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.
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.
Qiaolin Deng. Photo: Sanjiv Risal
Project picture: Genetic mouse models and in vitro hPG-CLCs differentiation of KS-iPSCs as tools to study global gene dosage effects.
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.