Integrative Molecular Phenotyping

KI News

Updated: 2 hours 17 min ago

Promising results for new acute porphyria treatment

Wed, 06/02/2019 - 23:05
Acute porphyria is a group of uncommon diseases that can cause severe, potentially life-threatening attacks of abdominal pain, nausea, vomiting and paralysis. Liver transplantation is currently the only effective treatment available for the most seriously afflicted patients. A clinical trial conducted in collaboration with researchers at Karolinska Institutet in Sweden now shows that a new drug candidate can prevent attacks in these patients. The study is published in The New England Journal of Medicine. Porphyria is caused by different inherited disorders in the synthesis of heme, the oxygen-binding component of red blood cells. Heme is also necessary for the metabolism of certain drugs and hormones by the liver. When the liver is unable to synthesise heme properly, toxic substances called porphyrin metabolites accumulate in the body, resulting in acute porphyria attacks. A small group of porphyria patients suffer recurrent acute attacks, which cause them chronic debilitating symptoms requiring constant hospital care. Acute intermittent porphyria (AIP) is the most common form of acute porphyria. Patients suffering from acute attacks are treated using an infusion containing a form of heme called hemin, which suppresses the formation of the toxic metabolites. “Hemin has saved the lives of many patients and will continue to be important, but it’s only for acute treatment,” says the study’s lead author Eliane Sardh, researcher at the Department of Molecular Medicine and Surgery, Karolinska Institutet, and consultant at Karolinska University Hospital. “For patients with recurrent attacks, no other curative treatment is available than liver transplantation.” Reduced the number of acute attacks However, the new drug candidate givosiran, developed by Alnylam Pharmaceuticals, has shown promising results in a clinical phase I study in 40 patients. The study has been conducted in close, long-standing collaboration with Porphyria Centre Sweden, which has also provided the majority of the patients. The administration of givosiran reduced the number of acute attacks in the patients by up to 79 per cent, and the need for hemin decreased by up to 83 per cent. Most of the reported side effects were mild or moderate, and no clear link was observed between adverse reactions and dose. Severe adverse reactions were reported in six patients, including one death that was deemed unrelated to givosiran. The drug candidate is based on a natural method of inhibiting gene expression called RNA interference (RNAi). “Givosiran down-regulates ALAS1, the key regulator of the hepatic heme synthesis pathway, which reduces the toxic metabolites without the use of hemin,” says Dr Sardh. “It also has a lasting effect of at least one month, which gives us an effective means of preventing acute attacks in seriously afflicted porphyria patients who have limited treatment options.” Accelerated review process The drug candidate has been given PRIME and Breakthrough Designation by the European Medicines Agency and the U.S. Food and Drug Administration, which in speeding up the review process could mean that the drug may be available by early 2020. The patients that took part in the phase I study will remain on givosiran in a combined phase I/II study, and complete results from a phase III study in 94 patients from around the world are expected in the spring of 2019. The study design and study research was conducted by Karolinska University Hospital, Karolinska Institutet, Porphyria Centre Sweden, the Icahn School of Medicine at Mount Sinai (New York), King’s College Hospital (London), the University of California (San Francisco), the University of Utah (Salt Lake City), Wake Forest University (Winston-Salem), and the University of Texas Medical Branch (Galveston). It was financed by Alnylam Pharmaceuticals. Publication “Phase 1 Trial of an RNA Interference Therapy for Acute Intermittent Porphyria” Eliane Sardh, Pauline Harper, Manisha Balwani, Penelope Stein, David Rees, D. Montgomery Bissell, Robert Desnick, Charles Parker, John Phillips, Herbert L. Bonkovsky, Daphne Vassiliou, Craig Penz, Amy Chan-Daniels, Qiuling He, William Querbes, Kevin Fitzgerald, Jae B. Kim, Pushkal Garg, Akshay Vaishnaw, Amy R. Simon and Karl E. Anderson. The New England Journal of Medicine, online 6 February 2019, doi: 10.1056/NEJMoa1807838

Treatable mechanism identified in patients with schizophrenia

Mon, 04/02/2019 - 17:00
For reasons that are unclear, schizophrenia patients have fewer connections between the neurons in the brain. Researchers at Karolinska Institutet, Sweden, and Massachusetts General Hospital, USA, have now succeeded in creating human cell models that show that there is an excessive degradation of connections in the brain of these patients, and they have been able to link this to a genetic risk variant for the disease. They have also been able to show that the antibiotic minocycline inhibits the degradation and that treatment in adolescence can be linked to a reduced risk of developing schizophrenia. The study is being published in the journal Nature Neuroscience. In the late teenage years, a normal extensive pruning of the number of connections between nerve cells, so-called synapses, takes place through microglia (the brain’s immune cells) selectively degrading less desirable connections. The process, referred to as synaptic pruning, is of great importance for the development of functional neural networks. Many individuals succumb to schizophrenia in their late teens, a period of intensive pruning in the brain. The researchers behind the study have created iPS cells (induced pluripotent stem cells) from schizophrenia patients and have reprogrammed them into neurons (brain cells). Using a proprietary method, they have then created a model of the microglia synaptic pruning in a test tube. Comparisons with matched control subjects indicated a clear increase in the pruning of synapses in schizophrenia patients. “We also conducted experiments where we combined nerve cells from healthy individuals and diseased microglia, and vice versa, and could conclude that the excessive pruning in the disease models was due to both a disrupted function of microglia and aberrations in the synapses,” says Jessica Gracias, doctoral student at the Department of Physiology and Pharmacology, Karolinska Institutet, and co-author of the study. Increased degradation of synapse The researchers also studied how different gene variants of the C4 gene (complement factor 4) affect the pruning. One variant of the complement factor proved to bind more strongly to synapses and result in the increased degradation of synapses. This is consistent with previous genetic findings indicating that this specific C4 risk variant increases the risk of schizophrenia. “The use of human cells from patients made it possible to study the risk variants directly because mice lack these specified variants of the C4 gene,” says Carl Sellgren Majkowitz, research group leader at the Department of Physiology and Pharmacology, Karolinska Institutet, and senior consultant at Region Stockholm, who led the research project together with Roy Perlis at Massachusetts General Hospital. Antibiotic proved to inhibit the synaptic pruning Finally, microglia in the cell models were also “treated” with an antibiotic, minocycline, which proved to inhibit the synaptic pruning. By then using electronic data records from more than 20,000 individuals who had received either minocycline or another antibiotic during adolescence, for treatment of acne, they were able to demonstrate a clear protective effect from minocycline treatment in relation to schizophrenia onset. The researchers hope that the findings will lead to more effective treatments for schizophrenia, which can then also be initiated early on in the event of an elevated genetic risk, for example. The research was conducted at Massachusetts General Hospital and Karolinska Institutet. The National Institute of Mental Health, the Marianne and Marcus Wallenberg Foundation and the Swedish Research Council contributed to fund the research. Publication “Increased synapse elimination by microglia in schizophrenia patient-derived models of synaptic pruning” Carl M. Sellgren, Jessica Gracias, Bradley Watmuff, Jonathan D. Biag, Jessica M. Thanos, Paul B. Whittredge, Ting Fu, Kathleen Worringer, Hannah E. Brown, Jennifer Wang, Ajamete Kaykas, Rakesh Karmacharya, Carleton P. Goold, Steven D. Sheridan and Roy H. Perlis. Nature Neuroscience, online 4 February, 2019, doi: 10.1038/s41593-018-0334-7

Increased internationalisation requires commitment across the entire organisation

Mon, 04/02/2019 - 11:12
At the end of January, KI hosted a national workshop on international and intercultural perspectives in teaching. Here, representatives from Swedish higher education institutions gathered under the leadership of international researchers. The organiser was SUHF, the Association of Swedish Higher Education Institutions. Eva Åkesson, Vice-Chancellor of Uppsala University and Chair of the expert group for internationalisation issues within SUHF, was among those started off the day’s proceedings. “The educational domain is becoming increasingly global and competition is intensifying. Maybe in the past internationalisation was viewed as a sideline activity, but that is no longer the case. Nowadays, it goes without saying that this is something that affects our entire organisation,” said Eva Åkesson. Among the invited members were vice-chancellors and deputy vice-chancellors with responsibility for internationalisation and pedagogical support, as well as students’ union representatives from all over the country. The reason for hosting the workshop at KI is explained by an ongoing development project, where five degree programmes participate with the aim of increasing the internationalisation of the teaching. “In the past we discussed internationalisation in terms of mobility and teaching in English. All with the intention of attracting more international students to Sweden. Today it is more a question of preparing our students for living and working in a globalised world,” says Jennifer Valcke, pedagogical developer within the Unit for Medical Education at the Department of Learning, Informatics, Management and Ethics, and the person responsible for the three-year development programme. When the development project reaches 2020, there should be guidelines, practice and experience in place that not only allows KI’s other degree programmes to be included, but also other Swedish universities. “This is also the reason why we are hosting today’s workshop. SUHF’s goal is to gather expertise within the field in order to build tighter networks and arenas at the national level for increased internationalisation,” says Jennifer Valcke. Both Jeanine Gregersen, Pro-Vice-Chancellor of Glasgow Caledonian University, and Betty Leask, Pro-Vice-Chancellor of La Trobe University, Melbourne, were present for the entire day. They are both international experts within the field and are also involved in the development project at KI. During her lecture, Betty Leask presented a rundown of methods and tools for increased internationalisation, and also highlighted several specific problems and obstacles. According to her, an important component is that the entire organisation must be involved for a successful outcome. “We must challenge our perception of what internationalisation means within all levels of our organisations, and focus on the staff as well as the students. How can we help our staff to develop the same skills as our students to strengthen internationalisation?” suggested Betty Leask. Among the other participants was also KI’s President Ole Petter Ottersen and European Parliamentarian Cecilia Wikström (L).

Short anti-rejection therapy protects transplants in diabetic animals

Fri, 01/02/2019 - 06:00
Transplanted pancreatic islets in diabetic animals can survive for a long period of time if the animals are treated with short anti-rejection therapy around the time of the transplant. This has been shown by researchers at Karolinska Institutet, Sweden, and the Diabetes Research Institute, University of Miami Miller School of Medicine, USA, in a new study published in the scientific journal Diabetologia. The results might have a significant impact on clinical islet transplantation in the treatment of type 1 diabetes. Transplantation of pancreatic islets with their insulin-secreting cells is a promising therapy in type 1 diabetes. However, one complication is that anti-rejection therapy, in the form of generalised immune suppression, is required to ensure the survival and function of the transplanted islets by preventing the immune system from attacking the transplants. It is well known that extended use of generalised immune suppression might have serious side effects that harm the transplanted patient. Moreover, immune attack against the transplanted islets can still occur despite continued immune suppression. Therefore, the transplantation field has been looking for new ways to ensure the long-term survival and function of transplanted islets with little or even no immune suppression. This new study demonstrates the potential for achieving long-term survival and function of transplanted pancreatic islets with short-term anti-rejection therapy around the time of the transplant. In transplanted mice and monkeys, this strategy resulted in immune tolerance that enabled survival of the transplanted islets long after the anti-rejection treatment was stopped. “These findings support the establishment of immune tolerance towards the transplanted islets and thereby their long-term protection from an immune attack in the transplanted patient after stopping the use of anti-rejection therapy,” says first author Dr Midhat H Abdulreda at the Diabetes Research Institute. Hope for effective treatment This new way of achieving immune tolerance might minimise the need for life-long immune suppression, which raises hope for an effective treatment of type 1 diabetes with fewer side effects. “If these findings are repeated in humans, this approach may serve as a game changer and positively impact on the success of islet transplantation for future treatment of type 1 diabetes,” says senior author Professor Per-Olof Berggren at the Department of Molecular Medicine and Surgery and Rolf Luft Research Center for Diabetes and Endocrinology at Karolinska Institutet. The research was supported by funds from the Diabetes Research Institute Foundation (DRIF) and the Diabetes Wellness Foundation and by grants from the Stanley J. Glaser Foundation Research Award, the NIH/NIDDK/NIAID, the Swedish Diabetes Association Fund, the Swedish Research Council, Novo Nordisk Foundation, the Family Erling-Persson Foundation, the Strategic Research Program in Diabetes at Karolinska Institutet, the ERC-2013-AdG 338936-BetaImage, 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 cofounder and CEO of Biocrine, an unlisted biotech company that is using the approach of cell transplant in the anterior chamber of the eye as a research tool. Midhat H Abdulreda is a consultant for the same company. More information about the technique can be found in the scientific article. Publication “Operational immune tolerance towards transplanted allogeneic pancreatic islets in mice and a non-human primate” Midhat H. Abdulreda, Dora M. Berman, Alexander Shishido, Christopher Martin, Maged Hossameldin, Ashley Tschiggfrie, Luis F. Hernandez, Ana Hernandez, Camillo Ricordi, Jean-Marie Parel, Ewa Jankowska-Gan, William J. Burlingham, Esdras A. Arrieta-Quintero, Victor L. Perez, Norma S. Kenyon, Per-Olof Berggren Diabetologia (the journal of the European Association for the Study of Diabetes [EASD]), online 31 January 2019, doi: 10.1007/s00125-019-4814-4

Comments on information in the media concerning the external investigation of the Macchiarini case

Thu, 31/01/2019 - 12:49
Comments: Information in the media claims that the basic data for the external investigation of the so-called Macchiarini case at KI has disappeared or cannot be found. This information is also found in a newly published book by Harriet Wallberg and Kristina Appelqvist, När lögnen blir sanning (When the lie becomes truth).  KI comments on this information as follows. The investigation was external and was led by Sten Heckscher. None of the external investigators were an employee at KI. Thus, KI had no obligation to archive material in the investigation. This is confirmed in a decision by the Ombudsman (JO) on 17 February 2017 (JO serial number 299/2017, KI serial number 2-1259/2017) in connection with a JO notification by Harriet Wallberg. The information that the investigation material might have disappeared is not correct. All information that has been obtained from the KI archive is still available. The background to the external investigation was a decision by the Konsistoriet (the university’s board) and it was commissioned in 2016 by the board members at the time. The report Karolinska Institutet and the Macchiarini case (in Swedish) was presented on 5 September 2016. The investigators used information from KI's archives and records to review Karolinska Institutet's handling of the whole case – from the recruitment of Macchiarini in 2010 and onwards. This consisted of large quantities of decision records, e-mail messages etc. All the material that the investigators used in their work and which consists of public documents is archived at KI, but not collected under a single case heading. The external inquiry was also based on information that the investigators developed through conversations with KI employees and other sources. If any documentation of these conversations had been submitted to KI, it would have been registered. No such documentation has been received.

PFAS chemicals pass from mother to fetus throughout pregnancy

Wed, 30/01/2019 - 09:51
In a study published in Environment International researchers at Karolinska Institutet in Sweden show how PFAS industrial chemicals, which are used in many consumer products, pass through the placenta throughout pregnancy to accumulate in fetal tissue. Further research is now needed to ascertain the effect that highly persistent PFAS chemicals have on the fetus. The PFAS (perfluoroalkyl substances) group comprises thousands of human-made chemicals, which, thanks to their water- and grease-resistant properties, are used in everything from frying pans and food packaging to clothes, cleaning agents and firefighting foams. “We’ve focused on six of these PFAS substances and found that all appear to the same extent in fetal tissue as in the placenta,” says Richelle Duque Björvang, doctoral student at the Department of Clinical Science, Intervention and Technology, Karolinska Institutet. “So when the baby is born, it already has a build-up of these chemicals in the lungs, liver, brain, and elsewhere in the body.” High levels in the lung and liver PFAS levels were highest in the lung and liver tissue, in some cases as high as in adults, and lowest in the brain. The study included tissue samples from 78 embryos and fetuses aged 7 to 42 weeks, sourced from biobanks in Sweden and Denmark. Amongst the six PFAS substances studied were PFOS and PFOA, which are the best known. PFOS was banned by the EU in 2008, and at the start of the year the European Food Safety Authority sharpened its appraisal of PFOS and PFOA and lowered the tolerable daily intake thousandfold. “This shows how important it is for more research to be done on the health effects of different chemicals, especially in the longer term,” says Pauliina Damdimopoulou, senior researcher at the Department of Clinical Science, Intervention and Technology. “Today’s threshold values are based on an adult population rather than fetuses, which are much more susceptible.” The accumulation of PFAS substances was also higher in male fetuses than female. “We know that there are slight differences in the function of the placenta depending on the sex of the fetus, which is something we need to do more studies on in relation to impact on fetal chemical exposures,” says Dr Damdimopoulou. “We also need to find out what effects these substances have on different fetal organs.” Food is the main source PFAS substances have been used since the early 1900s and are ubiquitous in our environment. “The main source of PFAS substances today is food, in the form of fish, milk, meat and eggs, or in the drinking water, if you happen to live in a polluted area,” continues Dr Damdimopoulou. “We ingest them as a cocktail of substances that can also interact with each other. It would be in line with the precautionary principle in the restriction of chemical substances to make sure that all PFAS substances disappear from our society.” The study was conducted in collaboration with researchers from Copenhagen University and Rigshospitalet, and was financed by the EU ReproUnion project, the Novo Nordisk Foundation, Formas (the Swedish Research Council for Environment, Agricultural Sciences and Spatial Planning) and the Jane and Aatos Erkko Foundation. Publication  “Concentration of perfluoroalkyl substances (PFASs) in human embryonic and fetal organs from first, second, and third trimester pregnancies” Linn Salto Mamsen, Richelle D. Björvang, Daniel Mucs, Marie-Therese Vinnars, Nikos Papadogiannakise, Christian H. Lindh, Claus Yding Andersena and Pauliina Damdimopoulou Environment International, online 24 January 2019, doi: 10.1016/j.envint.2019.01.010

New strategy expands the benefits of Internet-delivered CBT

Wed, 30/01/2019 - 06:01
Scientists at Karolinska Institutet have experimented with a new adaptive treatment strategy for Internet-delivered cognitive behavioural therapy (ICBT) that identifies patients within the first month who face a major risk of treatment failure. Published in the scientific journal American Journal of Psychiatry, the results also suggest that such patients may nevertheless benefit if their treatment is adjusted to accommodate their specific needs and challenges. Internet-delivered CBT effectively addresses depression, panic and sleep disorders, and several other psychological issues. Many studies over the past 20 years have demonstrated benefits that are comparable with traditional face-to-face treatment, and clinical practice has adopted the approach throughout much of Sweden. As is the case with any method, not everyone benefits enough. Researchers have not yet found a way to prior to treatment separate those who are likely to benefit from those who are not. The adaptive treatment strategy evaluated by scientists at Karolinska Institutet permits such a classification within a few weeks into therapy. The study included 251 patients who were receiving Internet-delivered CBT for insomnia. “The findings indicate that an accurate assessment of patients who are likely and unlikely to benefit is possible by the fourth week of treatment. The strategy also reduces the risk of insufficient outcome since it enables additional support and adaptation for those who need it,” says Erik Forsell, psychologist and PhD student at the Department of Clinical Neuroscience, Karolinska Institutet. After four weeks of Internet-delivered CBT, the scientists performed a structured assessment of the individual risk of failure with a questionnaire and algorithm-based tool. Patients were then classified as either facing a low risk or high risk of failure, i.e., obtaining insufficient benefits. Those at high risk were randomly assigned to either continuing the treatment or receiving additional support and an adjusted treatment. High risk patients who continued with the standard treatment obtained less reduction in sleep problems, whereas those who received additional support and the adjusted treatment obtained similar benefits as those in the low-risk group. A first step in customising Internet-delivered CBT The scientists regard the study as a first step in customising Internet-delivered CBT, and ultimately traditional therapy as well, by constructing structured systems that identify and assist those who do not appear likely to benefit. “The strategy will help a greater number of patients and minimise the risk of extended therapies without desired benefits. The long-run consequences may be fewer failures and less time between diagnosis and effective treatment. The healthcare system would be less burdened and individual patients would suffer less,” says Viktor Kaldo, psychologist and associate professor at the Department of Clinical Neuroscience, Karolinska Institutet, and the principal researcher, The study was financed by the Söderström-Königska sjukhemmet Foundation, the L.J. Boëthius Foundation, the Bror Gadelius Minnesfond Foundation, the Stockholm County Council, the Erling-Persson Family Foundation and the Swedish Research Council. Publication ”Proof of concept for an Adaptive Treatment Strategy to prevent failures in Internet-delivered Cognitive Behavior Therapy: a single-blind Randomized Clinical Trial with insomnia patients” Forsell, E., Jernelöv, S., Blom, K., Kraepelien, M., Svanborg, C., Andersson, G., Lindefors, N. & Kaldo, V. American Journal of Psychiatry, online 30 January, 2019, doi: 10.1176/appi.ajp.2018.18060699

EU and Russia collaborate in new project on infectious diseases

Mon, 28/01/2019 - 12:37
A new EU project on the theme of HIV, hepatitis C and tuberculosis is a door opener for collaboration between researchers from EU countries and Russia. One of the project’s initiators is Anders Sönnerborg, Professor of Clinical Virology and Infectious Diseases at KI’s Departments of Laboratory Medicine, and Medicine Huddinge. The project Common Actions Against HIV/TBC/HCV Across the Regions of Europe (CARE) will mainly focus on the spread of the infections and resistance to treatment. Tell us more about the research you’ll be doing. “It’s generally about understanding and preventing the spread of HIV, hepatitis C and tuberculosis in Europe and Russia, with emphasis on counteracting development of multi-resistance to TB and HIV. There’s a high rate of treatment-resistant tuberculosis in Russia and we are afraid that a similar scenario may arise also for HIV. We’ll compare data from different patient groups in EU and Russia to learn from each other as well as developing methods for the identification of mechanisms of drug resistance. The long-term goal is to describe approaches for optimal treatment in all three areas and also to establish a research infrastructure which allows a continuation of research collaboration between EU and Russia after the project end.” What are your and KI’s roles in the project? “We’re in charge of the HIV part and will be studying how the virus spreads and what the different viral strains look like. There’s also the issue of resistance when it comes to HIV, too. The virus is constantly mutating and we want to compare the different strains circulating in Europe and Russia. The WHO now recommends a triple therapy in which a new drug, integrase inhibitors, is added. We want to see how any resistance can emerge to this drug and the consequences thereof.” You were one of the project’s initiators. What difference might this make further down the line? “Our project scored maximum points at the reviews of both EU and the Russian Ministry of Science and Education which is promising for the long-term sustainability. The idea is to set up a common infrastructure and contacts and networks for future research. The aim is to establish a research partnership between the EU and Russia for the field that can continue after this initial project phase. The project we’re now running is scheduled to last two years, forming a platform for continuing knowledge-exchange and data comparison and I am convinced that KI will play a role.” Can you say more about the background and how the new collaboration is structured? “Presently Russia can only exceptionally be a partner in EU-sponsored projects. This new innovative call is structured along two parallel processes. The EU and the Russian ministry of science and education are in charge of and finance their respective parts. These parts are combined into one project, so we’re mutually dependent on each other in our research. The project also involves researchers from Georgia, Moldavia and Ukraine, as well as from EU countries. Why study these issues now? “We need to know about how these three infections spread and to avoid resistance problems in the future. Not only do they spread quickly, but more people are travelling more often between countries.” More about Professor Sönnerborg Many new EU projects at KI this spring KI is involved in many EU projects starting this spring. In 19 new collaborations, which span a wide range of fields, KI is either the coordinator or a partner. “There are, for instance, infrastructure projects and technology-development projects, as well as projects aimed at developing new methods for studying toxicity; examining the effects of exercise on cancer treatment; analysing cyber risks in hospitals; or investigating the relationship between the microbiome and cancer,” says Carolina Kristell, coordinator for some of the EU grants at KI’s Grants Office. The number of new projects changes over the years. “It naturally varies depending on how well the EU Commission’s calls fit with the research being done at KI that particular year,” she says. “But it’s still nice to see that KI has more new projects on the go than in the past few years.” Most EU projects last 4 or 5 years. These 19 new projects represent a total of approximately 9,500,000 Euro in grants for KI. “But the form of collaboration and the sums for the individual projects vary, since each call is specific,” she says. Dr Kristell identifies a clear trend in the EU’s framework programmes for research. In the past few years, the Commission has emphasised that researchers applying for grants must describe their work from a societal perspective and show how it helps to bring about improvements. KI’s grants come from many different EU funding programmes. The collaborative project CARE, for example, is funded by a grant from Health, demographic change and wellbeing, a funding scheme within the EU’s Societal Challenges programme. In total there are currently close to 200 ongoing EU projects at KI. Besides collaborative projects, KI also takes part in individual projects like Marie Sklodowska Curie (MSCA) individual fellowships and grants from the European Research Council (ERC). The figures for this year’s new programmes do not include the MSCA or the ERC programmes.

New insights about the role of myelin-producing cells in MS

Wed, 23/01/2019 - 19:00
Subpopulations of oligodendrocytes, myelin-producing cells in the brain that are targeted by the immune system in multiple sclerosis (MS), are altered in MS and might therefore have additional roles in the disease than previously described. The results are published in the journal Nature, in a study led by researchers at Karolinska Institutet in Sweden and University of Edinburgh in the UK. Around the world 2.5 million people are living with MS. MS develops when the immune system’s white blood cells attack the insulating fatty substance known as myelin, which is produced by oligodendrocytes and coats nerve fibres in the central nervous system. This interferes with the proper transmission of nerve electric signals and causes the symptoms of the disease. Previously the researchers have investigated oligodendrocytes in a mouse model of MS and shown that they might have a significant role in the development of the disease. In the current study they have mapped oligodendrocytes in human samples from post-mortem brains of MS patients. “While we found some similarities between the mouse model of MS and human MS, our results also unveil differences. We found changes in different oligodendrocyte subpopulations in MS, suggesting a more complex role of these cells in the pathology of the disease, but also in regeneration of new cells,” says Gonçalo Castelo-Branco, Associate Professor at the Department of Medical Biochemistry and Biophysics, Karolinska Institutet, one if the lead researchers of the study. The results show that oligodendrocyte precursor cells, which are thought to have a crucial role in relapsing-remitting MS to restore myelin, are depleted in the progressive disease. “In addition, the proportions of different resident oligodendrocytes in the lesions are changed, along with their properties, suggesting that they might have important roles in MS,” says Eneritz Agirre, postdoctoral researcher in Castelo-Branco’s group at Karolinska Institutet. The researchers used single-nuclei RNA sequencing, which allows determination of genetic activity of individual cells, to investigate the cellular composition of MS lesions with unprecedented resolution. Oligodendrocytes are a diverse population of cells “We found that oligodendrocytes are a diverse population of cells and that different types are likely to have different functions in the brain,” says Professor Charles ffrench-Constant, of the Medical Research Council Centre for Regenerative Medicine at the University of Edinburgh. “Understanding which types of oligodendrocytes are most beneficial in repairing myelin will be crucial for maximising the chances of developing much-needed treatments for MS,” says Professor Anna Williams of the Medical Research Council Centre for Regenerative Medicine at the University of Edinburgh. Novel markers also identified The researchers also found novel markers that can be useful for the neuropathological characterisation of MS. “Our findings illustrate the power of this technology to study the neuropathology of human diseases such as MS. We predict that the widespread use of this technology with larger numbers of samples will further enhance our understanding of MS and lead to revision of current concepts of the disease,” says Gonçalo Castelo-Branco. Another paper is published simultaneously in Nature, from Professor Jonas Frisén’s group also at Karolinska Institutet, arriving at overlapping conclusions, with a different methodology, The study was conducted in collaboration with F. Hoffmann – La Roche, Ltd, where two of the authors are employed. It was financed by several funding bodies, including the Wellcome Trust, UK Multiple Sclerosis Society, European Research Council and Marie-Skłodowska Curie Actions, the European Committee for Treatment and Research of Multiple Sclerosis (ECTRIMS), Swedish Research Council, Swedish Brain Foundation, Swedish Cancer Society, Stockholm City Council, the Ming Wai Lau Centre for Reparative Medicine, Karolinska Institutet and La Roche, Ltd. Publication “Altered human oligodendrocyte heterogeneity in multiple sclerosis” Sarah Jäkel, Eneritz Agirre, Ana Mendanha Falcão, David van Bruggen, Ka Wai Lee, Irene Knuesel, Dheeraj Malhotra, Charles ffrench-Constant, Anna Williams and Gonçalo Castelo-Branco. Nature, online 23 January, 2019

Old cells repair damage in the brains of MS patients

Wed, 23/01/2019 - 19:00
A new study shows that there is a very limited regeneration of cells in the brain of patients diagnosed with multiple sclerosis (MS). These findings underline the importance of treating MS at an early stage of the disease progression, when the affected cells can repair the damage as they are not replaced by new ones. The results are published in the journal Nature by researchers from Karolinska Institutet and Uppsala University. Nerve cells in the brain communicate with one another through nerve fibres that form complex networks. Many nerve fibres are insulated by a casing of myelin, which contributes to the high-speed transmission of nerve impulses. Myelin is not formed by the nerve cells but by another type of cells called oligodendrocytes. MS is a disease caused by the body’s immune system attacking the myelin and oligodendrocytes. This leads to deteriorated transmission of signals in the nerve fibres and can entail nerve cell death, a combination that causes serious neurological impairments and in severe cases the patient’s death. Old oligodendrocytes are able to form new myelin The disease progression in MS usually fluctuates between periods of deterioration and periods of remission. Studies in mice have shown that damaged myelin can be reformed, and that this requires generation of new oligodendrocytes that make the myelin. It has been assumed that periods of remission in MS patients are caused by newly formed oligodendrocytes replacing the lost myelin. But in this study, a research group has been able to show that there is no regeneration of oligodendrocytes in MS patients in those areas where the myelin seems to have been reformed. Instead, it appears as if old oligodendrocytes that have survived the attack from the immune defence are able to form new myelin.   “We were highly surprised that humans proved to be so different from the animals that have been studied. In humans, there is very limited regeneration of oligodendrocytes, but they seem to have a greater capacity to contribute to repair,” says Jonas Frisén, Professor at the Department of Cell and Molecular Biology at Karolinska Institutet, who led the study. These new findings indicate the importance of treating MS aggressively at an early stage of the disease progression, in order to prevent the loss of oligodendrocytes. “Since few oligodendrocytes are formed, it is important to save the ones you have as they can repair the damage caused by the disease,” says Jonas Frisén. Used the carbon-14 method to determine the age To determine the age of the oligodendrocytes in the MS patients, the researchers measured the amount of the isotope carbon-14 from nuclear detonations during the cold war, which was stored in the cells’ genome, i.e. the DNA. Since the detonations ceased, there has been a gradual decrease of carbon-14, which acts as a type of date mark for when the cells were formed. This method of determining the age of a cell was developed by Jonas Frisén’s team in the early 2000s. Another paper is published simultaneously in Nature, from Associate Professor Gonçalo Castelo-Branco's group also at Karolinska Institutet, arriving at overlapping conclusions, with a different methodology, The study was funded by the Swedish Research Council, the Swedish Cancer Society, the Tobias Foundation, the Strategic Research Foundation (SSF), the Knut and Alice Wallenberg Foundation, the European Research Council (ERC) and the Torsten Söderberg Foundation.   Publication "Oligodendrocyte generation dynamics in multiple sclerosis" Maggie S.Y. Yeung, Mehdi Djelloul, Embla Steiner, Samuel Bernard, Mehran Salehpour, Göran Possnert, Lou Brundin and Jonas Frisén. Nature, online 23 January, 2019

Research projects with sex-and-gender perspective receive MSEK 16.6

Tue, 22/01/2019 - 11:09
The EU agency GenderNet recently decided on grants for 13 international collaborations. Five of these projects have partners at KI. In total about SEK 16.6 million is granted to KI. The projects include sex-and-gender perspective in their respective subject areas. GenderNet includes 16 organizations from 13 countries. The purpose of the EU agency is to strengthen transnational collaboration that integrates the sex-and-gender dimension into research and promotes gender equality through institutional change. A decision has now been made to finance 13 international collaboration projects within the GenderNet Plus Co-Fund. Ten of the collaborations that have been granted financing include Swedish participants, who will receive funding from the Swedish Research Council. The Swedish Research Council's support for the Swedish participants is a total of over SEK 28 million during the period 2018/19–2021. The five collaborative projects with partners at KI who are supported are: Christopher Cederroth at the Department of Physiology and Pharmacology receives funding of SEK 4 108 562 as partner in the project "The combined role of genetic and environmental risk factors in the gender-specific development of severe tinnitus (TIGER)" Hanna Eriksson at the Department of Oncology-Pathology receives funding of SEK 2 549 874 as partner in the project "Sex differences and side effects of immunotherapy: a study to optimize cancer treatment (GEISHA)" Stefan Fors at the Department of Neurobiology, Care Sciences and Society receives funding of SEK 2 871 750 as partner in the project "Evolving gender differences in health & care across cohorts (FUTUREGEN)" Karolina Kublickiene at the Department of Clinical Science, Intervention and Technology receives funding of SEK 3 081 420 as partner in the project "Gender Outcomes INternational Group: to Further Well-being Development (GOING-FWD)" Mariano Salazar at the Department of Public Health Sciences receives funding of SEK 3 951 457 as partner in the project "Masculinities and violence against women among young people- Identifying discourses and developing strategies for change using a mixed method approach (PositivMas)"

KI, Ferring and Rebiotix extend collaboration to research next generation of microbiome treatments

Tue, 22/01/2019 - 10:43
KI and Ferring Pharmaceuticals announced today a five-year extension of their collaboration to explore the potential of the human microbiome in reproductive medicine and women’s health and gastroenterology. The collaboration brings together specialist expertise from Karolinska Institutet in early stage research, Rebiotix Inc. (acquired by Ferring in 2018), a late-stage clinical microbiome company, and Ferring’s therapeutic area and commercialisation capabilities. The collaboration brings together expertise from Ferring, Rebiotix and Karolinska Institutet to unlock the potential of the human microbiome. The collaboration will investigate the role of the microbiome in reproductive medicine and women’s health and gastroenterology through 10 clinical studies involving approximately 9,000 people. The data collected will support future research and development in areas of high unmet need, including recurrent pregnancy loss, preterm birth and inflammatory bowel disease. The extension includes six reproductive health clinical studies of approximately 6,000 women and babies and four gastroenterology studies of approximately 3,000 adults and children, to further investigate the role of the microbiome in areas of high unmet need including recurrent pregnancy loss, preterm birth and inflammatory bowel disease. “The extension of this partnership presents an exciting research opportunity, bringing together unique capabilities of Ferring, Karolinska Institutet and Rebiotix across the clinical development continuum in the mircrobiome space,” said Lee Jones, Founder, President and Chief Executive Officer, Rebiotix, Inc. “This, together with Ferring’s significant experience in reproductive medicine and gastroenterology, offers the potential to drive future research and development for the next generation of microbiome treatments needed to help more people build healthy families and live better lives.” Up to 5 percent of couples face the heartache of recurrent pregnancy loss and around 15 million babies are born preterm every year around the world, with approximately 1 million children dying each year due to related complications. Over 10 million people worldwide live with the pain and discomfort of inflammatory bowel disease. With reproductive health and inflammatory bowel concerns on the rise, there is a need to increase understanding of their causes and develop new solutions. “This innovative public-private partnership demonstrates our ongoing, shared commitment to investigating the human microbiome,” said Lars Engstrand, Professor at Karolinska Institutet and Director of the Center for Translational Microbiome Research. “It will support the expansion of Karolinska Institutet’s foundation of robust biological data and drive our understanding of the microbiome’s impact on important reproductive and gut health challenges.”  

New study raises hopes of eradication of malaria

Tue, 22/01/2019 - 06:00
After major global successes in the battle against malaria, the positive trend stalled around 2015 – apart from in Zanzibar in East Africa, where only a fraction of the disease remains. In a new study published in BMC Medicine, researchers at Karolinska Institutet in Sweden explain why this was and show that new strategies are needed to eradicate the disease. One of the problems is a change in mosquito behaviour and selection in the parasites. The years around 2000 Professor Anders Björkman described as catastrophic with respect to the global spread of malaria. This triggered a world-wide initiative that was given a boost by new kinds of drug and the widespread distribution of impregnated mosquito nets and domestic anti-mosquito sprays. The outcome was a halving of the global spread of the disease by 2015. “But after that, the decline tailed off,” says Professor Anders Björkman at the Department of Microbiology, Tumour and Cell Biology, Karolinska Institutet, who has been running the malaria project for 18 years. “Except for in Zanzibar, where the action taken for its 1.4 million citizens has led to approximately a 96 per cent decline in the incidence of malaria. We’ve optimised these measures with the Zanzibar Malaria Control Programme and can now explain why malaria has not yet been fully eliminated.” Resistant to modern pesticides The study reveals altered behaviour in the malaria mosquitoes, which now bite outdoors instead of indoors. They have also developed a kind of resistance to modern pesticides. Furthermore, there has been a process of selection in the pathogenic parasite, where the remaining form is more difficult to detect but still spreads the disease as before. The researchers have been monitoring 100,000 or so residents of two districts in Zanzibar since 2002. “Both the mosquitoes and the parasites have found ways to avoid control measures,” says Professor Björkman. “We now need to develop new strategies to overcome this if we’re to attain the goal of eliminating the disease from Zanzibar, an endeavour that can prove a model for the entire continent.” What surprised the researchers was the dramatic decline in child mortality in Zanzibar, where malaria control has caused more than a 70 per cent drop in the total child mortality rate. It was previously estimated that only 20 per cent of child deaths in Africa were malaria-related; the researchers now think the reason for this dramatic reduction is that the disease has a greater and more chronic effect on the general health of babies than suspected, thus lowering their resistance to other diseases throughout early childhood. Global initiatives gives hope “Malaria is still the greatest obstacle to a healthy childhood in Africa,” says Professor Björkman. “If you ask African women today, their greatest concern is usually that malaria doesn’t affect their pregnancy and their babies. The global community must continue the fight for improved strategies and control measures. If this happens, I think we’ll be able to reach the goal of ultimate elimination.” Zanzibar was one of the first countries to put the global initiatives against malaria to use and has since been tireless in its work to control the disease. The researchers now hope that these lessons can revive anti-malaria strategies throughout Africa. The study was mainly financed by the Erling-Persson Family Foundation and the Swedish Research Council. Publication “From high to low malaria transmission in Zanzibar - challenges and opportunities to achieve elimination”. Anders Björkman, Deler Shakely, Abdullah Ali, Ulrika Morris, Humphrey Mkali, Abdul-Wahid Al-Mafazy, Khamis Haji, Juma Mcha, Rahila Omar, Jackie Cook, Kristina Elfving, Max Petzold, Michael Sachs, Berit Aydin-Schmidt, Chris Drakeley, Mwinyi Msellem and Andreas Mårtensson. BMC Medicine, online 22 January 2019, doi: 10.1186/s12916-018-1243-z.

Clear link between nurse work environment and patient safety

Thu, 17/01/2019 - 10:33
Lisa Smeds Alenius will defend her doctoral thesis on 22 January 2019 at Karolinska Institutet. Her thesis focuses on factors in the nurse work environment relating to quality of care and patient safety. The thesis shows that the experience of adequate staffing and resources, leadership on ward and hospital levels, and teamwork with physicians are all of great importance for how nurses assess patient safety. The thesis also shows that those assessments are consistent with objective measures of patient safety. Lisa Smeds Alenius is a RN and a doctoral student at the Department of learning, informatics, management and ethics, LIME, at Karolinska Institutet. Why did you want to investigate this topic? “Since the resources available for care, both human and economic, are limited, I wanted to investigate how nurses perceive their work situation to make better and more full use of their competence to benefit both patients and the hospital as an organisation.”   What methods did you use? “The thesis is based on data from the Swedish component of the international, EU-funded project "Registered Nurse Forecasting" (RN4CAST), with survey responses from 11,000 nurses working in medical and surgical wards at all the acute care hospitals in Sweden. Data from the National Patient Register were also used, as well as data on hospitals.” What conclusions did you arrive at? "The factor with the most influence on nurses’ assessments of patient safety on their wards was whether they felt sufficient staff and resources were available. Leadership, both at ward level and at hospital management level, was also influential, as was teamwork with physicians. The thesis also shows that nurses’ assessments of the safety and quality of care can provide an important basis for decision making. When the nurses assessed patient safety and quality of care as excellent, objective measures also showed a clearly reduced risk of patients dying within 30 days. In free-text responses to an open question, many nurses described how they felt they were expected and required to maintain a high level of quality and safety in care, while at the same time they had little opportunity to influence the necessary conditions for care provision. Several organisational factors that make it difficult for nurses to utilise their professional competence to the fullest, were also made visible.” What was surprising? "We saw in the survey responses that nurses had a strong sense of commitment and a desire to make use of and share their knowledge, so it is disheartening to learn that organisational conditions do not really support that. It was also clear that the nurses were very happy with their chosen profession but not necessarily with their place of work. I see that as a force that could be utilised more constructively. Given the right conditions, many might want to continue working as a nurse.” What do you hope your results will lead to? "I hope that the results of the thesis will stimulate nurses and managers at different levels to investigate how nurses’ competencies and capacities are being utilised. Nursing is a central part of patient care and because nurses constitute the largest occupational group in hospitals, it is important their professional knowledge is used in a more strategic and effective way. Nurses should not only be self-evident as indispensable actors in organizing and influencing care processes. It is also about providing the necessary conditions, for example adequate staffing and resources, and supportive organisational structures for care provision. It would also be reasonable to imagine that if there were more opportunities for nurses to make full use of their professional competence, hospitals would become more attractive as workplaces which, in turn would improve chances of recruiting and retaining skilled personnel.” What are you going to do now? "I want to continue researching how healthcare can utilise staff competencies in the best possible ways, which also benefits patients. I also want to explore other professional groups to see how they perceive their work situation and how their skills are utilised.” Text: Helena Mayer

DNA origami: a precise measuring tool for optimal antibody effectiveness

Mon, 14/01/2019 - 17:00
Using DNA origami – DNA-based design of precise nanostructures – scientists at Karolinska Institutet in collaboration with researchers at University of Oslo, have been able to demonstrate the most accurate distance between densely packed antigens in order to get the strongest bond to antibodies in the immune system. The study, which is published in the journal Nature Nanotechnology, may be of significance to the development of vaccines and immunotherapy used in cancer. Vaccines work by training the immune system with harmless mixtures of antigens (foreign substances that trigger a reaction in the immune system), from a virus, for example. When the body is then exposed to the virus, the immune system recognises the antigens that the virus carries and is able to effectively prevent an infection. Today, many new vaccines make use of something called “particle display”, which means that the antigens are introduced into the body/presented to the immune system in the form of particles with lots of antigens densely packed on the surface. Particle display of antigens works in some cases better as a vaccine than simply providing free antigens and one example is the HPV vaccine, which protects against cervical cancer. Antibodies, or immunoglobulins, perhaps the most important part of the body's defence against infection, bind antigens very effectively. The antibodies have a Y-shaped structure where each "arm" can bind an antigen. In this way, each antibody molecule can usually bind two antigen molecules. Were able to accurately measure distances for best binding In the current study, the researchers examined how closely and how far apart from each other the antigens can be packed without significantly affecting the ability of an antibody to bind both molecules simultaneously. "We have for the first time been able to accurately measure the distances between antigens that result in the best simultaneous binding of both arms of different antibodies. Distances of approximately 16 nanometres provide the strongest bond”, says Björn Högberg, professor at the Department of Medical Biochemistry and Biophysics, Karolinska Institutet, who led the study. The study also shows that immunoglobulin M (IgM), the first antibody involved in an infection, is significantly larger reach, that is the ability to bind two antigens, than previously thought. IgM also has a significantly greater reach than the IgG antibodies produced at a later stage of an infection.   DNA-origami a relatively new technique The technology the scientists used is based on a relatively new technique known as DNA origami, which has been in use since 2006, that allows precise nanostructures to be designed using DNA. However, it is only in recent years that scientists have learned to use this technique in biological research. The application used in the study is newly developed. "By putting antigens on these DNA origami structures, we can manufacture surfaces with precise distances between the antigens and then measure how different types of antibodies bind to them. Now we can measure exactly how antibodies interact with several antigens in a manner that was previously impossible”, says Björn Högberg. The results can be used to better understand the immune response, for example why B lymphocytes, a type of white blood cell, are so effectively activated by particle display vaccines, and to design better antibodies for immunotherapy when treating cancer. Important insight for tailor-made treatment The research has been conducted in close collaboration with the Laboratory of adaptive immunity and homeostasis led by Jan Terje Anderson, at the University of Oslo and Oslo University Hospital. “We study the relationship between the structure and function of antibodies. Such insight is important when we design the next generation of vaccines and antibodies for tailor-made treatment of serious diseases. We have long been looking for new methods that can help us get detailed insight into how different antibodies bind to the antigens. The collaboration with Björn Högberg has opened completely new doors,” says Jan Terje Andersen. The study was funded by the Swedish Research Council, the Swedish Foundation for Strategic Research, the Knut and Alice Wallenberg Foundation, the StratRegen/Karolinska Institutet and the Research Council of Norway. Publication "Binding to Nanopatterned antigens is Dominated by the Spatial Tolerance of antibodies" Alan Shaw, Ian T Hoffecker, Ioanna Smyrlaki, Joao Rosa, Algridas Grevys, Diane Bratlie, Inger Sandlie, Terje Enar Michaelsen, Jan Terje Andersen and Björn Högberg. Nature Nanotechnology, online 14 January 2019, doi: 10.1038/s41565-018-0336-3 Film (with subtitles in English) Björn Högberg berättar om DNA origami

The Swedish Childhood Cancer Fund distributes just over SEK 43.5 million to Karolinska Institutet

Thu, 10/01/2019 - 16:33
A little over a third of the SEK 137 million distributed in the Swedish Childhood Cancer Fund major call goes to research projects at Karolinska Institutet. Karolinska Institutet is thus the university that receives the largest part of the total sum. Of the 100 grants, five were awarded to clinical project and 28 to project grants. To find out which projects have received funding, please see below links to the Swedish Childhood Cancer Fund's website.

New insights into a rare type of cancer open novel avenues of study

Mon, 07/01/2019 - 16:01
Undifferentiated uterine sarcoma is a very rare but extremely aggressive cancer type. It can be divided into four groups with different characteristics of clinical importance - a new study at Karolinska Institutet reveals. The results, published in the journal Clinical Cancer Research, also show that the survival rate of patients with a certain type of tumour is better than predicted. Sarcoma is a collective name for 50 different cancers in the body’s mesenchymal (soft) tissues. Undifferentiated sarcoma of the uterus is a cancer with a very poor prognosis, with a typical survival of less than two years. The only treatment of any importance for the survival of a patient is surgery, whereas radiation therapy and chemotherapy do not have any pronounced effect. Since the tumour is so rare, we have limited knowledge of it. In the current study the researchers examined tumour material from 50 patients with the help of both advanced molecular analyses and with more traditional clinical laboratory analyses. The aim was to gain new knowledge about the tumour’s biological characteristics and relate these to the patient’s survival and the routine methods which are used in the laboratory. The tumours could be divided into four groups By means of molecular mapping and analysis of gene expression the tumours could be divided into four previously unknown groups. The four groups had different biological characteristics which are considered by the researchers to be of importance for patients. Firstly, the patients had different survival rates depending on the group that the tumour belonged to. Secondly, the most aggressive tumours were characterised by a distinctive microscopic appearance and protein expression, which makes them identifiable with the help of common laboratory techniques. New potential treatment targets With the help of additional analyses, the researchers were able to identify new potential treatment targets. "It is too early to propose a new treatment that will be useful for the patients today, but the study opens up new avenues for future research, which will create in time new treatment possibilities for women who suffer from these rare tumours," says Joseph Carlson, Associate Professor at the Department of Oncology-Pathology, Karolinska Institutet, who has led the study. The study also shows that some of the patients’ life expectancy is not as gloomy as one thought before the study, since there is a group of patients who survive for a much longer time than two years, and this group can be identified by means of current laboratory techniques.   The study was financed with the support of Radiumhemmet’s research funds, the Stockholm County Council, the Swedish Cancer Society, the Magnus Bergvall Foundation, Thermo Fisher Scientific and the Foundation for Research on Diagnostics and Treatment of Sarcoma at Radiumhospitalet in Norway.   Publication “Integrated Molecular Analysis of Undifferentiated Uterine Sarcomas Reveals Clinically Relevant Molecular Subtypes” Amrei Binzer-Panchal, Elin Hardell, Björn Viklund, Mehran Ghaderi, Tjalling Bosse, Marisa R. Nucci, Cheng-Han Lee, Nina Hollfelder, Pádraic Corcoran, Jordi Gonzalez-Molina, Lidia Moyano-Galceran, Debra A. Bell, John K. Schoolmeester, Anna Måsbäck, Gunnar B. Kristensen, Ben Davidson, Kaisa Lehti, Anders Isaksson and Joseph W. Carlson. Clinical Cancer Research, online 7 January, 2019, doi: 10.1158/1078-0432.CCR-18-2792

Protein map using new method of analysis shared in open database

Thu, 03/01/2019 - 17:01
Researchers at Karolinska Institutet and SciLifeLab have developed a new method of analysis that maps the location of proteins in the cell. The information has been compiled in a database that is accessible to researchers around the world. The method of analysis, which has been published in the journal Molecular Cell, can also provide in-depth knowledge of disrupted cell function in cancer and other diseases. Every cell in the body is made up of thousands of different proteins that are perfectly organised for the cell, and by extension our body organs, to function optimally. Cells can be compared with miniature advanced factories, where each protein has a given function and location. Proteins on the surface of the cell are used for communication between the cell and its environment. Other proteins in the cell nucleus can copy genetic material or protect it from damage. Proteins in the mitochondria produce energy for the cell, while other proteins in the proteasomes, the cell’s waste stations, break down obsolete proteins, and so on. These processes are hugely complex. Mapped the cellular locations of proteins The researchers have mapped the cellular locations of proteins by developing their own method of analysis based on mass spectrometry. This information has been compiled in a large database and released in a new publication. The database can now be used by researchers around the world who are searching for information on proteins whose function is still unknown. "The method we have developed can also be used to study whether certain diseases, such as cancer, are caused by dislocated proteins that disturb normal cell functions. It is also possible to study how cell proteins move from one location to another when the cell’s external milieu changes," says Janne Lehtiö, professor at the Department of Oncology-Pathology at Karolinska Institutet in charge of the study. Protein movement provides important information One example of the latter is the study of how around ten proteins move when cancer cells are treated with specific drugs. This provides important information about which proteins are involved in the cell's response to treatment, and thus knowledge of the drugs’ mechanisms of action. "The method also allows the published database to be expanded by other researchers worldwide, with the aim of mapping the cell’s architecture and protein functions in more detail," says Lukas Orre, researcher at the Department of Oncology-Pathology at Karolinska Institutet and principal author of the study. Complements the Human Protein Atlas The study, in combination with another Stockholm, Sweden, based project, the Human Protein Atlas, that has systematically mapped the human proteome (network of proteins), provides a greater understanding of the cell and a comprehensive map of cell proteins. Database: The study was funded by the Swedish Foundation for Strategic Research, the Swedish Cancer Society, the Swedish Research Council, the Swedish Childhood Cancer Fund, AstraZeneca, the Cancer Research Funds of Radiumhemmet and the Stockholm County Council. Publication ”SubCellBarCode: Proteome-wide mapping of protein localization and relocalization” Lukas Minus Orre, Mattias Vesterlund, Yanbo Pan, Taner Arslan, Yafeng Zhu, Alejandro Fernandez Woodbridge, Oliver Frings, Erik Fredlund and Janne Lehtiö. Molecular Cell online 3 January, 2019.  

New insights into how genes are activated

Wed, 02/01/2019 - 19:00
In a study in Nature, researchers at Karolinska Institutet present a new method for analysing how instructions in the genome control how our genes are activated in individual cells. The results give new insights into how the genome encodes for its own use, which increases our basic understanding of how genes are activated in different types of cell in the body in both good and ill health. Almost all cells in the body have the same set of DNA and can in principle become any kind of cell at all. What distinguishes the cells is the way in which the genes in our DNA are used. All the DNA in a cell is called the genome, our genetic material, but only a very small part of a human’s genome consists of genes. Instead extensive areas of the genome are used to regulate when and in which cells nearby genes are active. These regions contain “enhancers” and the gene sequences located right next to the genes, “promoters”. In a diseased body, these regions are often mutated and a deeper understanding of the function of these regions would bring light to the course of the disease in question. In order for a gene to be used, it must be translated from DNA to copies of RNA. RNA is similar to DNA but its structure is slightly different and it can be used as a template for producing protein. The translation of DNA to RNA is called transcription. Method to sequence RNA in individual cells There are still many things that are not clearly understood about how transcription takes place and how it is regulated. For example, if a gene is used by a cell, the gene’s DNA is not translated to RNA all the time. That would require too much energy. Instead, the transcription takes places in bursts, when the transcription machinery is recruited and several RNA molecules are produced in a short time. The transcription of each gene can be characterised on the basis of the kinetics of this process, that is, the frequency of the bursts and the number of molecules produced during the bursts. ”It used to be difficult to measure the kinetics and how many RNA molecules had been produced by a gene in an individual cell. The methods that have existed up to now were only able to follow a few genes at a time. Moreover, mammals have two sets of almost all their genes so it has been difficult to distinguish between the RNA that comes from the mother’s version of the gene and that from the father’s version,” says Rickard Sandberg, professor at the Department of Cell and Molecular Biology at Karolinska Institutet, who has led the study in question. In the study, the researchers used a method which they had developed themselves to sequence RNA in individual cells. The method makes it possible to measure the number of RNA molecules for almost all the genes used in a cell. Variation found in the genes of two different types of mouse The researchers sequenced cells of connective tissue and embryonal stem cells from a crossbreed of two distantly related mice. With the help of the natural variation found in the genes of the two different types of mouse, the researchers were able to distinguish between the sequenced RNA from the mother’s and the father’s versions of the gene and in that way measure the transcription exactly. They then used a mathematical model to make estimations, for each of the versions, of how often the gene is transcribed and how much RNA is then produced. ”We discovered that enhancers did affect how often a gene was transcribed in the two different cell types but not how many RNA molecules were produced. We also found that certain DNA sequences located at the beginning of a gene can influence how much RNA is produced in a burst. In that way, we have begun to chart how the genome encodes for its own use,” says Anton Larsson, the first author of the study in question and a doctoral student in Rickard Sandberg’s research group.  ”It will be possible to make wide use of our method to chart at a much deeper level how different proteins affect the transcription process,” says Rickard Sandberg. The research was funded with support from the European Research Council, the Swedish Research Council, the Knut and Alice Wallenberg Foundation and the Vallee Foundation. Publication “Genomic encoding of transcriptional burst kinetics” Anton Larsson, Per Johnsson, Michael Hagemann-Jensen, Leonard Hartmanis, Omid R. Faridani, Björn Reinius, Åsa Segerstolpe, Chloe M. Rivera, Bing Ren and Rickard Sandberg. Nature, online 2 January 2018.

SEK 10,5 million have been awarded from the Sjöberg Foundation

Thu, 20/12/2018 - 16:51
Two researchers at Karolinska Institutet have been awarded funds from the Sjöberg Foundation. The foundation promotes cancer research, and research on health and the environment. Simon Ekman, at the Department of Oncology-Pathology, has been awarded SEK 4.5 million for the research project: "Novel therapy using modulation of microRNAs in treatment refractory non-small lung cancer". Mikael Karlsson, at the Department of Microbiology, Tumor and Cell Biology, has been awarded SEK 6 million for the research project: "New immunotherapy for pancreatic cancer by reprogramming macrophages". The funding will be distributed over a three-year period. The foundation aims to promote scientific research with a main focus on cancer, health and the environment. To a lesser extent, other charitable purposes in health and the environment can be promoted.