CMM Group Leader and professor at the Department of Molecular Medicine and Surgery at Karolinska Institutet, is the recipient of the Mayo Clinic Cancer Center and Karolinska Institutet Cancer Research Award 2022.
The research project "Multi-Omics Studies of BTK Inhibitor Resistance in Chronic Lymphocytic Leukemia" will be headed by Professor Richard Rosenquist Brandell in collaboration with Dr. Neil E. Kay at the Mayo Clinic in Rochester, Minnesota.
The project includes multi-omic analysis in patients with chronic lymphocytic leukemia, who develop drug resistance against precision therapy with BTK inhibitors.
This article is based on a press release in Swedish from Karolinska Institutet.
Richard Rosenquist Brandell
Photo: Rick Guidotti
The repurposing of FDA-approved drugs for alternative diseases is a faster way of bringing new treatments into the clinic. Researchers at CMM together with collaborators have repurposed a cancer drug for treatment of neuroinflammatory diseases such as multiple sclerosis. A novel drug carrier was also developed to facilitate drug delivery to target myeloid cells. These pre-clinical findings are described in a paper in the journal EMBO Reports.
Microglia are an organ-specific type of macrophage in the central nervous system. In the majority of chronic neurodegenerative disease conditions, such as amyotrophic lateral sclerosis (ALS), Alzheimer’s disease and chronic multiple sclerosis (MS), dysfunctional microglia play an important role. Modifying the activation of these disease-promoting microglia is an attractive therapeutic principle.
Keying Zhu (photo: private), Bob Harris (photo:Ulf Sirborn).
“The biotechnology industry has realized the potential for microglia-targeting strategies, and at least 20 new companies have started during recent years,” says Professor Bob Harris Group Leader at CMM and the Department of Clinical Neuroscience, Karolinska Institutet. “Compared to novel drug discovery programs that can take 20 years before a new medicine is approved, using existing prescribed drugs can halve that time.”
The researchers used in silico drug screening to identify candidates for microglial modulation and selected a Topoisomerase 1 (TOP1) inhibitor for further study. TOP1 was highly expressed in neuroinflammatory conditions both in mice and in tissues from MS patients, and TOP1 inhibition using camptothecin (CPT) and its FDA-approved analog topotecan (TPT) reduced inflammatory responses in microglia and macrophages in in vitro cultures, as well as ameliorating neuroinflammatory diseases in vivo.
Old drugs become new drugs
“The data-mining of open access databases is an approach that is both time and economically efficient, and there is so much data available nowadays,” says first author Keying Zhu, PhD student in Bob Harris' Group at CMM and the Department of Clinical Neuroscience, Karolinska Institutet. “We were lucky to identify four compounds with the properties we wished for, and one of these proved to be promising for our continued investigations, ultimately demonstrating significant therapeutic effect in our experimental model of MS.”
To specifically target microglia and macrophages, a nanosystem using β-glucan-coated DNA origami (MyloGami) loaded with TPT (TopoGami) was developed in collaboration with Professor Björn Högberg’s group at the Department of Medical Biochemistry and Biophysics at Karolinska Institutet. MyloGami had enhanced specificity for myeloid cells and also prevented the degradation of the DNA origami scaffold. Myeloid-specific TOP1 inhibition using TopoGami significantly suppressed the inflammatory response in microglia and mitigated MS-like disease progression.
The study was financed by the Swedish Research Council, the Swedish Neurofonden Foundation, the StratNeuro funding for Collaborative Neuroscience Projects at Karolinska Institutet, the Swedish MS Research Foundation, Allitd Litt Sterkere (Norwegian ALS Association), Ulla Carin Lindquists foundation, and KI Doctoral funding.
This article is based on a press release from Karolinska Institutet.
“Myeloid cell-specific topoisomerase 1 inhibition using DNA origami mitigates neuroinflammation.” Zhu K, Wang Y, Sarlus H, Geng K, Nutma E, Sun J, Kung SY, Bay C, Han J, Min JH, Benito-Cuesta I, Lund H, Amor S, Wang J, Zhang XM, Kutter C, Guerreiro-Cacais AO, Högberg B, Harris RA. EMBO Reports, online May 20, 2022, doi: 10.15252/embr.202154499
April S. Caravaca (photo: private), Peder S. Olofsson (photo:MedTechLabs).
The nervous system is known to communicate with the immune system and regulate inflammation in the body. Researchers from CMM now show how electrical activation of a specific nerve can promote healing in acute inflammation. The finding, which is published in the journal PNAS, opens new ways to accelerate resolution of inflammation.
The way the body regulates inflammation is only partly understood. Previous research by Peder Olofsson’s group at Karolinska Institutet and CMM and other research groups has shown that electrical stimulation of the vagus nerve can reduce inflammation. Such nerve stimulation has been used with encouraging results in clinical studies of patients with inflammatory bowel disease and rheumatoid arthritis. However, how nerve signals regulate active resolution of inflammation was unclear.
“We have now studied effects of signals between nerves and immune cells at the molecular level,” says April S. Caravaca, a researcher in Peder Olofsson’s group at CMM and the Department of Medicine, Solna, Karolinska Institutet as well as the Stockholm Center for Bioelectronic Medicine at MedTechLabs. “A better understanding of these mechanisms will allow for more precise applications that harness the nervous system to regulate inflammation.”
The researchers showed that electrical stimulation of the vagus nerve in inflammation shifts the balance between inflammatory and specialised anti-inflammatory molecules, which promotes healing.
“Inflammation and its resolution plays a key role in a wide range of common diseases, including autoimmune diseases and cardiovascular diseases,” says Peder Olofsson. “Our findings provide insights on how the nervous system can accelerate resolution of inflammation by activating defined signalling pathways.”
The researchers will continue to study how nerves regulate the healing of inflammation in more detail.
“The vagus nerve is only one of many nerves that regulate the immune system. We will continue to map the networks of nerves that regulate inflammation at the molecular level and study how these signals are involved in disease development,” says Dr Olofsson. “We hope that this research will provide a better understanding of how pathological inflammation can resolve, and contribute to more effective treatments of the many inflammatory diseases, such as atherosclerosis and rheumatism.”
The study was supported by grants from the Knut and Alice Wallenberg Foundation, the Swedish Research Council, the Swedish Heart-Lung Foundation, MedTechLabs and Novo Nordisk. Peder Olofsson holds shares in Emune AB. Co-author Jesmond Dalli is the founder of and head of research at Resolomics Ltd.
This article is based on a press release from Karolinska Institutet.
”Vagus nerve stimulation promotes resolution of inflammation by a mechanism that involves Alox15 and requires the α7nAChR subunit”. April S. Caravaca, Alessandro L. Gallina, Laura Tarnawski, Vladimir Shavva, Romain A. Colas, Jesmond Dalli, Stephen G. Malin, Henrik Hult, Hildur Arnardottir, Peder S. Olofsson. PNAS (Proceedings of the National Academy of Sciences), online 27 May 2022, doi: 10.1073/pnas.2023285119.
Lars Klareskog (photo: Gustav Mårtensson).
EIT Health Scandinavia International has awarded SEK 23 million in research grants to support international collaboration in precision prevention in rheumatology, with almost half of the grant distributed to Karolinska Institutet and Region Stockholm. The project is led by researchers based at CMM and the scope includes creating the conditions for the early diagnosis of risk factors for developing RA (rheumatoid arthritis) and enabling patients at risk of developing RA to manage the risk through lifestyle changes.
Today, it can be difficult to identify individuals who are at high risk of developing RA, as these individuals often seek out care for diffuse symptoms (e.g.muscle pain or joint pain) that are also common in individuals who are not at risk of developing RA. Researchers at KI have now been awarded a grant from EIT Health Scandinavia.
The research project is being led by the CMMers Lars Klareskog, professor at the Department of Medicine, Solna and CMM Group Leader, as well as Martina Johannesson, project coordinator, in collaboration with the rheumatologists at Karolinska University Hospital and the Center for Rheumatology at the Academic Specialist Center, SLSO. The study includes an international partnership with the University of Erlangen-Nuremberg, Germany and Leiden University in the Netherlands, institutions known for their work with the prevention of RA.
“What makes this project unique is that the patients themselves are a driving force in the effort to prevent RA, which we can follow up on thanks to the international collaboration”, says Lars Klareskog, professor at KI. “For starters, the group in Erlangen has recently shown that a six-month course of treatment with a particular antirheumatic drug (DMARD) reduced the risk of developing RA by about 75%. Our project will now provide an opportunity to conduct additional clinical trials for the prevention of RA in a collaboration between KI, Region Stockholm and our international partners”, says Klareskog.
About the research project
The research project aims, in part, to make it easier to identify at-risk patients. This includes a digital questionnaire where individuals with joint and muscle problems respond to a series of questions. The answers are then analysed using an algorithm that identifies patients who are at risk of developing RA. Individuals who are found to be "positive", i.e. at-risk, using this algorithm are offered a blood test and an antibody analysis (developed by one of the project partners, ThermoFisher) to determine if their individual risk of developing RA is actually elevated. High risk patients are referred to rheumatology units for further follow-up.
In the next step, at-risk patients will use an app (which will be developed by the project partner, Elsa Science) to report several lifestyle factors that are associated with the risk of developing RA. This step also aims to provide an opportunity to reduce the risk of developing the disease by enabling patients to take preventative measures on their own. Another benefit of the study is that when patients are not in pain, the number of days a patient takes sick leave will also decrease. This is, of course, a tremendous benefit for the individual, but it benefits society as well.
The project builds on a previous Vinnova-funded project that was based in Stockholm on the prevention and early treatment of RA.
Several partners are included in the research project.
ThermoFisher Scientific (Uppsala)
Friedrich Alexander, the University of Erlangen-Nuremberg, Germany
Leiden University Medical Center (the Netherlands) with consultation and participation from the Swedish Rheumatism Association and the Dutch Arthritis Foundation.
In total, the grant amounts to SEK 23 million, of which approximately SEK 10 million will go to Stockholm.
Period: May 2022 – December 2024
This article is based on a press release from Karolinska Institutet.
Six predictors could help determine the amount of lithium needed to treat patients with bipolar disorder, according to a large study led by researchers at CMM and Karolinska Institutet. The study, published in the journal Lancet Psychiatry, also pinpoints for the first time genetic markers that seem to influence how quickly the body eliminates lithium from its system.
“Our model could already now be used to predict how much lithium a patient with bipolar disorder will need. This could cut valuable time spent on finding the right dose for each patient, potentially with life-saving impact,” says the study’s senior author Martin Schalling, professor at the Department of Molecular Medicine and Surgery, Karolinska Institutet and shared CMM Group Leader of the C. Lavebratt and M. Schalling Group.
Lithium is one of the most important treatments for patients with bipolar disorder, a condition that has been linked to an increased risk of suicide. The chemical substance works as a mood stabilizer and reduces episodes of depression and mania. How much is needed varies greatly between individuals and finding the right dose for each patient is key as too much can be toxic while too little is ineffective. To minimize the risk of side-effects, clinicians tend to initiate treatment at low doses that increase over time, meaning it could take months before the treatment has an effect.
Vincent Millischer (photo: Irene Gutierrez Perez), Martin Schalling (photo: Ulf Sirborn).
Studied more than 2,300 patients
To overcome this, researchers have long sought to find a model that could predict dose response in individual patients. Previous studies have identified markers such as age, sex and kidney function as possible predictors of how quickly the body eliminates lithium from its system (lithium clearance), which can be used to determine the amount needed on a daily basis. However, most studies have been limited by small sample sizes.
In the current study, the researchers examined electronic health records and registry data from 2,357 patients with bipolar disorder, which may represent the largest sample size for this kind of study to date. Both men and women in ages ranging from 17 to 89 were included, mainly of European ancestry.
Help in treatment decisions
The study found associations between the speed of lithium clearance and age, sex, kidney function (measured as eGFR), serum lithium concentrations and medication with diuretics and substances targeting the renin-angiotensin-aldosterone system (RAAS), which could be used to treat hypertension and other conditions.
“Our findings suggest that older patients, women, patients with reduced kidney function, and those taking certain medications require lower doses of lithium. Interestingly, we also discovered that the amount of lithium taken and lithium concentrations in the blood do not seem to be completely proportional, which goes somewhat against current thinking. Our model based on these predictors explained around 50-60 percent of the variance in lithium clearance, which is better than previous models and could be used to inform treatment decision,” says first author Vincent Millischer, a postdoctoral researcher at the Department for Molecular Medicine and Surgery, affiliated researcher at CMM and resident in psychiatry at the Medical University of Vienna.
The study also found associations between a lower lithium clearance and one genetic locus on chromosome 11 and could also show that genetic variants affecting BMI and kidney function were associated with lithium clearance. Even though adding the genetic markers only marginally improved the model’s predictive capability, the researchers say it opens the opportunity of personalized medicine in lithium treatment in the future.
“Next we will test our model in a clinical trial to see if it can reduce the time it takes to find the right amount of lithium for each patient,” Martin Schalling says. “If the outcome is positive, we will develop a digital app that could be used by psychiatrists in the future to help assess lithium dosage for patients with bipolar disorder.”
The study was funded by the Stanley Medical Research Institute, the Swedish Research Council, the Swedish Foundation for Strategic Research, the Swedish Brain Foundation, the Söderström Königska Foundation, the Bror Gadelius Minnesfond, the Swedish Mental Health Fund, Karolinska Institutet and Karolinska University Hospital. Some of the authors have declared receiving consulting and lecture fees from various pharmaceutical companies while others have declared no competing interests.
Publication: ”Improving lithium dose prediction using population pharmacokinetics and pharmacogenomics: a cohort genome-wide association study in Sweden,” Vincent Millischer, Granville J Matheson, Sarah E Bergen, Brandon J Coombes, Katja Ponzer, Fredrik Wikström, Karolina Jagiello, Martin Lundberg, Peter Stenvinkel, Joanna M Biernacka, Olof Breuer, Lina Martinsson, Mikael Landén, Lena Backlund, Catharina Lavebratt, Martin Schalling, The Lancet Psychiatry, online May 12, 2022, doi: 10.1016/PIIS2215-0366(22)00100-6
This press release was also published on Karolinska Institutet's webpage.
Mattias Bronge (photo: Erik Holmgren), Hans Grönlund (photo:Jens Sølvberg).
A new publication by researchers from CMM sheds light on new target molecules of potential significance for personalised treatment of multiple sclerosis (MS). The study was published in Science Advances.
MS, a chronic inflammatory disease of the central nervous system, is one of the most common causes of neurological disability among young adults. Immune cells mistakenly attack the so called myelin sheaths, a fatty layer surrounding nerve fibers. Consequently, the electric signal cannot be transmitted properly in the nerve and eventually the nerve fibers are lost. MS causes neurological symptoms such as sensory disorders, difficulties with walking and balance and impaired vision. Current treatments reduce the number of disease relapses and alleviate symptoms, but no cure is available yet.
“Existing MS treatments are quite indiscriminate in their effect on the immune system, which risks eventually causing complications, such as infections,” says the first author Mattias Bronge, PhD student in Hans Grönlund’s CMM Group and at the Department of Clinical Neuroscience, Karolinska Institutet. “Guiding future treatments more accurately towards the immune cells driving the disease can therefore lead to greater efficacy and fewer side effects.”
The researchers analysed 63 proteins in blood samples from MS patients and healthy controls and identified four new molecules, called autoantigens that are targeted by the autoimmune T cell attack in MS. The tested proteins were selected in collaboration with the Human Protein Atlas and Professor Torbjörn Gräslund at KTH Royal Institute of Technology, and the study was conducted by KI, KTH and Region Stockholm.
Hans Grönlund’s and Tomas Olsson’s Groups at CMM have previously developed a method that makes it possible to identify the T cells that react to specific autoantigens. Thanks to this method, four new molecules can be added to the few already known autoantigens, thus making a significant contribution to future developments in diagnosis and treatment.
“Our method makes it possible to present these autoantigens in a way that enables us to identify and subsequently disable the T cells that react to them,” says Hans Grönlund.
Not all MS patients react to the same autoantigens but by applying precision medicine methods such as the identification of each patient’s autoantigen-specific and disease-driving immune cells, personalized treatments can be created.
“Once a patient’s individual autoantigen profile is identified, a treatment can be adapted accordingly,” explains Dr Grönlund the last author of the study. “Most autoimmune diseases are driven by T cells and, if we can find a way to target them in diseases like MS, we can pave the way for more precise treatments with fewer side effects for other autoimmune diseases. Thanks to our long-standing collaboration with Professor Roland Martin at the University of Zürich, our method will be included in a phase 2 clinical study that aims to ‘switch off’ the aggressive T cells which drive MS development and progression.”
The study was financed by Vinnova, the Swedish Research Council, the Swedish Brain Fund, Neuro, the Margareta af Uggla Foundation, Stratneuro and Region Stockholm. Hans Grönlund is founder of NEOGAP Therapeutics AB which has patented the method used and jointly holds the patent for the autoantigens featured in the study with Mattias Bronge. Co-authors Claudia Carvalho-Queiroz, Ola B. Nilsson, Andreas Kaiser and Guro Gafvelin are employed by NEOGAP Therapeutics AB.
This article is based on a press release from Karolinska Institutet.
”Identification of four novel T cell autoantigens and personal autoreactive profiles in multiple sclerosis”. Mattias Bronge, Klara Asplund Högelin, Olivia G. Thomas, Sabrina Ruhrmann, Claudia Carvalho-Queiroz, Ola B. Nilsson, Andreas Kaiser, Manuel Zeitelhofer, Erik Holmgren, Mathias Linnerbauer, Milena Z. Adzemovic, Cecilia Hellström, Ivan Jelcic, Hao Liu, Peter Nilsson, Jan Hillert, Lou Brundin, Katharina Fink, Ingrid Kockum, Katarina Tengvall, Roland Martin, Hanna Tegel, Torbjörn Gräslund, Faiez Al Nimer, André Ortlieb Guerreiro-Cacais, Mohsen Khademi, Guro Gafvelin, Tomas Olsson och Hans Grönlund. Science Advances, online 27 April 2022, doi: 10.1126/sciadv.abn1823.
In a unique cohort of patients who have been treated for malaria in Sweden, CMM researchers have studied the stages of the immune response during the course of malaria infection. Their findings provide an important contribution to the question of how disease tolerance in malaria develops. The results are now published in the journal Cell Reports.
Malaria is caused by parasites that are spread to humans through the bites of infected mosquitoes. Once the parasites enter the body, they follow the bloodstream to enter the liver were they grow, divide and enter the bloodstream again, where they infect red blood cells. People who have malaria usually feel very sick with a high fever and shaking chills. The disease itself is partly a result of the immune response to the blood-stage of the infection, which
induces a strong inflammatory response. According to the WHO, the disease affected more than 241 million people and caused more than 600,000 deaths in 2020, mainly among young children in sub-Saharan Africa.
Natural immunity to malaria develops over time with repeated malaria episodes but protection against severe malaria develops more rapidly through so-called tolerance. It is important to gain a better understanding of how humans fight this serious disease in order to develop more efficient vaccines or treatments.
Investigated immune cells in different disease stages.
PhD student Julius Lautenbach is the first author of the Cell Reports publication. Together with his colleagues, he investigated the immune cells and proteins in blood samples from patients who had been treated for acute malaria infection at Karolinska University Hospital in Solna, Sweden and had recovered.
The patients were tested on six occasions during one year following the onset of the disease. A total of 53 patients were included, 17 of whom had contracted malaria for the first time, while 36 had grown up in malaria endemic areas, had had malaria many times before and now contracted the disease again after travel.
“Since we have followed the patients here in Sweden, we can study the natural course of the immune response after a malaria infection, without the risk of a new infection interfering with the results. This cohort has proved to be very valuable for studying the immunology of malaria," says co-author Professor Anna Färnert, Group Leader at CMM and Senior infectious diseases physician at Karolinska University Hospital.
In patients who had been infected for the first time, there was a strong inflammation produced by the innate immune system, while people who were re-infected had an ability to suppress the inflammation.
“In those who have had malaria before, we saw that the early presence of parasite-specific antibodies interrupt the first stages of the inflammation and prevent a certain type of inflammatory T-cells, called ɣ𝛿 T cells, from expanding," says Christopher Sundling, CMM Team Leader and last author of the study.
Possibility to improve vaccines
Currently, there is only one vaccine against malaria, called Mosquirix, and it was recommended for use by the WHO in October 2021. It targets the stage when the parasite first moves from the mosquito into the liver. Once it enters the bloodstream and gives symptoms, the parasite has transformed and at that stage, the vaccine does not work.
“This is a weakness of the current vaccine. Understanding how tolerance develops and what happens in the blood stage can help us develop other types of vaccines, which may not fully protect against infection but will lessen the chances of becoming seriously ill. If such a vaccine can enable people to survive the first infections that kill so many, we could save many lives," Christopher Sundling explains.
Even though efforts such as distribution of mosquito nets, improved diagnostics and treatments have led to a global decrease of malaria incidence over the past decades, the covid pandemic broke that positive trend.
“We now need to continue to ensure that people are protected from being bitten by infected mosquitoes and have access to rapid and effective treatment. But to further reduce the burden of disease and eventually eradicate malaria, new tools are required. An effective vaccine is really needed; that is how we have been able to manage other infections, also in poor countries," says Anna Färnert.
The research has been funded by the Swedish Research Council, Magnus Bergvall Foundation, the Åke Wiberg Foundation, Region Stockholm, and the Marianne and Marcus Wallenberg Foundation, as well as doctoral grants from Karolinska Institutet. The researchers declare that there are no conflicts of interest.
This article is based on a press release from Karolinska Institutet.
”Systems analysis shows a role of cytophilic antibodies in shaping innate tolerance to malaria.” Maximilian Julius Lautenbach, Victor Yman, Carolina Sousa Silva, Nadir Kadri, Ioanna Broumou, Sherwin Chan, Sina Angenendt, Klara Sondén, David Fernando Plaza, Anna Färnert, Christopher Sundling. Cell Reports, online 19 April 2022, doi: 10.1016/j.celrep.2022.110709.
Julius Lautenbach (photo: private), Anna Färnert (photo: Ulf Sirborn) and Christopher Sundling (photo: private).
Michael Sundström. Photo. Anne-Li Engström
The Board of the Center for Molecular Medicine (CMM) has appointed Michael Sundström as the new Director of CMM. An experienced scientist, business leader and manager, Michael assumed his position on April 1, 2022.
Michael Sundström received his PhD from Uppsala University, followed by postdoctoral studies at Karolinska Institutet. He has more than 30 years of international experience in leading pharmaceutical and biotechnology organisations. He has held positions as Director for structure-based drug design and oncology Research & Development portfolio management at Pharmacia, as well as senior positions at Actar and Biovitrum. In 2003, he was one of the co-founders of the Structural Genomics Consortium (SGC) working at the University of Oxford as Chief Scientist. After moving to the positions of Managing Director for the Novo Nordisk Foundation Center for Protein Research in Copenhagen, and later Vice President of Discovery Research at Karolinska Development in Stockholm, he rejoined the SGC in mid-2014. As Scientific Director for the SGC Karolinska laboratory based at CMM, he mainly focuses on leading large European projects in partnership with the pharmaceutical industry. The projects aim to generate high-quality research tools, such as antibodies and chemical probes, for use in translational medicine research studies.
As CMM Director Michael Sundström will work in close cooperation with the Karolinska University Hospital, Karolinska Institutet and Region Stockholm in order to continue strengthening the connection between clinical and molecular research. In addition, together with the scientists, the CMM Board, CMM Steering Group and support personnel, he will further develop the Center as a leading and attractive cross-disciplinary research environment.
“I am very glad to have Michael Sundström on board as the new CMM Director. With his profile and experience, he is the right candidate to shoulder the responsibility of further developing our internationally recognised research center, with excellent foundations laid by previous Directors Professor Lars Terenius, Professor Lars Klareskog and Professor Helena Erlandsson Harris. With Michael Sundström leading the way, we are looking forward to continuing our close collaboration with the Karolinska University Hospital, Karolinska Institutet and Region Stockholm. I strongly believe Michael Sundström will lead CMM into the next phase. The future is bright.”, says Liselotte Jansson, Chair of the Board of the Center for Molecular Medicine.”
“It is truly exciting to take on this new role and set out to further develop CMM together with all the professionals who are the basis for its creative research environment. I believe that CMM has an excellent model for working at the lead of translational research, connecting the real health-related needs with intellectual capital, forefront scientific knowledge and technological possibilities. I am looking forward to further strengthening the organisation and our collective research outputs.”
CMM is a foundation instituted by the Stockholm County Council (SLL), currently Region Stockholm and works in close collaboration between Karolinska University Hospital and Karolinska Institutet.
Fredrik Wermeling and Gustavo Monasterio
Photos: Erik Holmgren and private, respectively.
Two CMM researchers, Fredrik Wermeling and Gustavo Monasterio, have received funding from the Swedish Cancer Society (Cancerfonden).
Associate Professor and CMM Team Leader Fredrik Wermeling received the Senior Investigator award, which will cover his salary during six years. The title of Fredrik’s research project is ”Identification of new drug targets and innovative therapeutic modalities to overcome drug resistance”. The purpose of the Senior Investigator Award is to give established and highly qualified researchers who have not yet reached a final academic position, the opportunity to do full time cancer research during six years.
Gustavo Monasterio, postdoctoral researcher in Eduardo Villablanca’s CMM Group, was awarded a Postdoctoral Position funded by the Swedish Cancer Society. The grant will cover Gustavo's salary for 3 years and the awarded postdoctoral project is titled ”Defining the role of B cells during intestinal cancer”. The purpose of the Swedish Cancer Society’s funding of Postdoctoral Positions is to benefit cancer research by recruiting successful young researchers to the field.
Nikolaos Taxiarchis Skenteris and Ljubica Matic.
Photos: Private and Tintin Vidhammer, respectively.
CMM Researchers from the Vascular surgery group, at the Department of Molecular Medicine and Surgery (MMK), Karolinska Institutet, have for a number of years studied vascular calcification as a prominent pathophysiological process characterised by the deposit-ion of calcium crystals in the media or intima of vessels. In the new study led by CMMer PhD candidate Nikolaos Taxiarchis Skenteris and Associate Professor Ljubica Matic (CMM Team Leader), published in the Clinical and Translational Medicine journal, they utilised several large patient cohorts to investigate common mechanisms of vascular calcification in different vascular territories. Osteomodulin (OMD), a proteoglycan previously involved in bone mineralisation, was identi-fied as a novel biomarker in this context. The study reports a consistent and broad association of both circulating and tissue OMD levels with various forms of cardiovascular calcification, highlighting its’ potential for further biomarker evaluation in larger clinical trials.
Calcification is a key feature of late-stage diabetes, renal and cardiovascular disease, linked to major adverse events such as myocardial infarction and stroke. Other pathological vascular changes encompass inflammation, lipid accumulation, extracellular matrix remodeling and alterations in smooth muscle cell function. Understanding mechanisms of these processes as well as their interplay in disease progression, is of key importance for finding new clinical biomarkers or therapeutic targets. This study shows that OMD is an important early modulator of cardiovascular calcification processes, enriched in association with vessel wall inflammation and osteoblastic transition of vascular smooth muscle cells, with the capacity to attenuate matrix calcification once it is secreted in the extracellular tissue.
This study was organized as an international collaboration utilizing clinical material and data from several large cohorts of atherosclerosis (Biobank of Karolinska Endarterectomy, KI), chronic kidney disease (Kärl Tx biobank, Karolinska Institutet in collaboration with Prof Peter Stenvinkel) and calcific aortic valve disease material obtained by Prof Leon Schurgers’ group, Maastricht University. Through these collaborations we had access to unique patient material, but were also able to study advanced murine models of vascular calcification in order to understand the mechanisms regulated by OMD. Our findings imply that OMD has the potential both as a plasma bio-marker and as a therapeutic target for assessing cardiovascular calcification”, says Ljubica Matic, Team Leader in the Vascular Surgery group, MMK, Karolinska Institutet and corresponding author of the study.
Illustration of deposited calcium in the arteries.
Image: Wikimedia Commons, author: www.scientificanimations.com
The study was conducted in the framework of the EU Horizon 2020 International Training Network INTRICARE which was initiated in 2017 as collaboration among Maastricht University, The Netherlands, Aachen University Clinic, Germany and Karolinska Institute. The aim of INTRICARE, that gathered totally 15 PhD students across three Universities, was to study risks of vascular Intimal calcification and roads to regression of cardiovascular disease.
This research was funded by a research grant from the European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement No 722609 (INTRICARE); Dutch Thrombosis Society, Netherlands Organization for Scientific Research, grants from the Swedish Research Council (VR), Swedish Heart-Lung Foundation (HLF), Swedish Society for Medical Research (SSMF), CIMED, Stockholm County Council (ALF), and research funding from the Mats Kleberg, Sven and Ebba Hagberg, Tore Nilsson, Magnus Bergvall and Karolinska Institutet Foundations, Sweden.
Skenteris NT, Seime T, Witasp A, Karlöf E, Wasilewski GB, Heuschkel MA, Jaminon AMG, Oduor L, Dzhanaev R, Kronqvist M, Lengquist M, Peeters FECM, Söderberg M, Hultgren R, Roy J, Maegdefessel L, Arnardottir H, Bengtsson E, Goncalves I, Quertermous T, Goettsch C, Stenvinkel P, Schurgers LJ, Matic L. Clin Transl Med. 2022 Feb;12(2):e682. doi: 10.1002/ctm2.682.
Read the Karolinska Institutet press release here.
Eduardo Villablanca (photo: Knut och Alice Wallenberg Foundation, Magnus Bergström).
Which genes are expressed in the large intestine during tissue repair and where exactly? Using a technique called spatial transcriptomics, Eduardo Villablanca and members of his Group at CMM, together with other researchers, created a unique expression map of individual genes in mouse intestinal tissue and compared it to expression data from cell types in the human colon. This model can be used as a tool for understanding how different diseases affect the colon. The study is published in the journal Nature Communications.
Spatial transcriptomics is a technique that allows the visualization of the gene expression landscape in a tissue. It was developed at SciLifeLab by scientists from KTH Royal Institute of Technology and Karolinska Institutet. In the study performed by Eduardo Villablanca and co-workers, the technique was applied in
a novel way. To visualize a long tubular organ like the colon, they rolled up the tissue like a Swiss roll, and thus managed to fit and map the entire gene expression landscape of a long organ.
“Our spatial transcriptomics-driven visualisation enabled us to discover several previously unknown aspects, such as that the colon is divided into more segments than once thought,” says the study’s corresponding author Eduardo J. Villablanca, CMM Group Leader and docent at the Department of Medicine, Solna at Karolinska Institutet.
Based on combined transcription data human colon tissue and the spatial transcriptomics from the whole mouse colon, the researchers found that the location of certain intestinal and immune cells was the same in both mice and humans. This model is thus suitable for translational studies of human diseases. Using the novel gene expression map of the colon in the context of recovery after injury, the research group could also show that the genes for the more difficult to treat forms of the ulcerative colitis were found in tissue that was more damaged.
Image showing different gene expression programs in specific compartments of the murine colon. Credit: Ludvig Larsson.
Eduardo Villablanca’s Group worked on this study together with other researchers from Karolinska Institutet, Science for Life Laboratory, University Medical Center Hamburg-Eppendorf and Heidelberg University.
The researchers now aim at creating a reference map for the gene expression of all tissues of the digestive organs, from the mouth to the rectum.
Pipeline for the processing and analysis of the whole murine colon using spatial transcriptomics. Credit: Ludvig Larsson.
The Swedish Research Council, the Swedish Research Council for Environment, Agricultural Sciences and Spatial Planning (Formas), the Swedish Cancer Society and the Knut and Alice Wallenberg Foundation, among others, provided funding for this study, conducted at Karolinska Institutet.
Declarations of interest: Eduardo J. Villablanca has received research funding from the pharmaceutical company F. Hoffmann-La Roche; and Camilla Engblom, Ludvig Larsson and Joakim Lundeberg are scientific advisors to 10X Genomics, which acquired the company Spatial Transcriptomics in 2018.
This article is based on a press release from Karolinska Institutet:
”The spatial transcriptomic landscape of the healing mouse intestine following damage”, Sara M. Parigi, Ludvig Larsson, Srustidhar Das, Ricardo O. Ramirez Flores, Annika Frede, Kumar P. Tripathi, Oscar E. Diaz, Katja Selin, Rodrigo A. Morales, Xinxin Luo, Gustavo Monasterio, Camilla Engblom, Nicola Gagliani, Julio Saez-Rodriguez, Joakim Lundeberg och Eduardo J. Villablanca, Nature Communications, online Feb. 11, 2022, doi: 10.1038/s41467-022-28497-0
Marie Wahren-Herlenius (photo: Hjärt-Lungfonden).
CMM Group Leader Professor Marie Wahren-Herlenius receives a total of SEK 5,100,000 from the Swedish Heart-Lung Foundation for researching the rare and serious children's syndrome Kawasaki's disease. Typically, the patients initially present with a high and persistent fever. The syndrome is a form of general blood vessel inflammation, vasculitis. It mainly affects children under 5 years of age and the causes are unknown. Without treatment, around 20 percent of the patients develop abnormal local swellings of the coronary arteries – the blood vessels that supply blood to the heart muscle. These artery swellings are called aneurysms and lead to death in approximately one percent of the affected children.
"We want to identify the prevalence of Kawasaki's disease in Sweden and examine how genetic and environmental factors contribute to the development of the disease" says Marie Wahren-Herlenius in Karolinska Institutet’s press release.
Marie Wahren-Herlenius and her research group will search for yet unknown disease mechanisms that are suitable for the development of new treatment methods with the aim of more efficient prevention of coronary artery aneurysms.
Onur Parlak (photo: Magdalena Lindén).
In March 2021 the European Innovation Council (EIC) was launched with the aim of identifying, developing and scaling up breakthrough technologies and game-changing innovations. This funding program is split into four different but linked funding schemes to support innovations throughout their lifecycle; from early-stage research, to proof of concept, technology transfer, and the financing and scale up of start-ups and small-medium enterprises.
The CMMer Assistant Professor Onur Parlak is the responsible investigator for the Karolinska Institutet part of a multicenter collaboration that is one of 56 selected projects to receive the first financing from the Pathfinder program (EIC’s fund for early-stage development of future technologies). The project aims at developing a bioelectronic skin patch that can predict epileptic seizures before they happen. The project received in total EUR 3.7 million from EIC and involves four academic partners and two
companies: University of Portugal (coordinates the project), Karolinska Institutet, Danish Epilepsy Center, Centre National de la Recherche Scientifique, Biostrike and Kinetikos Health.
Epilepsy is a neurological disease that is characterized by epileptic seizures, which are bursts of abnormal activity in the brain. The symptoms of a seizure vary, but can include uncontrollable jerking and shaking, collapsing or losing awareness and staring blankly into space. Epilepsy is one of the most common serious central nervous system disorders worldwide. Prediction of epileptic seizures is particularly important for prevention of the fatal complication, called sudden unexpected death in epilepsy (SUDEP). The epidermal biosensor that will be developed in this EIC-awarded project is a patch that measures cortisol secreted through the skin through built-in microelectronic technology. The patch also has medication-containing capsules. The registered cortisol measurements are continuously processed by an algorithm that will signal if a risk level is reached, which in turn will lead to immediate drug administration. Simultaneously the device will send an alarm signal to healthcare workers and family members, alerting them to a potential epileptic seizure.
Karolinska Institutet receives ~EUR 1 million for the sensor design and prototyping of the epidermal electronic device, a work headed by Onur Parlak in the lab at CMM.
Illustration of the project, edited by Onur Parlak
Richard Rosenquist Brandell (photo: Pär Olsson).
Professor Richard Rosenquist Brandell is a Group Leader at CMM, Senior Physician at the Karolinska University Hospital and Director of Genomic Medicine Sweden (GMS). He has been named Networker of the Year by the Swedish Network Against Cancer (Nätverket mot cancer).
The aim of the network is to raise common issues for the cancer-profiled patient associations through opinion formation and knowledge-raising activities. Networker of the Year is a honorary award given to a person or business that, through its commitment, supports the Network against the cancer's goal of strengthening the patient's influence and opportunities for optimal care.
The motivation of the jury:
“Richard is a true enthusiast who is passionate about better and equal cancer care in Sweden and for patient collaboration in research and care. He is well liked among patients, colleagues and in all networks. Richard has supported the Network Against Cancer's goal of strengthening the patient's opportunities for optimal care. His research and involvement in precision medicine inspires the profession, academia, patients and business as well as political decision-makers.”
“This is a great honor for me and I am really moved to receive this award from the Network Against Cancer. We have worked closely with each other to achieve equal access to precision medicine in healthcare. The Network Against Cancer has been part of the whole journey with GMS”, says Richard Rosenquist Brandell in a press release from Karolinska Institutet.
The award was presented at World Cancer Day on February 4 and it consists of a diploma and the honor.
CMMers Hildur Arnardottir (photo: Stefan Zimmermann) and Magnus Bäck (photo: Leonard Gren).
CMM researchers publish a study in Journal of Clinical Investigation, showing that a receptor activated by substances formed from omega-3 fatty acids plays a vital role in preventing inflammation in blood vessels and reducing atherosclerosis.
Cardiovascular diseases are the major cause of deaths worldwide. Atherosclerosis is a cardiovascular disease that is characterized by chronic inflammation in the blood vessels, which leads to the formation of lesions and subsequent thickening of the inner lining of the artery walls.
Both risk factors and protecting factors for atherosclerosis have been identified. Intake of food that is rich in omega-3 fatty acids has been associated with lower risk for atherosclerosis and now a study published in the Journal of Clinical Investigation sheds light on an important molecular player behind this protection. The CMMers Hildur Arnardottir and Magnus Bäck are the first and last author of the study, respectively.
When omega-3 fatty acids are metabolized, a type of anti-inflammatory compounds called resolvins, are formed. Resolvins switch off the inflammation and stimulate tissue healing. The authors of the study found that the resolvin receptor GPR32 is dysregulated in patients with atherosclerosis. This led them to create a mouse model for atherosclerosis where the GPR32 receptor is overexpressed. They found that signalling via the GPR32 receptor counteracted atherosclerosis and inflammation in the blood vessels and stimulated healing.
“This discovery can pave the way for completely new strategies for treating and preventing atherosclerosis by arresting inflammation in the blood vessels, while also turning on the body’s healing processes with the help of omega-3 fatty acids, for example,” says Hildur Arnardottir.
The researchers are planning to continue investigating the implications of dysregulated signaling through GPR32 receptors.
“We’ll now be studying the mechanisms behind the failed management of inflammation in the blood vessels and how omega-3 mediated stop signals can be used to treat atherosclerosis,” says professor Magnus Bäck, Group Leader at CMM and principal investigator behind the research project.
The study was mainly financed by the Swedish Research Council, the Swedish Heart-Lung Foundation, King Gustaf V and Queen Victoria's Foundation of Freemasons and Region Stockholm. There are no reported conflicts of interest.
This article is based on a press release from Karolinska Institutet.
Hildur Arnardottir, Silke Thul, Sven-Christian Pawelzik,Glykeria Karadimou, Gonzalo Artiach, Alessandro L. Gallina, Victoria Mysdotter, Miguel Carracedo, Laura Tarnawski, April S. Caravaca, Roland Baumgartner, Daniel F.J. Ketelhuth, Peder S. Olofsson, Gabrielle Paulsson-Berne, Göran K. Hansson, Magnus Bäck. The resolvin D1 receptor GPR32 transduces inflammation-resolution and atheroprotection. The Journal of Clinical Investigation, 15 December 2021, doi: 10.1172/JCI142883.
Olle Kämpe. Photo: Private
Professor Olle Kämpe is a Group Leader at CMM and his passion is to understand what autoimmunity is. In November, he was awarded the Minerva Foundation’s Bror-Axel Lamberg Prize in Endocrinology during the Annual Meeting of the Finnish Endocrine Society. The Finnish Endocrine Society nominates three distinguished Finnish or Nordic scientist in the field of endocrinology from whom the Minerva Foundation selects the winner. The prize is €10 000 and this was the third time the prize was awarded.
The motivation of the Prize Committee:
“Olle Kämpe has a record of accomplishment in endocrine research spanning three decades and covering studies from basic genetic studies to registry and epidemiology research. The red thread in his research has been autoimmune endocrine diseases.
Kämpe has described several autoantigens and autoantibodies in organ-specific autoimmune diseases. His research is characterized by broad and complementary methodological approaches including the use of non- traditional disease models to understand the pathogenesis of autoimmune diseases and his work has significantly improved the diagnosis, treatment and follow-up of patients.”
Olle Kämpe has received numerous awards for his work. In 2010 he was elected member of The Swedish Royal Academy of Science and in 2016 member of the Nobel Assembly. He is currently member of the Nobel Committee for Medicine or Physiology. He received the Swedish Medical Society's Jubilee Prize in 2016 and the European Hormone Medal in 2020.
CMMers Maribel Aranda-Guillén and Nils Landgren, authors of the PNAS publication. Photo: Olle Kämpe
The most common approach to finding what causes a disease is to study many affected patients in order to find a common denominator. In this new study published in Proceedings of the National Academy of Sciences (PNAS), however, the researchers started from the opposite end by testing whether a suspected autoantigen can be matched with a disease.
Autoantigens are the body’s own proteins that the immune system reacts against in autoimmune diseases. Transglutaminase 1 (TGM1), which is found in the skin, belongs to a protein family with many known autoantigens. TGM1 has been previously linked to a hereditary skin disease and now the researchers wanted to know if TGM1 was also involved as an autoantigen in acquired skin diseases. They searched for it in more than 500 patients with a wide range of autoimmune and unexplained skin diseases. Eventually, they found a match.
“We saw that patients with the cancer-associated and severe blister-causing skin disease paraneoplastic pemphigus presented antibodies against TGM1. We confirmed the findings in a larger group of patients and
could conclude that TGM1 antibodies were completely specific for paraneoplastic pemphigus,” says Nils Landegren, medical doctor and researcher specialising in autoimmune diseases at Uppsala University and affiliated to Olle Kämpe’s group at Karolinska Institutet and CMM. Nils lead this study, which was conducted together with other CMM researchers, Karolinska Institutet, Uppsala University as well as Osaka City University, Japan.
Knowing which autoantigens are associated with a specific disease is important, both to understand the disease mechanisms and to be able to diagnose autoimmune diseases and to give patients the correct treatment.
“We believe that TGM1 antibodies can be valuable as a diagnostic marker in investigations of blister-forming diseases. Patients that test positive should be quickly investigated to eliminate the possibility of undiscovered cancers,” says Nils Landegren.
The researchers believe that this new approach to identifying biomarkers can be used in studies of all sorts of autoimmune diseases, and that this could be a way to leverage the growing amount of openly available data on gene expression and function.
This study was funded by the Swedish Research Council, the Knut and Alice Wallenberg Foundation, the Swedish Society for Medical Research, the Göran Gustafsson Foundation and the Novo Nordisk foundation, among others. The contributing researchers have applied for a patent for the diagnostic use of TGM1 antibodies.
Nils Landegren, Norito Ishii, Maribel Aranda Guillen, Horður Ingi Gunnarsson, Fabian Sardh, Åsa Hallgren, Mona Ståhle, Eva Hagforsen, Maria Bradley, Per-Henrik Edqvist, Fredrik Ponten, Outi Mäkitie, Liv Eidsmo, Lars Norlén, Adnane Achour, Ingrid Dahlbom, Ilma Korponay-Szabo, Daniel Agardh, Mohammad Alimohammadi, Daniel Eriksson, Takashi Hashimoto, Olle Kämpe. A gene-centric approach to biomarker discovery identifies transglutaminase 1 as an epidermal autoantigen. PNAS 2021 vol. 118, DOI: 10.1073/pnas.2100687118, http://doi.org/10.1073/pnas.2100687118
Anna Färnert (photo: Ulf Sirborn), Kristina Broliden (photo: Stefan Zimmermann), Christopher Sundling (photo: private)
On December 2, the Swedish Research Council published the decisions on applications to be awarded project grants within Development research this year.
Three researchers from CMM obtained grants within this category:
Anna Färnert was awarded SEK 4 499 000 for the project titled ”Malaria immunitet: studier av immunsvar mot variabla parasitantigen”.
Kristina Broliden was awarded SEK 4 451 370 for the project titled ”Identifiering av molekylära signaler i genitalslemhinnan hos kvinnor som avgör känslighet för sexuellt överförbara infektioner”.
Christopher Sundling was awarded SEK 4 439 000 for the project titled ”Utvärdering av nya diagnostiska tester för detektion av progression från latent till aktiv tuberkulos”.
Karolinska Institutet press release (in Swedish)
Top to bottom, left to right: Magdalena Paolino (photo: Ragnar Söderberg Foundation), Karin Loré (photo: Ulf Sirborn), Anna Lindstrand (photo: Ola Lindström), Annika Lindblom (photo: Karolinska Institutet), Taras Kreslavisky (photo: Ulf Sirborn)
The Swedish Cancer Society (Cancerfonden) has awarded five researchers from CMM with grants for the following projects:
Taras Kreslavisky received a total of SEK 3 000 000 during 3 years for the project titled "Do tumor –infiltrating gamma-delta T lymphocytes recognize tumor antigens?"
Magdalena Paolino received a total of SEK 2 400 000 during 3 years for the project titled "A new ubiquitin-related gene in colorectal cancer: preclinical studies to test the effects of its inhibition in tumor growth and metastasis".
Annika Lindblom received a total of SEK 2 000 000 during 2 years for the project titled "Cancer predisposition and prevention".
Anna Lindstrand received a total of SEK 1 800 000 kr during 3 years for the project titled "Using zebrafish to develop combination therapies to overcome drug resistance in AML".
Karin Loré received a total of SEK 1 600 000 kr during 2 years for the project titled "SARS-CoV-2 vaccination in highly immunocompromised recipients of CAR T cell therapy and allogeneic stem cell transplantation".
The list of awarded projects can be found here.
Susanna Brauner. Photo: Ulf Sirborn
The Swedish Society for Medical Research (SSMF) annually awards SSMF’s Large Grant to young and promising medical researchers. This year the CMMer Susanna Brauner is one of the three recipients from Karolinska Institutet. In total, the foundation received 158 applications out of which eight were granted. Susanna’s grant consists of 5 256 000 SEK for four years research part time for the project “Myasthenia gravis- towards improved prognostication and treatment.”
Myasthenia gravis is a serious, potentially life-threatening neuromuscular disease. It is caused by an autoimmune reaction directed against the nerve connection on the skeletal muscles, resulting in fluctuating muscular fatigability (decrease of the muscle’s ability to perform over time).
Susanna's research has three “arms” that span from pathogenesis to treatment in myasthenia gravis (MG).
"It is nice that there are people who believe in you as a researcher and want invest money in a relatively uncommon disease such as MG. It makes you feel that you are on the right track. This establishment grant allows me to combine research time with my clinical work and hire more people to the research team", says Susanna Brauner.
Read the Karolinska Institutet press release here.
Long Jiang and Fredrik Wermeling. Photos: Erik Holmgren
CRISPR/Cas9 gene editing is a promising technique in the rapidly developing field of precision medicine. In a recent publication, the CMMers Long Jiang (PhD Student), Fredrik Wermeling (Team Leader), and co-authors show that the editing technique can lead to the enrichment of cells with mutations in a broad p53-linked network of cancer-related genes. p53 is a protein that is central to the cellular response following DNA damage. Notably, inactivating p53 mutations are the most common genetic alterations found in cancer, and several viruses have evolved mechanisms to interfere with the activity of p53. In the study recently published in Cancer Research, CRISPR gene editing was found to give survival advantages to cells with inactivating mutations in the p53 gene, as well as in genes part of a CRISPR-p53 interactome. The enrichment of the potentially cancerous cells was due to the survival advantage compared to cells with a fully functional p53 pathway. By studying the biology of p53 in the context of CRISPR-induced DNA damage, the researchers additionally identified several strategies to enable safer CRISPR use. In follow-up studies Fredrik Wermeling and his research team plan to explore those strategies in more clinic-centered tests.
The study was conducted in collaboration with David P. Lane’s group (MTC) and financed by the Swedish Research Council, the Swedish Cancer Society, Karolinska Institutet, the Magnus Bergvall Foundation, the China Scholarship Council, and the Nanyang Technological University-Karolinska Institutet Joint PhD Program.
Read more in Karolinska Institutet’s press release.
“CRISPR/Cas9-induced DNA damage enriches for mutations in a p53-linked interactome: implications for CRISPR-based therapies”, Long Jiang, Katrine Ingelshed, Yunbing Shen, Sanjaykumar V. Boddul, Vaishnavi Srinivasan Iyer, Zsolt Kasza, Saikiran Sedimbi, David P. Lane, and Fredrik Wermeling. Cancer Research, 18 November 2021, doi:10.1158/0008-5472.CAN-21-1692.
Åsa Wheelock, Team Leader at CMM, has received SEK 3 million from the Swedish Research Council within the category of postcovid research. The awarded project led by Åsa, aims at developing a home monitoring system to facilitate continuous follow-up of long-COVID patients.
During the pandemic, a large group of severely affected individuals has emerged, with late onset persistent disease. While those requiring hospital care are largely elderly or multi-morbid individuals, the majority of long-COVID patients are formerly young, healthy individuals who due to mild initial symptoms generally did not seek hospital care. It is important to follow-up and understand the disease of this group of patients.
The project, titled ”Home monitoring and molecular phenotyping of patients with long-COVID for sub-grouping and follow-up of efficacy of interventions” aims at home monitoring the daily fluctuations in symptoms, activity and physiological parameters of the patients. This will help to identify sub-groups of the disease, with specific emphasis on those with lung involvement. The molecular phenotyping of the patients will be done in lung samples collected with bronchoscopy, and from particles in exhaled air. To evaluate the molecular biomarkers, the researchers will use a systems medicine workflow. With the help of the fully developed system, Åsa Wheelock and her colleagues plan to evaluate the effectiveness of various forms of treatment of long-COVID.
Low Levels of MicroRNA-210 in Red Blood Cells Causes
Blood Vessel Injury in Type 2 Diabetes Patients
Zhichao Zhou and John Pernow. Private photos.
Patients with type 2 diabetes develop damage to the blood vessels over time, which in turn increases the risk for blood cloths and complications such as heart attack and stroke. The mechanisms behind the vascular injury are however unknown. Associate Professor Zhichao Zhou and Professor John Pernow (CMM Group Leader) have, together with colleagues from CMM and Karolinska Institutet, published a paper in the journal Diabetes, showing that the effect is caused by low levels of the molecule microRNA-210 in red blood cells of type 2 diabetes patients and mice.
The researchers analyzed molecular changes in red blood cells from 36 patients with type 2 diabetes and from 32 healthy subjects, as well as in red blood cells from mice. They found that levels of the small molecule microRNA-210 were significantly reduced in blood cells from type 2 diabetes patients and diabetic mice. The reduction in microRNA-210 caused alterations in specific vascular protein levels, and impaired blood vessel endothelial cell function. Using a laboratory experimental setup, the researchers were able to restore dysfunctional blood vessel walls to normal by increasing the microRNA-210 levels in diabetic human red blood cells.
The results of this study may open up for new therapies targeted at increasing red blood cell microRNA-210 levels in type 2 diabetes patients.
Read more: Karolinska Institutet's press release
Published: 2021-10-29, updated 2021-11-25
CMM Researchers Awarded Swedish Research Council Grants
Researchers from CMM have been awarded this years’ grants from the Swedish Research Council. The grant decision was announced on Thursday the 28th of October.
The following CMM researchers were awarded the 2021 project grants:
Robert Harris receives SEK 9 800 000 in project grant for the project “Nya immunterapier för neurodegenerativa sjukdomar”.
Marie Wahren-Herlenius receives SEK 9 800 000 in project grant for the project "Molekylär patogenes vid kongenitalt hjärtblock".
Taras Kreslavskiy receives SEK 5 200 000 in project grant for the project “Kartläggning av dynamiken i minnes B-cell- och plasmacellsdifferentiering”.
Ann Nordgren receives SEK 5 200 000 in project grant for the project “Medfödda genetiska faktorers betydelse för barncancer”.
Fredrik Wermeling receives SEK 5 200 000 in project grant for the project “Studier av neutrofila granulocyter vid autoimmun ledinflammation”.
Eduardo Villablanca receives SEK 5 200 000 in project grant for the project “Bestämning av den cellulära och molekylära arkitekturen av tarmregeneration efter akut inflammation.”
Helena Erlandsson Harris receives SEK 4 800 000 in project grant for the project “Inflammation, destruktion, smärta och neuroinflammation vid juvenil artrit, med ett särskilt fokus på alarminet HMGB1”.
Alexander Espinosa receives SEK 4 800 000 in project grant for the project “En ny humaniserad musmodell för att kartlägga IL8:s roll i cancer och immunterapi”.
Anna Färnert receives SEK 4 800 000 in project grant for the project “Hur blir och förblir man immun mot malaria”.
Ulf Hedin receives SEK 4 800 000 in project grant for the project “Instabil ateroskleros: från patient till molekyl till patient”.
Lara Kular receives SEK 4 800 000 in project grant for the project “Epigenetik av lung-hjärnaxeln vid multipel skleros: att reda ut effekterna av rökning på sjukdomspatogenes och progression”.
Kristina Broliden receives SEK 3 600 000 in project grant for the project “Identifiering av molekylära mekanismer för känslighet mot mukosala virusinfektioner”.
Sebastian Lewandowski receives SEK 2 400 000 in project grant for the project “Terapeutisk hämning av perivaskulär fibroblastaktivitet i ALS-modeller”.
Pontus Naucler receives SEK 2 400 000 in project grant for the project “Datadriven precisionsmedicin för ökad patientsäkerhet”.
Ola Nilsson receives SEK 2 400 000 in project grant for the project “Oklara tillväxt och skelettsjukdomar hos barn – från klinik till molekylära mekanismer”.
Read Swedish Research Council decision here.
Read Karolinska Institutet press release here.
Per Svenningsson receives 1.86 million US dollar for studies on Parkinson’s disease
Per Svenningsson, Group Leader at CMM, has received a grant from About the Aligning Science Across Parkinson’s (ASAP) initiative, consisting of approximately 1.86 million US dollar for three years.
The purpose is to study how abnormal protein aggregates may spread from the gut to the brain to drive the early stages of Parkinson’s disease.
The grant is part of a project led by Project Director, Dr. Kaplitt, professor of neurological surgery, at Weill Cornell Medicine (US).
Read more in the Karolinska Institutet press release here.
Per Svenningsson. Photo: Ulf Sirborn.
New Clues Linking Obesity and Type 2 Diabetes
Photo: Karolinska Institutet
The CMM Team Leader Carolina Hagberg, from the Department of Medicine, Solna, is the joint first author of a recent publication in Nature Medicine titled “Obesity and hyperinsulinemia drive adipocytes to activate a cell cycle program and senesce”. Qian Li is the other joint first author and the study was led by Kirsty Spaldling from the Department of Cell and Molecular Biology, Karolinska Institutet.
Obesity is considered an important risk factor for many chronic diseases, including diabetes, cardiovascular disease and cancer. The expansion of fat tissue (adipose tissue) in obesity is due to an increase in both fat cell progenitor maturation (differentiation) and mature fat cell size, with the latter dominating in human obesity. Fat cells, also called adipocytes, however, were previously thought to be unable to divide or enter cell cycle, and many conclusions about their behaviour have been based on this belief.
This is normal for many types of fully differentiated cells like adipocytes. In contrast, cells that retain their capacity to proliferate can upon the right ques enter the cell cycle, and following a series of events it grows and eventually divides. Before division, cells must first double their genetic material via replication in preparation for cell division.
“In the current study, we demonstrate that freshly isolated, mature human adipocytes unexpectedly displayed a gene and protein signature indicative of an active cell cycle program, expressing cell cycle markers such as KI67 and cyclins”, Carolina Hagberg explains.
“Adipocytes, however, do not seem to divide, rather they undergo an endoreplicative cell cycle, passing through the interphase without dividing, and thereby becoming polyploid, i.e. having more than the normal two copies of DNA.” This is in fact a more common practice then commonly known, and among other hepatocytes, megakaryocytes and trophoblasts (a cell type in the placenta) also undergo endoreplication without cell division.
For this study, the authors analyzed adipose tissue from 63 non-obese individuals (BMI under 30) who underwent surgery for umbilical hernia or cholecysectomy for gallstone disease, as well as 196 overweight individuals who underwent bariatric surgery for obesity.
It is well known that obesity is associated with a highly increased risk for insulin resistance, and insulin is necessary to regulate energy, glucose, for the body's cells. A persistent failure of the body’s cells to respond to insulin leads to the development of type 2 diabetes. High insulin levels have also been proposed to have direct pathological effects on tissues. In the study presented in Nature Medicine the researchers investigate the relationship between high insulin levels, obesity and the active cell cycle in adipocytes.
“Adipocyte cell cycle progression associates with patient obesity and hyperinsulinemia, and we could identify a concomitant increase in cell size, nuclear size and nuclear DNA content in freshly isolated fat cells,” says Carolina Hagberg. “In vitro, insulin stimulation was able to induce adipocyte DNA replication, measured via EdU incorporation and the doubling of adipocyte DNA content by FACS. We also show that insulin can act as a mitogen and stimulate AKT-phosphorylation in adipocytes independent of patient insulin resistance.”
In obese individuals, the adipose tissue shows signs of inflammation, but the molecular mechanism has been debated. “We found that, in contrast to normal fluctuations in insulin levels, chronic hyperinsulinemia in vitro or in patients, was associated with a subsequent cell cycle exit, leading to a premature senescent transcriptomic and pro-inflammatory secretory profile in adipocytes. This is important as premature senescence is rapidly becoming recognized as an important mediator of stress-induced tissue dysfunction, and has been implicated in the pathogenesis of obesity and type 2 diabetes but never shown to occur in mature adipocytes. By demonstrating that adipocytes can activate a cell cycle program we define the mechanism whereby mature human adipocytes senesce and demonstrate that by targeting the adipocyte cell cycle program using metformin, a common drug for treatment of type-2 diabetes, it is possible to impact adipocyte senescence and obesity-associated adipose tissue inflammation.”
"The results are important for understanding basal fat cell biology and the pathological changes to fat tissue function that occur during obesity and insulin resistance", says Carolina Hagberg, shared first author on the publication.
Qian Li*, Carolina E. Hagberg*, Helena Silva Cascales, Shuai Lang, Mervi T. Hyvönen,
Firoozeh Salehzadeh, Ping Chen, Ida Alexandersson, Eleni Terezaki, Matthew J. Harms,
Maria Kutschke2,7, Nahida Arifen2, Niels Krämer1, Myriam Aouadi 2,5, Carole Knibbe8,
Jeremie Boucher, Anders Thorell and Kirsty L. Spalding. Obesity and hyperinsulinemia drive adipocytes to activate a cell cycle program and senesce. Nature Medicine, (2021) Oct 4, online ahead of print.
*Shared first authors
Link to Karolinska Institutet press release here.
Vinnova Funding to Precision Medicine in Rheumatoid Arthritis
Photo: Karolinska Institutet
Vinnova, Sweden’s innovation agency, recently funded eleven innovation environments in
precision medicine across the country. Professor Per-Johan Jakobsson, Group Leader at CMM, is the project leader and contact person for one of the three funded environments at Karolinska Institutet.
The project is called “Prevention and early therapy of rheumatoid arthritis using precision medicine”. The partners are Karolinska Institutet, Region Stockholm (where Karolinska Universitetssjukhuset and Centrum för Reumatologi are involved), Thermo Fisher Scientific, Elsa Science and Uppsala University. At Karolinska Institutet Per-Johan Jakobsson is the principal investigator for the project, with support from Lars Klareskog and Dr Martina Johannesson who is the project coordinator. They will receive SEK 20 million for 2.5 years that will be distributed between the different partners. CMM News met Per-Johan through Zoom for a short interview.
Where are we at today when it comes to the use of precision medicine in diagnostics, treatment and prevention of rheumatoid arthritis (RA)?
“We are at the beginning of the new era. We can identify individuals at high risk of developing rheumatoid arthritis (RA), using information such as serology (mainly identification of antibodies through blood samples), environmental risks like smoking, certain musculoskeletal symptoms and genetics. In our risk cohort (a group of individuals who are at very high risk of developing disease) close to 40% of the included individuals develop RA within 2 years. Now, with this project, we are going one step further and we actually like to use the term “precision prevention”. Recent data show that treatment of high-risk individuals with the T-cell inhibiting antibody Abatacept (commonly used treatment for moderate to severe RA) delayed and potentially prevented the development of RA in those individuals (Rech J et al., 2021, ACRabstracts.org). With data and knowledge gathered so far, there is thus a promising future for precision prevention medicine in RA.”
What is the plan for “Prevention and early therapy of rheumatoid arthritis using precision medicine” with the funding from Vinnova?
“Our RA research is already an innovation environment where we integrate quality registers, clinical as well as molecular data. The project that Vinnova has invested in is a natural continuation for us. We will use a web-based screening test “Rheumatic?” and an application for self-monitoring under development by one of the project partners, the e-health company Elsa Science. If the answers in “Rheumatic?” by a study participant matches with inflammation-like musculoskeletal symptoms, the persons will be asked to leave samples for genetic and serological analysis using diagnostic tests developed by another company-partner, Thermo Fisher Scientific. Then the person gets to see a doctor. Through the app for self-monitoring, the study participants will be able to track their symptoms and eventually share them with health-care. If the subsequent results identify the person to be at high risk for developing RA, the person will then be followed by the rheumatologists involved in the study and may also be included in clinical trials for prevention of RA. These tools will provide a coherent system that supports not only precision prevention of RA, but also enables rapid diagnosis and very early therapy for those who develop arthritis despite our prevention efforts. Today the average time from getting arthritis to receiving first treatment is 6 months. By applying the methods in this project, our goal, in addition to preventing the disease, is to be able to give the patients targeted treatment very soon after the first episode of arthritis. Our biggest goal of the project, however, is prevention.”
Large Investment in Precision Medicine
Richard Rosenquist Brandell
Photo: Rick Guidotti
Genomic Medicine Sweden (GMS) has received 220 million SEK for continued introduction of precision medicine into Swedish healthcare. Through Sweden’s innovation agency Vinnova, the Swedish government has invested SEK 96 million in GMS and Swedish regional health authorities and universities have added another SEK 124 million.
Richard Rosenquist Brandell, Group Leader at CMM, is the director of the Swedish national infrastructure Genomic Medicine Sweden (GMS), launched in 2018. The aim of GMS is to translate innovation in genomics into clinical practice and to implement a sustainable infrastructure for precision medicine in Sweden. Precision medicine a more personalised approach to healthcare, seeking to take into account individual variability in genes, environment, and lifestyle for each person. The individual patient can thus be more effectively diagnosed and treated with a reduced risk of short and long-term side-effects.
GMS has coordinated development and implementation of genomic technologies for clinical use in healthcare throughout Sweden. By performing broad gene panel and whole-genome sequencing these tests detect genetic variations in cancer and rare diseases, that in turn improve diagnostics, treatment and follow-up of the patients. In all Swedish regions with university healthcare, there are now established regional Genomic Medicine Centers (GMC). A national genomics platform has been developed to enable the analysis and sharing of huge amounts of data in a harmonized and secure way. The genomic platform is also an important resource for research and development of new, targeted drugs. During the upcoming phases, GMS will also focus the work on linking the refined genetic diagnostics to clinical studies.
The aim of the recent funding of GMS is to contribute to the ongoing introduction of precision medicine into healthcare, strengthening Swedish research and promoting new research and innovation collaborations between industry, healthcare and academia. The long-term goal is that eventually every individual in Sweden should have access to personalised and more precise diagnostics and treatment.
Albin Björk is Awarded the Swedish Rheumatological Association's Prize for Best Dissertation
Photo: Saga Rebecka Herlenius
The CMMer Albin Björk won the Swedish Rheumatological Association's (SRF) prize for best dissertation in 2021. His thesis, "Immunopathogenic mechanisms in primary Sjögren's syndrome", was focused on the characterization of exogenous and endogenous factors contributing to the immunopathology of the autoimmune disease primary Sjögren’s syndrome.
In the studies included in the thesis, Albin Björk and colleagues found that cigarette smoking does not appear to increase the risk of the disease, but that it may instead be a protective factor. A history of infections, however, was associated with a higher risk of development of Sjögren’s syndrome.
When studying lymphocytes from patients with Sjögren’s syndrome, they found aberrances in B cell gene expression patterns and dysregulation of the CXCR5/CXCL13 axis, which is important for lymphocyte migration.
In the thesis, Albin and his co-authors also found additional support for the hypothesis of infections as an environmental risk factor for systemic autoimmune disease. They did so by testing serological and cellular responses against viral antigens in patients with systemic autoimmune disease on no or mild treatment and found that the patients developed higher levels of virus-specific antibodies compared to healthy controls.
Albin Björk defended his thesis on April 23rd 2021 with Marie Wahren-Herlenius and Alexander Espinosa as supervisor and co-supervisor, respectively. Currently he is working as a physician at the Center for Rheumatology, which is a part of the Academic Specialist Center, and will continue his research on rheumatic diseases in parallel.
38 million SEK to Per Svenningsson’s Research on Parkinson’s Disease
Per Svenningsson, Group Leader at CMM, has received funding from Nordstjernan Holding AB and Axel Johnson Group consisting of 38 millions SEK for five years.
The purpose of the funding is to support Per Svenningsson’s research on basic mechanisms in the pathogenesis of Parkinson’s disease as well as the search for a future tailored treatment slow down disease progression.
Read more: Karolinska Institutet press release
Per Svenningsson. Photo: Ulf Sirborn.
CMM Researchers Find That Autoantibodies Are Possible Contributors in Causing Fibromyalgia
Emerson Krock. Photo: Private
Camilla Svensson. Photo: Ulf Sirborn
Emerson Krock, Postdoc, and Camilla Svensson, Professor and Group Leader, are co-first and last authors, respectively, of a recent publication in the Journal of Clinical Investigation, showing that autoantibodies are possible contributors to fibromyalgia, a disorder characterized by chronic widespread pain in muscles and bones.
Researchers at Karolinska Institutet, King’s College London and the University of Liverpool, UK conducted the study as a collaboration.
The results pave the way for new approaches to the treatment of fibromyalgia.
Read more: Karolinska Institutet press release
“Passive transfer of fibromyalgia symptoms from patients to mice,” *Andreas Goebel, *Emerson Krock, Clive Gentry, Mathilde R. Israel, Alexandra Jurczak, Carlos Morado Urbina, Katalin Sandor,Nisha Vastani, Margot Maurer, Ulku Cuhadar, Serena Sensi, Yuki Nomura, Joana Menezes, Azar Baharpoor, Louisa Brieskorn, Angelica Sandström, Jeanette Tour, Diana Kadetoff, Lisbet Haglund, Eva Kosek, Stuart Bevan, *Camilla I. Svenssonand *David A. Andersson, Journal of Clinical Investigation, online 1 July, 2021, doi: 10.1172/JCI144201 (*co-first/last authors)
Nine CMM Researchers Receive Funding from the Swedish Brain Foundation (Hjärnfonden) 2021
Photo: Unsplash, Robina Weermeijer
The Swedish Brain Foundation awards scholarships and grants to researchers and research groups to enable or enhance important basic and clinical research regarding the central nervous system.
This year the following researchers from CMM received grants:
(Name, Project Title, Research Area)
Faiez al Nimer, Detailed characterization of immune cells in multiple sclerosis, with focus on EBV, MS and other neuroinflammatory diseases
Eric Herlenius, Inflammation, neural networks, breathing difficulties and inspiration!, The brain of children and adolescents
Jan Hillert, Individualized treatment of multiple sclerosis for optimal long term outcome, MS and other neuroinflammatory diseases
Maja Jagodic, Epigenetics: New functional and therapeutic applications in multiple sclerosis, MS and other neuroinflammatory diseases
Ingrid Kockum, Genetic and protein biomarkers for risk and severity of multiple sclerosis, MS and other neuroinflammatory diseases
Ann Nordgren, Genetic mapping of children with neurological disabilities without diagnosis, The brain of children and adolescents
Tomas Olsson, Risk genes and pathogenesis in multiple sclerosis, MS and other neuroinflammatory diseases
Fredrik Piehl, Is myelin repair a realistic possibility in multiple sclerosis?, MS and other neuroinflammatory diseases
Per Svenningsson, GBA-Parkinson disease as a target for precision medicine, ALS, Parkinson’s disease, Huntington and other neurodegenerative diseases
CMMers Receive StratNeuro Funding
Maja Jagodic. Photo: Karolinska Institutet
Bob Harris. Photo: Karolinska Institutet
The strategic research area neuroscience at Karolinska Institutet (StratNeuro) has awarded a total of 18 MSEK to six Collaborative Neuroscience Research Projects. Each project is funded with 3 MSEK.
Maja Jagodic and Bob Harris, both CMM Group Leaders and Professors at the Department of Clinical Neuroscience, have received funding for one collaborative project each. The purpose of the funding is to establish new collaborations.
Maja Jagodic was the main applicant for a project titled: "Targeting neuroinflammation and neurodegeneration using artificial ligands". The co-applicant was John Löfblom, Department of Protein Science, The Royal Institute of Technology (KTH).
Bob Harris, applied for funding of the project titled: "Novel immunotherapy targeting myeloid cells for neurological diseases: Drug repurposing and nanoengineering" and his co-applicant was Björn Högberg, Department of Medical Biochemistry and Biophysics, Karolinska Institutet.
The strategic research areas are efforts by the Swedish government in certain selected areas that has been ongoing for more than ten years. Karolinska Institutet receives governmental strategic funding for six fields: stem cells, diabetes, neuroscience, cancer, epidemiology and health research.
StratNeuro has the mission to integrate clinical and basic research and to foster a new generation of leaders and scientists in translational neuroscience.
The external evaluator panel for the collaborative StratNeuro funding 2021 consisted of the following researchers:
David Engblom, Linköping University
Cecilia Lindberg, Lund University
Paolo Medini, Umeå University
Håkan Olausson, Linköping University
Åsa Petersén, Lund University
Mart Saarma, Helsinki University, Finland
Pontus Naucler Leads COVID-19 Vaccine Research Platform Funded by the Swedish Research Council
Pontus Naucler. Photo: Private
Pontus Naucler, researcher in Anna Färnert’s Group at CMM, will lead FASTER, a national COVID-19 vaccine research platform, one of six research environments awarded with a total of SEK 100 million from the Swedish Research Council.
FASTER will include register-based research and clinical trials as a basis for studying the immune response to the vaccines, as well as their safety and effectiveness.
This national platform will be a part of the large EU network called “VACCELERATE” which has the aim of evaluating ongoing and future vaccinations as well as making the process of clinical testing of vaccines faster in the future.
Strategic Research Funding for Germline Development Studies
Qiaolin Deng, Associate Professor and CMM Team Leader, is one of the six 2021 Junior Grant awardees in the Karolinska Institutet Strategic Research Area in Stem Cells and Regenerative Medicine. Qiaolin’s research team is interested in the developmental principles of the germline (the cells that pass on genetic information to the progeny, i.e. the egg and sperm) in health and disease and the title of the awarded project is ‘Revealing deleterious gene dosage effects on germline specification and testicular stem cell niche in Klinefelter syndrome by single-cell technology’. The project will be supported with 4 MSEK for 2 years.
Project picture: Genetic mouse models and in vitro hPG-CLCs differentiation of KS-iPSCs as tools to study global gene dosage effects.
Qiaolin Deng. Photo: Sanjiv Risal
Why did you choose germline development as your research niche and why is this research relevant?
“As a researcher, I have always been very inter-ested in the early development of the embryos, and the germline is the basis for this development. The development of the germline in an individual is in itself a process of continuous maturation that goes beyond puberty. There is intricate regulation at the molecular level involved in this process. Many cases of non-heritable variation involve germline epigenetics, and these are questions that have not been extensively studied before. The epigenetic regulation influences the development at all levels, also processes such as clonality and migration of the germ cells. Over the past few years new technological advances have made it possible to study these questions with a deeper resolution. When I chose my research focus, I also caught the moment of technology advancement.“
Klinefelter syndrome is caused by the presence of at least one additional X-chromosome in the male. There are few distinguishing features of the syndrome before puberty which makes early diagnosis difficult. However, after puberty, the testicular environment starts to degenerate and sperm can usually not be produced as a result. Thus, one of the main features of the syndrome is male infertility.
Can you briefly explain the aim of the project for which you were awarded the Junior Grant?
“In the present project we will use Klinefelter- derived iPS cells*. We want to study how the extra chromosome influences germline devel-opment. Persons with Klinefelter syndrome suffer from infertility but it is not because they lack the germ cells from the beginning. At the start of puberty, the germ cell pool is still there however, there is a “toxic” process in the testicular environment that starts at puberty in individuals with Klinefelter syndrome. We ask the question why the extra X chromosome does not do much harm initially. What is the impact of gene dosage and allelic gene expression on germ cell maturation? I always think about allelic expression since my postdoc projects were focused on that. Our preferred method in this project is single cell sequencing and at CMM we have a great core facility for that!”
With whom do you collaborate?
“Our main collaborators are Jan-Bernd Stukenborg at KBH, KI (his team works on fertility preservation) and at CMM we collaborate with Ning Xu Landén in the single sequencing studies of wound healing.”
What is the relevance of these studies from a patient/public health perspective?
“Klinefelter syndrome is estimated to occur as frequently as 1 in 600 births, thus contributing significantly to male infertility on a population level. Even though our research is very basic, I would say that one ambitious goal is to be able to find ways to save their fertility earlier. We strive to do that by understanding the molecular mechanisms of their germline development better.”
*The iPS cells (induced pluripotent stem cells) originate from skin biopsies from patients with Klinefelter syndrome. The fibroblasts are then re-programmed back to an embryonic state. This helps us to study human disease in a better way.