Ischemic stroke and COVID-19

Wouter Sluis and Annemijn Algra

Ischemic stroke does not often occur in patients with COVID-19 admitted to the hospital, but the ischemic strokes that occur are often serious. This is one of the results from research led by Annemijn Algra and Wouter Sluis. You can find their results here.


Biological discovery heralds new medication

Proteins that regulate nerve cells bind to that cell’s receptor to give their instructions. It was thought that when two of those proteins arrive at the same time, either one protein or the other binds. But this is not the case, according to research by UMC Utrecht and Oxford University: instead of competing, the signaling proteins both bind. This temporarily “switches off” the cell, which offers opportunities for all kinds of new therapies.

Jeroen Pasterkamp

He thinks it is a great find, one that actually requires a reprint of the cell biology textbooks. Jeroen Pasterkamp, Professor of Translational Neursciences, has been researching proteins that control nerve fibers and nerve cells for some time. Jeroen: “These signaling proteins have all manner of functions. They act, for example, as a kind of traffic controller for the nerve cells, which make their way through the body during their development. They do this by binding to the receptor of a nerve cell – the landing platform as it were – and sending a signal that directs the cell in a certain direction. This creates healthy nerve pathways, but also determines, for example, how a tumor grows and spreads.”

Cell biology
Because there are quite a few of these types of signaling proteins – roughly a hundred – and because they continuously bind to nerve cells, Jeroen and his research team wondered what happens when multiple proteins arrive at the receptor at the same time. “We already knew that the proteins we are currently working with bind in the same place. The guiding principle in cell biology is that there is competition and there is a winner: either one or the other protein binds. We were particularly interested in that competition. We thought that if we had a better understanding of how that process works, we might be able to manipulate it to address a number of disease states at the molecular level.”

Large protein complex
To that end, the research team at the Oxford University laboratory first made large amounts of the receptor and ligands (the signaling proteins) and then put them together to make crystal structures. Jeroen: “To our surprise we saw that all those proteins bind to each other. Instead of competing with each other, they create a large protein complex comprising 2 ligands and 1 receptor.” They were even more astounded when they saw the biochemical result: no signal was passed on; in fact, nothing really happened anymore. “That means that the receptor effectively switches off,” says Jeroen, “and the cell becomes insensitive to the signals.” They published on this newly discovered biological principle together with colleagues from Oxford University in the journal Cell, in an article entitled: ‘Simultaneous binding of Guidance Cues NET1 and RGM blocks extracellular NEO1 signalling’.

General biological principle
While they only investigated a single combination of receptor and ligands for the scientific publication, Jeroen believes it is a general biological principle. “We are not entirely sure yet – for that, we need to make crystal structures of other complexes first – but we are also working with other receptor-ligand complexes in the lab and they all look very similar. At first, we did not understand how two ligands can bind to the receptor at the same time, but this soon became clear when we gained more insight into the 3D structure of the receptor-ligand complex.”

What is more, the fact that the receptor “switches off” has a logical function. Nerve fibers, for example, are designed to make contact with other nerve cells. That means that they first have to grow towards the cell and then stop moving. Jeroen: “It was not yet known that this ‘stopping’ happens this way, according to this new principle. But because nobody expected this outcome, we also started functional testing in the nervous system, with all kinds of manipulated proteins that we can make. Then we saw that it is true that if two ligands arrive at the same time, no signals are passed on and nothing happens at all.”

Brain damage
The research initially focused on the effect of the principle in a healthy situation, but it is now clear that the outcome is potentially very interesting for the development of new medicines against various diseases. “We have collected so much information about protein interactions that we can start manipulating them,” says Jeroen. “Take an adult’s nerve system, for example. There is hardly any recovery in case of damage to the brain or spinal cord. Scar tissue prevents nerve fibers from regenerating. This tissue is full of signal proteins that have an inhibitory effect: they instruct the fibers to stop growing. Wouldn’t it be great if we could turn off this inhibitory effect until the nerve fibers have grown through the scar?”

Cancer
That is one use he intends to study, to investigate whether it is possible to switch the responsible receptor-ligand complex on and off with specific antibodies or chemicals. Another example is cancer. Signaling proteins play a role in the growth and spread of tumors by attracting or repelling cells. Jeroen says, “In that case, we would like to achieve the same by blocking the sensitivity of the tumor cells to those signaling proteins, possibly causing them to grow less rapidly and spread less far. These are two important applications; others include diseases such as ALS and defects in the immune system.”

Fundamental discovery
Contacts have already been established with companies to conduct further research, for example into nervous system damage. Discussions are also underway about a collaboration for the development and testing of specific antibodies. But, Jeroen wants to emphasize, this does not mean that new medicines will be available overnight. “It will take a while. This is a fundamental discovery at the very beginning of the medical science chain. It does show, however, how molecular biology can lay the foundations for possible new therapies for patients.”

This research was funded by ALS Foundation Netherlands, Netherlands Organisation for Scientific Research (Vici grant ), Netherlands Organisation for Scientific Research and Ministry of Education, Culture and Science (Gravitation Program ‘Brainscapes), Stichting ParkinsonFonds and Utrecht University (research theme ‘Dynamics of Youth’).


Aftermovie Brain Center Research Day 2020

Aftermovie Brain Center Research Day 2020 – November 27

Data from dead experimental animals can be reused in new experiments

How can you use statistics to increase the power of animal experiments? Low statistical power reduces the reliability of animal research; yet, increasing sample sizes to increase statistical power is problematic for both ethical and practical reasons. Valeria Bonapersona and her colleagues present an alternative solution using Bayesian priors based on historical control data, which capitalizes on the observation that control groups in general are expected to be similar to each other. Their article is published in Nature Neuroscience.

Valeria Bonapersona

Bonapersona made a systematic review of over 1900 studies. “Based on this, at best 12% of preclinical studies are sufficiently powered. The paradox is: to be more ethical, you need more animals. So we asked ourselves the question: can we reduce the number of animals without compromising statistical power?” That’s why they developed RePAIR: Reduction by Prior Animal Informed Research. “In this simulation study we show that including data from control groups of previous studies could halve the minimum sample size required to reach the canonical 80% power, or increase power when using the same number of animals.”

Previous experiments
Currently, the number of control animals is equal to the number of the experimental animals. But by using information of previous experiments it is possible to decrease the number of control animals. Bonapersona: “To prove our method, we launched the Relacs consortium: Rodent Early Life Adversity Consortium on Stress. Ten laboratories around the world shared their data so the sample size was large enough for a validation study. It was really good to see that cooperative science is possible in animal research.”

Open-source tool
Bonapersona and her colleagues also present an open-source tool: RePAIR.
“We think it is important that this tool can be widely used to apply this approach and increase statistical power, thereby improving the reliability of animal experiments.”

Collaboration
The research and development of RePAIR was a collaboration between UMC Utrecht and UMCG, where prof. Marian Joëls is the dean. Joëls is also affiliated to the UMC Utrecht as group leader of translational stress research.
All main authors of this article are financed by the Consortium of Individual Development of Utrecht University.


Vidi grant Michael van Es

We congratulate Michael van Es with his NWO Vidi grant!
With this grant (€800.000) NWO enables laureates to develop their own, renewing research projects. The Vidi’s are meant for excellent researchers who have obtained their doctorates and have subsequently successfully been conducting research for a number of years. Michael received this grant for RECALS: Reanalysis of clinical trials in ALS trials.

“I am very happy and proud to have received a Vidi grant! With this funding we aim to improve clinical trials in amyotrophic lateral sclerosis (ALS) and thereby accelerate therapy development. To date, there is no effective treatment for ALS. We aim to incorporate new insights in ALS into old trials by linking existing data sets together. By doing so, we will for instance be able to look at the effect of drugs in different genetic subgroups of patients, as it has been shown that they may respond differently to treatment. Through this approach we may be able to find to patients that did benefit from previous drugs and we will improve future ALS trials.”


UMC Utrecht Brain Center is renewing its five-year strategy

To anticipate on the constantly changing health care environment, opportunities in research and new initiatives in education, the UMC Utrecht Brain Center renews its strategy every five years. In December 2020, the current strategy ended. With this new strategy, the UMC Utrecht Brain Center will be ready for the future.

Starting points for drafting the new strategy were the launch of the UMC Utrecht ‘Connecting Worlds’ 2020-2025 strategy and recommendations that were received during the SEP evaluation in 2019. Members of the management team and advisory board, that represent all division and departments that participate the UMC Utrecht Brain Center, were asked, in consultation with their colleagues, where the center should focus on in the coming years.

This resulted in an ambitious list of goals and actions. These included, for example, increased coherence of brain imaging research, improved support for (young) talented researchers, convergence of neuroscience laboratory research into an UMC Utrecht Brain Center laboratory, and continued support for patient participation and value-based research.

After gathering and converging all the input listed above, the new five-year strategy is almost ready.

Curious about our future goals? Keep your eye on future Bulletin editions.


Faces of BRAINSCAPES

UMC Utrecht is one of the partners in BRAINSCAPES, a NWO Gravitation Programme. The aim of BRAINSCAPES is to map in detail the biological mechanisms underlying multiple brain disorders (‘brainscaping’). The Dutch Research Council (NWO) has granted this partnership a Gravitation grant of more than nineteen million euros for ten years. But who are the Brain Center faces of BRAINSCAPES?

This time: dr. Onur Basak.

I did my bachelor of science study on molecular biology and genetics at Bilkent university, Ankara, Turkey. My long-term ambition on understanding brain development led me my PhD work on the role of Notch signaling in neural development, which was performed at the Max Planck Institute of Immunobiology and Epigenetics in Freiburg, Germany. Shortly after, I gained an invaluable postdoctoral training opportunity at the lab of Hans Clevers at the Hubrecht Institute in the Netherlands.

Onur Basak

Using genetic mouse models, organoids and single cell techniques, my focus was to quantitatively analyze the cellular and molecular mechanisms behind the cell cycle control of somatic stem cells. At the end of 2017, I started my own group at the Translational Neuroscience department at the UMC Brain Center. The primary research interest of my group is to determine the contribution of Autism spectrum disorder linked histone modifiers in forebrain development. A secondary goal is to understand how cellular heterogeneity of the adult brain is generated and maintained. 

As a young talent, my main role in Brainscapes is to bridge the technological and neurobiological expertise with the consortium. My group will implement new single cell techniques developed by some of the members for the analysis of the heterogeneity of the adult reward system. More specifically, we aim to determine the transcriptomic and epigenetic diversity in the ventral tegmental area, a brain region highly affected in addiction, psychiatric and mood disorders, among others. This highly benefits from my past expertise that covers several grounds that the consortium is built on.

The essence of good science is collaborative and often require expertise exceeding that of one group. The gravitation programme provides a long-term platform to bring in expertise from distinct fields together. The Brainscapes consortium brought me a new perspective on how to integrate genetic data in my own research, state of the art analysis of brain circuitry and brain disorders. Despite the current lockdown, regular online meetings not only keep me mentally engaged in others work, but also give the students an invaluable training (and eventually a successful career) opportunity.


Fellowship & prizes

On our annual research day we announced various prize winners. Once again we congratulate them all with their prizes!

Rudolf Magnus Young Talent Fellowship winners are Emma van Bodegraven & Sharon Berendsen. The aim of their proposal is to identify the determinants of the mechanical microenvironment in glioblastoma that drive poor clinical outcome to gain insight in novel treatment targets. The Fellowship (€200,000 to be shared between the two applicants) allows junior researchers to develop a strong and recognizable research profile and set up interdisciplinary collaborations. Emma & Sharon won this fellowship among others because it is a new collaboration between the UMC Utrecht and Institu Pasteur (Paris). It fits in our bench-to-bedside approach. It is preclinical research with input from the translational neuroscience field.

The winner of the thesis prize is Herm Lamberink. He worked on his thesis called ‘Antiepileptic Drug Withdrawal’ in the group of Kees Braun. Herm is now working as a resident neurology at Haaglanden MC.

Divya Raj is the winner of the publication prize in 2020. She works as a postdoc in the group of Jeroen Pasterkamp. Her article titled Remotely Produced and Axon-Derived Netrin-1 Instructs GABAergic Neuron Migration and Dopaminergic Substantia Nigra Development was published in Neuron. Divya is shared first author on this article.

The Outreach prize is won by Inez Koopman for the development of medical animations and illustrations of subarchanoid bleedings and unruptured intercranial aneurysmas to improve patient information and education. Inez is a PhD candidate in the group of Mervyn Vergouwen. She is now working at Curaçao.


Genes discovered that play a role in aneurysm

Ynte Ruigrok and Jan Veldink

To predict on the basis of genes who is at risk of an aneurysm in the head, that is the goal of Ynte Ruigrok, neurologist at the UMC Utrecht. It is not yet that far. However, with her colleagues in a large international consortium, she has discovered 17 areas on the DNA that contribute to this. The research was conducted under the direction of Ynte Ruigrok in collaboration with Jan Veldink, neurologist and professor of neurogenetics at the UMC Utrecht. Their findings were published in Nature Genetics on November 16.

Three percent of the Dutch population develop an aneurysm in the head. An aneurysm is a weakening in a blood vessel that can lead to the vessel’s rupture. If this happens in the head, blood leaks into the area between the skull and the brain: the subarachnoid space. This is a severe form of stroke that kills a third of patients.

Hereditary

One in ten patients with such an aneurysm have a family history of subarachnoid hemorrhages. Ynte Ruigrok: “We’ve already found six pieces of hereditary material, and with the results of our latest research we can now identify seventeen spots on the DNA.”

The DNA variations that have been found are in most cases common variations that each cause a small increase in the risk of a head aneurysm. “Many of these variations together can pose a substantial risk,” says Ynte. “With all the known variations on the DNA together, we can explain twenty percent of the genetic risk.”

This research is the world’s largest genetic study in the field of head aneurysms. The DNA of more than ten 10,000 patients was examined and compared with 300,000 random volunteers. UMC Utrecht worked together with doctors and researchers from fourteen countries in Europe, Asia and North America.

Antiepileptics
Above all, these results mean more knowledge of aneurysms. Ynte: “This research is a step forward in the whole complex field of genetic and environmental factors. For example, it is clear that most of these genetic abnormalities are related to the endothelium of the vascular wall, the layer on the inside. These are genetic leads for further research. It also seems that the protein structures of some of the genes involved have a link with antiepileptics. That could mean that these medications have an effect on it. That effect can be positive or negative, which requires further research, but could be a starting point for a treatment.”

In addition, this research shows that a genetic predisposition to high blood pressure and genetic sensitivity to smoking play an important role in the development of a head aneurysm. “We already knew from epidemiological research that these were risk factors of course, but now it can also be seen genetically.”

Predicting
Besides more knowledge of the role of genes in aneurysms, these results also help to predict who is at risk in the future. “We’re now working on analyses to determine the risk contribution of the various DNA abnormalities. This will hopefully enable us to make better predictions over time about which groups of people have a potentially increased risk of contracting the disease.”


Twitter thread – Ania Fiksinski

Ania Fiksinski & Jacob Vorstman had their study published in Nature Medicine. They made a thread for Twitter, or as Jacob called it ‘a quick 12-step tour of our findings’. (Click here to read the whole thread) It turned out really successful with over a 70 retweets and lots of reactions. Ania Fiksinski tells us more about the power of sharing on social media.

Why did you choose to create this twitter thread?
We wanted to share this Nature Medicine publication with an audience as wide as possible, given the novelty of the findings and the potential relevance they have for other researchers. We thought it would make our study and findings more accessible if we would use visuals. Also, it was a nice exercise to do it!

Who came up with that idea, and how did you create it?
Amongst the four members of the core writing group of this paper we came up with the idea and created it: Jacob Vorstman as lead senior author, Carrie Bearden as co-senior author, and Robbie Davies and myself (Ania Fiksinski) as shared first authors.

Ania Fiksinski

First, we thought of what steps should be included for the thread to be complete but concise. Then, we assembled the visuals that would support the story: most are figures from the manuscript that we slightly adjusted, or figures that we used for presentations of this and other studies. We created the GIF’s in powerpoint, and tweaked them amongst the four of us.

Any tips for fellow researchers who want to do this too?
We have seen that it worked really well to spread our manuscript, so we would definitely recommend to do this! And to do it in a way that suits your study best, but definitely to think of your audience (e.g., what background information do you need to include for your study to be understood and for your audience to be interested). And do it together!


Earlier recognition of children with sleep epilepsy

Medical researcher Bart van den Munckhof obtained his PhD in mid-October for research into causes, early recognition and better treatment of sleep epilepsy.

Some children have continuous epileptic activity in their brains at night, while they seldom if ever have epileptic seizures during the day. This relatively invisible form of epilepsy is called ESES syndrome. As a result, children often develop learning and behavioral problems. Not much is yet known about this syndrome.

ESES stands for Electrical Status Epilepticus Sleep. It is a kind of short circuit in the brain, which hinders recovery in sleep. Bart explains, “During the day new brain connections are constantly being made through everything you experience and learn. During sleep those connections are usually classified and tidied up. That which must be preserved is given a good place and that which is superfluous is broken down. If this goes well, the brain will have room again the next day to make new connections. With ESES, the short-circuits disturb this classification greatly, freeing up less room for new connections. The head is, as it were, still too full. In our research we measured the brain activity of children with ESES in sleep. We have found that the epileptic activity does in fact disrupt the normal recovery function of sleep. This disruption was the clearest in children who have not only learning problems but also behavioral problems.”

Damage control
It is not known how often ESES occur, because parents do not always notice that their child suffers from it: it just seems to sleep well. Of the children who sometimes or often have epileptic seizures during the day, a small percentage – less than two percent – also have ESES. In puberty children almost always grow over it, but until then it may have caused considerable damage. If the diagnosis is made in good time, treatment can be started to limit the damage.

In his research Bart found that ninety percent of children who suffer damage to the thalamus (an essential control center deep inside the brain) around birth will eventually get ESES. “The severity of that thalamic damage predicts how these children will develop in the long run. In addition, we found that increased inflammatory activity plays a role in the development of epilepsy and, in particular, ESES. As such we advocate that all children who have thalamic damage or inflammation of the brain should be monitored by a neonatologist and pediatric neurologist to recognize ESES at an early stage.”

Which treatment
By means of a meta-analysis of the literature and a study at the UMC Utrecht’s epilepsy center, Bart corroborated the theory that normal epilepsy drugs (antiepileptics) are often ineffective in the treatment of ESES. “Whereas tranquilizers (benzodiazepines) or anti-inflammatory drugs (corticosteroids) prove to be more effective. A European randomized trial, RESCUE ESES, is currently underway, which compares treatment with a tranquilizer (clobazam) with treatment with anti-inflammatory drugs (corticosteroids). In addition, we are looking whether, by measuring inflammatory activity, we can predict which children will and will not respond to treatment. The results of this study are likely to be useful in a few years’ time.” The studies for which Bart obtained his PhD make an important contribution to the knowledge about ESES and can help in the early recognition and treatment of this severe epilepsy syndrome. Bart says, “In this way we hope to improve the development of children with ESES over time.”


Publications

A selection of Brain Center publications

Kees M.van Hespen, Jaco J.M.Zwanenburg, JeroenHendrikse, Hugo J.Kuijf Subvoxel vessel wall thickness measurements of the intracranial arteries using a convolutional neural network. Medical Image Analysis, 2021 Jan;67:101818, Pubmed

Bakker, M.K., van der Spek, R.A.A., van Rheenen, W. et al. (2020). Genome-wide association study of intracranial aneurysms identifies 17 risk loci and genetic overlap with clinical risk factorsNat Genet 52. 2020; 1303–1313. Pubmed

Van Lieshout ECC, Jabobs LD, Pelsma M, Dijkhuizen RM, Visser-Meily JMA. Exploring the experiences of stroke patients treated with transcranial magnetic stimulation for upper limb recovery: a qualitative study. BMC Neurol. 2020 Oct 6;20(1):365. Pubmed

Genzel et al. How the COVID-19 pandemic highlights the necessity of animal research. Curr Biol. 2020 Sep 21; 30(18): R1014–R1018. Pubmed

Slooter AJC, Otte WM et al. Updated nomenclature of delirium and acute encephalopathy: statement of ten societies. Intensive Care Med 2020;46:1020-2. Pubmed

Schelven F v, van der Meulen E, Kroeze N, Ketelaar M, Boeije H. Patient and public involvement of young people with a chronic condition: lessons learned and practical tips from a large participatory program. Res Involv Engagem. 2020 Sep 30;6:59.  doi: 10.1186/s40900-020-00234-1. Pubmed

Van Dellen et al. Functional brain networks in the schizophrenia spectrum and bipolar disorder with psychosis. NPJ Schizophr. 2020; 6: 22. Pubmed

Scholten EWM, Ketelaar M, Visser-Meily JMA, Roels EH, Kouwenhoven M, POWER Group, Post MWM. Prediction of psychological distress among persons with spinal cord injury or acquired brain injury and their significant others. Arch Phys Med Rehabil 2020 Dec;101(12):2093-2102. doi: 10.1016/j.apmr.2020.05.023. Pubmed

Vaes JEG, Kosmeijer CM, Kaal M, Van Vliet R, Brandt MJV, Benders MJNL, Nijboer CH  Regenerative Therapies to Restore Interneuron Disturbances in Experimental Models of Encephalopathy of Prematurity, International Journal of Molecular Sciences,Pubmed


Grants & awards

Some highlights

Janna de Boer and Alban Voppel (UMCG) received an Open Mind grant (NWO) for Say no more! Natural Language Processing for diagnosis and screening in psychiatry.

Neurologist and researcher Ynte Ruigrok received the Michele Sale award for Women in Stroke Genetics of the International Stroke Genetics Consortium (ISGC). The award is a mid-career researcher award for talented female scientists involved in Stroke genetics research. She was awarded the research prize last night during the Virtual Mini Workshop of the ISGC.

The BioClock consortium received 9,7 million euro of the NWO within the NWA-ORC program to study the biological clock in modern society. As part of the consortium, Jeroen Dudink will study the effect of sleep on brain development in neonates.

Kevin Kenna, in collaboration with James Mills (AMC), received a grant of the Frick Foundation to identify the heritable disruptions of RNA regulation that contribute to the development of ALS. It brings together novel analyses of large scale ALS whole genome sequencing data with single molecule labelling of RNA transcripts in autopsy material donated by ALS patients. (Amount: 100,000 EUR. Duration: 2yrs)

Ruben van Eijk is awarded with the Paulo Gontijo Award for his research into broadening the inclusion criteria in ALS drug research. The prize is for young talented researchers of which research contributed in the ALS field.


Jan Veldink and Leonard van den Berg with the team of Project MinE were awarded with the Healey Center Prize for Innovation for developing the largest single disease whole genome sequencing project in the world. As team they successfully sequenced the genomes of 22,500 people and increased the understanding of the genetic variations that alter the risk of ALS as well as other clinical aspects of the disease.

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