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: 1 hour 42 min ago

Mice with access to soil have greater resistance to allergies

Tue, 07/08/2018 - 14:30
When mice live in cages with an added earthen floor, it increases their resistance towards allergic inflammations. Close contact with micro-organisms in the soil triggers anti-inflammatory genes in the mice and stimulates their gut microbiota. Researchers from Karolinska Institutet have performed the study, which was published in the Journal of Allergy and Clinical Immunology. Earlier research has shown that the past decade’s dramatic increase of chronic, inflammatory illnesses is due partly to a decrease in contact with natural micro-organisms. The researchers at Karolinska Institutet have now mapped the connection in more detail, by comparing mice that live in cages with an added earthen floor with those that live in clean cages with sawdust. "Our hypothesis was that the microbes in the soil help to develop our immune system, and that it is when we lose contact with these that inflammatory diseases and allergies increase. We observed that mice with soil in their cages had an improved expression of anti-inflammatory genes and more active regulatory T-cells in the small intestine," says Noora Ottman, a researcher at the Institute of Environmental Medicine at Karolinska Institutet. Milder inflamation with earthern floor  When the mice were subjected to allergic lung inflammation, the researchers noticed that the mice that lived with an earthen floor developed a considerably milder inflammation compared with the mice in the clean cages; something that can be explained by the fact that the higher degree of active regulatory T-cells in the mice suppresses the immune system's allergic reaction. "Even if both groups of mice developed allergic inflammations, the mice that lived with soil in their cages were able to handle their response better," says Noora Ottman. Allergic inflammation affects gut flora   The allergic inflammations in turn affected the composition of microbes in the intestinal tract of mice, which suggests a direct communication in both directions between the individual anatomical sections. If a change in the immune system and microbial composition occurs in one place, then the other is also affected. The results continue to build on the realisation that close contact with nature increases our physical and psychological well-being. "By allowing more greenery into our daily environment, such as in offices, schools and homes, we could positively affect our health. We now need to look closer at the microbes we have found; several of them are not very well characterised yet, as well as the soil in which they live. Another important aspect is to examine in more detail which mechanisms the microbes use in order to calibrate the immune system and increase immune tolerance, both locally and systematically," Noora Ottman explains. The study has been conducted by Karolinska Institutet and the University of Helsinki. The research was financed by the Jane & Aatos Erkko Foundation, The Swedish Cultural Foundation in Finland and the Academy of Finland. Publications ”Soil exposure modifies the gut microbiota and supports immune tolerance in a mouse model”. Noora Ottman, Lasse Ruokolainen, Alina Suomalainen, Hanna Sinkko, Piia Karisola, Jenni Lehtimäki, Maili Lehto, Ilkka Hanski, Harri Alenius and Nanna Fyhrquist. Journal of Allergy and Clinical Immunology, online 7 augusti 2018, doi:10.1016/j.jaci.2018.06.024.

A university for diversity at the EuroPride parade

Tue, 07/08/2018 - 10:59
Under the motto A university for diversity, KI and Medicinska Föreningen's HBTQ section Queerolinska participated for the fifth consecutive year in Stockholm's Pride parade. From the KI management, KI's Vice President Karin Dahlman-Wright participated, who has the overall responsibility for equal rights and opportunities at KI, Dean Anders Gustafsson and one or our heads of departments Mats Olsson. "The Pride parade is not just an opportunity to gather and stand for equal rights but is part of a continuous work throughout the year," says Karin Dahlman-Wright. The theme of this year's Pride parade was "Two cities, one country - for a united Europe, open to the world" as it was the EuroPride and this inspired the universities in the Stockholm area to participate together as Academic Pride. Photos: Erik Flyg

Red blood cells cause cardiovascular injury in type 2 diabetes

Mon, 06/08/2018 - 20:05
Harmful effects of substances secreted from red blood cells could explain the increased risk of cardiovascular diseases in patients with type 2 diabetes, the results of two new studies conducted at Karolinska Institutet in Sweden indicate. It is a known fact that patients with diabetes are at considerable risk of developing cardiovascular diseases caused by organ-vessel damage that leads to heart attack, stroke, kidney disease, eye damage etc. Patients with diabetes also have a worse prognosis following a heart attack. However, the underlying causes of cardiovascular injury in diabetes are largely unknown, and there is no specific treatment to prevent it. Research suggests that the red blood cells that transport oxygen to the body’s tissues are more inclined to adhere to the vessel wall in diabetes. Researchers at Karolinska Institutet have now studied how red blood cells change in type 2 diabetes and if they contribute to the cardiovascular injury occurring. Their results are presented in The Journal of the American College of Cardiology and JACC: Basic to Translational Science. “We found that healthy blood vessels exposed to red blood cells from patients with type 2 diabetes suffer damage to their innermost cell layers, the endothelial cells,” says Professor John Pernow at Karolinska Institutet’s Department of Medicine in Solna who led both the studies. “This phenomenon, which is called endothelial dysfunction, appears early on in the development of diabetes-related vessel injury and greatly reduces the ability of the vessels to dilate while aggravating the inflammation.” Using an experimental model, the team was also able to show that red blood cells from diabetic patients or diabetic mice impair heart function and cause greater myocardial injury in the event of a heart attack than red blood cells from healthy individuals. Their detailed analyses of rat and human blood vessels also demonstrate that the harmful effects are caused by elevated activity of the enzyme arginase, reduced production of the vasodilating molecule nitric oxide and increased formation of harmful oxygen-derived free radicals in the red blood cells. “We also found that treatment that targeted arginase or oxygen-derived free radicals normalised red blood cell function, which meant that their harmful effect on cardiovascular function could be prevented,” explains Professor Pernow. “Our hope is that this knowledge will give rise to new treatments, specifically targeted at red blood cells, that prevent vascular injury and protect the heart in the event of heart attack in patients with type 2 diabetes.” The studies were financed by the Swedish Research Council, the Swedish Heart and Lung Foundation, Stockholm County Council’s ALF project fund, the Torsten Söderberg Foundation, the Novo Nordisk Foundation and the Diabetes Wellness Research Foundation. Publications “Red blood cells from patients with type 2 diabetes induce endothelial dysfunction via arginase I”, Zhou Z, Mahdi A, Tratsiakovich Y, Zahorán S, Kövamees O, Nordin F, Gonzalez AEU, Alvarsson M, Östenson CG, Andersson DC, Hedin U, Hermesz E, Lundberg JO, Yang J, Pernow J. Journal of the American College of Cardiology, online Aug 6 2018, doi: xxx “Red blood cells in type 2 diabetes impair cardiac post-ischemic recovery through an arginase-dependent modulation of nitric oxide synthase and reactive oxygen species”, Yang J, Zheng X, Mahdi A, Zhou Z, Tratsiakovich Y, Jiao T, Kiss A, Kövamees O, Alvarsson M, Catrina CB, Lundberg JO, Brismar K, Pernow J. JACC: Basic to Translational Science, online 18 July 2018, doi: xxx

New potential target for treatment of diabetes

Tue, 24/07/2018 - 17:00
Researchers at Karolinska Institutet have discovered that one of the building blocks in the calcium channels in the pancreatic beta cells play an important role in regulating our blood glucose values. Treatments aimed at this building block may be a new way to combat diabetes the researchers suggest in an article in the scientific journal Cell Reports. Beta cells in the pancreas produce the hormone insulin, which regulates the blood glucose level in our bodies. In diabetes, the beta cells have lost part or all of their function. Calcium ions (Ca2+) act as an important signal for the release of insulin. When blood glucose increases, this causes the levels of Ca2+ in the beta cells to increase, triggering the release of insulin. Under normal conditions the Ca2+ signal displays a specific regular pattern when the cells are stimulated by glucose. When, on the other hand, the beta cells are not able to release normal amounts of insulin, as in diabetes, this pattern changes. Identified cause of reduced release of insulin The level of Ca2+ increases in the beta cell when a specific calcium channel, made up of several different building blocks, opens in the beta cell’s wall. Per-Olof Berggren’s research group at Karolinska Institutet has previously shown that one of the building blocks in the channel, the so-called β3 subunit, plays an important regulatory role. “In our new study, we are able to show that beta cells from diabetic mice have an increased amount of the β3 subunit and that this causes an altered Ca2+ pattern, a reduced release of insulin, and thereby impaired blood glucose regulation,” says Per-Olof Berggren, Professor at the Rolf Luft Research Centre for Diabetes and Endocrinology at the Department of Molecular Medicine and Surgery at Karolinska Institutet, who led the study. Better regulation of the blood glucose levels When the researchers reduced the amount of the β3 subunit in the beta cells in the diabetic mice, the Ca2+ signal normalised and thereby the release of insulin, resulting in better regulation of the blood glucose levels. They also saw that mice that totally lacked the β3 subunit demonstrated a better beta cell function and blood glucose regulation when they were given a diabetogenic diet. When the researchers tried transplanting beta cells without the β3 subunit into mice with diabetes, the blood glucose regulation of the mice improved. Experiments with human beta cells showed that the release of insulin deteriorates with increased amounts of the β3 subunit. “Our findings indicate that just this building block in the calcium channel can be a new target for treating diabetes,” says Per-Olof Berggren. The research was financed by the National Research Foundation of Korea (NRF), the Korea-Sweden Research Cooperation Programme, the Swedish Foundation for Strategic Research, the Swedish Diabetes Association, Karolinska Institutet’s Foundations and Funds, the Swedish Research Council, the Novo Nordisk Foundation, the Erling-Persson Family Foundation, the Strategic Research Programme in Diabetes at Karolinska Institutet, the European Research Council (ERC), the Knut and Alice Wallenberg Foundation, Skandia insurance company Ltd, the Diabetes and Wellness Foundation, the Berth von Kantzow Foundation, and the Stichting af Jochnick Foundation. Per-Olof Berggren is managing director of the bioetech company Biocrine AB, and co-authors Martin Köhler and Shao-Nian Yang are consultants at the company. No other corporate interests have been reported. Publication Blocking Ca2+-channel β3 subunit reverses diabetes Kayoung Lee, Jaeyoon Kim, Martin Köhler, Jia Yu, Yue Shi, Shao-Nian Yang, Sung Ho Ryu, and Per-Olof Berggren Cell Reports, online 24 July 2018

Three questions to Paulina Nowicka, coordinator of KI’s participation in Europe’s biggest research project on childhood obesity

Mon, 23/07/2018 - 11:23
STOP, the most comprehensive European project in the field of childhood obesity, has just begun. It involves 31 organisations from 16 countries. Karolinska Institutet is present as the sole Swedish partner. Paulina Nowicka, associate professor in paediatric science at the Department of Clinical Science, Intervention and Technology (CLINTEC), is in charge of the STOP project at Karolinska Institutet. STOP stands for Science and Technology in childhood Obesity Policy. Her research fields include childhood obesity, eating habits and effective early-year interventions. There is a trend towards more people being overweight from childhood onwards. This may result in over one third of adults in certain European countries being overweight by 2025. How will the STOP project turn this tide? “As it has proved very difficult to treat obesity in adults, teenagers and school-age children, we should offer early-year intervention,” comments Paulina Nowicka. “By meticulously evaluating the efficiency of measures in early childhood (up to 5 years old), this study will fill current gaps in what we know about evidence-based obesity treatment. Only a few studies have done this” she adds. The project will be investigating early signs of biological changes caused by behaviour that leads to obesity. A pilot study in Sweden, Spain and Romania is to test if, especially in areas with few resources, digital technology can help very young obese children and their families achieve sustainable improvements in body weight. The project will involve the food industry and other commercial bodies in preventive activities. In this connection, it will also investigate the opportunities for European governments to use, for example, taxes, nutritional value statements and marketing restrictions in respect of foodstuffs and drinks. The proportion of children with obesity has more than doubled in ten years. How is research tracing the causes of this? “The answer to how we are to tackle the childhood obesity epidemic lies in, for example: our ability to identify the obesogenic exposure that has the greatest impact; employing effective measures and incentives to counteract such exposure; and, improving children’s ability to deal with said exposure,” relates Paulina. Finding the causes of childhood obesity entails investigating behavioural changes in environments where there is a trend towards increased incidence of obesity (i.e. obesogenic environments). Descriptions of such environments include: building and transport patterns; access to foodstuffs; foodstuff prices and nutritional content; exposure to advertising; and, technologies used in children’s schoolwork and play (as also in adults’ work and leisure).  The STOP method sees external obesogenic influences as the ones that have most impact on children’s behaviour and their resultant health. Obesity is spreading rapidly amongst the children who are most exposed and vulnerable to these influences.  What shape has the collaboration between the parties in the research project taken and what is Karolinska Institutet’s role? "The STOP project is coordinated by a group at Imperial College Business School in London. Karolinska Institutet is one of the project’s partner organisations. These latter include: other universities; research bodies; public authorities; international organisations (WHO and OECD); civil society organisations that deal with issues involving health and children," says Paulina Nowicka.  European consortia promoting innovation in the foodstuffs and health sectors are also invloved. Karolinska Institutet will be leading the part of the project dealing with healthcare.  Above all else, the aim is to carry out systematic analyses to establish best practice in health and medical care. There is to be special focus on: initiatives such as recruitment, compliance and monitoring; and, socioeconomically disadvantaged households and immigrant groups. Working from an earlier study (the More and Less Study) that proved effective in reducing Body Mass Index (BMI) or the risk of obesity, we also want to generate new evidence about interventions.  STOP (Science and Technology in childhood Obesity Policy) is financed by the EU’s Horizon 2020 programme for “Healthy and safe foods and diets for all” (grant no. 774548).  In total, the project is receiving SEK 100,000 million.

Sleep disturbances linked to increased dementia risk

Tue, 17/07/2018 - 08:00
Researchers at Karolinska Institutet in Sweden report that sleep disturbances in midlife or in late life are associated with a higher risk for developing dementia in old age. The results are published in Alzheimer’s & Dementia: The Journal of the Alzheimer's Association. The results show that in midlife, when participants were in their 40s or 50s, insomnia was associated with a 24 per cent increased risk for dementia later in life. In late life, when participants were in their 60s or 70s, terminal insomnia (waking up too early) was associated with a doubled risk for later dementia, while long sleep duration (more than 9 hours of sleep per night) was associated with a fourfold increased risk for later dementia. The latter finding among this older population may be due to already existing (undiagnosed) dementia-related pathology, as dementia is often linked with sleep disturbances, including increased sleep duration. “Our findings have direct clinical implications, and combined with previous studies they indicate that different stages in the life course are sensitive to sleep disturbances, which in turn increase the risk for dementia. These sleep disturbances necessitate closer clinical attention and the implementation of tailored interventions,” says lead author Shireen Sindi, postdoctoral researcher at Karolinska Institutet’s Department of Neurobiology, Care Sciences and Society. Assessment of multiple sleep parametres The analysis included three population-based studies from Sweden and Finland with large sample sizes of men and women (more than 2 000), long follow-up durations, assessment of multiple sleep parameters, and standardised dementia diagnoses, adjusting for potential influencing factors such as levels of physical activity, genetics and sleep medications. Dr. Sindi works within the Nordic Brain Network team (led by Professor Miia Kivipelto at Karolinska Institutet), focusing on lifestyle interventions for dementia. They published the landmark Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (Finger) trial, which showed that a ‘multidomain intervention’ including diet, exercise, cognitive training and management of vascular risk factors has a positive impact on cognitive functioning. More recently, many countries are adapting the Finger model to their local settings (e.g. USA, China, Singapore, Canada), within the World-Wide Fingers platform. Interventions to improve sleep “It is promising that lifestyle changes can positively impact cognition. So far, there has been insufficient evidence regarding the role of sleep disturbances as a risk factor for dementia. Our current study indicates that future interventions to prevent dementia may benefit from also including interventions to improve sleep,” says Dr. Sindi. The team will now continue investigating the association between sleep disturbances and cognitive performance and dementia among different populations, including memory clinic patients. They will also examine the role of underlying biological mechanisms. The study was done in collaboration with researchers at Karolinska Institutet’s Aging Research Center (Sweden), Centre for Ageing and Health - University of Gothenburg (Sweden), the National Institute for Health and Welfare in Helsinki (Finland), the University of Eastern Finland (Finland), and Stockholm University - Stress Research Institute (Sweden). The research was financed by Alzheimerfonden, the Swedish Research Council, the Swedish Research Council for Health, Working Life and Welfare, Cimed (Karolinska Institutet), Le Fonds de recherche du Québec – Santé, Konung Gustaf V:s och Drottning Victorias Frimurarestiftelse, the Knut and Alice Wallenberg Foundation, the Swedish Brain Foundation, and Swedish Brain Power. Publication “Sleep disturbances and dementia risk: a multi-centre study”. Shireen Sindi, Ingemar Kåreholt, Lena Johansson, Johan Skoog, Linnea Sjöberg, Hui-Xin Wang, Boo Johansson, Laura Fratiglioni, Hilkka Soininen, Alina Solomon, Ingmar Skoog, and Miia Kivipelto. Alzheimer’s & Dementia: The Journal of the Alzheimer's Association, online 17 July 2018, doi: 10.1016/j.jalz.2018.05.012

KI hosted a discussion concerning world health in Almedalen

Thu, 12/07/2018 - 10:12
Only four out of ten Swedes are aware of the 17 global objectives that the UN set for sustainable development by 2030. An increase in awareness of these objectives and why they are necessary, is a first step in increasing commitment across parts of society. This was noted at KI's seminar in Almedalen. Do you know the world’s PIN code? It is 1114. The code was an educational device created by former KI professor Hans Rosling, with the idea being that the code would symbolise the geographical distribution of the world’s population. Approximately one billion people live in America, one billion in Europe, one billion in Africa and four billion in Asia: 1114. But the population is still increasing in Africa and Asia. By 2100, the pin code is expected to read as 1145 instead. The majority of these people will be between 15 and 74 years old.  Knowing what the world looks like is important for health improvement work. This was the opening message at Tuesday’s KI seminar in Almedalen. In some places, health has improved dramatically in the past few decades. For example, the average life span today is as high as 72 years. Many no longer die from infections such as HIV, malaria or pregnancy and birth-related ailments, and instead die from non-infectious diseases which affect people far later on in life. Although large parts of the world have improved considerably, others have changed very little. In countries with lower incomes, women still give birth to five children on average, and child and mother morality is very high. A vision for a better world “Without a clear map of the world we cannot work on these important issues,” said Tobias Alfvén, researcher for Public Health Sciences at KI. He and his colleague Helena Nordenstedt introduced the seminar, which had the title “Who takes responsibility for world health”. The aim was to discuss how the 17 objectives of the 2030 Agenda, a vision for a better world, as assumed in 2015 by the United Nations General Assembly, should be achieved. And the challenges facing the future naturally contain a range of clean health issues such as antibiotic resistance and new infections, among other problems.  “Climate change deems large areas inhabitable and war and nationalism leads to poverty and depletion of resources. Ten years ago, Syria was a middle-income country with good health and medical care accessible for the vast majority, however today it is a low-income country where child mortality is on the rise. Poverty is perhaps the most important objective to combat, if we are to progress further”, said Tobias Alfvén.   Unexpected alliances The final objective concerns working together in order to achieve the objectives. And it is going to be crucial, according to Ole Petter Ottersen, President of KI.  “According to the declaration, responsibility rests not only with the UN and governing politicians, but also with civil society, entrepreneurs and indeed everyone else. And this is what is so fantastic about the 2030 Agenda – that it gives us all responsibility for doing something. However giving everyone responsibility also risks resulting in nobody taking responsibility”, he said. In the subsequent panel discussion, participants were invited to discuss how unexpected alliances could increase opportunities for creating a sustainable world. Ingrid Petersson, Chairman of the government’s 2030 Agenda delegation, said that this requires both profound expertise, a horizontal thinking and a holistic approach. She wants to see increased partnership within higher education. “Humanities, social science, natural science, technology and medicine: United for a better world!” she said. Highlighting the economic aspects of health problems could be a way of getting politicians to engage in these issues according to Sofia Arkelsten, Moderate MP.  “It can be a matter of addressing finance ministers and prime ministers and also discussing the economic gains, instead of talking with health ministers”, she said.  Niklas Adalberth, founder of Klarna and the Norrsken foundation, said that economic growth is necessary in order to counteract poverty.  “Today, many entrepreneurs invest in the technology industry. However, it would be great if we could persuade more of these enthusiasts and risk takers to focus on technologies that can solve real societal problems, instead of developing a new image sharing app”, he said.  As an example, he mentioned Matsmart, an app that reduces food wastage. “By turning community entrepreneurs into tomorrow's rock stars, we are taking a step in the right direction”, he said.  Future markets The opportunity to create future markets could be a way of motivating companies to invest in long-term projects in low-income countries, which simultaneously leads to health benefits. One example was provided by Suzanne Håkansson, manager of social affairs at AstraZeneca. The company has worked in Kenya together with an American aid organisation which focuses on HIV and Aids and has set-up clinics for simultaneous blood pressure measurements and HIV tests.  She explained that many do not come to HIV testing because the disease is very stigmatised, but they do come to have their blood pressure measured, and you can take the opportunity to take an HIV test as well.   Stefan Swartling Peterson, Chief of Health at UNICEF, New York, also emphasised that these issues are not limited to the field of healthcare and medicine.  “Health is about food, water, homes and schools, and to a small, small extent about healthcare. We must spread this message”, he said. Create a movement Pernilla Bergström, Project Manager of the 2030 Agenda of the United Nations Association of Sweden agreed that the dissemination of knowledge is important.  “It does not matter how much we stand here and talk about responsibility and ownership if people are not aware that the global objectives exist. Today, approximately four out of ten Swedish people are aware of the objectives. We want to create a movement to increase awareness of the objectives, why they exist and why they are important, even for us in Sweden. But also to discuss the consequences of not working with the objectives, as well as what everybody can do within their organisations”, she said. When asked who their ideal partner would be for working on the global objectives, researchers, the food industry and the world’s private pension capital were all brought up. For KI’s President Ole Petter Ottersen, it is the students. “They are future leaders and it is our mission to make sure they are prepared”. The seminar’s moderator was Carl Johan Sundberg, Professor at the Department of Physiology and Pharmacology at Karolinska Institutet.

Combination of blood test and imaging improves detection of prostate cancer

Mon, 09/07/2018 - 12:00
New research from Karolinska Institutet shows that the blood test Stockholm3 together with magnetic resonance imaging and targeted prostate biopsies may lead to a significant decrease in the number of biopsy procedures and diagnoses of harmless disease. The study is published in European Urology. The study compares traditional detection of prostate cancer with a novel practice using a blood test, the Stockholm3 test, in combination with magnetic resonance imaging (MRI) and targeted prostate biopsies. More men get a correct diagnosis and treatment The results show that the suggested diagnostic strategy decreased the number of biopsy procedures with 38 per cent and the number of men getting a diagnose with harmless disease by 42 per cent. At the same time, the number of men diagnosed with potentially harmful cancer increased with 10 per cent. The study was performed in collaboration with Swedish (Stockholm) and Norwegian (Oslo, Tönsberg) urology practices and includes 532 men. ”We show that a combination of the Stockholm3 test and targeted prostate biopsies might increase the number of men with potentially dangerous disease that get a diagnosis. At the same time, we can spare many men from unnecessary prostate biopsies. This means that more men get a correct diagnosis and treatment, and that we can decrease unnecessary discomfort and risks, says Tobias Nordström, researcher at the Department of Medical Epidemiology and Biostatistics, Karolinska Institutet and urologist at Danderyd Hospital. Need for improved diagnosis In the European Union, prostate cancer is the most frequently diagnosed cancer among men, with around 365,000 new cases yearly and 77,000 men dying from prostate cancer. Current practice includes a so called PSA test and systematic prostate biopsies where 10-12 samples are taken from the prostate. The PSA test has been controversial because it only poorly differentiates between lethal and harmless prostate cancer. The Stockholm3 test is an alternative test method that combines five biomarkers, over 100 genetic markers and clinical data such as age, previous biopsies and family history of prostate cancer to better assess the risk of potentially harmful prostate cancer. “The current study confirms our previous findings showing the value of the Stockholm3 test as part of the diagnosis of prostate cancer. Studies of this type have been requested by the National Board of Health and Welfare in Sweden,” says Tobias Nordström. The research was funded by the Swedish Cancer Society, the Swedish Research Council, the Swedish Research Council for Health, Working Life and Welfare, The Strategic Research Programme in Cancer at Karolinska Instituet (StratCan), Karolinska Institutet och The Swedish e-Science Research Centre (SeRC). The Stockholm3 test was developed by researchers at Karolinska Institutet in collaboration with Thermo Fisher Scientific. Professor Henrik Grönberg, lead author of this study, has patent applications for the Stockholm3 test licensed to Thermo Fisher Scientific, and might receive royalties from sales related to these patents. Co-author Martin Eklund is named on some of these patent applications. Publication Prostate cancer diagnostics using a combination of the Stockholm3 blood-test and multiparametric magnetic resonance imaging.  Henrik Grönberg, Martin Eklund, Wolfgang Picker, Markus Aly, Fredrik Jäderling, Jan Adolfsson, Martin Landquist, Erik Skaaheim Haug, Peter Ström, Stefan Carlsson, Tobias Nordström. European Urology, online 9 july 2018.

Higher risk of heart defects in babies of mothers with type 1 diabetes

Thu, 05/07/2018 - 06:00
Pregnant women with type 1 diabetes run a higher risk of having babies with heart defects, especially women with high blood glucose levels during early pregnancy, a study from Karolinska Institutet and the Sahlgrenska Academy in Sweden published in The BMJ shows. It has long been known that patients with type 1 diabetes are at increased risk of complications. A new study now shows that pregnant women with type 1 diabetes are at a higher risk of having babies with heart defects. “This confirms previous findings that there is a higher risk of birth defects, primarily of the heart,” says Professor Jonas F. Ludvigsson at the Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, and consultant at the Paediatric Clinic at Örebro University Hospital. “The risk of birth defects is especially sensitive to factors during early pregnancy, and here blood glucose plays a vital part.” A clear correlation The study demonstrates a clear correlation between elevated levels of blood glucose (HbA1c) in the mother and the risk of heart defects in her baby. However, even those women who followed the current guidelines had a higher, albeit still small, risk of heart defects. The results show that 3.3 per cent of pregnant women with type 1 diabetes and blood glucose levels within the recommended span gave birth to a baby with a heart defect. The corresponding figure for women without diabetes was 1.5 per cent. Pregnant women with type 1 diabetes who had very high blood glucose levels (an HbA1c reading of 9.1 per cent or higher) were at much greater risk. “Here, the risk of the baby having a heart defect was as much as 10.1 per cent – or one in every ten babies,” says Professor Ludvigsson. “The reason why the risk of deformity can be linked to blood glucose levels in early pregnancy is that it is then that the fetus’s organs develop. Also, many women aren’t aware that they’re pregnant during the first few months.” This, he stresses, is why women must know about the dangers before trying to have children. Opportunity to influence the risk “There’s an opportunity here for women to influence the risk of their baby developing a heart defect by keeping their blood glucose levels low. Yet we as doctors also know that many pregnant women struggle valiantly to keep their blood glucose down, as it is no easy task. The potential benefit of intensified insulin treatment to reduce the risk of heart defects should also be weighed against possible risks with hypoglycaemia in the mother and foetus,” says Professor Ludvigsson. The study was done by cross-referencing the National Diabetes Register with the National Patient Register and the Medical Birth Registry, and comparing 2,458 living newborns of mothers with type 1 diabetes with 1,159,865 babies of mothers without diabetes. Since this is an observational study no definitive conclusions can be drawn regarding causality. The researchers are now planning to make further investigations in the field. The study was financed with grants from the Swedish Diabetes Association, the Strategic Research Area in Epidemiology (SfoEpi) at Karolinska Institutet, the Swedish Research Council and Stockholm County Council. Publication  “Periconceptional glycemic control in type 1 diabetes and the risk of major birth defects: population based cohort study in Sweden” Jonas F. Ludvigsson, Martin Neovius, Jonas Söderling, Soffia Gudbjörnsdottir, Ann-Marie Svensson, Stefan Franzén, Olof Stephansson, Björn Pasternak The BMJ, online 5 July 2018, doi: 10.1136/bmj.k2638

Solvents and smoking linked to increased risk of MS

Wed, 04/07/2018 - 06:00
People who carry genes that make them more susceptible to developing multiple sclerosis (MS) are at much greater risk of developing the disease if they have been exposed to paint, varnish and other solvents, according to a new study from Karolinska Institutet published in the journal Neurology. If they have also been smokers, the risk of developing MS is multiplied. The study shows that people who have been exposed to paint or other solvents are 50 per cent more likely to develop MS than people with no exposure. People with exposure to solvents who also carry certain gene variants that make them more susceptible to MS are ten times as likely to develop the disease as people with no solvent exposure who do not carry the MS genes. Different risk factors People with exposure to solvents who carry the MS genes and in addition to that have been smokers are as much as 30 times more likely to develop MS, compared to those who have never smoked or been exposed to solvents and who do not have the genetic risk factors. How these different factors interact to create a much greater risk than they do on their own is not yet known. ”It’s possible that exposure to solvents and smoking may both involve lung inflammation and irritation that leads to an immune reaction in the lungs,” says lead author Anna Karin Hedström at the Institute of Environmental Medicine and the Department of Clinical Neuroscience, Karolinska Institutet. “How this cocktail of MS genes, organic solvents and smoking contributes so significantly to MS risk warrants investigation,” comments Gabriele C. DeLuca, MD, PhD, of the University of Oxford in the United Kingdom, in an accompanying editorial. “In the meantime, avoiding cigarette smoke and unnecessary exposure to organic solvents, particularly in combination with each other, would seem reasonable lifestyle changes people can take to reduce the risk of MS, especially in people with a family history of the disease.” Study included 5,000 people The study included more than 2,000 people who had recently been diagnosed with MS in Sweden and almost 3,000 people of the same age and sex without MS. Blood tests were used to determine which human leukocyte antigen gene variants the participants had. They were also asked about previous exposure to organic solvents, painting products or varnish and whether they had ever been a smoker. One limitation of the study is that it is possible that the participants may not have remembered correctly. Moreover, since it is an observational study no definitive conclusions can be drawn regarding causality. The study was funded by the Swedish Research Council, Swedish Research Council for Health, Working Life and Welfare, Knut and Alice Wallenberg Foundation, AFA Insurance, Swedish Brain Foundation and Neuro Sweden. This news article is based on a press release from the American Academy of Neurology. Publication ”Organic solvents and MS susceptibility; interaction with MS risk HLA genes” Anna Karin Hedström, Ola Hössjer, Michail Katsoulis, Ingrid Kockum, Tomas Olsson, Lars Alfredsson. Neurology, online 3 July 2018, doi: 10.1212/WNL.0000000000005906

Molecular brake on human cell division prevents cancer

Thu, 28/06/2018 - 17:00
Researchers at Karolinska Institutet and the University of Sussex have discovered that the process of copying DNA generates a brake signal that stalls cell division. This molecular brake ensures that the cell has two complete copies of DNA before it divides and thus prevents DNA damage and cancer development. The study is published in the scientific journal Molecular Cell. One of biology’s great mysteries is how a single fertilised egg can generate millions of cells that together make up a human body, while simultaneously restricting growth to prevent lethal diseases such as cancer. This process is strictly regulated by our DNA, the genetic cookbook carried by each single cell in our body. Before a cell divides and generates two new daughter cells, it has to copy its DNA. How cells decide when to divide is a long-standing question in science. Now, an international collaboration between Karolinska Institutet, Sweden, and the University of Sussex, England, led to the discovery of a built-in molecular brake on human cell division. The researchers revealed that the process of copying DNA generates a brake signal that stalls cell proliferation. This mechanism ensures that the cell has two complete copies of DNA before it divides and that all cells in a human contain similar genomes. “By creating cells that cannot copy their DNA and by following protein activities over time in single cells, we found that DNA replication blocks the enzymes that trigger cell division. Immediately after DNA replication is completed, the machinery that starts cell division is activated. This fundamental mechanism contributes to determining when human cells will divide,” says Arne Lindqvist, senior researcher at the Department of Cell and Molecular Biology at Karolinska Institutet who led the study. The researchers also show that the molecular brake ensures that the amount of DNA damage is minimised. When the brake is not functional, the cell divides before it is ready resulting in large amounts of DNA damage. “Our study highlights the dangerous consequences of hasty cell division and provides important clues on how cells might gain DNA mutations that ultimately give rise to cancer,” says lead author Bennie Lemmens, postdoctoral researcher at the Department of Medical Biochemistry and Biophysics at Karolinska Institutet. The research was supported by the Wenner-Gren Foundation, the Swedish Research Council and the Swedish Cancer Society, among others. Publication “DNA replication determines timing of mitosis by restricting CDK1 and PLK1 activation” Bennie Lemmens, Nadia Hegarat, Karen Akopyan, Joan Sala-Gaston, Jiri Bartek, Helfrid Hochegger, Arne Lindqvist. Molecular Cell, online 28 June 2018, doi: 10.1016/j.molcel.2018.05.026

Seven researchers responsible for scientific misconduct in Macchiarini case

Mon, 25/06/2018 - 13:44
On 25 June, the President of Karolinska Institutet made the decision to find seven researchers responsible for scientific misconduct in research. The case concerns six articles published in the scientific journals The Lancet, Biomaterials, The Journal of Biomedical Materials Research and Thoracic Surgery Clinics. Paolo Macchiarini is one of the main authors of the articles. The research reported in the articles relates to the transplantation of synthetic tracheal prostheses and describes the clinical course of treatment of three patients who were transplanted at Karolinska University Hospital 2011–2013. According to the President's decision, an additional 31 authors are blameworthy for their contributions to the articles, however not responsible for scientific misconduct. Another five authors are cleared of blame and of responsibility for scientific misconduct. Karolinska Institutet is requesting that the six articles be retracted without undue delay. Today's decision was made following a new investigation of the six articles, and overturns the decision made on 28 August 2015 by the President at the time. The case was reopened in February 2016. The new investigation points to serious inaccuracies and misleading information in the reviewed articles. The articles contain fabricated and distorted descriptions of the patients’ conditions before and after the operations. Justification is lacking for treatment of the patients on the grounds of so-called vital indication (when a given treatment is the last resort for survival), and one misses reference to relevant animal experiments which must precede human studies that involve unproven methods. Furthermore, ethical approvals are lacking, as are appropriate informed consents. “This decision has been made after careful investigations in a case that has had major impact on Karolinska Institutet, on the scientific community at large, and on public confidence in medical research. In particular, the case has had tragic consequences for patients and their relatives, for which I am deeply sorry. Karolinska Institutet will now continue to implement the measures that are necessary to prevent something like this from happening again,” says Ole Petter Ottersen, President of Karolinska Institutet. One of the authors that was found responsible for misconduct was among those who blew the whistle on Macchiarini in 2014. “The investigation points to inaccuracies for which Paolo Macchiarini is ultimately responsible but for which several of the co-authors also bear responsibility. The four whistle blowers are to be commended for their action in this case that has contributed to the investigation. However, it is KI:s firm opinion that a whistle blower who has participated in a scientific study and also as author of a scientific article, despite reporting, cannot be freed from blame or absolved from responsibility”, says Ole Petter Ottersen. According to Chapter 1, § 16 of the Higher Education Ordinance, a university that becomes aware of suspected scientific misconduct at said institution is obliged to investigate. In the course of an ongoing investigation, the higher education institution may solicit the opinion of the Expert group for misconduct in research at the Central Ethical Review Board, CEPN. According to KI procedure, suspected scientific misconduct is to be reported to the president of the university, and the president shall initiate an investigation and make a decision in the case. The university where the research was conducted has an obligation to investigate suspected scientific misconduct even if all the involved researchers are not employed at or affiliated to that university. Today's decision differs from the report of the Expert group for misconduct in research at the Central Ethical Review Board, CEPN, who considers all authors responsible for scientific misconduct. Karolinska Institutet's investigation has examined the responsibility of each individual author (a total of 43 researchers). Only a few of the authors are currently employed at or affiliated to Karolinska Institutet. The decision made on 25 June 2018 relates to the following articles: - Tracheobronchial transplantation with a stem-cell-seeded bioartificial nanocomposite: a proof-of-concept study, Lancet 2011; 378(9808): 1997–2004, - Engineered whole organs and complex tissues, Lancet 2012; 379(9819): 943–952, - Verification of cell viability in bioengineered tissues and organs before clinical transplantation, Biomaterials 2013; 34(16): 4057–4067, - Are synthetic scaffolds suitable for the development of clinical tissue-engineered tubular organs? Journal of Biomedical Material Research 2014; 102(7): 2427–2447, - Airway transplantation, Thoracic Surgery Clinics 2014; 24(1): 97–106, - Biomechanical and biocompatibility characteristics of electrospun polymeric tracheal scaffolds, Biomaterials 2014; 35(20): 5307–5315.

KI launches global alumni chapter in Vietnam

Thu, 21/06/2018 - 11:18
Một hai ba uống! (One two three, cheers!) filled the room as joyful KI alumni raised glasses to sing a celebratory song in unison. Gathered in the idyllic village of Ninh Bình KI:s alumni in Vietnam united to celebrate the launch of the KI Alumni Vietnam global chapter on Saturday 16 June 2018. – The official launch of the KI Alumni chapter is important for everyone in Vietnam. The establishment of the chapter confirms that we are important to the university, and provides greater opportunity to maintain our connection with KI, says Nguyễn Thị Thanh Hương, ambassador of KI Alumni Vietnam Chapter. A short dinner program began with a video greeting sent by KI President Ole Petter Ottersen. – This is a major step forward for KI and for our profile in southeast Asia. You, our alumni, are our most important ambassadors. You contribute to our vision, which is to improve human health, not only in Sweden, but globally. Sida-funded sandwich model Ingeborg van der Ploeg, or ”Chị In” as she is affectionately known, has been a key facilitator between KI and Vietnam as a coordinator for the Sida-funded sandwich model PhD program. Ingeborg has followed the progress of more than twenty alumni including exchange students since 2000. KI has had collaborations with Vietnam for several decades, and today has several ongoing projects including the collaborative Stint-funded Trac (Teaching and Research Academic Collaboration) project, and Edushare, a capacity-building project led by Tartu University in Estonia. Professor Marianne Schultzberg, Dean of Doctoral Education, is the chair of the Trac owner group. – The establishment of the KI Alumni Vietnam global chapter will add great value to Trac and similar projects by facilitating a consistent network through which further collaboration can arise – both with KI and between our alumni, remarks Marianne Schultzberg. The KI alumni in Vietnam hope that the establishment of the chapter will foster the KI spirit in Vietnam, bring about better contact between KI and the alumni, and increase opportunities regarding teaching, and clinical and research exchange in both directions.

Lennart Nilsson Award 2018 is awarded to Thomas Deerinck

Wed, 20/06/2018 - 17:26
Bio-artist and scientist Thomas Deerinck wins the 2018 Lennart Nilsson Award. He gets the prize for developing novel microscopy techniques and methods to improve the ability to obtain information from biological specimens. Thomas Deerinck is a research scientist, technical specialist and bio-artist at the National Center for Microscopy and Imaging Reseach (NCMIR) and the Center for Research on Biological Systems at the University of California, San Diego. Over the past four decades he has developed novel techniques and methods to improve our ability to obtain information from biological specimens using many types of microscopes. He has made many important contributions to the field of bioimaging, including key work on developing chemical, molecular and genetic tagging methods for studying cells and tissues by both light and electron microscopy. Thomas Deerincks latest work is focused on improving serial block-face scanning electron microscopy; a method that is revolutionizing automated 3D imaging of cells and tissues at nanometer-scale resolution. He not only developed the now gold-standard protocol for preparing samples for this imaging technique, but also just recently co-developed a method to greatly extend the resolution and usefulness of this approach in the field of biomedical research. Thomas is married to the artist Karla Renshaw, who taught him to bring an artistic eye common to nature photography to scientific imaging with microscopes. The resulting images of even common everyday objects are turned from the invisible into beautiful works of art, and have appeared not only on the cover of numerous top tier scientific journals, but also in many non-scientific magazines, periodicals, documentaries as well as public art exhibitions.  

Mechanism controlling multiple sclerosis risk identified

Tue, 19/06/2018 - 11:01
While the DNA sequence remains the same throughout a person’s life, the expression of the encoded genes may change with time and contribute to disease development in genetically predisposed individuals. Researchers at Karolinska Institutet have now discovered a new mechanism of a major risk gene for multiple sclerosis (MS) that triggers disease through so-called epigenetic regulation. They also found a protective genetic variant that reduces the risk for MS through the same mechanism. The study is published in Nature Communications. Multiple sclerosis is a chronic inflammatory disease of the central nervous system, affecting people at a relatively young age. Most are between 20 and 40 years old when they get the first symptoms, in the form of, for example numbness in the arms and legs, visual impairment and dizziness, but also fatigue and depression. The symptoms are caused by an inflammation in the brain and the spinal cord that breaks down the myelin sheath protecting the nerves, thus damaging the axons. Currently there is no cure for MS, but the disease activity can often be halted through medication. Strongest risk factor Already over 40 years ago it was discovered that genetic variation in the so-called HLA region is the strongest risk factor for developing disease. HLA encodes molecules that are involved in the immune system. However, the specific genes and molecular mechanisms behind the emergence of the disease are not fully established. By using molecular analyses and combining several studies (so-called meta-analysis), including around 14,000 patients with MS and a control group of more than 170,000 healthy individuals, researchers at Karolinska Institutet found that people with the major risk variant HLA-DRB1*15:01 have an increased expression of the HLA-DRB1 gene, thus increasing the risk for the disease. The researchers further discovered a so-called epigenetic regulation of HLA expression as the mechanism mediating this effect. “We show for the first time that epigenetic mechanisms can cause the disease. In addition, we can connect this mechanism to the genetic variant with the strongest risk for developing MS,” says Maja Jagodic, researcher at the Department of Clinical Neuroscience at Karolinska Institutet and one of the authors of the article. Protective variant The researchers also discovered a new HLA gene variant, rs9267649, which reduces the risk of developing MS. This protective variant decreases the HLA-DRB1 gene expression – through the same epigenetic regulation mechanism – thus reducing the risk for MS. The results open new avenues for potential alternative treatments based on specific epigenetic modulation, i.e. to prevent gene expression artificially. This gives hope for people with MS, as well as other autoimmune diseases. “Almost all autoimmune diseases are associated with HLA,” says Lara Kular, co-author and researcher at the same department. The study was carried out through an international collaboration with researchers in the US, Germany, Norway, Denmark, and Iceland (the deCode company). Financing has been granted through funding from, among others, the Swedish Research Council, Neuro, the Swedish Brain Foundation, the European MS Foundation, Petrus and Augusta Hedlund Foundation, AFA Insurance, Knut and Alice Wallenberg Foundation, Stockholm County Council, and AstraZeneca. Several of the researchers are employed by deCode genetics/Amgen Inc. For more information, see the scientific article. Publication ”DNA methylation as a mediator of HLA-DRB1*15:01 and a protective variant in multiple sclerosis” Lara Kular, Yun Liu, Sabrina Ruhrmann, Galina Zheleznyakova, Francesco Marabita, David Gomez-Cabrero, Tojo James, Ewoud Ewing, Magdalena Lindén, Bartosz Górnikiewicz, Shahin Aeinehband, Pernilla Stridh, Jenny Link, Till F. M. Andlauer, Christiane Gasperi, Heinz Wiendl, Frauke Zipp, Ralf Gold, Björn Tackenberg, Frank Weber, Bernhard Hemmer, Konstantin Strauch, Stefanie Heilmann-Heimbach, Rajesh Rawal, Ulf Schminke, Carsten O. Schmidt, Tim Kacprowski, Andre Franke, Matthias Laudes, Alexander T. Dilthey, Elisabeth G. Celius, Helle B. Søndergaard, Jesper Tegnér, Hanne F. Harbo, Annette B. Oturai, Sigurgeir Olafsson, Hannes P. Eggertsson, Bjarni V. Halldorsson, Haukur Hjaltason, Elias Olafsson, Ingileif Jonsdottir, Kari Stefansson, Tomas Olsson, Fredrik Piehl, Tomas J. Ekström, Ingrid Kockum, Andrew P. Feinberg, and Maja Jagodic Nature Communications, online 19 June 2018, doi: 10.1038/s41467-018-04732-5

Russian research centre delegation visits KI

Sat, 16/06/2018 - 11:36
Thursday 14 June saw a visit to Karolinska Institutet by a Russian delegation from the Almazov National Medical Research Centre. The purpose of the visit was to discuss ongoing and strengthened collaboration. The Almazov National Medical Research Centre is a medical institute in St. Petersburg, primarily specialising in cardiology, cardiovascular surgery, haematology and endocrinology. A number of researchers at the Russian research centre have defended their theses at Karolinska Institutet under the supervision of Göran Hansson, Per Eriksson, Ulf Hedin, Thomas Sejersen, Olle Söder, Boris Zhivotovsky and Anna Kostareva, among others. The latter is an associate at Karolinska Institutet’s Department of Women's and Children's Health and is at the same time head of the Institute of Molecular Biology and Genetics at Almazov National Medical Research Centre in Russia. International challenges require collaboration The Russian research centre, which recently achieved the status of national centre, lists Karolinska Institutet as its foremost collaboration partner. “The challenges currently facing healthcare systems and the medical environments in various countries are not national, but international. This demands joint efforts on the part of research institutes and universities in different countries to identify new solutions and innovative methods. Our almost 20 years of collaboration with Karolinska Institutet has so far proved successful and I believe that the current stage of our relationship is the most important for both parties,” says Professor Evgeny Shlyakhto, Director General of the Almazov National Medical Research Centre and President of the Russian Society of Cardiology. Important collaboration for KI The delegation was received in Aula Medica in the presence of Karolinska Institutet’s President Ole Petter Ottersen, together with researchers who in various ways participate in the Russian collaboration. “Our collaboration with the Almazov Medical Centre is important to KI as it is Russia’s leading institute for cardiological research. Much of the research collaboration takes place with the Department of Women's and Children's Health here at KI, something that is well aligned with the goals of Agenda 2030, both with regard to good health and wellbeing, and gender equality,” says President Ole Petter Ottersen.

No link found between oral antifungal drug and stillbirth

Wed, 13/06/2018 - 09:56
New research led from Karolinska Institutet does not support a suggested link between treatment with the oral antifungal drug fluconazole during pregnancy and an increased risk of stillbirth. The study is published in the prestigious medical journal JAMA. Vaginal candidiasis is common in pregnancy. Intravaginal formulations of topical antifungal drugs are first-line treatment for the infection, but oral antifungal drugs – typically fluconazole – are used in cases with severe symptoms, recurrent candidiasis episodes, or when topical treatment has failed. Although use of oral fluconazole during pregnancy is generally discouraged, between 0.5 and 4 per cent of pregnant women use this drug anyway; with the lower numbers representative of the Nordic countries and the higher numbers reported from the United States. “In a study published in JAMA 2016, we reported that fluconazole use in pregnancy was linked to an increased risk of spontaneous abortion, and our results suggested that the drug might also be associated with stillbirth. There are concerns based on animal data that oral fluconazole use in pregnancy may lead to fetal death. Given this concern and the paucity of studies in humans, we wanted to investigate the issue further,” says Björn Pasternak, associate professor at Karolinska Institiutet’s Department of Medicine in Solna who led the new study. Swedish and Norwegian register data  The researchers at Karolinska Institutet have now conducted an independent study in collaboration with the Norwegian Institute of Public Health to investigate if fluconazole use in pregnancy is associated with stillbirth and neonatal death. More than 10 000 women using fluconazole during pregnancy were identified using nationwide Swedish and Norwegian register data and compared to 100 000 women who did not use the drug. The study, published in JAMA, shows that use of fluconazole was not associated with increased risk of stillbirth or neonatal death, and the results were similar for different drug doses. “The findings are reassuring but need to be interpreted considering other pregnancy safety issues with fluconazole, such as malformations, before recommendations to guide clinical decisions are made,” concludes Dr Pasternak. The study was supported by the Thrasher Research Fund, the Magnus Bergvall Foundation, and the Karolinska Institutet Research Foundation. Björn Pasternak and Olof Stephansson were also supported by the Strategic Research Area Epidemiology program at Karolinska Institutet. Publication “Oral fluconazole in pregnancy and risk of stillbirth and neonatal death” Björn Pasternak, Viktor Wintzell, Kari Furu, Anders Engeland, Martin Neovius, Olof Stephansson JAMA, online 12 June 2018, doi: 10.1001/jama.2018.6237

Genome-editing tool could increase cancer risk

Mon, 11/06/2018 - 17:01
Therapeutic use of gene editing with the so-called CRISPR-Cas9 technique may inadvertently increase the risk of cancer, according to a new study from Karolinska Institutet and the University of Helsinki published in Nature Medicine. Researchers say that more studies are required in order to guarantee the safety of these ‘molecular scissors’ for gene-editing therapies. CRISPR-Cas9 is a molecular machine first discovered in bacteria that can be programmed to go to an exact place in the genome, where it cuts the DNA. These precise ‘molecular scissors’ can be used to correct faulty pieces of DNA and are currently being used in clinical trials for cancer immunotherapy in the US and China. New trials are expected to be launched soon so as to treat inherited blood disorders such as sickle cell anaemia. Activates the p53 protein Two independent articles published in the journal Nature Medicine now report that therapeutic application of the genome-editing tool may, in fact, increase the risk of cancer. In one of the studies, scientists from Karolinska Institutet and the University of Helsinki report that use of CRISPR-Cas9 in human cells in a laboratory setting can activate a protein known as p53, which acts as a cell’s ‘first aid kit’ for DNA breaks. Once active, p53 reduces the efficiency of CRISPR-Cas9 gene editing. Thus, cells that do not have p53 or are unable to activate it show better gene editing. Unfortunately, however, lack of p53 is also known to contribute to making cells grow uncontrollably and become cancerous. “By picking cells that have successfully repaired the damaged gene we intended to fix, we might inadvertently also pick cells without functional p53”, says Dr Emma Haapaniemi, researcher at the Department of Medicine, Huddinge, Karolinska Institutet and co-first author of the study. “If transplanted into a patient, as in gene therapy for inherited diseases, such cells could give rise to cancer, raising concerns for the safety of CRISPR-based gene therapies.” A powerful tool “CRISPR-Cas9 is a powerful tool with staggering therapeutic potential”, adds Dr Bernhard Schmierer, researcher at the Department of Medical Biochemistry and Biophysics at Karolinska Institutet, and Head of the High Throughput Genome Engineering Facility of Science for Life Laboratory (SciLifeLab), who co-supervised the study. “Like all medical treatments however, CRISPR-Cas9-based therapies might have side effects, which the patients and caregivers should be aware of. Our study suggests that future work on the mechanisms that trigger p53 in response to CRISPR-Cas9 will be critical in improving the safety of CRISPR-Cas9-based therapies.” Parts of the study were carried out at the Swedish National Genomics Infrastructure, funded by SciLifeLab. The Knut and Alice Wallenberg Foundation, the Swedish Cancer Society, the Swedish Childhood Cancer Fund and the Academy of Finland supported the research. Publication “CRISPR/Cas9-genome editing induces a p53-mediated DNA damage response” Emma Haapaniemi, Sandeep Botla, Jenna Persson, Bernhard Schmierer and Jussi Taipale Nature Medicine, online 11 June 2018, doi: 10.1038/s41591-018-0049-z

Immune system does not recover despite cured hepatitis C infection

Mon, 11/06/2018 - 11:01
Changes to the immune system remain many years after a hepatitis C infection heals, a new study by researchers at Karolinska Institutet and Hannover Medical School shows. The findings, presented in Nature Communications, increases understanding about chronic infection and the way it regulates and impacts composition of the immune system. Infection with hepatitis C virus (HCV) turns almost always chronic and poses a major health problem around the world. The infection can lead to cirrhosis and cancer of the liver when the immune system fails to fight the virus. Eventually the immune system becomes exhausted. Since a couple of years, however, most patients with HCV can now be cured in a matter of a few weeks with revolutionary new medications. New measurement method used The current study included 40 patients with chronic HCV infection whom researchers followed before, during and after treatment with these new medications to investigate impact on the composition and diversity of the immune system. Diversity is vital to the ability of the immune system to fight infections. Of particular importance are natural killer cells (NK), a type of white blood cells. The researchers used flow cytometry and a new measurement method to derive the composition of the immune system, as well as the appearance of NK cells and their function in the blood. “Researchers in the field previously focused on analysing individual components but were unable to draw any comprehensive conclusions,” says Niklas Björkström, physician and associate professor at the Department of Medicine, Huddinge, Karolinska Institutet, who led the study. “The immune system is extraordinarily complex, incorporating a large number of interacting parts. We adapted new methods in order to assess and analyse that complexity in a fresh manner.” The immune system was affected The results showed that the overall composition of the immune system was affected by the chronic infection, with significantly reduced diversity among the NK cells. Many of the changes remained long after the virus had been eliminated by means of medication. Researchers have not yet determined the long-term implications but are currently exploring whether patients have a harder time fighting future infection. “One strength of our study is that we monitored patients for more than two years following elimination of the virus,” Benedikt Strunz, physician and doctoral student at the same department. “To the best of our knowledge, nobody has ever monitored over such a long term like this before.” Nevertheless, a number of questions are outstanding. Researchers would like to investigate consequences for a good deal longer than two years, as well as identify strategies for rejuvenating the immune system and increasing its diversity. The study was financed by the Swedish Research Council, Swedish Cancer Society, Strategic Research Foundation, Swedish Foundation for Medical Research, Radiumhemmet Research Foundation, Knut and Alice Wallenberg Foundation, NovoNordisk Foundation, Åke Wiberg Foundation, Centre for Innovative Medicine at Karolinska Institutet, Stockholm County Council, Karolinska Institutet, International Research Training Group with support by the German Research Foundation, Centre Research Grants, 900 with support of DFG, German Centre for Infection Research and German Liver Foundation. Publication ”Chronic hepatitis C virus infection irreversibly impacts human NK cell repertoire diversity” Benedikt Strunz, Julia Hengst, Katja Deterding, Michael P. Manns, Markus Cornberg, Hans-Gustaf Ljunggren, Heiner Wedemeyer, and Niklas K. Björkström. Nature Communications, online 11 June, 2018, doi: 10.1038/s41467-018-04685-9

Makerere University and KI strengthen partnership

Fri, 08/06/2018 - 15:05
A delegation from Uganda’s Makerere University visited Karolinska Institutet on 7-8 June for talks on strengthening the collaborative partnership between the two universities.   The delegation, which was led by Makerere University’s vice-chancellor Professor Barnabas Nawangwe, met the Karolinska Institutet (KI) management to discuss the long-standing collaboration between the two institutions. The partnership, which began back in 2003  with the first memorandum of understanding, enables doctoral students to obtain a joint PhD from both universities. “The partnership with Makerere University is one of our most important and far-reaching international partnerships, including as it does student and teacher exchange, joint doctoral education and research collaboration,” says KI president Ole Petter Ottersen. Discussed research collaboration During the visit, which included a tour of KI’s new Neo and Biomedicum research facilities, discussions were held on common research interests surrounding non-communicable diseases, such as cardiovascular diseases, cancer, diabetes and chronic respiratory infections that can lead premature death. Apart for the human suffering they cause, they are also a major global economic burden and most countries are doing all they can to develop their healthcare systems to prevent and treat the diseases. KI and Makerere University are now working on strengthening their research and collaboration in the NCD field and will be launching a pilot study in August on conducting longitudinal studies of risk factors for cardiovascular disease in Uganda.   Locally targeted research project To date, some 40 doctoral students from Uganda have graduated through the partnership and joint degree scheme, and over 500 peer-reviewed scientific articles have been published. It is hoped that the enlarged pool of researchers and locally targeted research on health issues and healthcare systems will have an impact on the development of Ugandan civil society. In many cases, the outcome has been policy reforms and  changes in practice. More than 300 students and teachers from KI and Makerere University have been on exchange at a Bachelor’s and Master’s level at each university, and strong research capacity has been built in both countries over the years. There are now many alumni from the partnership, and both universities consider them a group worth taking better care of.

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