Integrative Molecular Phenotyping
INTEGRATIVE MOLECULAR
PHENOTYPING
WHEELOCK LABORATORY
DEPARTMENT OF MEDICAL
BIOCHEMISTRY AND BIOPHYSICS
WHEELOCK LABORATORY
DEPARTMENT OF MEDICAL
BIOCHEMISTRY AND BIOPHYSICS
WHEELOCK LABORATORY
DEPARTMENT OF MEDICAL
BIOCHEMISTRY AND BIOPHYSICS
WHEELOCK LABORATORY
DEPARTMENT OF MEDICAL
BIOCHEMISTRY AND BIOPHYSICS
WHEELOCK LABORATORY
DEPARTMENT OF MEDICAL
BIOCHEMISTRY AND BIOPHYSICS
WHEELOCK LABORATORY

KI News

Updated: 29 min 24 sec ago

A new method to select the right treatment for advanced prostate cancer

Thu, 02/05/2019 - 17:00
Researchers at Karolinska Institutet in Sweden have identified blood-based biomarkers that may determine which patients will benefit from continued hormonal therapy for advanced prostate cancer. The results are published in the journal JAMA Oncology. The researchers envision that this discovery may eventually result in a test that contributes to a more personalised treatment of the disease. Prostate cancer is the most common male cancer in Sweden. Approximately one in four will be diagnosed with or progress to metastatic prostate cancer. Initial systemic hormonal treatment works well for most patients with metastatic prostate cancer. But over time, the tumour develops resistance, resulting in metastatic castration-resistant prostate cancer (mCRPC). A continued hormonal treatment for the mCRPC condition with drugs such as Zytiga (abiraterone acetate) and Xtandi (enzalutamide) provides additional clinical benefit, however not all patients respond to these treatments. Thus, in order to avoid unnecessary side effects and pharmaceutical expenses, it is necessary to identify those men who will benefit from the medicines before treatment is started. This problem is now closer to being resolved through new results by researchers at Karolinska Institutet. “Our method can identify patients who are likely to have a poor outcome to these treatments and therefore should be offered other alternatives, if available,” says lead author Bram De Laere, postdoc at the Department of Medical Epidemiology and Biostatistics. Several biomarkers studied simultaneously The researchers’ methodology is based on an analysis of prognostic biomarkers, with known associations with therapy resistance, in the blood of patients with mCRPC. In prostate cancer, treatment resistance can be caused by changes in genes such as the androgen receptor (AR) and a gene called TP53. Most often, these resistance markers have been studied on a one by one basis, which has led to conflicting results between independent scientific publications. Instead, the researchers at Karolinska Institutet have developed a method for investigating all known resistance markers in AR and TP53 simultaneously. This was first done in a larger patient cohort, in a study published last year, where the researchers were able to show that individual markers in AR were not independently associated with outcome, when correcting for clinical characteristics, circulating tumour burden estimates and mutations in TP53. They now show that in the subset of the patients without TP53 mutations, the number of AR resistance markers can indeed provide independent prognostic information. “We see that the prognosis is poorest for men with three or more resistance markers in AR,” says Johan Lindberg, researcher at the Department of Medical Epidemiology and Biostatistics at Karolinska Institutet, and senior author of the study. “This suggests that patients with a normal TP53 gene, without or with a small number of AR resistance markers would benefit more from continued hormonal treatment with medicines such as Zytiga and Xtandi.” Consequently, the research group is introducing a new concept, the AR-burden – a measure of the number of treatment relevant changes in the AR gene. New clinical study initiated The researchers are now working on improving their method of measurement and validating it retrospectively in patients recruited during the recently initiated ProBio clinical trial (NCT03903835).  “Our goal is to create a test that can be used routinely in clinical practice, so that patients can receive more personalised treatment,” says Johan Lindberg.  The research was funded by the Belgian Foundation against Cancer, the Flemish Cancer Society, Cancer Research UK, the Radiumhemmet Research Funds, the Erling-Persson Family Foundation, the Swedish Research Council and the Cancer Foundation. The researchers have filed a patent application related to their findings.  Publication  “AR burden can identify poor responders to abiraterone or enzalutamide in TP53 wild-type metastatic castration-resistant prostate cancer". Bram De Laere, Prabhakar Rajan, Henrik Grönberg, Luc Dirix and Johan Lindberg, on behalf of The CORE-ARV-CTC and ProBIO Investigators. JAMA Oncology, online 2 May 2019, doi: 10.1001/jamaoncol.2019.0869.

More individual MSCA grants to KI

Tue, 30/04/2019 - 14:25
Marie Skłodowska-Curie Actions (MSCA) is the collective name for the European Commission's program aimed at researchers' career development. Karolinska Institutet has now been selected as host organisation for 6 new individual fellowships within the MSCA, with a total funding of SEK 12.6 million (EUR 1.2 million). The individual grants usually cover two years' salary and expenses for travel, research, education and such.  Individual researchers submit proposals for funding in liaison with a PI at their planned host organisation. The purpose of the individual MSCA programme is to offer young, successful researchers an opportunity for international exchange and development in their respective research areas. The following applications related to KI in the MSCA call for proposals from 2018 have been awarded: Project: Imaging tumor vessels as a marker for p53 mutation status in cancer (IMaP) Fellow: Pavitra Kannan PI: Sir David Lane, Department of Microbiology, Tumor and Cell Biology Project: Plasma cell heterogeneity and dynamics in patient tumors (PCinBC) Fellow: Camilla Engblom PI: Jonas Frisén, Department of Cell and Molecular Biology Project: The molecular diversity of regeneration in the zebrafish spinal cord (SCSC) Fellow: Kimberly Siletti PI: Sten Linnarsson, Department of Medical Biochemistry and Biophysics Project: Synthetic Natural Killer Cells for Immunotherapy (SYNKIT) Fellow: Quirin Hammer PI: Karl-Johan Malmberg, Department of Medicine Huddinge Project: Ribosomal frameshifts as a novel mechanism to control RNA turnover in stress (TERMINATOR) Fellow: Lilit Nersisyan PI: Vicente Pelechano, Department of Microbiology Tumor and Cell Biology  Project: Transcriptional characterization of human postnatal and adult neural progenitors and of the stem cell niches (HUMANE). Fellow: Ionut Dumitru. PI: Jonas Frisén, Department of Cell and Molecular Biology

Pregnant women with type 1 diabetes are at risk of giving birth prematurely

Tue, 23/04/2019 - 13:13
Pregnant women with type 1 diabetes are at increased risk of delivering their baby prematurely. The risk increases as blood sugar levels rise, however women who maintain the recommended levels also risk giving birth prematurely. These are the findings from researchers at Karolinska Institutet and the Sahlgrenska Academy in Sweden, published in Annals of Internal Medicine.  In a previous study published in The BMJ, the research group showed that pregnant women with type 1 diabetes were at an increased risk of having babies with heart defects. Now, a new study is published that shows how women with type 1 diabetes have an increased risk of giving birth prematurely. “High long-term blood sugar, so called HbA1c, during pregnancy is linked to an increased risk for complications, including preterm birth. The risk is highest amongst those with HbA1c levels above 8-9 per cent (approximately 60-70 mmol/mol), but even those who maintain their HbA1c (below 6.5 per cent, equivalent to <48 mmol/mol) are at an increased risk of giving birth prematurely,” explains Jonas F. Ludvigsson, Professor at the Department of Medical Epidemiology and Biostatistics at Karolinska Institutet and Senior Physician at the Department of Paediatrics at Örebro University Hospital. Risk increases as blood sugar levels rise The study involved linking the Swedish Medical Birth Register (MFR) to the Swedish National Diabetes Register (NDR) for the years 2003 to 2014. Researchers identified 2,474 infants born to women who recorded long-term glycosylated haemoglobin levels (HbA1c) during pregnancy. These were compared to 1.16 million infants born to women without diabetes.  Approximately 22 per cent of infants born to women with type 1 diabetes were born prematurely, which can be compared to below five per cent of infants born to women without type 1 diabetes. 37 per cent of women with type 1 diabetes and an HbA1c level above 9 per cent gave birth prematurely. Yet even 13 per cent of those with adhering to the current recommendations for blood sugar gave birth too early. “This is the first study large enough to demonstrate a clear relationship between different HbA1c levels and preterm birth. Our study has been conducted nationally and thus provides a result that can be applied to the average woman with type 1 diabetes,” says Jonas F. Ludvigsson. Increased risk of other complications The study also found an increased risk of these newborns being “large for gestational age”, being injured during childbirth, experiencing respiratory problems, low blood sugar and suffering from lack of oxygen (“asphyxia”) in addition to higher neonatal mortality rates amongst those exposed to high blood sugar during pregnancy. Also the risk of stillbirth was linked to HbA1c levels in pregnant women with type 1 diabetes. “Now, we want to examine the long-term outcome of these children.” says Jonas F. Ludvigsson. The study was conducted with support from the Swedish Diabetes Fund.  Publication “Maternal Glycemic Control in Type 1 Diabetes and the Risk for Preterm Birth: A Population-Based Cohort Study”. Jonas F. Ludvigsson, Martin Neovius, Jonas Söderling, Soffia Gudbjörnsdottir, Ann-Marie Svensson, Stefan Franzén, Olof Stephansson, Björn Pasternak. Annals of Internal Medicine, online 23 April 2019, doi: 10.7326/M18-1974

Detailed map of lung immune response in TB

Tue, 23/04/2019 - 13:07
The picture above shows a tuberculosis (TB) infection in a mouse lung, in which immune cells form a granuloma around the bacteria. The different symbols represent working copies of active genes, called messenger RNA, which are different in the granuloma centre in comparison to the surrounding cells. KI researchers Berit Carow and Martin Rottenberg and their colleagues at SciLifeLab, and the Boston University School of Medicine created this picture using a technique called in situ sequencing to simultaneously identify 34 immune markers and their localization in the lung. Generating this detailed map of an immune response in the lung, the researchers want to close a knowledge gap on what actually happens at the site of a TB infection.   The researchers defined central patterns for different granuloma types and which immune parameters are located close to bacteria. These findings may contribute to the understanding of a devastating disease and could speed up the design and evaluation of new vaccine candidates against TB.  The study has been published in the journal Nature Communications, and is funded by the Swedish Heart and Lung foundation, the Swedish Research Council, and the Swedish Institute for Internationalisation of Research (STINT), among others. Publication Spatial and temporal localization of immune transcripts defines hallmarks and diversity in the tuberculosis granuloma Berit Carow, Thomas Hauling, Xiaoyan Qian, Igor Kramnik, Mats Nilsson and Martin E Rottenberg Nature Communications, online 23 April 2019, doi: 10.1038/s41467-019-09816-4.

Rare disease gives new insight into regulatory T cell function

Tue, 23/04/2019 - 09:23
An international study led from Karolinska Institutet provides new insights into the regulatory T cells’ role in protecting against autoimmune disease. By mapping the targets of the immune system in patients with the rare disease IPEX, they were able to show that regulatory T cells control immunotolerance in the gut. The results are published in the Journal of Allergy and Clinical Immunology. Patients with the rare disease IPEX lack regulatory T cells and develop serious autoimmune diseases in which the immune system attacks the body’s own tissue, such as type 1 diabetes, enteritis and dermatitis. In studies of 17 patients with IPEX, a research group at Karolinska Institutet has now been able to define which self-molecules are targeted by the immune system when regulatory T cells are lacking. “Gut-related proteins were significantly over-represented amongst the target molecules we identified. We interpret this as regulatory T cells having a particularly important function in regulating the immune system in the gut,” says corresponding author Daniel Eriksson, researcher at the Department of Medicine, Solna, Karolinska Institutet. “Our findings fit well with clinical presentation of the disease, in which symptoms from the gut dominate.” The researchers took advantage of a method that makes it possible to examine the immune response against 9,000 proteins in parallel. “Our study is the first large-scale assay of how the immune system attacks the organs of IPEX patients,” says Dr Eriksson. Police of the immune system Regulatory T cells have been called the “police” of the immune system, as they can prevent other immune cells from attacking the body’s own tissues, discoveries that were awarded the 2017 Crafoord Prize. “We hope that our results will make it easier to diagnose patients with IPEX and monitor them during treatment,” says Nils Landegren, researcher at the same department and the study’s last author. “The next question is how understanding of regulatory T cell function can be used for developing new treatments for autoimmune diseases.” The study was conducted in close collaboration with numerous international researchers from Stanford University School of Medicine and elsewhere. It was financed by several bodies, including the Swedish Research Council, Region Stockholm, the Swedish Society for Medical Research (SSMF), the Crafoord foundation, and the Torsten and Ragnar Söderberg Foundation. Publication “The autoimmune targets in IPEX are dominated by gut epithelial proteins” Daniel Eriksson, Rosa Bacchetta, Hörður Ingi Gunnarsson, Alice Chan, Federica Barzaghi, Stephan Ehl, Åsa Hallgren, Frederic van Gool, Fabian Sardh, Christina Lundqvist, Saila M Laakso, Anders Rönnblom, Olov Ekwall, Outi Mäkitie, Sophie Bensing, Eystein S. Husebye, Mark Anderson, Olle Kämpe and Nils Landegren. Journal of Allergy and Clinical Immunology, online 23 April 2019.

Genetic analysis can provide better dosage of antipsychotic drugs

Tue, 16/04/2019 - 08:00
An initial gene analysis may yield better outcomes when patients are treated with the antipsychotic drugs risperidone and aripiprazole. A novel study shows how the activity of a specific enzyme, which metabolises the two drugs, affects the individual dose that should be given for optimal treatment. The study is published in The Lancet Psychiatry and has been conducted by researchers at Karolinska Institutet, in collaboration with the Diakonhjemmet Hospital in Oslo, Norway. The enzyme CYP2D6 metabolises many different drugs in the body, including the antipsychotic drugs risperidone and aripiprazole. The activity of the enzyme differs widely in the population due to variations in the CYP2D6 gene. In collaboration with Espen Molden’s group at the Diakonhjemmet Hospital in Oslo, researchers at Karolinska Institutet have studied how CYP2D6 gene variants affect the treatment result in 2,622 patients with psychosis or schizophrenia receiving either risperidone or aripiprazole. The results show that patients with low CYP2D6 enzyme activity were given the drugs at too high a dose, while patients with high enzyme activity were given the drugs at too low a dose. As a consequence, many of them switched medication. “In patients with too low or too high activity of the CYP2D6 enzyme, treatment failed to a larger extent, most likely due to side effects and lack of efficacy, respectively,” says Marin Jukic, researcher at the Department of Physiology and Pharmacology at Karolinska Institutet and the study's first author. Compare dose changes “Interestingly, we found that without knowing which gene variant the patient had, the psychiatrists had in the main altered the dose based on the clinical outcome, and this correlated with the anticipated effects of the patient's specific CYP2D6 genotype,” says Magnus Ingelman-Sundberg, Senior Professor at the same department at Karolinska Institutet and the study’s last author. “However, the dose changes were insufficient to avoid side effects or lack of effect. This is the first time we have been able to retrospectively compare dose changes during routine clinical treatment with the patient's specific genotype.” The researchers believe that genotyping, i.e. the identification of the specific gene variant the patient carries, before initiation of risperidone or aripiprazole treatment, would result in much more effective treatment for millions of patients globally. “Further studies are now needed to test other psychoactive drugs in order to generate additional scientific evidence to support new recommendations in psychiatry,” says Magnus Ingelman-Sundberg. “Psychiatrists also need more education in this area.” In the early 1990s, Magnus Ingelman-Sundberg's research group was the first in the world to show the presence of several variants of the CYP2D6 gene explaining why some people, the so-called ultra-rapid metabolisers, require higher drug doses than others. The research was funded by Horizon 2020 (the EU Research and Innovation Programme), the Swedish Research Council, the Brain Fund, and the South-Eastern Norway Regional Health Authority (Helse Sør-Øst RHF). Publication Effect of CYP2D6 genotype on exposure and efficacy of risperidone and aripiprazole: a retrospective, cohort study Marin Jukic, Robert L Smith, Tore Haslemo, Espen Molden, and Magnus Ingelman-Sundberg. The Lancet Psychiatry, online April 15, 2019, doi: 10.1016/S2215-0366(19)30088-4

Pathway contributing to fatty liver disease discovered

Thu, 11/04/2019 - 11:00
Researchers from Karolinska Institutet have found a protein that is a critical regulator in the development of fatty liver disease in mice, according to a study published in the journal Nature Communications. Analysis of liver biopsies of patients indicate that the identified mechanisms may help explain the diverse susceptibility of patients to develop more severe stages of fatty liver disease. Non-alcoholic fatty liver disease (NAFLD) is a condition where fat accumulates in the liver and has become the most common liver disease worldwide. While NAFLD shows few or no symptoms at initial stages, it is a potentially serious disease which can progress to an inflammatory state called steatohepatitis (NASH), which can lead to liver cirrhosis and cancer. Fatty liver disease can be managed by weight loss, but there is currently no approved medical treatment. Thus, a better understanding of how the disease develops is critical for its prevention and treatment. A critical regulator Researchers at Karolinska Institutet now show that a protein called GPS2 (G-protein pathway suppressor 2) is a critical regulator of lipid metabolic pathways in hepatocytes. Their results indicate that this mechanism may influence the development of the disease in both mice and in humans. The study is published in Nature Communications and was led by Assistant Professor Rongrong Fan and Professor Eckardt Treuter from the Department of Biosciences and Nutrition at Karolinska Institutet. To find out the function and targets of GSP2 in hepatocytes, the researchers generated knockout mice which lack GPS2 in hepatocytes but not in other cell types. The mice were exposed to a special diet that induces the disease state NASH, and analysed with the help of clinical researchers and pathologists from the Karolinska University Hospital and Karolinska Institutet in Huddinge. Surprising discovery ”We were surprised to find that GPS2 knockout mice were protected from developing disease”, says Ning Liang, PhD student at the Department of Biosciences and Nutrition and lead author of the study. The team then used sequencing-based techniques to shed light on the GPS2-dependent changes in gene expression. They identified a previously unknown role of GPS2 in specifically repressing a fatty acid receptor called PPARα. The partnership of GPS2 and PPARα was validated by an extensive physiological and histological analysis of the knockout mice.   In collaboration with clinical researchers from Belgium and France, the team analysed gene expression data from liver biopsies of patients diagnosed with different NAFLD stages. They found significant correlations of GPS2 levels with the expression of signature genes for the disease stage NASH. May have therapeutic relevance ”This suggests that the in mice discovered pathway might be relevant for humans as well,” says Rongrong Fan. “The identified mechanisms may help to explain the differential susceptibility of individual patients to develop more severe stages of fatty liver disease.” The researchers believe that this new hepatocyte pathway could be relevant for future therapeutic strategies, but emphasise the need to know more about additional GPS2 functions in other cell types of the liver.  ”We definitely should have a closer look at GPS2 pathways in the liver immune cells,” says Eckardt Treuter. The study was supported, amongst others, by grants from the Center for Innovative Medicine at Karolinska Institutet (CIMED, Region Stockholm), the Swedish Research Council, the Swedish Cancer Society, the Swedish Diabetes Foundation, the Swedish Diabetes Research & Wellned Foundation, the Novo Nordisk Foundation, the European Union FP7, the European Foundation for the Study of Diabetes and by a doctoral education grant (KID) from Karolinska Institutet. Publication ”Hepatocyte-specific loss of GPS2 in mice reduces non-alcoholic steatohepatitis via activation of PPARα” Ning Liang, Anastasius Damdimopoulos, Saioa Goñi, Zhiqiang Huang, Lise-Lotte Vedin, Tomas Jakobsson, Marco Giudici, Osman Ahmed, Matteo Pedrelli, Serena Barilla, Fawaz Alzaid, Arturo Mendoza, Tarja Schröder, Raoul Kuiper, Paolo Parini, Anthony Hollenberg, Philippe Lefebvre, Sven Francque, Luc Van Gaal,  Bart Staels, Nicolas Venteclef, Eckardt Treuter, and Rongrong Fan Nature Communications, online 11 April 2019, doi: 10.1038/s41467-019-09524-z

WHO Director-General Dr. Tedros Adhanom Ghebreyesus visited KI

Thu, 11/04/2019 - 10:26
WHO Director-General Dr. Tedros Adhanom Ghebreyesus, visited Karolinska Institutet and Campus Solna on Tuesday morning. In the presence of students, teachers, researchers and other KI employees, he discussed the education and research and KI's role for the WHO and for the opportunities of achieving the UN Global Goals for Sustainable Development. Basic research, knowledge development, education and communication about this are crucial keys to a more equitably distributed global health. The World Health Organization is currently in the process of strengthening its research-oriented knowledge development activities, and in this context, it is important to expand and cooperate with the research that is taking place around the world. Here, a recognized medical university like KI has a great and crucial part. It was one of the messages from the WHO Director-General Dr. Tedros' message he spoke in Biomedicum’s aula before Tuesday morning. The visit to KI took place at President Ole Petter Ottersen's invitation. For just under two hours, the Director-General got to know KI's activities and discuss various approaches and issues based on WHO's role, the UN's 17 global goals for sustainable development and what research and education can contribute. President Ole Petter Ottersen led a discussion on this subject with a panel of six KI researchers: Danuta Wasserman, Kristina Gemzell Danielsson, Emily Holmes, Marie Arsenian Henriksson, Johan von Schreeb and Knut Lönnroth – all in many ways very active in international health issues. In addition, KI students Tianqi Charles Zhang and Anne Flint were given the opportunity to post and ask questions directly to the Director-General. The morning at KI became intense and committed and there were many very interesting questions and discussions that were raised. As often as such occasions, the meeting could safely continue for several hours. The Ministry of Foreign affairs was next on the agenda for Dr. Tedros, Ole Petter Ottersen had to round off the seminar with some closing words. However, there is good hope that the WHO Director-General will visit KI again soon, he has provisionally accepted an invitation to a conference that is still at the planning stage. More on this later. For the WHO Director-General, the Stockholm visit continued with the conference Introduction WHO Partners Forum, which began on Tuesday afternoon and continued throughout Wednesday. Watch movie from the visit  

Mutation behind incurable disease mapped

Wed, 10/04/2019 - 12:52
Researchers at Karolinska Institutet have mapped the genetic mutation behind the incurable disease systemic mastocytosis. The results give insights into the origin of the disease, and the researchers also discovered a protein with potential to improve disease diagnosis. The results are published in the journal EBioMedicine. Systemic mastocytosis is an incurable disease characterised by accumulation of mast cells, a type of immune cell. Mild disease forms often cause severe allergy-like symptoms, whereas the advanced form, mast cell leukaemia, leads to complete organ failure and death. A common feature in most of the patients is a mutation in a gene called KIT. Researchers at Karolinska Institutet and Uppsala University have now traced which cells in the body that harbor the KIT mutation. Map of the mutation’s propagation Analysing more than 10,000 bone marrow cells allowed the researchers to generate a map of the mutation’s propagation. “The mutation could be traced all the way back to the blood stem cell in some patients,” says Joakim Dahlin, researcher at Karolinska Institutet’s Department of Medicine in Solna, and principal investigator of the study. “It was also obvious that the mutated mast cells outcompete the normal mast cells in the patients.” An incidental finding was also that mast cells in patients expressed extreme levels of a protein called CD45RA. “There was a large difference in protein levels between patients and the control group,” says Jennine Grootens, PhD student at the same department and first author of the study. “We are now investigating if we can use this protein to diagnose systemic mastocytosis.” Insights into the origin of the disease According to the researchers, the study provides deep insights into the origin of the disease. They also note that the presence of mutated blood stem cells could explain why the disease is difficult to cure. The study is a result of a collaborative effort between scientists and physicians at the Centers of Excellence in Mastocytosis in Stockholm and Uppsala. The research was funded with grants from the Swedish Research Council, the Swedish Cancer Society, the Stockholm Cancer Society, Magnus Bergvall’s Foundation, Tore Nilsson’s Foundation for Medical Research, Karolinska Institutet, and ALF-funding. Publication ”Single-cell analysis reveals the KIT D816V mutation in haematopoietic stem and progenitor cells in systemic mastocytosis” Jennine Grootens, Johanna S. Ungerstedt, Maria Ekoff, Elin Rönnberg, Monika Klimkowska, Rose-Marie Amini, Michel Arock, Stina Söderlund, Mattias Mattsson, Gunnar Nilsson and Joakim S. Dahlin EBioMedicine, online April 8, 2019, doi: 10.1016/j.ebiom.2019.03.089

A new way of finding compounds that prevent ageing

Tue, 09/04/2019 - 17:00
Researchers at KI have developed a new method for identifying compounds that prevent ageing. The method is based on a new way of determining age in cultured human cells and is reported in a study in the journal Cell Reports. Using the method, the researchers found a group of candidate substances that they predict to rejuvenate human cells, and that extend the lifespan and improve the health of the model organism C. elegans. Ageing is an inevitable process for all living organisms, characterised by their progressive functional decline at the molecular, cellular, and organismal level. This makes ageing a key determinant for human lifespan and a major risk factor for many so-called age-related diseases, such as Alzheimer's disease, diabetes, cardiovascular diseases and cancer. Preventing ageing by pharmaceutical means is therefore an attractive strategy to help people live healthier and longer lives. Finding substances that prevent ageing is challenging. Experiments on mammals are costly and time consuming. Using cultured human cells, it is possible to test a larger number of substances, but ageing is a complex process that is difficult to measure at the cellular level. A solution to this problem is now presented by researchers at Karolinska Institutet, in a study published in the journal Cell Reports. Biological age of cells “With our method, cell culture systems can be used to see how different substances affect the biological age of the cells,” says Christian Riedel, researcher at the Department of Biosciences and Nutrition who led the study. The researchers’ method is based on a new way interpreting cellular information, in particular the so-called transcriptome. The transcriptome represents the information about all the RNA present in a particular cell or tissue at a given time. Recently, it has been shown that the transcriptome of a human cell can be used to predict the age of the person from whom the cell came. The researchers used a large amount of transcriptome data from published sources to develop their method. With machine learning methods, so-called classifiers were built that can distinguish transcriptomes coming from “young” versus “old” donors. Found several substances The classifiers were used to analyse changes in the transcriptome of human cells, induced by over 1,300 different substances (data is openly available from the Connectivity Map, Broad Institute, USA). In this way, the researchers wanted to identify substances that could shift human transcriptomes to a “younger” age. The method identified several candidate substances, both those already known to extend the lifespan in different organisms and new candidate substances. The most interesting substances were further investigated in the worm C. elegans, which is a common model organism for studying ageing. Two substances that could prolong the life of the worms belong to a substance class not previously shown to have this ability; inhibitors that block a protein called heat shock protein 90 (Hsp90). These substances are Monorden and Tanespimycin. Beyond extending lifespan Mondoren also improved the health of these model animals. Innovative method “We have developed an innovative method for finding substances that can prevent aging and we identify Hsp90 inhibitors as new and promising candidate substances,” says Christian Riedel. “Hsp90 inhibitors are already being tested for other treatment purposes, and now further studies are needed to investigate their effect on human ageing.” The researchers show that the substances work by activating a protein called heat shock transcription factor 1 (Hsf-1). This is known to lead to the expression of so-called chaperone proteins that improve the animals’ ability to keep their proteins correctly folded and thus in a functional state throughout their lifetime. The research was supported through funding from the Swedish Research Council, the European Cooperation in Science and Technology and an ICMC project grant (ICMC is a joint research center between Karolinska Institutet and AstraZeneca). Publication ”Transcriptomics-based screening identifies pharmacological inhibition of Hsp90 as a means to defer aging” Georges E. Janssens, Xin-Xuan Lin, Lluís Millan-Ariño, Alan Kavšek, Ilke Sen, Renée I. Seinstra, Nicholas Stroustrup, Ellen A. A. Nollen, Christian G. Riedel Cell Reports, online 9 April 2019, doi: 10.1016/j.celrep.2019.03.044

New resource expands use of lab technique to visualise DNA in cells

Tue, 09/04/2019 - 11:00
Researchers at Karolinska Institutet present a publicly available resource that can accelerate the use of so-called FISH techniques for studying how the genome is spatially organised in the cell nucleus. The new platform, which enables more cost-effective analyses for both research and diagnostic labs, is described in the scientific journal Nature Communications. DNA fluorescence in situ hybridisation (FISH) is a powerful technique established in the 1980s that uses fluorescent probes to visualise specific DNA loci or entire chromosomes under a microscope. In the past three decades, DNA FISH has been widely used in both research and diagnostics. However, the use has been limited due to the challenging design and generation of large amounts of different probes (complementary DNA sequences conjugated with fluorescent dyes). Making probes that target multiple genomic loci of interest has been challenging for most labs, while commercially available probes are typically limited to a few loci and are very costly. To solve this problem, researchers at Karolinska Institutet and SciLifeLab established a platform named iFISH, that allows generation of hundreds of DNA FISH probes in parallel, in a simple and cost-effective way. Continuously expanding repository Using iFISH, they generated a large repository of more than 400 probes targeting all the human autosomes and chromosome X, which is now continuously expanding. In addition to probes, the researchers also created a database of optimally designed short sequences and a set of tools for designing DNA FISH probes, which can be freely accessed. “This is a timely resource that will enable many groups in the field of 3D genome architecture to have fast access to DNA FISH probes for virtually any locus in the human genome and freely use our state-of-the-art tools for designing probes,” says Magda Bienko, one of the two principal investigators who led the study and senior author of the paper. The repository will not stay limited to DNA FISH probes, but is now expanding to include probes for RNA FISH probes. “Our ambition is to go big and create a repository of probes targeting every single gene in the human and mouse genomes. This will be a precious resource for the ever-growing community of researchers that use single-molecule RNA FISH as a companion assay for single-cell RNA-seq or spatial transcriptomics,” says Nicola Crosetto, the other PI involved in the study. Open-source science “We believe this is a great example of open-source science that will facilitate the use of FISH technologies not only in research, but potentially also in diagnostic labs, particularly in disadvantaged countries where commercial FISH probes are very difficult to obtain,” concludes Magda Bienko. Magda Bienko and Nicola Crosetto are both assistant professors at Karolinska Institutet’s Department of Medical Biochemistry and Biophysics and SciLifeLab, where they lead two research groups working closely together on the broad topic of genome architecture and fragility. The research was supported by grants from Sony Imaging Products & Solutions Inc., the Swedish Research Council, the Knut and Alice Wallenberg Foundation, the Ming Wai Lau Centre for Reparative Medicine, the Ragnar Söderberg Foundation, the Swedish Cancer Society, Science for Life Laboratory, the Karolinska Institutet KID Funding Program, the Human Frontier Science Program, the European Research Council, and the Swedish Society for Medical Research (SSMF). Publication “iFISH is a publicly available resource enabling versatile DNA FISH to study genome architecture” Gelali E, Girelli G, Matsumoto M, Wernersson E, Custodio J, Mota A, Schweitzer M, Ferenc K, Li X, Mirzazadeh R, Agostini F, Schell JP, Lanner F, Crosetto N, Bienko M. Nature Communications, online 9 April 2019, doi: 10.1038/s41467-019-09616-w

Portrait of researchers and their innovations in a new brochure

Mon, 08/04/2019 - 12:58
A number of products and solutions have been developed out of research at Karolinska Institutet and contribute to great social benefit. To highlight this, KI Innovations AB has produced a brochure that presents twenty researchers and their innovations. ”The purpose is to illustrate the variety and breadth that exists amongst innovations from KI to inspire future innovators. The selection was a real challenge, it was gleaned from the unbelievable number of stories of value that are worthy of attention,” said Lilian Wikström, CEO of KI Innovations. The brochure was launched on Friday 29 March in connection with a seminar in Biomedicum on the theme of 20 years of innovation @Karolinska Institutet.  Three of the twenty innovators told of their experiences with combining their research to realise it in the form of a product or service to benefit patients. Mattias Nilsson from the company, Lexplore recounted his story about the early identification of children with dyslexia. Klas Wiman, co-founder of the pharmaceutical company, Aprea has been involved in developing a new cancer treatment based on p53. At that time, doctoral student Johan Lundberg was involved in developing a completely new medical device, namely a microcatheter with unique properties, which amongst other things makes it possible to deliver medication directly to organs that are hard to reach. The final presentation was from Berkeh Nasri, who has relatively recently taken the step to reach out with her idea. She is one of the founders of Mindmend, which is developing an e-health platform for psychological treatment. Today, the company is part of the KI Innovation business incubator, DRIVE. ”We actually have the opportunity to re-establish Sweden as a strong player in the global life sciences area. There are political ambitions at national, regional and municipal levels. Here, I see that KI has an important role to play and a responsibility,” said Ole Petter Ottersen, president of KI.

A sleep-deprived brain interprets impressions negatively

Mon, 08/04/2019 - 09:40
A sleepless night not only leaves us fatigued and distracted, it also makes us interpret things more negatively and makes us more likely to lose our temper. Moreover, people suffering from a pollen allergy are at a high risk of some form of sleep disruption from the outset. This according to a new doctoral thesis from Karolinska Institutet that takes a neuroimaging approach to sleep loss. “Ultimately, the results can help us understand how chronic sleep problems, sleepiness and tiredness contribute to psychiatric conditions, such as by increasing the risk of depression,” says Sandra Tamm, who has recently defended her doctoral thesis at the Department of Clinical Neuroscience. Sleep deprivation is already known to potentially affect the way we react to emotional impressions. For her thesis, Sandra Tamm and her colleagues used functional MRI and PET techniques to examine under experimental conditions three emotional functions: emotional contagion (i.e. our natural tendency to mimic other people’s emotions in our facial expressions); empathy for pain (i.e. how we react to other people’s pain); and emotional regulation (i.e. how good we are at consciously controlling our emotional reaction to emotional images). One study also examined low-grade inflammatory activity in the brain as a possible mechanism for non-specific symptoms such as sleepiness, fatigue and depression in people with severe seasonal allergy. A total of 117 participants were involved in the thesis’s constituent papers. A negativity bias The results of these various studies show that experimentally induced sleep loss leads to what the researchers call a negativity bias, which is to say a more negative interpretation of emotional stimuli, negative mood along with impaired emotional regulation. The ability to empathise with other people’s pain, however, was found to be less affected. So, while we might be grumpy in the morning, we still care if our partner happens to scold themselves when making the tea. Researchers also found that the participants with a pollen allergy had disrupted sleep both during and outside the pollen season, and that the amount of deep sleep they had was higher during the pollen season than at other times of the year. “Regrettably, we were unable to trace the underlying change mechanisms behind sleep deprivation-induced negativity bias by showing differences in the brain’s emotional system as measured by functional MRI,” says Sandra Tamm. “For people with a pollen allergy, we found signs of inflammation in their blood readings, but not in the brain.” The studies were financed with grants from numerous bodies, including the Stockholm Stress Center, the Bank of Sweden Tercentenary Foundation, the Swedish Brain Foundation, Karolinska Institutet and Region Stockholm. The principle supervisor was Professor Mats Lekander at the Department of Neuroscience, Karolinska Institutet, and the Stress Research Institute at Stockholm University. Sandra Tamm defended her thesis on 5 April 2019. Doctoral thesis A neuroimaging perspective on the emotional sleepy brain Sandra Tamm, Karolinska Institutet 2019, ISBN:  978-91-7831-373-0

KI's Biomedicum named Building of the Year!

Thu, 04/04/2019 - 15:21
Biomedicum on the Campus Solna has been namedthe Building of the Year. The motivation reads: “The winner of the 2019 Building of the Year award has succeeded with a project that was both complicated and extensive. The project team set their sights high as regards developing collaboration, work climate and a safety mindset – and succeeded. The project was also completed before time and at a vastly lower cost than budgeted.” A jury consisting of leading players in the construction sector selects the Building of the Year – a prestigious award that showcases examples of the best that the construction sector produced regarding quality, collaboration, finances and design over the previous year. The 20 projects nominated this year included KI’s new research building Biomedicum, which was officially opened last autumn. Commissioned by KI, the building was erected by Akademiska Hus with Skanska as main contractor. KI Facilities Director Rikard Becker was present when the award was presented in  an event held at the Cirkus in Stockholm on 26 March. “Incredibly gratifying and inspiring. Biomedicum is KI’s biggest ever construction project and this award is further proof that we made the right decisions. We are also very happy with the collaboration with Akademiska Hus and all the various contractors during the entire project and construction period,” Rickard Becker says. Flagship “We are naturally extremely pleased and proud to have received this award. Biomedicum is a flagship for experimental basic research on health and diseases – both in Sweden and around the world. Biomedicum gives KI the best possible prerequisites for successful world-class research and is designed to develop and facilitate creative encounters and collaboration and encounters across disciplinary borders and sectors and thereby initiate creativity and development. This is an important and long-term investment for KI and for Swedish research in general,” says President Ole Petter Ottersen in a statement. Akademiska Hus are naturally also very happy to have received the award: “We are extremely proud that Biomedicum has been named Building of the Year. Our objective was to create a unique meeting-point for cross-border research and collaborate. This award is acknowledgement that we have succeeded in our work process and through good collaboration with all parties involved generate the best balance between finances, time and quality,” says Hayar Gohary, project director at Akademiska Hus. As a point of interest, Biomedicum’s neighbour and KI’s auditorium Aula Medica won the same competition five years ago.

Students in focus at conference on global goals

Thu, 04/04/2019 - 13:25
How the UN’s Global Goals for Sustainable Development are to be integrated into higher education and the importance of engaging students in these efforts were the topics of lively debate at the recent conference “Rethinking Higher Education – Inspired by the Sustainable Development Goals”. The conference, which was held in Aula Medica on Saturday 30 March, attracted over 500 participants. It was organised by KI, with Gothenburg University, Chalmers University of Technology and the Royal Swedish Academy of Sciences as partners. Keynote speakers were Helen Clark, former head of the UNDP, Michael Marmot, head of the Institute of Health Equity in London, and KI president Ole Petter Ottersen. Also on the programme were group activities and panel debates. The participants were students, teachers, researchers, administrative personnel, decision-makers and representatives from the business and government sectors. The global goals concern us all Ole Petter Ottersen, Helen Clark and Michael Marmot opened the conference. “The global goals are specific and concern us all. We now need to integrate them into higher education by being ourselves specific, creative and collaborative,” said Ole Petter Ottersen. Universities have an important part to play in putting students on the right path towards creating a sustainable society. Action must be taken now, and all sectors of society must be involved. Current levels of environmental degradation pose a grave threat to global health.  ”We have been mortgaging the future and we can’t go on like this. To grow now and clean up later is not a sustainable approach. This will undermine the health gains that we have made in the last century,” said Helen Clark. A sustainable society is impossible without health equality, however, which is to say that everyone must have the same opportunities to keep themselves healthy and obtain the medical care they need. ”Getting rich is not the way to a better society. Health is the measure of a good society” One way to greater equity in health is to reduce poverty and degradation. Evidence-based policy and a spirit of social justice will take us far,” said Michael Marmot. So how do we go about integrating the sustainability goals into higher education? We must engage the students in the design of their education and cooperate more across disciplines and subject fields. These were two of the conclusions that came from the group activities, which addressed everything from health inequality to antibiotic resistance. Many answers were also given by the participants of the two panel debates.  “The sustainability goals should be addressed even at the teacher recruitment stage,” said Göran Finnveden, vice president for sustainable development at the Royal Institute of Technology. Teachers have an important part to play, inspiring students with their knowledge of sustainability and listening to their opinions and concerns. “The most important group we should be focusing on is the teachers. Apart from teaching, they should also be encouraging critical thinking, cross-disciplinary collaboration and a willingness for change in their students,” says Annika Östman Wernerson, academic vice president for education at Karolinska Institutet. “We must not only teach our students about the global goals but also encourage them to get involved in activities around sustainable development outside their studies. But to do this, teachers must also be receptive to the students and capture the knowledge they have about sustainability and the world they live in,” said Kerstin Sahlin, professor of business economics at Uppsala University and representative of the Royal Swedish Academy of Sciences. The conference Rethinking higher education – Inspired by the Sustainable Development Goals will be followed up with a conference in Gothenburg on 28 March 2020.   “It’s going to take a lot to surpass this excellent conference,” said Eva Wiberg.

Screening also prevents rare types of cervical cancer

Thu, 04/04/2019 - 07:00
Rare types of cervical cancer can be effectively prevented with screening, a comprehensive study of identified cases of rare cervical cancer over a ten-year period in Sweden concludes. The study was conducted by researchers at Karolinska Institutet and is published in The BMJ. The main aim of cervical screening is to discover and treat lesions that could otherwise become cancerous. There has been a nationwide cervical screening programme in Sweden since the 1960s. While earlier studies have shown that screening reduces the risk of the most common types of cervical cancer, little has been known about the link between screening and the risk of rarer types of the cancer. This has now been investigated by researchers at Karolinska Institutet in a study published in The BMJ, in which they investigated all Swedish cases of invasive cervical cancer from 2002 to 2011, identified using the National Swedish Cancer Registry. Of these over 4,200 cases, 338 were identified as not belonging to the most common types of cervical cancer (squamous epithelial cancer and adenocarcinoma). The researchers randomly selected 30 age-matched controls from the Swedish female population for each case and then calculated the risk of so-called adenosquamous cell carcinoma and other rare types of cervical cancer, in relation to being screened. Less likely The results show that women who had participated in the screening program on the last two occasions they were invited, were over 75 per cent and 65 per cent less likely to have developed adenosquamous and other rare types of cervical cancer, respectively, than women who had not  been screened. “This shows that rare types of cervical cancer can be effectively prevented through screening,” says co-author Professor Pär Sparén at the Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, guarantor of the study. The decrease in risk was greater for women who had been screened twice instead of just once in the past two screening periods. Leading cause High-risk human papillomavirus (HPV) is the leading cause of cervical cancer and was identified by the study in 70 per cent of the rare tumours in which such typing was possible. The most common type was HPV 18, followed by HPV 16. This suggests, according to the researchers, that most cases of rare cervical cancer can be prevented by HPV vaccination. The study reported no difference in the effect of screening between women with and without high-risk HPV in their tumours. The researchers note that continued monitoring of these rare types of cervical cancer is necessary when the screening of cervical cancer now is to be done by HPV testing instead of primary cytological analysis of cell samples. The research was financed by the Swedish Foundation for Strategic Research, the Swedish Research Council, the China Scholarship Council and the Centre for Research and Development at Uppsala University/Region Gävleborg. Co-author Joakim Dillner has received grants from Roche and Genomica for research on HPV tests. Publication “Cervical screening and risk of adenosquamous and rare types of invasive cervical carcinoma: a population-based nested case-control study”. Jiayao Lei, Bengt Andrae, Alexander Ploner, Camilla Lagheden, Carina Eklund, Sara Nordqvist Kleppe, Jiangrong Wang, Fang Fang, Joakim Dillner, K. Miriam Elfström and Pär Sparén. The BMJ, online 4 April 2019, doi: 10.1136/bmj.l1207.

New way to tackle mitochondrial disease

Wed, 03/04/2019 - 20:00
Diseases affecting mitochondria, the powerhouses of our cells, are often caused by mutations in the mitochondrial DNA. Symptoms of such mitochondrial diseases in mice can be ameliorated by increasing their levels of mitochondrial DNA, according to a study by researchers at Karolinska Institutet. The study is published in Science Advances and can, according to the researchers, lead to a novel treatment strategy for such mitochondrial diseases. Mitochondria are highly dynamic structures inside cells that provide cellular energy. Mitochondria contain their own DNA (mitochondrial DNA, mtDNA), and there are thousands of copies of mtDNA in a cell. Dysfunctional mitochondria can lead to serious diseases, which mostly affect tissues with high energy demands such as brain, skeletal muscle, and heart. To date, these diseases are still lacking effective treatments and clinical management remains mostly symptomatic. Mitochondrial disorders are often caused by mutations – genetic changes – in the mitochondrial DNA. But in most disease cases there are still some copies of normal mitochondrial DNA. Therefore, mutated and normal mitochondrial DNA co-exist in the same cell. The mutated mtDNA will only cause symptoms when the number of copies exceed a critical threshold. Towards new treatment strategies Researchers at Karolinska Institutet now show that it is possible to improve mitochondrial disease in mice by increasing the total number of mtDNA copies. The results are published in a study in the journal Science Advances. ”Our study demonstrates that the increase of the absolute levels of mtDNA in mice can improve mitochondrial function and improve symptoms of mitochondrial disease, even though the absolute amount of mutated mtDNA increase”, says Roberta Filograna, researcher at the Department of Medical Biochemistry and Biophysics at Karolinska Institutet and first author of the study. ”This suggests that approaches to increase mtDNA copy number could provide a novel therapeutic strategy for treatment of mitochondrial diseases.” Manipulated the levels of mtDNA The study was made using a mouse model with a pathogenic mtDNA mutation. The levels of mitochondrial DNA were manipulated by either increasing or decreasing the expression of a protein (TFAM), known to control the mitochondrial copy number. The researchers then looked at both the general condition of the mice and at molecular changes in different organs and at different disease stages, to see how they depended on the mtDNA levels. The study was made in collaboration with researchers at the Max Planck Institute for Biology of Ageing in Cologne in Germany. The research was funded with grants from the Max Planck Society, the Novo Nordisk Foundation, the Swedish Research Council and Knut and Alice Wallenberg Foundation. Publication ”Modulation of mtDNA copy number ameliorates the pathological consequences of a heteroplasmic mtDNA mutation in the mouse”. R. Filograna, C. Koolmeister, M. Upadhyay, A. Pajak, P. Clemente, R. Wibom, M. L. Simard, A. Wredenberg, C. Freyer, J. B. Stewart, and N. G. Larsson. Science Advances, online 3 April 2019.

Increased risk of substance abuse in people with treatment resistant depression

Tue, 02/04/2019 - 08:00
People suffering from treatment resistant depression are at a higher risk of developing substance use disorders than other patients with depression, reports a study by researchers at Karolinska Institutet in Sweden published in the journal Addiction. The risk is highest for sedatives or opiates, which includes the analgesic morphine and heroin. Major depressive disorder – clinical depression – is a common and frequently recurrent form of depression that has major consequences for both the individual patient and society as a whole. Antidepressants help many but far from all patients with clinical depression. According to a Swedish study from 2018, 13 per cent of specialist psychiatry patients had treatment resistant depression that did not respond to different antidepressant drug regimens. Researchers at Karolinska Institutet now show that people with treatment resistant depression are at a higher risk of developing substance use syndrome (formerly known as substance abuse or addiction) than other patients with clinical depression. The study was conducted in collaboration with pharmaceutical company Janssen Pharmaceuticals. Higher risk of substance use syndrome “We observed a generally higher risk of substance use syndrome both in people who have no history of substance use syndrome and in those who have had such problems,” says corresponding author Philip Brenner, doctor and researcher at the Department of Medicine, Karolinska Institutet (Solna). Amongst patients with no history of substance use syndrome, the risk of substance abuse – regardless of kind – was 51 per cent higher in treatment resistant patients in the year following the onset of antidepressive treatment, than it was for other patients with clinical depression. The risk was highest for opiates (analgesic opioids or heroin) and sedatives – almost two and three times as high respectively. In patients with a history of substance abuse, the increase in risk was 23 per cent, with an elevated risk in the sub-categories of sedatives and multiple substance use. The study was based on data from over 121,000 Swedish patients between the ages of 18 and 69 with a diagnosis of clinical depression, who were prescribed antidepressants at least once between 2006 and 2014. The data was gathered from national health and healthcare registries. Patients who had begun at least three treatments during one and the same disease episode were counted as treatment resistant. Patients with treatment resistant depression were then compared with the group as a whole as regards the risk of being diagnosed with substance use syndrome or prescribed drugs to counter it. Shed light on the consequences “Our results shed light on the consequences that people with insufficiently treated depression may be at higher risk for, and the importance of quickly identifying those who do not respond to antidepressants in order to provide the most intense therapy needed to avoid these consequences,” says Dr Brenner. Dr Brenner notes that as the study was observational it cannot provide answers as to the causes of the correlations found. The study was financed through the Söderström-Königska Foundation, the Fredrik and Ingrid Thuring Foundation and a collaboration between Karolinska Institutet and Janssen Pharmaceuticals. One of the researchers is in receipt of funding from the Swedish Research Council and two are employees of and shareholders in Janssen. Publication “Treatment resistant depression as risk factor for substance use disorders – a nationwide register-based cohort study”. Philip Brenner, Lena Brandt, Gang Li, Allitia DiBernardo, Robert Bodén and Johan Reutfors. Addiction, online 2 April 2019, doi: 10.1111/add.14596.

ERC grant for research on insulin-producing cells

Thu, 28/03/2019 - 12:05
The ERC Advanced Grant is one of the most prestigious funding programmes for research in Europe. Per-Olof Berggren, professor of experimental endocrinology at Karolinska Institutet, is now awarded this grant for the second time. It is the European Research Council that awards the ERC Advanced Grants, which are aimed at established and world-leading researchers who strive for ground breaking breakthroughs with the highest scientific quality. The researchers are being funded with up to EUR 2.5 million over a five-year period. Of the 2052 applicants in 2018, 222 have now been awarded the grant, of which 6 are from Swedish universities. The most successful country is the UK, with 47 awarded applicants. Per-Olof Berggren's research is about understanding how the insulin producing beta-cells function under normal conditions and why they cease to work in diabetes. One major challenge when it comes to research on beta-cell physiology and pathology is to translate information obtained from isolated cells in a laboratory test-tube into the conditions that exists in the living human body. Together with his colleagues, Per-Olof Berggren have established the anterior chamber of the eye (ACE) as a favorable environment for long term survival of islet grafts, and the cornea as a natural body window for non-invasive, longitudinal optical monitoring of islet function. ACE engrafted islets are able to maintain blood glucose homeostasis in diabetic animals, and the researchers are now starting up human clinical trials. Tissue engineering of native islets is technically difficult, and the researchers will therefore apply genetically engineered islet organoids. Regenerative medicine approach The objective in the current project, funded by the ERC, is to combine tissue engineering of islet cell organoids, transplantation to the ACE, synthetic biology, local pharmacological treatment strategies and the development of novel micro-electronic/micro-optical readout systems for islet cells. This regenerative medicine approach will follow the clinical trial programs and be transferred into the clinic to combat diabetes. “We hypothesize that genetically engineered islet organoids transplanted to the ACE are superior to native pancreatic islets to monitor and treat insulin-dependent diabetes”, comments Professor Berggren. “Our overall aim is to create a platform allowing monitoring and treatment of insulin-dependent diabetes in mice that can be transferred to large animals for validation.” Diabetes is one of the major and severe public health issues, spreading like an epidemic globally. Per-Olof Berggren was awarded the ERC Advanced Grant for the first time in 2013, and he has also received funding through the ERC Proof of Concept, a programme aimed at researchers who want to explore the commercial potential of their findings.

First disease caused by defective myoglobin discovered

Wed, 27/03/2019 - 11:00
Researchers at Karolinska Institutet have discovered the underlying cause of a hereditary muscle disease first characterised in a Swedish family in 1980. It proves to be the first identified disease caused by defective myoglobin, the protein that transports oxygen in muscle cells. The study is published in Nature Communications. Sarcoplasmic body myopathy (SBM) was first characterised in a large Swedish family by Edström et al in 1980, described as a novel late onset distal myopathy with characteristic sarcoplasmic inclusions. The disease manifests in adulthood with proximal weakness that progresses to involve distal muscles and causes respiratory and, in some patients, cardiac failure. All had the same mutation  Using modern techniques for genome analysis, researchers at Karolinska Institutet and SciLifeLab in Sweden, in collaboration with colleagues in Perth, Australia and Barcelona, Spain, report that they have found the cause of the disease. Six large unrelated European families were studied, including the first Swedish family. The researchers found that all affected individuals had the same mutation in the myoglobin gene, causing one amino acid replacement in the protein. The two closely related proteins myoglobin and haemoglobin transports oxygen in muscle cells and red blood cells, respectively, and were the first globular proteins structurally resolved by X-ray crystallography, an achievement resulting in a Nobel Prize in Chemistry in 1962. “Inherited defects of haemoglobin, haemoglobinopathies, resulting in anaemia are well known causes of human disease, but defects of its muscular counterpart, myoglobin, have been unknown until now,” says Martin Engvall, PhD student at the Department of Molecular Medicine and Surgery, Karolinska Institutet and shared first author of the new study. Acquires novel function In addition to its function in oxygen transport, myoglobin is implicated in the control of so-called redox pathways in skeletal and cardiac muscle cells, acting as scavenger of reactive oxygen species and nitric oxide metabolism. The mutated protein has altered binding of oxygen and heme, but the exact mechanisms by which the mutation causes muscle degeneration are not known. However, as the same mutation is found in all known families, the disease is likely caused by a novel function acquired by the mutant protein, rather than resulting from loss of its normal function. “This means that a potential therapeutic strategy would be to suppress expression of the mutant version of the gene using e.g. antisense technology, an approach that has recently been successful in other rare inherited diseases,” says Anna Wedell, professor at the Department of Molecular Medicine and Surgery, Karolinska Institutet and shared last author of the study. The Swedish part of the project was supported by the Swedish Research Council, Stockholm County Council, the Swedish Brain Foundation and the Knut and Alice Wallenberg Foundation. Publication “Myoglobinopathy is an adult-onset autosomal dominant myopathy with characteristic sarcoplasmic inclusions” Montse Olivé, Martin Engvall, Gianina Ravenscroft, Macarena Cabrera-Serrano, Hong Jiao, Carlo Augusto Bortolotti, Marcello Pignataro, Matteo Lambrughi,  Haibo Jiang, Alistair R. R. Forrest, Núria Benseny-Cases, Stefan Hofbauer, Christian Obinger, Gianantonio Battistuzzi, Marzia Bellei, Marco Borsari, Giulia Di Rocco, Josep Cladera, Kristina Lagerstedt-Robinson, Fengqing Xiang, Anna Wredenberg, Francesc Miralles, Juan José Baiges,  Edoardo Malfatti, Norma B Romero, Nathalie Streichenberger, Christophe Vial, Kristl G Claeys, Chiara SM Straathof, An Goris, Christoph Freyer, Martin Lammens, Guillaume Bassez, Juha Kere, Paula Clemente, Thomas Sejersen, Bjarne Udd, Noemí Vidal, Isidre Ferrer, Lars Edström, Anna Wedell, Nigel G Laing Nature Communications, online 27 March 2019, doi: 10.1038/s41467-019-09111-2

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