that shortly circulate in the blood before migrating into tissue. Once there, they transform themselves into effector cells (phagocytes) and destroy foreign tissue in the central nervous system (CNS) – or which, during MS, they wrongly identify as such. “This process,” Mildner says, “leads to inflammation and tissue damage in the brain.”

The team discovered unknown types of monocytes

In the current study published in Nature Immunology, which he conducted in collaboration with an Israeli team led by Professor Ido Amit from the Department of Immunology at the Weizmann Institute of Science, Mildner and his team also focused on monocytes. “During the last recent years we realized that several types of these immune cells exits, which might carry out different functions,” the researcher says. “We therefore wanted to examine in our mouse model of MS the monocytes in greater detail using single-cell sequencing and to find out, which monocyte subsets are present in the brain in MS and are responsible for tissue damage.”

He and his colleagues identified six different monocyte subtypes, four of which were previously unknown. As in his earlier study, Mildner injected the mice with antibodies against a specific monocyte surface protein. As expected, the cells died and the MS symptoms in the mice decreased within a short period of time. “But what surprised us was that the antibodies did not destroy all monocyte subsets in the brain that have this surface protein,” Mildner says.

Not all monocytes destroy the protective myelin sheath

“Only a certain type of monocyte, the Cxcl10+ cells, was destroyed by the antibody treatment,” Mildner says. “These are apparently the cells that are primarily responsible for causing MS tissue damage in the brain.” With the help of single-cell sequencing, he and his team also discovered that this cell type differs from other monocytes in two essential ways: First, Cxcl10+ cells have a particularly large number of receptors for a signal protein secreted by T cells that induces tissue damaging properties in monocytes. Second, these cells produce large amounts of interleukin-1-beta, a substance that opens the blood-brain barrier, enabling immune cells to more easily pass from the blood to the brain and exacerbate the symptoms. “Our research suggests that T cells, as disease initiators, travel to the CNS in order to lure there the monocytes that are responsible for the primary tissue damage,” Mildner explains.

The other monocyte subsets that were identified, he speculates, are perhaps even involved in repair processes in which the body tries to rebuild the damaged myelin. In light of the study’s findings, he thinks it is also possible that the T and B cells are not even directly involved in stripping away the myelin sheath, but only indirectly in that they prompt the Cxcl10+ monocytes to attack the protective layer of the axons.

Many side effects may be preventable

“If that is the case, in the future most forms of MS could be treated by specifically deactivating the Cxcl10+ monocytes instead of targeting the T or B cells of the immune system,” Mildner says. “This would protect the body’s immune memory and prevent many side effects of current MS therapies.” The researcher and his team next plan to investigate whether the Cxcl10+ monocytes are also present outside the CNS. “If they exist in the body’s periphery, for example, in the lymph nodes,” he says, “there they would be easier to target with therapeutics than in the brain.”

Text: Anke Brodmerkel

Literature

Amir Giladi et al. (2020):  „Cxcl10+ monocytes define a pathogenic subset in the central nervous system during autoimmune neuroinflammation”, Nature Immunology, DOI: 10.1038/s41590-020-0661-1

 

Source: https://www.mdc-berlin.de/news/press/new-therapeutic-options-for-multiple-sclerosis

www.mdc-berlin.de

Research / 17.04.2020
The Lipid Code: New chemical tools can control the concentration of lipids in living cells.

Lipids, or fats, have many functions in our body: They form membrane barriers, store energy or act as messengers, which regulate cell growth and hormone release. Many of them are also biomarkers for severe diseases. So far, it has been very difficult to analyze the functions of these molecules in living cells. Researchers at the Max Planck Institute of Molecular Cell Biology and Genetics (MPI-CBG) in Dresden and the Leibniz Research Institute for Molecular Pharmacology (FMP) in Berlin have now developed chemical tools that can be activated by light and used to influence lipid concentration in living cells. This approach could enable medical doctors to work with biochemists to identify what molecules within a cell actually do. The study was published in the journal PNAS.

Every cell can create thousands of different lipids (fats). However, little is known how this chemical lipid diversity contributes to the transport of messages within the cell, in other words, the lipid code of the cell is still unknown. This is mainly due to the lack of methods to quantitatively study lipid function in living cells. An understanding of how lipids work is very important because they control the function of proteins throughout the cell and are involved in bringing important substances into the cell through the cell membrane. In this process it is fascinating that only a limited number of lipid classes on the inside of the cell membrane act as messenger molecules, but they receive messages from thousands of different receptor proteins. It is still not clear, how this abundance of messages can still be easily recognized and transmitted.

The research groups led by André Nadler at the MPI-CBG and Alexander Walter at the FMP, in collaboration with the TU Dresden, have developed chemical tools to control the concentration of lipids in living cells. These tools can be activated by light. Milena Schuhmacher, the lead author of the study, explains: “Lipids are actually not individual molecular structures, but differ in tiny chemical details. For example, some have longer fatty acid chains and some have slightly shorter ones. Using sophisticated microscopy in living cells and mathematical modelling approaches, we were able to show that the cells are actually able to recognize these tiny changes through special effector proteins and thus possibly use them to transmit information. It was important that we were able to control exactly how much of each individual lipid was involved.” André Nadler, who supervised the study, adds: “These results indicate the existence of a lipid code that cells use to re-encode information, detected on the outside of the cell, on the inner side of the cell.”

The results of the study could enable membrane biophysicists and lipid biochemists to verify their results with quantitative data from living cells. André Nadler adds: “Clinicians could also benefit from our newly developed method. In diseases such as diabetes and high blood pressure, more lipids that act as biomarkers are found in the blood. This can be visualized with a lipid profile. With the help of our method, doctors could now see exactly what the lipids are doing in the body. That wasn't possible before.”

Original Publication: Milena Schuhmacher, Andreas T. Grasskamp, Pavel Barahtjan, Nicolai Wagner, Benoit Lombardot, Jan S. Schuhmacher, Pia Sala, Annett Lohmann, Ian Henry, Andrej Shevchenko, Ünal Coskun, Alexander M. Walter, André Nadler “Live cell lipid biochemistry reveals a role of diacylglycerol side chain composition for cellular lipid dynamics and protein affinities” PNAS, 25. März 2020. Doi: 10.1073/pnas.1912684117

About the Leibniz Research Institute for Molecular Pharmacology (FMP)
The FMP conducts basic research in Molecular Pharmacology with the aim to identify new bioactive molecules and characterize their interactions with their biological targets in cells or organisms. These compounds are useful tools in basic biomedical research and may be further developed for the treatment, prevention, or diagnosis of disease. About the MPI-CBG The Max Planck Institute of Molecular Cell Biology and Genetics (MPI-CBG) is one of over 80 institutes of the Max Planck Society, an independent, non-profit organization in Germany. 600 curiosity-driven scientists from over 50 countries ask: How do cells form tissues? The basic research programs of the MPI-CBG span multiple scales of magnitude, from molecular assemblies to organelles, cells, tissues, organs, and organisms.

Source: https://www.leibniz-fmp.de/press-media/press-releases/press-releases-single-view1/article/the-lipid-code.html

www.leibniz-fmp.de

Research / 31.03.2020
Phage capsid against influenza: perfectly fitting inhibitor prevents viral infection

Phage shell docks on and inhibits the influenza virus (visualization Barth van Rossum)
Phage shell docks on and inhibits the influenza virus (visualization Barth van Rossum)

A new approach brings the hope of new therapeutic options for suppressing seasonal influenza and avian flu: On the basis of an empty – and therefore non-infectious – shell of a phage virus, researchers from Berlin have developed a chemically modified phage capsid that “stifles” influenza viruses. Perfectly fitting binding sites cause influenza viruses to be enveloped by the phage capsids in such a way that it is practically impossible for them to infect lung cells any longer. This phenomenon has been proven in pre-clinical trials, also involving human lung tissue. Researchers from the Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP), Freie Universität Berlin, Technische Universität Berlin (TU), Humboldt-Universität (HU), the Robert Koch Institute (RKI) and Charité-Universitätsmedizin Berlin were involved in this groundbreaking work. The results are also being used for the immediate investigation of the coronavirus. The findings have now been published in Nature Nanotechnology.

Influenza viruses are still highly dangerous: The World Health Organization (WHO) estimates that flu is responsible for up to 650,000 deaths per year worldwide. Current antiviral drugs are only partially effective because they attack the influenza virus after lung cells have been infected. It would be desirable – and much more effective – to prevent infection in the first place.

This is exactly what the new approach from Berlin promises. The phage capsid, developed by a multidisciplinary team of researchers, envelops flu viruses so perfectly that they can no longer infect cells. “Pre-clinical trials show that we are able to render harmless both seasonal influenza viruses and avian flu viruses with our chemically modified phage shell,” explained Professor Dr. Christian Hackenberger, Head of the Department Chemical Biology at the Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP) and Leibniz-Humboldt Professor for Chemical Biology at HU Berlin. “It is a major success that offers entirely new perspectives for the development of innovative antiviral drugs.”

Multiple bonds fit like hook-and-loop tape
The new inhibitor makes use of a feature that all influenza viruses have: There are trivalent receptors on the surface of the virus, referred to as hemagglutinin protein, that attach to sugar molecules (sialic acids) on the cell surface of lung tissue. In the case of infection, viruses hook into their victim – in this case, lung cells – like a hook-and-loop fastener. The core principle is that these interactions occur due to multiple bonds, rather than single bonds.
It was the surface structure of flu viruses that inspired the researchers to ask the following initial question more than six years ago: Would it not be possible to develop an inhibitor that binds to trivalent receptors with a perfect fit, simulating the surface of lung tissue cells?

We now know that this is indeed possible – with the help of a harmless intestinal inhabitant: The Q-beta phage has the ideal surface properties and is excellently suited to equip it with ligands – in this case sugar molecules – as “bait”. An empty phage shell does the job perfectly. “Our multivalent scaffold molecule is not infectious, and comprises 180 identical proteins that are spaced out exactly as the trivalent receptors of the hemagglutinin on the surface of the virus,” explained Dr. Daniel Lauster, a former PhD student in the Group of Molecular Biophysics (HU) and now a postdoc at Freie Universität Berlin. “It therefore has the ideal starting conditions to deceive the influenza virus – or, to be more precise, to attach to it with a perfect spatial fit. In other words, we use a phage virus to disable the influenza virus!”
To enable the Q-beta scaffold to fulfill the desired function, it must first be chemically modified. Produced from E. coli bacteria at TU Berlin, Professor Hackenberger’s research group at FMP and HU Berlin use synthetic chemistry to attach sugar molecules to the defined positions of the virus shell.

Virus is deceived and enveloped
Several studies using animal models and cell cultures have proven that the suitably modified spherical structure possesses considerable bond strength and inhibiting potential. The study also enabled the Robert Koch Institute to examine the antiviral potential of phage capsids against many current influenza virus strains, and even against avian flu viruses. Its therapeutic potential has even been proven on human lung tissue, as fellow researchers from the Medical Department, Division of Infectiology and Pneumology, of Charité were able to show: When tissue infected with flu viruses was treated with the phage capsid, the influenza viruses were practically no longer able to reproduce.

he results are supported by structural proof furnished by scientists at Freie Universität Berlin from the Research Center of Electron Microscopy (FZEM): High-resolution cryo-electron microscopy and cryo-electron microscopy show directly and, above all, spatially, that the inhibitor completely encapsulates the virus. In addition, mathematical-physical models were used to simulate the interaction between influenza viruses and the phage capsid on the computer. “Our computer-assisted calculations show that the rationally designed inhibitor does indeed attach to the hemagglutinin, and completely envelops the influenza virus,” confirmed Dr. Susanne Liese from the AG Netz of Freie Universität Berlin. “It was therefore also possible to describe and explain the high bond strength mathematically.”

Therapeutic potential requires further research
These findings must now be followed up by more preclinical studies. It is not yet known, for example, whether the phage capsid provokes an immune response in mammals. Ideally, this response could even enhance the effect of the inhibitor. However, it could also be the case that an immune response reduces the efficacy of phage capsids in the case of repeated-dose exposure, or that flu viruses develop resistances. And, of course, it has yet to be proven that the inhibitor is also effective in humans.
Nonetheless, the alliance of Berlin researchers is certain that the approach has great potential. “Our rationally developed, three-dimensional, multivalent inhibitor points to a new direction in the development of structurally adaptable influenza virus binders. This is the first achievement of its kind in multivalency research,” emphasized Professor Hackenberger. The chemist believes that this approach, which is biodegradable, non-toxic and non-immunogenic in cell culture studies, can in principle also be applied to other viruses, and possibly also to bacteria. It is evident that the authors regard the application of their approach to the current coronavirus as one of their new challenges. The idea is to develop a drug that prevents coronaviruses from binding to host cells located in the throat and subsequent airways, thus preventing infection.

Berlin university alliance at its best
Cooperation between scientists from different disciplines played a major role in the discovery of the new influenza inhibitor. Biologists, chemists, physicists, virologists, medical scientists and imaging specialists from three Berlin universities HU, Freie Universität Berlin and TU, the Robert Koch Institute, Charité and, last but not least, FMP were all involved in the project. “In my opinion, such a complex project could only have been undertaken in Berlin, where there truly are experts for every issue,” stated Professor Dr. Andreas Herrmann, Head of Molecular Biophysics at HU Berlin. “It was the Berlin university alliance at its best,” he added, “and I hope that the follow-up studies will be equally successful.”

The project was funded within Collaborative Research Center 765 (Speaker Professor Dr. Rainer Haag, Freie Universität Berlin) of the German Research Foundation (DFG).

Text press release: Beatrice Hamberger

Source: https://www.leibniz-fmp.de/press-media/press-releases/press-releases-single-view1/article/phage-capsid-against-influenza-perfectly-fitting-inhibitor-prevents-viral-infection.html

 

www.fmp-berlin.de

Research / 31.03.2020
Millions for cancer research

Cancer consists not only of cancer cells (red), but also of stroma cells including immune cells (green). (© Blankenstein Lab, MDC)
Cancer consists not only of cancer cells (red), but also of stroma cells including immune cells (green). (© Blankenstein Lab, MDC)

Thomas Blankenstein receives an ERC Advanced grant for cancer research. The scientist from the MDC wants to find out if T cells control the development of cancer by a process called immunosurveillance. For this purpose he now proposes a new research model.

The European Research Council (ERC) has announced it will support Professor Thomas Blankenstein to the tune of €2.5 million over five years. This year the ERC is awarding Advanced Grants to a total of 158 scientists across Europe.

“I am glad to announce a new round of ERC grants that will back cutting-edge, exploratory research, set to help Europe and the world to be better equipped for what the future may hold. That’s the role of blue sky research”, says Professor Mauro Ferrari, the President of the ERC in an official statement on March 31, 2020. “These senior research stars will cut new ground in a broad range of fields, including the area of health. I wish them all the best in this endeavour and, at this time of crisis, let me pay tribute to the heroic and invaluable work of the scientific community as a whole.”

In Blankenstein’s research group, scientists at the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC) and from Charité – Universitätsmedizin Berlin study specialized cells of the immune system called T cells. With his new research project Blankenstein wants to find out how T cells respond when their specific receptors detect a new antigen on a cancer cell. This line of research promises to identify more effective immunotherapy strategies for treating cancer.

Difficult conditions for research on immunosurveillance
Scientists have been discussing the immunosurveillance theory for some 50 years. The Australian virologist Sir Frank MacFarlane Burnet suspected in 1970 that the immune system is constantly on the lookout for cancer cells in order to eliminate them. According to his hypothesis, certain properties presented on the surface of cancer cells enable T cells to recognize tumors. “There is no doubt that T cells often detect cancer by recognizing these antigens and destroy tumor cells,” Blankenstein says. He assumes that there is a form of immunosurveillance that is triggered by virus-induced cancer, but says that “in spontaneously growing tumors we don’t yet know if this actually starts a program of destruction in the T cells.”

Blankenstein has been working for years on immune therapies against cancer. "In our new research project we want to find out how a T cell reacts as soon as it recognizes a tumor antigen," says Blankenstein.  He wants to know: "Does the T cell then induce the destruction of the cancer cells? Does this mean that immunosurveillance is also possible for cancer that develops spontaneously in the body?

To answer these questions, Blankenstein suggests a new research approach. . Conventional research models, he says, have always a hitch. Scientists often study immunosurveillance in mice by using, for example, chemical substances to induce tumor growth in a normal cell. He explains the problem: “Either such research models fail to reflect tumor growth in humans or we cannot clearly say whether, and how, T cell behavior actually affects the tumor.”

A promising new research approach
What Blankenstein will do differently is transplant tumors into the mice. He has developed two mouse models for this purpose, but first he had to overcome several hurdles. The biggest problem, Blankenstein explains, is that an invasive procedure such as a transplant always causes inflammations in the mouse. This means it is difficult to investigate how T cells behave when cancer arises, because one doesn’t know if the T cells are just responding to the tumor antigen as a result of the interventional procedure on the tissue. Blankenstein’s research group has succeeded in reestablishing non inflammatory conditions that mimic sporadic cancer development in humans. He has not yet published his research models, which he will use for the first time in the new project. They allow him not only to regulate the presentation of tumor antigens, but also to measure T cells’ behavior to cancer recognition.

Blankenstein plans to hire additional postdocs and PhD students to support his new research project. He says: “The project could change the way we look at immunosurveillance in spontaneous tumor growth.”

About ERC Grants
The funding program of the European Research Council (ERC) is one of the most important in Europe. Since 2009, ERC Advanced Grants have covered all scientific disciplines. Recipients are awarded up to €2.5 million for a period of five years.

https://www.mdc-berlin.de/news/press/millions-cancer-research

 

www.mdc-berlin.de

Research / 31.03.2020
Understanding the Formation of Nerve Cell Contacts - Volker Haucke receives 2.5 Million Euros of Funding from the European Research Council (ERC)

Figure: Dr. Dmytro Puchkov, FMP
Figure: Dr. Dmytro Puchkov, FMP

Professor Volker Haucke from the Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP) and the Freie Universität Berlin receives a prestigious ERC Advanced Grant of the European Research Council (ERC). The biochemist is granted a total funding of up to 2.5 million euros for a period of five years for his highly innovative research on the assembly of synapses.

Our ability to remember the first day at school or the birth of our child is based – as most other functions of our brain – on the communication between nerve cells at specialized contact points called synapses. At synapses, signals are transmitted from one nerve cell to another. During this process, the nerve cell upstream releases messenger substances (neurotransmitters) from vesicles of the presynapse into the cleft between both nerve cells. The messengers proceed to the postsynaptic part of the nerve cell downstream, where they bind to receptors that pass the stimulus on.

During decades of research, a wealth of knowledge has been accumulated on the mechanisms by which neurotransmitters stored in synaptic vesicles are released at the presynaptic membrane. In contrast, we know much less about the formation of synaptic vesicles during the development of the brain and about the assembly of the complex molecular machinery, which forms a functioning presynaptic membrane. Where and how the precursors of synaptic vesicles form within the neuronal cell body, is not understood. Likewise, it remains unknown in which way these vesicles are transported to the presynaptic membrane and which maturation steps they undergo to transform into functional units for neurotransmitter release. Finally, the coordination and adjustment of the whole process remains unresolved.  The awarded project SynapseBuild is based on the molecular analysis of human nerve cells, which are generated from stems cells genetically modified via CRISPR technology.

“We are still at the very beginning”, says Volker Haucke and adds that “understanding synapse formation and assembly could open up entirely new avenues for combating neurological and neurodegenerative diseases”. Volker Haucke is director at the Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP), professor of pharmacology at the Freie Universität Berlin, and member of the excellence cluster NeuroCure. His research focuses on the formation and function of synapses as well as on deciphering cellular mechanisms, which regulate the equilibrium between cell growth and the degeneration of metabolic products. Gaining knowledge on such mechanisms is fundamental for understanding diseases such as cancer, diabetes, and neurodegeneration. Volker Haucke aims at developing new pharmacological approaches for treating such diseases. Internationally, he holds a leading position in research on molecular cell- and neurobiology and has received numerous scientific awards – amongst others the Feldberg Prize 2020.

About ERC Grants: The funding program of the European Research Council (ERC) is one of the most prestigious in Europe. Since 2009, the ERC awarded Advanced Grants to all disciplines, which are endowed with up to 2.5 million euros over five years. Up to now, FMP researchers have received in total 7 ERC-Grants, among them 3 Advanced Grants.

The Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP) is part of the Forschungsverbund Berlin e.V. (FVB), who legally represents eight non-university research institutes - members of the Leibniz Association - in Berlin. The institutions pursue common interests within the framework of a single legal entity while maintaining their scientific autonomy. More than 1,900 employees work within the research association. The eight institutes were founded in 1992 and emerged from former institutes of the GDR Academy of Sciences.

https://www.leibniz-fmp.de/press-media/press-releases/press-releases-single-view1/article/understanding-the-formation-of-nerve-cell-contacts-volker-haucke-receives-25-million-euros-of-fun.html

Research / 30.03.2020
Diet influences the course of multiple sclerosis

Patients with multiple sclerosis (MS) have an altered gut microbiome composition and produce less of a certain fatty acid. This was reported by a team of researchers from Ruhr-Universität Bochum, the MDC and the ECRC in Cell. Their findings show that propionic acid might be relevant for MS immunotherapy.

Gut bacteria function as an extra organ: They influence the immune system and the brain via their metabolites. The short-chain fatty acid propionic acid for example affects the intestine-mediated immune regulation in people with multiple sclerosis (MS). This has been demonstrated by a team from the Department of Neurology of Ruhr-Universität Bochum (RUB) at St. Josef Hospital, in an international study led by Professor Aiden Haghikia. The administration of propionic acid along with MS medication reduced the relapse rate and the risk of disability progression in the long term. In addition, initial magnetic resonance imaging studies indicated that propionic acid may reduce brain atrophy as a sign of neuronal cell death. The team recently published their results in the journal Cell. Also involved in the study were researchers from the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC) and from the Experimental and Clinical Research Center (ECRC ).

An independent organ within the gut
“Not only MS, but also many other diseases influence the bacterial colonization of the gut,” says Dr. Sofia Forslund, head of the Host-Microbiome Factors in Cardiovascular Disease Lab at the ECRC. Forslund and her team are studying how the gut microbiome develop in health and disease. Within the gut, the interaction between dietary components, microbiota, their metabolites, and the immune system takes place in the intestinal wall. “This is how gut bacteria can directly and indirectly affect anatomically distant structures such as the brain,” Haghikia explains. “The gut microbiome is accordingly an independent endocrine organ that interacts with its environment.”

Short-chain fatty acids can suppress inflammatory reactions
In the current study, the researchers successfully translated the results previously demonstrated in both cell cultures and in an experimental model to MS patients: short-chain fatty acids such as propionic acid (or its salt propionate) increased the number and function of regulatory T cells in the gut. “These cells stop excessive inflammatory reactions and reduce the number of autoimmune cells in autoimmune diseases like MS,” says Professor Ralf Gold, Director of the Department of Neurology at St. Josef Hospital.

At the MDC and the ECRC and at Martin Luther University Halle-Wittenberg, the researchers showed that the microbiome composition is altered in MS patients. “As part of an earlier collaboration with Aiden Haghikia, we had already established analytics for short fatty acids at the MDC’s Berlin Institute for Medical Systems Biology,” says Dr. Stefan Kempa, head of the Proteomics and Metabolomics Platform at the MDC. “Back then we did this out of pure curiosity.” In the current study, the researchers demonstrated a deficiency of propionic acid in the feces of MS patients, which was most pronounced in the earliest phases of the disease.

Gut bacteria and cellular power plants are of paramount importance
In collaboration with researchers from Bar-Ilan University in Israel, who had developed an intestinal model for the functional analysis of the microbiome, it emerged that propionate-associated changes of the gut microbiome play a crucial role in the differentiation of regulatory cells. The increased function of these cells was due to their improved energy utilization through an altered function of the mitochondria – the power plants of cells – as the research team demonstrated in collaboration with the Molecular Cell Biology research group at the RUB Faculty of Medicine.

The gut as a target for future therapeutic approaches
The short-chain fatty acids represent only a fraction of the metabolites of gut bacteria that are generated from the diet. “Further research into this largely unknown organ and the knowledge gained from it will enable us, going forward, to develop innovative dietary measures to complement the known therapeutics,” Haghikia says.

Text: Meike Drießen

The original version of this article was published by RUB on March 10, 2020.
https://www.mdc-berlin.de/news/news/diet-influences-course-multiple-sclerosis

www.mdc-berlin.de

Innovation / 27.03.2020
Eckert & Ziegler: Executive Board Proposes Dividend and Share Split

Eckert & Ziegler AG (ISIN DE0005659700, S-DAX), a specialist for isotope-based applications in medicine, science and industry achieved earnings per share of 4.29 EUR in the fiscal year 2019. At the General Shareholders’ Meeting the Executive Board and the Supervisory Board will propose a dividend of 1,70 EUR per share entitled to a dividend (previous year: 1.20 EUR per share).

In addition, the Executive Board and Supervisory Board today decided to propose to the Annual General Meeting a resolution to increase the share capital from company funds by EUR 15,878,949.00 from the current EUR 5,292,983.00 by EUR 15,878,949.00 to EUR 21,171,932.00 by issuing new shares (§§ 207 et seq. of the AktG) by way of converting free reserves into share capital of the company. In doing so, the shareholders of the Company shall receive three (3) new shares for each one (1) existing share.

The capital increase from company funds will not result in any changes to the shareholders' participations in the company. If the proposed resolutions are accepted by the General Meeting and the amendments to the Articles of Association are entered in the Commercial Register, each shareholder will be credited with the corresponding number of new shares in his or her securities account. The higher number of shares and the resulting reduction in the share price should make the Company's shares more liquid and even more attractive for investors.

The price of the Eckert & Ziegler share has risen continuously over the past few years. The aim of the increase in the share capital of Eckert & Ziegler AG from company funds by issuing new shares in a ratio of 1:3, to be proposed to the Annual General Meeting, is to make trading in the share more liquid and to make the share even more attractive for investors.    

The complete figures for the FY 2019 and the forecast for the current FY 2020 will be published on 31 March 2020.
In view of the current situation (COVID-19), a postponement of the Annual General Meeting currently planned for 17 June 2020 cannot be excluded.

Disclosure of inside information according to Article 17 MAR

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Innovation / 26.03.2020
Eckert & Ziegler receives CE approval for innovative irradiation applicators using 3D printing

Eckert & Ziegler BEBIG has received CE approval for the world's first applicators manufactured by 3D printing and designed for the treatment of gynecological tumors. Made of biocompatible and sterile plastic, the attachments extend the range of applications of conventional applicators. They are now also suitable for targeted, needle-assisted brachytherapy using HDR afterloading and can significantly increase the 3-year survival rate of cancer patients.

"Thanks to the new applicator add-on kits, we can now offer patients with advanced cervical cancer an optimal therapy that can be used to treat tumors with complex volumes that are difficult to properly cover. At the same time, it facilitates our work process, as the applicator is already delivered sterile. In order to be able to treat the patient-specific findings even better, the add-on kits are available in fifteen different forms," explained Professor Dr. Jean-Michel Hannoun-Levi, Head of the Radiotherapy Department at the Centre Antoine Lacassagne in Nice.

"The CE mark is an important milestone for us, as the add-on kits are the world's first 3D printed medical product family approved for needle-assisted brachytherapy", said Dr. Harald Hasselmann, member of the Executive Board of Eckert & Ziegler AG. "The 3D printing process, which has been specially developed and validated for the manufacture of sterile medical products, opens up completely new possibilities for the further development of our product portfolio and thus for the treatment of many types of cancer".

The add-on kits fit to nearly all common HDR treatment devices and thus can be used in many clinics.

HDR (high dose rate) brachytherapy is conducted with a so-called HDR afterloader, also known as a remote afterloading system. With the help of applicators and catheters, the very small radiation source is driven from a shielded safe – located inside the afterloader – directly into or next to the tumor. A computerized treatment planning program calculates precisely how long the source has to stay and radiate at the so-called dwell positions before being driven back into the safe. HDR brachytherapy can often be performed on an out-patient basis. It is conducted in only a few treatment sessions, destroys the tumor cells and spares surrounding healthy tissue as the radiation is applied from within the tumor. This noticeably increases the patient’s quality of life.

About Eckert & Ziegler.
Eckert & Ziegler Eckert & Ziegler Strahlen- und Medizintechnik AG with more than 800 employees, is one of the world's largest providers of isotope-related components for radiation therapy and nuclear medicine. Eckert & Ziegler shares (ISIN DE0005659700) are listed in the SDAX index of Deutsche Börse.
Contributing to saving lives.

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Research / 24.03.2020
Teamwork in a cell

Microscopic images of cells in which filaments of the actin cytoskeleton are labelled in yellow and focal adhesions are labelled in pink. (© Markus Müller, Rocks Lab, MDC)
Microscopic images of cells in which filaments of the actin cytoskeleton are labelled in yellow and focal adhesions are labelled in pink. (© Markus Müller, Rocks Lab, MDC)

For the first time ever, researchers are looking at the molecular processes in the cell’s skeleton – the cytoskeleton – from a bird’s eye perspective. These processes are important for cell movement and cell shape formation. In Nature Cell Biology, an MDC team shows how cells coordinate such processes at the right place and time.

The cytoskeleton is a permanent construction site: it consists of protein filaments that are continually lengthening and shortening in a dynamic process. Through these remodeling processes, the cell can change its shape and even move to a new location. In this way, it guides fundamental processes, such as cell division and differentiation, and processes at a higher level in the organism, such as embryonic development and wound healing. If something goes wrong at the cytoskeletal construction site – e.g., if protein filaments undergo remodeling at the wrong place or time – this could lead to diseases. Such an error in spatio-temporal control is also the reason why metastatic cancer cells start to migrate in the body.

Researchers at the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC) and other institutes, such as the European Bioinformatics Institute (EMBL-EBI) in Hinxton, UK, have investigated how a family of 145 proteins causes these remodeling events to occur at the right place and time. Up to this point, scientists had only examined these regulatory proteins in individual studies, and only a few proteins had been characterized. “In order to understand complex processes, including cell shape changes, we need to know how the regulatory proteins work together collectively. Until now, we lacked a bird’s eye perspective, so to speak,” says Dr. Oliver Rocks, head of the MDC research group “Spatio-temporal Control of Rho GTPase Signaling” and senior responsible author of a new study in the journal Nature Cell Biology. His research group with lead authors Dr. Paul M. Müller and Dr. Juliane Rademacher, together with the group led by Dr. Evangelia Petsalaki at EMBL-EBI and an international research team, has now systematically characterized all these regulatory proteins. The team was able to show that there are different signaling zones within the cell that coordinate the cytoskeleton in space and time and also how these zones are created and maintained.

A new perspective, thanks to a comprehensive database
At the cytoskeletal construction site, the Rho GTPase proteins set the tone. When these molecular switches are activated, they send commands to the machinery on site. There are 145 regulatory proteins that control these molecular switches: RhoGEF proteins turn them on, RhoGAP proteins turn them off. Now Rocks and his team have systematically investigated all these regulators for the first time and created a kind of library. Researchers from all over the world can access this library to see which molecular switches individual proteins control, where in the cell this occurs and which binding partners it has.

The comprehensive information contained in the protein library allows proteins to be analyzed at the systems level for the first time – i.e., from a bird’s eye perspective. This has revealed new collective properties of the regulators that were previously imperceptible. In this way, researchers discovered a new mechanism that explains how cell migration is controlled.

Focal adhesions control the balance of two opposing processes
Scientists were aware that two opposing processes controlled by the cytoskeleton – cell protrusion and cell contraction – need to occur in separate places in the cell to allow it to move. In one construction site at the front of the cell, the molecular switches give the command for cell protrusion in the migration direction. Further behind, towards the cell interior, they trigger a contraction of the cytoskeleton. The central question investigated by the MDC team was how Rho GTPases coordinate these two spatially separated processes.

The spatial organization of the two opposing processes is made possible through focal adhesions, explains Rocks. These are protein accumulations located directly below the cell membrane that anchor the cell to its environment. Focal adhesions occur close to the front of the cell, mature into more stable structures and eventually dissolve again. As the cell travels through focal adhesions during migration, these move from the front to the middle of the cell. “The cell exploits the fact that focal adhesions change their location,” Rocks says. Initially, his team discovered a surprising number of regulatory proteins on these structures. But the real surprise, he says, “was that we found a specific subgroup of regulators located almost exclusively on newly formed focal adhesions at the cell’s edge and another separate subgroup on mature structures towards the middle of the cell.” These subgroups control the opposing cytoskeletal processes mentioned above, creating the spatially separated signal zones. The researchers were also able to show that both processes are linked by mechanical forces in the cell, which can help maintain a balance between the number of newly formed focal adhesions and the number of mature ones.

Rocks next plans to investigate how precisely the collective Rho GTPase regulators on the focal adhesions communicate with the cytoskeletal machinery, whether the principle of spatial separation of these proteins also plays a role on other cell structures and how a defective regulatory function can ultimately lead to diseases.

Rocks confirms that gaining this systemic view of cell shape regulation has taken a great deal of effort. “However, it was absolutely essential to revitalize this research field and open up new conceptual approaches for further study,” the researcher says. The database and protein library are now available to all scientists worldwide.

Literature
Müller, Paul M. et al. (2020): “Systems analysis of RhoGEF and RhoGAP regulatory proteins reveals spatially organized RAC1 signalling from integrin adhesions”, nature cell biology, DOI: 10.1038/s41556-020-0488-x

Author: Christina Anders
Christina.Anders@mdc-berlin.de
https://www.mdc-berlin.de/news/news/teamwork-cell

www.mdc-berlin.de

Research / 24.03.2020
Changing how we think about warm perception

Infrared (thermal) imaging: Warm fingerprints left on a table surface after touching it with the hand. (Image: Lewin/Poulet Lab, MDC)
Infrared (thermal) imaging: Warm fingerprints left on a table surface after touching it with the hand. (Image: Lewin/Poulet Lab, MDC)

Perceiving warmth requires input from a surprising source: cool receptors. The finding published in Neuron by neuroscientists at the MDC challenges the theory that dedicated neurons convey either warm or cool sensations to the brain.

A team of neuroscientists at Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC) have made an unexpected discovery about the way mice perceive warming sensations. It’s counterintuitive: cooling receptors in the skin are critical for the perception of warmth.
The finding, recently published in the journal Neuron, challenges the predominant model of non-painful temperature perception, and provides clues about the way not just mice, but also humans, consciously detect warmth.

“When we grab a cup of coffee with our hands, and we can quickly feel its warmth, this is happening because not only neurons activated by warming are at play, but also neurons inactivated by it,” said Ricardo Paricio-Montesinos, co-first paper author and neuroscientist from the MDC. “Without the second type, our data from mice suggest that we would either need much longer to feel it or perhaps we wouldn't even sense warming at all.”

A mysterious sensation
Since the late 1800s, neuroscientists have theorized that dedicated pathways or “labeled lines” convey only warm or only cool sensations from the skin to the brain. While there has been some evidence of this in humans and primates, it has been difficult to prove.

Professor Gary Lewin, who heads MDC’s Molecular Physiology of Somatic Sensation Lab teamed up with Dr. James Poulet, who heads MDC’s Neural Circuits and Behavior Lab to study non-painful temperature perception in mice. “Temperature is still a mysterious sensation,” Poulet said. “It is very understudied, especially compared to vision, touch or hearing.”

The mouse’s ability to perceive non-painful temperature changes has not been closely investigated. Through a series of behavioral studies, they discovered that mice detect temperature changes with same high level of acuity as humans – licking a water dispenser in response to 1ºC of warming and 0.5ºC of cooling. “For the first time, we could show that mice basically feel warmth and cooling just exactly the same as we do,” Lewin said. “They have the exact same thresholds as humans.”

A bigger surprise
When neural pathways thought to be associated with warming were blocked, the mice would lick the dispenser in response to 2ºC of warming, revealing perception was diminished but not gone. This indicates those pathways are helpful, but not essential to perceive warmth. In contrast, when the pathway associated with cooling was blocked by turning off the trmp8 gene, the mice could not perceive warmth at all.
“We were really surprised,” said Dr. Frederick Schwaller, co-first author and post-doc in the Lewin Lab. “We initially tried to train these mice to detect skin warming as a control, but we stumbled on the most important finding in the paper sort of by chance.”

Upon closer inspection of nerve cells in the forepaw, the researchers observed two things. First, no nerve cells were solely dedicated to warming. Rather, they found most nerve cells fired an electrical signal in response to temperature and blunt pressure.

“That is puzzling,” Lewin said, “How does the nervous system figure out if the neuron’s activity is because of warm, cold or mechanical force?”
The answer lies in the second thing the team found: a population of nerve cells that are always firing at the forepaw baseline temperature of 27ºC. As the temperature rises, these cells decrease their activity. That decrease appears to be the key.

Compared, not labelled
The team theorizes that the mouse is able to detect warmth because one population of neurons increases activity, while the cool neurons decrease activity. Two signals going in opposite directions generates a pattern that conveys “warm” to the brain. This is distinct from cooling, in which all the neurons increase activity, so the pattern is all going in the same direction.
“The use of two populations makes it much easier for the mouse to unambiguously say that’s warming, that’s cooling,” Lewin said.

When the cooling pathway was blocked, the cool cells were silent and no activity was transmitted to the brain. Without that contributing to an opposite signal pattern, the mice did not perceive warmth, the researchers conclude.

The researchers anticipate the mouse’s sensations reflect what is happening in humans because we have the same receptors and nerves that convey information from the skin to the spinal cord and brain. Further studies will be required to confirm humans exhibit the same pattern, and to determine where and how the signals are compared in the brain or spinal cord.

Text: Laura Petersen

https://www.mdc-berlin.de/news/press/changing-how-we-think-about-warm-perception

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Innovation / 22.03.2020
Eckert & Ziegler Classified in California as Essential Business

The production sites in California of Eckert & Ziegler Strahlen- und Medizintechnik AG (ISIN DE0005659700, S-DAX), in fiscal year 2019 responsible for more than one third of the groups revenue, will not be affected by “Safer at Home” orders for non-critical Manufacturing entities that went into effect in response to the COVID-19 pandemic there Friday evening Pacific Time. As is the case with Eckert & Ziegler’s European plants, most products manufactured in California are categorized as being part of the health systems or of essential infrastructure. Therefore, the sites are exempt from governmental closing orders. This also applies to the production site in New York.

In other locations and the European Union, where the remainders of Eckert & Ziegler’s production sites are located, so far no closing orders have been issued. In the opinion of the Management Board, however, the situation in almost all places is similar to California, not only for the live saving cancer treatment devices or radiopharmaceuticals that are manufactured in these other locations, but also for services and industrial products. Cobalt irradiation sources, seemingly just a technical component, are for example needed for the gamma sterilization of medical devices and lately see a soaring demand.

“The group’s economic performance will nevertheless be affected by the global governmental reactions to the corona crisis” cautions the CEO of the group, Dr. Andreas Eckert. “The turmoil caused by social thinning-out measures, curfews, school closures, or travel restrictions has already led to the delay or cancellation of orders and increased cost. Furthermore, the widespread paralyzation of public institutions and the interruptions of well-established routines may influence the ability to implement countermeasures swiftly.”

The group will provide further details on the 2020 outlook together with the details of the 2019 annual report on 31 March 2020.

About Eckert & Ziegler.
Eckert & Ziegler Eckert & Ziegler Strahlen- und Medizintechnik AG with more than 800 employees, is one of the world's largest providers of isotope-related components for radiation therapy and nuclear medicine. Eckert & Ziegler shares (ISIN DE0005659700) are listed in the SDAX index of Deutsche Börse.

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Research, Living / 14.03.2020
State-by-state breakdown of COVID-19 in Germany

Researchers at the MDC have developed a new online tool that displays the development of the COVID-19 epidemic in Germany clearly and by individual state. The map and timeline showing the spread of the coronavirus are freely available on the internet.

The Robert Koch Institute (RKI) currently publishes daily situation reports that show the number of reported COVID-19 cases in Germany in a table divided into states. Using this data, researchers at the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC) have now developed an online tool that goes a step further: Their map displays not only the total number of reported cases, but also the relative number of cases per 100,000 inhabitants for each German state. In addition, people can use a timeline to track the state-by-state development of the epidemic.

The map and timeline are available at https://covid19germany.mdc-berlin.de. The data is automatically retrieved and processed from the RKI website every day, with the exact time of data retrieval also noted.

“We searched the internet ourselves for similar representations and were surprised to find that nothing like this has ever really been created for Germany before,” says Professor Matthias Selbach, head of the research group on Proteome Dynamics at the MDC. So, a scientist in his research group, Dr. Henrik Zauber, got to work developing the tool. “We created a similar online tool before to give other researchers interactive access to mass spectrometric data,” says Zauber. Based on this experience, he says, it was relatively easy to develop a tool that visually depicts the spread of the COVID-19 epidemic in Germany. The researchers intend to expand the visualization tool as and when more detailed data becomes available.

A public service
“Of course, we cannot take responsibility for the accuracy of the data – we merely process it,” says Selbach. “We see this tool as providing a public service.” He goes on to explain that, in principle, a distinction must be made between the number of reported cases and those actually infected at any given time. How reliable the number of reported cases is depends on many factors – for example, how many people are actually tested.

Matthias Selbach’s research group investigates the interaction of all proteins in the cell (the proteome). Cellular proteins are responsible, among other things, for cell metabolism, proliferation and survival programs, and for signaling pathways both inside and outside the cell. In the past, the team has applied this expertise to investigate which factors influence the reproduction of avian flu viruses in human cells. Selbach and his colleagues are now also planning collaborations with other researchers in order to better understand the molecular characteristics of the SARS-CoV-2 virus.

Further information
    •    Online tool: COVID-19 Viewer
    •    Press release: What blocks bird flu in human cells?

www.mdc-berlin.de

Innovation / 10.03.2020
Eckert & Ziegler Starts Commercial Production of Lutetium-177

Eckert & Ziegler Strahlen- und Medizintechnik AG (ISIN DE0005659700, S-DAX) has developed a new technology for the production of carrier-free lutetium-177. It is based on the irradiation of ytterbium-176 and the subsequent separation of the resulting lutetium-177 in a radiochemical facility. The process has achieved a particularly high degree of purity. Following the successful validation of the production process, commercial production has now started and the first batches of material have been delivered.

"Lutetium-177 is a highly demanded substance in many new cancer drugs. We are pleased to be able to offer this nuclide now in carrier-free form and thus of particularly high quality to our customers in the pharmaceutical industry. Due to the large number of studies in which lutetium-177 is being clinically tested worldwide, we expect an increasing demand for this isotope and related services in the coming years. With the new technology and production facilities in Europe, Asia and North America, we see ourselves as being excellently positioned to meet this demand," explained Dr. Lutz Helmke, member of the Executive Board of Eckert & Ziegler AG.

Radiotherapeutic agents that are coupled with lutetium-177 prior to injection are currently under development for several types of cancer. Lutetium-177-based drugs for the treatment of metastatic prostate cancer are already in the clinical phase III trials. Therapeutic agents for other tumor types are also awaiting approval. In addition to its efficiency, the advantage of lutetium treatment is that it can be coupled with very precise diagnostics. The carrier substance of the therapeutic agent can be linked to a diagnostic radioisotope, for example gallium-68. Using special devices, so-called PET scanners, the response rate for the patient and thus the usefulness of treatment can be predicted with high precision in advance.

About Eckert & Ziegler.
Eckert & Ziegler Eckert & Ziegler Strahlen- und Medizintechnik AG with more than 800 employees, is one of the world's largest providers of isotope-related components for radiation therapy and nuclear medicine, including GalliaPharm® for the production of gallium-68. Eckert & Ziegler shares (ISIN DE0005659700) are listed in the SDAX index of Deutsche Börse.
Contributing to saving lives.

www.ezag.de

Research / 02.03.2020
Higher education, lower activity levels

Almost 250 participants wore a motion detector for seven days and nights. © NAKO Gesundheitsstudie
Almost 250 participants wore a motion detector for seven days and nights. © NAKO Gesundheitsstudie

A team led by Dr. Lina Jaeschke and Professor Tobias Pischon of the MDC has investigated the individual factors associated with high and low levels of physical activity. The results, which have been published in the journal Scientific Reports, contain some surprises.

Everyone knows that exercise does you good. In fact, the risk of almost all chronic diseases can be reduced by an active lifestyle. Many large-scale studies have already proved this to be true. However, the data has yet to provide clear evidence on which individual factors – such as age, gender, weight and education – influence physical activity.

"Until now, such studies have mostly been conducted with the help of questionnaires, which only produce data with limited validity regarding the actual activity levels of the participants,” says Dr. Lina Jaeschke from the MDC research group on Molecular Epidemiology, which is headed by Professor Tobias Pischon. “In addition, little is known about the specific factors that cause a person to spend more or less time in more or less physically demanding activities.”

A hip-mounted measuring device
Jaeschke and Pischon wanted more concrete knowledge, so they teamed up with 26 other scientists from Germany to carry out a study to measure the physical activity of participants via a device worn on the hips known as an accelerometer.

This device records the wearer’s acceleration, thus enabling the researchers to gain a comprehensive picture of his or her physical activity over several days – around the clock. These devices generally provide more reliable results than the widely used fitness wristbands. “Through our study, we wanted to identify groups of people with particularly low levels of activity in order to help develop public policies that can address these people more effectively and specifically,” says lead author Jaeschke. 

To this end, Jaeschke, Pischon and the team collected data from a pretest of the German National Cohort (NAKO) – a long-term, nationwide health study with around 205,000 participants aged between 20 and 69. The main objective of this study is to gain a better understanding of how the major chronic diseases develop. For their own study, Jaeschke’s group took data from 249 participants with an average age of 51.3 years, who had agreed to wear the motion detector constantly for seven days and nights – save for short interruptions when taking a shower, for example.  

Smokers spend less time in intense physical activity Based on the intensity of physical activity recorded, Jaeschke and her colleagues divided the participants’ activities into four categories: inactivity, low-intensity, moderate intensity (such as jogging, gardening or vacuuming) and vigorous-to-very-vigorous intensity (such as highly strenuous sports).

The team then analyzed to what extent the following factors were associated with these levels of physical activity: sex, age, body mass index (BMI), waist circumference, smoking, alcohol consumption, education, employment, income, marital status and reported pre-existing conditions of diabetes and dyslipidemia – a lipid metabolism disorder that usually leads to elevated cholesterol levels. “Some of our results were, of course, expected, such as a decrease in high-intensity activities with increasing age,” says Jaeschke.

The time participants spent in vigorous-to-very-vigorous-intensity activities, for example, was reduced by an average of 0.8 minutes per day every five years. In contrast, the duration of low-intensity activities showed a daily increase of 7.3 minutes over the same period. ”That may not sound like much,” says Jaeschke. “But if you start to look at greater age differences, age becomes an epidemiologically relevant influencing factor for physical activity.” The situation was similar when looking at the factor of smoking: Active smokers spent less time in vigorous-to-very-vigorous activities, but more time in low-intensity activities than those who had never smoked. A higher BMI was associated with less time in low-intensity activity.

Education brings people to a halt
“What was relatively surprising for us was the finding that those with a university entrance qualification spend more time in inactivity than those with a lower level of education,” says Jaeschke. “Earlier studies had suggested that a higher level of education goes hand in hand with increased physical activity – presumably because these people generally live more health-conscious lives and can also afford things like gym memberships, thus achieving a higher level of activity in their leisure time.”

However, Jaeschke explains, people with a high level of education generally pursue professions that are less physically demanding. This may explain why people with a university entrance qualification recorded longer periods of physical inactivity over the seven days of around-the-clock monitoring.

The researchers also found an unexpectedly clear correlation with the factor of employment: “People who are out of work spend much more time in physical inactivity than those who have a full-time job,” reports Jaeschke. The average daily difference between the two groups was 66.2 minutes. In addition, those without a job during the observation period spent 50.7 minutes less in low-intensity activities each day compared to those with full-time jobs.

Plans are in place for a larger study
Jaeschke admits that one of the limitations of their study is the relatively small number of participants. “In the foreseeable future, however, we will receive data from the first 30,000 or so participants in the NAKO study who have worn the accelerometer for a week,” the researcher says. She and her colleagues will then check their current results against this larger cohort.

Anke Brodmerkel