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The survival rate among extremely preterm babies has greatly improved in Sweden, a country that offers top-class neonatal care, a study led from Karolinska Institutet published in the esteemed journal JAMA reports. The researchers have analysed survival among Swedish babies born over 3.5 months prematurely in week 22-26 and compared the statistics from 2014-2016 to those from 2004-2007. All Swedish hospitals participated in the study, which included 2,205 women who had had complications during pregnancy leading to extremely preterm births. Between these two time periods, the stillbirth rate dropped from 30 to 23 per cent, while the survival rate rose from 70 to 77 per cent. Further, the higher survival was not achieved at the cost of more complications during the neonate period; on the contrary, the researchers observed a reduction in the number of brain and lung damage in the babies born between 2014 and 2016, while the number of other problems, such as eye and abdominal complications, remained unchanged. World class survival rate “Even if there are individual hospitals around the world that have been able to show similar results for selected patients, the survival of an entire population and for a whole country is world class,” says Mikael Norman, professor of paediatrics at the Department of Clinical Science, Intervention and Technology at Karolinska Institutet in Sweden and the researcher responsible for the study. By way of comparison, the survival rate for babies born in week 22-26 is around 50 per cent in the UK, France and the USA. And in many comparable countries, it is still rare for babies born in week 22-23 to survive. Greatest improvement in week 22 The Swedish study found the greatest improvement in survival in babies born in week 22 (from week 22+0 days to week 22+6 days) with birth weights of between 290 and 730 grams. Fifty-eight per cent of those from this group who were admitted to neonatal intensive care between the years 2014 and 2016 survived to at least one year-of-age. The results suggest that central care support initiatives are effective. In recent years, amendments to laws, guidelines and national recommendations have strengthened healthcare provision and the status of extremely preterm babies. Ultimately though, says Professor Norman, the results of the study are testimony to the capabilities of all the midwives, nurses and doctors who provide pregnant women and their babies the best available care 24 hours a day. “The profession and the authorities are both good at taking on board new knowledge and translating it into practice,” he says. “Even if certain problems related to adverse events and long-term complications amongst extremely preterm babies remain as vital areas for improvement, I really think that that Swedish neonatal care should fill us with a sense of pride and joy.” National collaboration Long-standing national collaboration between researchers and clinicians, and the establishment of the national neonatal quality register are other important contributors. “It has been essential to make available knowledge on how neonatal care has developed in Sweden,” says Professor Norman. The study was mainly financed by the Childhood Foundation of the Swedish Order of Freemasons in Stockholm. Mikael Norman has received research grants from the Heart and Lung Foundation and the EU through Horizon 2020. He has also received personal fees from Läkartidningen, the Swedish patient insurance, Liber AB, Studentlitteratur AB and AbbVie AB. Publication “Association Between Year of Birth and 1-Year Survival Among Extremely Preterm Infants in Sweden During 2004-2007 and 2014-2016” Mikael Norman, Boubou Hallberg, Thomas Abrahamsson, Lars J. Björklund, Magnus Domellöf, Aijaz Farooqi, Cathrine Foyn Bruun, Christian Gadsbøll, Lena Hellström-Westas, Fredrik Ingemansson, Karin Källén, David Ley, Karel Maršál, Erik Normann, Fredrik Serenius, Olof Stephansson, Lennart Stigson, Petra Um-Bergström, Stellan Håkansson JAMA, online 26 March 2019, doi: 10.1001/jama.2019.2021

If a particular protein is missing during the fetal stage, no neurons develop that convey pain, temperature and itch, a study from Karolinska Institutet published in the journal Cell Reports shows. The discovery can eventually lead to new drugs for pain conditions. Previous research into the genetics of nerve system development has discovered five genes that are associated with aberrant pain experiences. A person born with a mutation of one of these genes (PRDM12) is unable to feel pain, which causes considerable problems.  “But the exact mechanism the causes the faulty pain function is unknown,” says Saida Hadjab, senior researcher at the Department of Neuroscience, Karolinska Institutet.  Found a crucial protein To ascertain this cause, the team conducted an experiment on mice in which they blocked the expression of the PRDM12 gene in the stem cells that give rise to different kinds of neuron. They found that the mice developed no neurons that register pain, temperature and itch.  “We identified the molecule, a protein, that is required for the development of pain neurons from the stem cells,” says Dr Hadjab. “It’s surprising that the protein has such broad functionality.” In another experiment on chickens, the researchers instead enhanced the expression of the PRDM12 gene in the neuronal stem cells in the belief that more pain cells would develop, but this proved not to be the case. “This shows that the protein PRDM12 needs helper substances, or cofactors,” Dr Hadjab continues. “On the other hand, the development of all other cell types that usually form from these stem cells was stopped.” Could lead to new drugs In adult animals too, the PRDM12 gene is still expressed and only in the pain neurons, but the researchers do not yet know what part the protein plays in these mature cells. It is conceivable that the misregulation of the gene can contribute to chronic pain and other neuropathic pain conditions. “To find out more about this, we should start by removing the protein from adult animals’ pain neurons to see what happens,” says Dr Hadjab, who plans to lead further studies in this field at Karolinska Institutet. “Will they no longer be able to feel pain? If we can then identify the cofactors, we can develop new targeted drugs that can reduce pain symptoms in people with pain conditions.” The study was led by Saida Hadjab, Roman Chrast and Francois Lallemend at Karolinska Institutet in Sweden and was conducted in association with Munich University (Germany), UT Southwestern Medical Center (USA), Vienna medical university (Austria), Vita-Salute San Raffaele University in Milan (Italy) and the Inserm research institute in Montpellier (France). The research was financed by grants from several bodies, including the Swedish Research Council, the Knut and Alice Wallenberg Foundation, StratNeuro, the Ragnar Söderberg Foundation, the Ming Wai Lau centre, the Swedish Brain Fund, the Åke Wiberg Foundation, Karolinska Institutet, the European Research Council and Inserm. Publication “PRDM12 is required for initiation of the nociceptive neuron lineage during neurogenesis”. Luca Bartesaghi, Yiqiao Wang, Paula Fontanet, Simone Wanderoy, Finja Berger, Haohao Wu, Natalia Akkuratova, Filipa Bouçanova, Jean-Jacques Médard, Charles Petitpré, Mark A. Landy, Ming-Dong Zhang, Philip Harrer, Claudia Stendel, Rolf Stucka, Marina Dusl, Maria Eleni Kastriti, Laura Croci, Helen C. Lai, Gian Giacomo Consalez, Alexandre Pattyn, Patrik Ernfors, Jan Senderek, Igor Adameyko, Francois Lallemend, Saida Hadjab, Roman Chrast.  Cell Reports, online 26 March 2019, doi: 10.1016/j.celrep.2019.02.098.

KI Professor Olle Kämpe is one of five appointed Wallenberg Clinical Scholars in 2019. He will receive SEK 15 million to study why the immune system attacks and destroys specific tissues in the body in patients with autoimmune diseases. The prestigious research program Wallenberg Clinical Scholars is run by the Knut and Alice Wallenberg Foundation in partnership with the Royal Swedish Academy of Sciences. Awarded researchers each receive research funding worth SEK 15 million over a five-year period, with the potential to extend this for a further five years. “Sweden has excellent conditions for clinical research, and many important contributions have been made by researchers in this country. Unfortunately, the recent changes to the organisation of healthcare have had a negative effect on the working situation for clinical researchers, and thus Sweden’s position in this important field. Wallenberg Clinical Scholars provides some of the very best clinical researchers with the opportunity to conduct research that is directly linked to healthcare. This is of great importance, not only for medical research, but also for medical services and public health,” comments the general secretary of the Academy of Sciences, Göran K. Hansson, in a press release. Autoimmune problems for different reasons Olle Kämpe is Chief Physician and Professor at the Department of Medicine Solna, and studies how the immune system attacks and destroys specific tissues in the body in patients with autoimmune disease, such as multiple sclerosis, rheumatoid arthritis and vitiligo. Why does the immune system make this sometimes catastrophic mistake? This is a question that Olle Kämpe now will investigate further. To obtain as broad a picture as possible of the events at a molecular level, he will study people who have developed autoimmune problems for different reasons, such as rare genetic mutations or as an adverse event due to treatments with check-point blockade for cancer, the pharmaceutical principle that was awarded the Nobel Prize in physiology or medicine 2018. In another part of the project, he will investigate whether it is possible to restore fertility to women whose ovaries have been damaged by their immune system. The women will receive a pharmaceutical that is used to prevent the immune system from rejecting organs following transplantation. The hope is that the treatment will dampen the immune system’s attack, so that the ovaries can heal and the women regain their fertility. 

Researchers at Karolinska Institutet have identified a mechanism that can explain the impaired wound healing in diabetes which can lead to diabetic foot ulcers. The study is published in the scientific journal PNAS, Proceedings of the National Academy of Sciences. In diabetic mice, wound healing improved when the identified signalling pathway was blocked. Diabetic foot ulcerations are a common complication of diabetes that constitute a major medical, social and economic issue. The lifetime risk of a person with type 1 or type 2 diabetes developing a foot ulcer is around 15 per cent. The treatment options are currently limited due to a poor understanding of the pathogenic mechanisms. Now researchers at Karolinska Institutet have found a signalling pathway between cells, which plays an important role in the impaired wound healing in diabetes. The findings have been published in the scientific journal PNAS, and hopefully may lead to new treatments of diabetic foot ulcerations. Signalling pathway called Notch The identified signalling pathway is called Notch and is activated by interactions between so-called Notch receptors (Notch1-4) and their target molecules on neighbouring cells. This signalling pathway is previously known to be involved in cell differentiation, cell migration and building of new blood vessels. In this study, the researchers discovered an overactivated Notch1 signalling in skin from patients with diabetes and in skin from mouse models of type 1 and type 2 diabetes. The mechanism was studied through experiments in cultured skin cells. The researchers noted that high glucose levels contributed to the signalling pathway being kept activated. The study also investigates how the wound healing is affected when this signalling pathway is blocked. This was achieved by applying blocking substances locally on the skin wounds of diabetic mice, and by studying diabetic mice that had been genetically modified in order to block the signalling pathway in their skin. Attractive new target It was found that local inhibition of Notch1 signalling markedly improved the wound healing in diabetic animals, but not in non-diabetic animals. ”Our results indicate that this is an attractive new target for the treatment of diabetic foot ulcers,” says corresponding author Sergiu Catrina, senior lecturer at the Department of Molecular Medicine and Surgery at Karolinska Institutet. ”Substances that affect this cellular signalling have already been developed for use in other diseases.” The research was supported with grants from the Swedish Research Council, the Family Erling-Persson Foundation, Stockholm county council (ALF), Karolinska Institutet, Strategic Research Programme in Diabetes (SRP), the American Liver Foundation, Bert von Kantzow’s Foundation, the Swedish Society of Medicine and Swedish Cancer Society. Publication ”Triggering of a Dll4–Notch1 loop impairs wound healing in diabetes” Xiaowei Zheng, Sampath Narayanan, Vivekananda Gupta Sunkari, Sofie Eliasson, Ileana Ruxandra Botusan, Jacob Grünler, Anca Irinel Catrina, Freddy Radtke, Cheng Xu, Allan Zhao, Neda Rajamand Ekberg, Urban Lendahl, and Sergiu-Bogdan Catrina. PNAS, online 18 March 2019, doi: 10.1073/pnas.1900351116

Three researchers at Karolinska Institutet have been appointed Wallenberg Scholar in 2019: Ernest Arenas, Sten Linnarsson, and Randal S. Johnson. The researchers – among the foremost in their field in Sweden – receive SEK 18 million each from the Wallenberg Foundations in the form of a five-year grant for free research. “Free research is what it sounds like. The researchers’ own curiosity, expertise and knowledge determines the nature of their research. The Foundation sets no conditions as to results. Failure is allowed, if that’s how it turns out. But history has shown that most knowledge has been gained as a result of free research,” says Peter Wallenberg, Jr, Chairman of the Knut and Alice Wallenberg Foundation, in a press release. Wallenberg Scholars is a program designed to support and encourage some of the most successful researchers at Swedish universities. The aim is for the researchers to be able to adopt a long-term approach to their work, with less time and effort expended on seeking external funding, and with higher ambitions, so that their research has an even greater international impact. The grants also enable researchers to commit to more challenging and longer-term projects. In all, 22 researchers has been chosen for the Wallenberg Scholars programme in 2019. Here are a short descriptions of the three projects at KI: Ernest Arenas, Professor of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics. Summary: Parkinson’s disease is a very common neurodegenerative disorder. However, current therapies neither cure, nor slow down disease. Clinical trials have shown that it is possible to transplant and replace brain cells lost by the disease with cells from a fetus – but this approach poses several technical and ethical challenges. Ernest Arenas and his colleagues aim to identify the combination of genes controlling development of dopamine-producing neurons in the substantia nigra (SN), the cell type mainly affected by Parkinson’s disease. For this purpose they will use new methodologies such as single-cell RNA-sequencing and CRISPR/cas9 genome editing. They will apply the new knowledge to develop two methods to genetically control the formation of SN neurons. More about Ernest Arenas   Sten Linnarsson, Professor of Molecular Systems Biology, Department of Medical Biochemistry and Biophysics. Summary: A cell’s transcriptome shows which genes are active, and how active they are. This has enabled scientists to study how a large variety of specialized cell types develop in the nervous system of a human embryo, helping them to understand both healthy tissue development and the mechanisms behind hereditary developmental biological diseases. Sten Linnarsson and his colleagues have devised a method of measuring gene activity in several million individual cells, and how that activity changes with time. They now want to use the method to study the development of the human brain from the fertilized egg, and build a mathematical model describing and predicting gene activity over time. It will then be possible to use the model to predict the consequences of abnormal changes, for instance if a specific gene has been disrupted. More about Sten Linnarsson   Randall S. Johnson, Professor of Molecular Physiology and Pathology, Department of Cell and Molecular Biology. Summary: There are oxygen-deficient areas in almost all tumors. This impacts an oxygen-sensitive protein called HIF, which in turn influences the way the immune system reacts to the cancer. HIF has complex impacts on the cells of the immune system. On the one hand, immune cells (T-cells) are dependent on HIF to fight the cancer, and their function is also stimulated by hypoxia. On the other hand, HIF is present in macrophages, another type of immune cell, which inhibits the impact of T-cells on cancer, thereby making the cancer more aggressive. Randall Johnson wants to get to the bottom of this paradox to find strategies for manipulating the sensitivity of the immune system to oxygen, with the aim of improving current and future cancer therapies, and immunotherapies in particular. More about Randall Johnson  

A new research and cooperation programme has been launched, that will provide knowledge about sexual harassment in academia – and lead to research-based improvements. The initiative is led by KI jointly with KTH and Malmö University. The launch was introduced by the Minister for Higher Education and Research, Matilda Ernkrans, who, during her speech, said that there is a large number of unrecorded sexual harassment cases in academia. — We need to have a safe work environment in colleges and universities, so that everyone can pursue and develop their academic career. It is obvious that there is a lot left to do to deal with sexual harassment and abusive treatment, says Matilda Ernkrans (S), Minister for Higher Education and Research. The new research and collaboration programme will develop more knowledge about vulnerability, leading to research-based improvements in the work and study environment. The programme will start with a prevalence study, including all the country's academic institutions, which is expected to take two to three years to complete. During the presentation of the programme, Vice-President Karin Dahlman-Wright emphasised the programme will lead to improved quality in research and education. — We will not know how many unrecorded cases there are until we have completed the prevalence study, but the metoo movement indicates that it is a large number. Our hope is that this will lead to a long-term sustainable structure based on which we can continue working on these issues. The presentations today showed that there is a considerable need to develop new knowledge, says Karin Dahlman-Wright, Vice-President at KI. Is this the start of the transparent review of academia that has been missing after the #metoo? — We will do our very best to make sure it is. By uniting the sector and working together, we can achieve more than we have previously managed to achieve, says Karin Dahlman-Wright. The launch took place on 8 March, International Women's Day, and the Wallenberg hall was packed. — We are very pleased with the high level of interest and broad participation of both sectoral authorities, funders and universities from all over the country. This is a sign that we are on the right track and can implement this together, says Ulrika Helldén, coordinator of the research and cooperation programme at KI. During the day, the Swedish Research Council also presented an international scientific review on sexual harassment in academia. In addition, the Swedish Council for Higher Education (UHR) provided a snapshot of its ongoing work on a report regarding efforts to prevent sexual harassment in academic institutions. A research leader and a researcher will be recruited to lead the multidisciplinary prevalence study. These positions will be located at the Department of Learning, Informatics, Management and Ethics on Campus Solna and the application deadline is April 1. If you want more information on the research and cooperation programme to counteract sexual harassment and prevent gender-based vulnerability in Swedish academia, please contact Ulrika Helldén.

Researchers at Karolinska Institutet have found that type IgG antibodies play an unexpected role in atherosclerosis. A study on mice shows that the antibodies stabilise the plaque that accumulates on the artery walls, which reduces the risk of it rupturing and causing a blood clot. It is hoped that the results, which are published in the journal Circulation, will eventually lead to improved therapies. Atherosclerosis is the main underlying cause of heart attack and stroke, and is expected to be the leading cause of death in the world from a long time to come. Approximately a third of patients do not respond to statin treatment. The disease is characterised by the narrowing of the arterial walls resulting from the accumulation of lipids and cells – the so-called atherosclerotic plaque. When the plaque ruptures, blood clots can form that restrict the blood flow to vital organs, such as the heart and brain. To reduce the number of deaths from atherosclerosis, researchers are therefore trying to find ways to prevent this from happening. Clean up damaged tissue Immune system B lymphocytes produce antibodies that are involved in fighting infection. But the antibodies can also help to clean up damaged tissue, for instance in the form of atherosclerotic plaques. Scientists also know that the immune system has a bearing on the development of plaque, but exactly how this happens remains largely unresearched. The team behind the present study has studied how atherosclerotic plaque develops in mice that lack antibodies. “We found that plaque formed in an antibody-free environment was unusually small,” says study leader Stephen Malin, senior researcher at Karolinska Institutet’s Department of Medicine in Solna. “But on closer inspection, we discovered that the plaque looked different and contained more lipid and fewer muscle cells than normal. This suggested that the plaque is unstable and more prone to rupturing, which also turned out to be the case.” Surprising discovery The researchers found that the necessary ingredient for plaque stability was so-called IgG antibodies, the most common class of antibody in the blood. Further analyses showed that the smooth muscle cells of the aorta need these antibodies to divide correctly; when the cells cannot divide correctly, the plaque seems to become smaller and more unstable. “It came as a huge surprise to us that antibodies can play such an important role in the formation of arterial plaque,” says Dr Malin. “We now want to find out if it is some special type of IgG antibody that recognises plaque components. If so, this could be a new way of mitigating atherosclerosis and hopefully reducing the number of deaths from cardiovascular disease.” The study was financed with grants from the EU Seventh Framework Programme, the Swedish Research Council, the Professor Nanna Svartz Foundation, the Austrian Science Fund (FWF), the Ragnar Söderberg Foundation, the German Research Council  (DFG), the German Centre for Cardiovascular Research (DZHK), the European Research Council and Karolinska Institutet (KID funding). Publication “Germinal center-derived antibodies promote atherosclerosis plaque size and stability” Monica Centa, Hong Jin, Lisa Hofste, Sanna Hellberg, Albert Busch, Roland Baumgartner, Nienke Verzaal, Sara Lind Enoksson, Ljubica Matic Perisic, Sanjaykumar Boddul, Dorothee Atzler, Daniel Li, Changyan Sun, Göran Hansson, Daniel Ketelhuth, Ulf Hedin, Fredrik Wermeling, Esther Lutgens, Christoph Binder, Lars Maegdefessel, Stephen Malin Circulation, online 21 March 2019, doi: 10.1161/CIRCULATIONAHA.118.038534

On March 26th, the Karolinska Institutet and Karolinska University Hospital are launching a new study aimed at reducing online sexual exploitation of children. Recruitment of study participants will take place in forums on the encrypted part of the internet called the darknet. This study aims to evaluate a new way to help people stop consuming online child sexual abuse material, a behavior that is currently lacking any scientifically proven treatment. The treatment method being tested is a therapist-assisted online cognitive behavioral psychotherapy programme based on a new manual called Prevent it. Recruitment will take place in forums on the encrypted part of the internet called the darknet, where sharing of child sexual abuse material is common. “On the darknet there are people who are stuck in a behavior that they want to stop, but they need to find a way to do so. What if the same internet, the same network of interconnected computers which makes it possible to spread destruction and abuse, could also be used to provide treatment, even in the most remote and hidden places?”, says Dr Christoffer Rahm, psychiatrist and Principal Investigator of the study. Psychotherapy or placebo To assess the efficacy of the treatment the participant will be randomized into either active psychotherapy or so called psychological placebo, i. e. a controlled similar condition but without active cognitive behavioral psychotherapy interventions. There is also a waiting list group for comparison. The study will recruit globally and the participants will be anonymous. “Sexual exploitation of children online is a large-scale global problem. By recruiting patients via the darknet we will reach many nationalities. An important goal with this study is also to try to democratize the access to highly specialized care at university clinics”, says Dr Christoffer Rahm. Rahm and his team at the Anova clinic, including Dr Katarina Görts Öberg, Dr Stefan Arver, Professor Gerhard Andersson, Professor Viktor Kaldo and project coordinator Charlotte Sparre, will run the study for the next 18 months. Collaboration partners The study has been prepared in collaboration with World Childhood Foundation and ECPAT Sweden. “When a case of sexual abuse is documented and spread online, it increases the trauma suffered by the child. In order to truly prevent sexual abuse of children, we must work with those who are at risk of committing the abuse. There is a great lack of knowledge within this area, which is why Childhood is actively investing in this project.” says Paula Guillet de Monthoux, Secretary General at World Childhood Foundation. “To prevent sexual exploitation of children, many different measures are needed. We work to empower children and young people but preventive work for potential offenders is also necessary. That is why we are a knowledge partner in this project”, says Anna Karin Hildingson Boqvist, Secretary General at ECPAT Sweden. The Swedish Central Ethics Review Board approved the study protocol on the 18th of March.

Meet Johan Mesterton, doctoral student at the Department of Learning, Informatics, Management and Ethics at Karolinska Institutet. For his thesis, he analysed registry data from almost 140,000 births in seven Swedish regions between 2011 and 2012. What are your most interesting results? That there are large differences in outcomes in Swedish childbirth care, differences that can’t be explained by different hospitals treating patients with different characteristics. We’ve adjusted for differences in patient populations between the hospitals, and still there are large variations in how the patients are treated and in health outcomes. It’s also interesting that medical staff feel that data feedback on their results is motivating and can support their quality improvement efforts. What would have been the effect if all birth clinics had been as good as the best? During the period studied, 2,200 caesarean sections, 900 severe perineal tears, 1,500 infections and 2,700 haemorrhages, could have been avoided. That would have been the case if all clinics had performed as well as the 20 per cent that performed best on each quality indicator. What can be done to eradicate the differences? I think the key is to systematically measure healthcare outcomes and to feedback the information to healthcare staff. If you don’t know how many infections there are at your clinic, and even less how it compares to other clinics, it’s hard to motivate yourself to initiate a systematic change programme. Everyone in healthcare wants to give their patients the best possible care. With better feedback on outcomes and improvement potential to the staff, I think everyone will perform better. Why did you choose this particular concern for your thesis? I’ve been working for a long time with analysis of healthcare data and am really interested in how healthcare improvements can be supported. My research was linked to Sveus, a collaboration project involving seven regions in Sweden on the development of methods for monitoring of results in healthcare. Childbirth care was one of the patient groups included in Sveus and I found it fascinating. What will you do next? I’m an industry-financed doctoral student and will continue to work at my company, which develops analytical products for the healthcare sector. In the future I hope to carry on researching in one way or another.

Even premature babies carry anti-viral antibodies transferred from the mother, researchers at Karolinska Institutet in Sweden report in a paper on maternal antibodies in newborns, published in the journal Nature Medicine. The results should change our approach to infection sensitivity in newborns, they say. Antibodies are transferred from the mother’s blood to the fetus that give the newborn passive defence against infection. Since most of this process takes place during the third trimester of the pregnancy, doctors have regarded very premature babies as being unprotected by such maternal antibodies.However, now that the total repertoire of maternal anti-viral antibodies has been analysed in neonates by researchers at Karolinska Institutet and Karolinska University Hospital, another picture is emerging. “We saw that babies born as early as in week 24 also have maternal antibodies, which surprised us,” says corresponding author Dr Petter Brodin, physician and researcher at the SciLifeLab and the Department of Women’s and Children’s Health, Karolinska Institutet. The study comprised 78 mother-child pairs. 32 of the babies were very premature (born before week 30) and 46 were full-term. The analysis show that the repertoire of maternal antibodies was the same in both groups. “I hope that this makes us question some preconceived ideas about the neonate immune system and infection sensitivity so that we can take even better care of newborns,” says Dr Brodin. “Premature babies can be especially sensitive to infection, but that is not because they lack maternal antibodies. We should concentrate more on other possible causes, maybe like their having underdeveloped lung function or weaker skin barriers.” Newly developed method for analysis The study was conducted using a newly developed method for simultaneously analysing the presence of antibodies against all the viruses that can infect humans (with the exception of the Zika virus, which was identified later). The method is developed by US researchers and is based on a so-called bacteriophage display, a technique awarded with the 2018 Nobel Prize in Chemistry.  Briefly, it is based on the ability to make viral particles called bacteriophages display a specific surface protein. In this case, all in all the bacteriophage library displayed over 93,000 different peptides, short-chain proteins, from over 206 species of virus and over 1 000 different strains. The library is mixed with the blood plasma to be tested. Any antibodies in the plasma sample bind with the bacteriophages and can then be detected by the researchers.  The analysis was conducted on samples taken at birth and during the newborns’ first, fourth and twelfth week. The researchers found that the protection offered by the antibodies lasted different durations depending on the virus. This can suggest that their transfer during the fetal stage is regulated rather than random, a possibility the group is now examining further. Importance for vaccine development The study also shows which parts of the virus proteins that antibodies target, information that is important in the development of vaccines, notes Dr Brodin. “If all maternal antibodies target a specific part of a virus protein, that is important to know because then it is that part a vaccine should be based on,” he says. “I hope that our results can be used by others to develop better vaccines, such as against the RS virus that causes so much distress for babies every winter.” The study was financed by the European Research Council, the Marianne and Marcus Wallenberg Foundation, Karolinska Institutet and the Swedish Research Council. Publication “The repertoire of maternal anti-viral antibodies in human newborns” Christian Pou, Dieudonné Nkulikiyimfura, Ewa Henckel, Axel Olin, Tadepally Lakshmikanth, Jaromir Mikes, Jun Wang, Yang Chen, Anna-Karin Bernhardsson, Anna Gustafsson, Kajsa Bohlin and Petter Brodin. Nature Medicine, online 18 March 2019, doi: 10.1038/s41591-019-0392-8

Paracetamol or other painkillers taken during pregnancy are unlikely to cause asthma in the child, according to a large study by researchers at Karolinska Institutet and Queen Mary University of London. The study, which is published in the European Respiratory Journal, suggests that there is another factor linked to use of these drugs that increases the risk of asthma. The analysis includes prescription data on painkillers for almost 500,000 Swedish mothers. The results support earlier findings that women taking paracetamol during pregnancy are more likely to have children who develop asthma. However, they also suggest that the painkillers are not the cause of this increase. Children born to mothers who had been prescribed paracetamol during pregnancy had an increased risk of asthma, but the risk was similar when women had been prescribed different types of painkillers that work in different ways, such as opioids or migraine medication. For example, the increase in risk for asthma at five years of age was 50 per cent for paracetamol, 42 per cent for codeine and 48 per cent for migraine medication. Severe pain can have profound effects The results suggest that another factor linked to use of these drugs is responsible for the increase in asthma risk. One explanation could be that women who are taking prescribed painkillers are more likely to suffer from chronic pain or anxiety, or have a propensity to seek health care. “Severe pain, and the stress that it causes, have profound effects on the body, including on levels of some hormones, and there is evidence for a link between high levels of mothers’ stress in pregnancy and increased risk of asthma in the offspring,” says Professor Seif Shaheen at Queen Mary University of London, UK, who led the study in collaboration with Professor Catarina Almqvist Malmros and colleagues at Karolinska Institutet. Researchers say their results should give women reassurance to take painkillers during pregnancy when they are prescribed by a doctor. Financial support for the study was provided from the Swedish Research Council, the Stockholm County Council (ALF-projects), the Swedish Heart-Lung Foundation, FORTE and the Swedish Asthma and Allergy Association’s Research Foundation. This news article is based on a press release from the European Respiratory Journal. Publication “Prescribed analgesics in pregnancy and risk of childhood asthma” Seif O Shaheen, Cecilia Lundholm, Bronwyn K Brew, Catarina Almqvist European Respiratory Journal, online 18 March 2019, doi: 10.1183/13993003.01090-2018

Three new honorary doctors have been appointed by Karolinska Institutet. Paolo Chiesi, Douglas Easton, and Sophie Ekman will have their doctorates formally conferred at Stockholm City Hall on 10 May 2019. An honorary doctorate can be awarded to researchers who have contributed to science, humanity, or Karolinska Institutet (KI). It can also be awarded to individuals who do not have the official requirements of a PhD but have contributed to research and development relevant to KI. Paolo Chiesi Paolo Chiesi has as part of the family company Chiesi Farmaceutici S.p.A. since 1987 supported research on surfactant. In the early 1980’s researchers at KI developed a substance called Curosurf, intended on treating prematurely born children suffering from respiratory distress syndrome. Curosurf is derived from the lungs of pigs, and a collaboration with the pharmaceutical industry became necessary in order to produce a sufficient quantity. As head of research at Chiesi Farmaceutici, Paolo Chiesi supported the project from the start. Beyond financial support, Paolo Chiesi also launched Curosurf on the market and has continued to support annual international research meetings for neonatologists. With the support of Chiesi Farmaceutici, a synthetic version of surfactant has now been developed at KI, and is currently undergoing clinical tests. If successful, synthetic surfactant could lead to more premature born children being treated. “I feel honored to receive this honorary degree from one of the most prestigious and respected medical universities of the world. I am grateful, as it is totally unexpected and crowns a life I almost entirely devoted to chasing after the scientific research, I think with a curious, open-minded, perhaps not fully methodical approach. Finally, I must say I am moved, as the excellent researchers I met at the KI in the eighties and with whom I have been collaborating since then have also become cherished friends”, says Paolo Chiesi. Douglas Easton Douglas Easton has over the past three decades focused his research on identifying genetic determinants of breast cancer. His achievements have dramatically improved our understanding of how breast cancer is inherited. Douglas Easton was one of the co-founders of the Breast Cancer Linkage Consortium that was active between 1990 and 1996. He played an important role in defining how mutations in BRCA1 and BRCA2 genes contribute not only to breast cancer, but prostate and pancreatic cancer as well. In 2005 Douglas Easton initiated the Breast Cancer Association Consortium with the aim of identifying how single nucleotide polymorphisms can help in explaining breast cancer. His work has had positive clinical implications, both in Sweden and internationally. “I am deeply grateful to be receiving an honorary doctorate from KI. I have been involved in fruitful collaborations with scientists at the KI over many years and I feel this award is, in part, a recognition of the success of these collaborations, which have involved some of the largest ever studies in cancer genetics. I am particularly proud to be receiving an award from the KI, one of the most prestigious research institutes in the world, in recognition of the international impact of our work”, says Douglas Easton. Sophie Ekman In four decades, Sophie Ekman has worked as school doctor in Sweden, including 30 years as head of the school health services in Solna. In 1987 she co-founded Stiftelsen Läkare mot AIDS Forskningsfond together with colleagues from Föreningen Läkare Mot AIDS. Sophie Ekman has been the fundraiser for the trust fund and with inspiring effort collected the substantial capital, which annually is distributed within the HIV research field.  Sophie Ekman has on her own initiative started several large-scale and non-profit public health campaigns related to school health services, which have involved numerous parts of society. On a broad front she has fought for improved wellness among children, for instance through the anti-drug campaign Just Say No and the world’s first anti-smoke campaign with parents as the target audience. Sophie Ekman has also contributed to the effort of earlier detection of neuropsychiatric disabilities as ADHD and autism in society. “I am exceedingly happy and feel great gratitude about HIV issues again being in the spotlight. I thank KI from all of my heart. This international reward emphasizes the importance of traditional school health services. A local public health institute, until 2010 present in all Swedish schools, make a difference for the health of both children and parents”, says Sophie Ekman. The first honorary doctors of medicine at KI were appointed in 1910. Each year, about 20 nominations are submitted. Nominations are accepted from permanent staff members at KI with a doctorate. Between 2000 and 2018, 74 new honorary doctors have been appointed, of which 21 were women. 

The presence of oral bacteria in so-called cystic pancreatic tumours is associated with the severity of the tumour, a study by researchers at Karolinska Institutet in Sweden published in the journal Gut reports. It is hoped that the results can help to improve diagnosis and treatment of pancreatic cancer. Pancreatic cancer is one of the most lethal cancers in the west. The disease is often discovered late, which means that in most cases the prognosis is poor. But not all pancreatic tumours are cancerous. For instance there are so-called cystic pancreatic tumours (pancreatic cysts), many of which are benign. A few can, however, become cancerous. It is currently difficult to differentiate between these tumours. To rule out cancer, many patients therefore undergo surgery, which puts a strain both on the patient and on the healthcare services. Now, however, researchers at Karolinska Institutet have found that the presence of bacteria inside the cystic tumours is linked to how severe the tumour is. “We find most bacteria at the stage where the cysts are starting to show signs of cancer,” says corresponding author Margaret Sällberg Chen, docent and senior lecturer at the Department of Dental Medicine. “What we hope is that this can be used as a biomarker for the early identification of the cancerous cysts that need to be surgically removed to cure cancer, this will in turn also reduce the amount of unnecessary surgery of benignant tumours. But first, studies will be needed to corroborate our findings.” The researchers examined the presence of bacterial DNA in fluid from pancreatic cysts in 105 patients and compared the type and severity of the tumours. Doing this they found that the fluid from the cysts with high-grade dysplasia and cancer contained much more bacterial DNA than that from benign cysts. To identify the bacteria, the researchers sequenced the DNA of 35 of the samples that had high amounts of bacterial DNA. They found large variations in the bacterial composition between different individuals, but also a greater presence of certain oral bacteria in fluid and tissue from cysts with high-grade dysplasia and cancer. “We were surprised to find oral bacteria in the pancreas, but it wasn’t totally unexpected,” says Dr Sällberg Chen. “The bacteria we identified has already been shown in an earlier, smaller study to be higher in the saliva of patients with pancreatic cancer.” The results can help to reappraise the role of bacteria in the development of pancreatic cysts, she notes. If further studies show that the bacteria actually affects the pathological process it could lead to new therapeutic strategies using antibacterial agents. The researchers also studied different factors that could conceivably affect the amount of bacterial DNA in the tumour fluid. They found that the presence of bacterial DNA was higher in patients who had undergone invasive pancreas endoscopy, a procedure that involves the insertion of a flexible tube into the mouth to examine and treat pancreatic conditions thus the possible transfer of oral bacteria into the pancreas. “The results were not completely unequivocal, so the endoscopy can’t be the whole answer to why the bacteria is there,” she continues. “But maybe we can reduce the risk of transferring oral bacteria to the pancreas by rinsing the mouth with an antibacterial agent and ensuring good oral hygiene prior to examination. That would be an interesting clinical study.” The study was conducted in collaboration with researchers at the Department of Clinical Science, Intervention and Technology, the Department of Laboratory Medicine at Karolinska Institutet and Science for Life Laboratory. It was financed by the Swedish Cancer Society, Stockholm County Council (ALF funding), Styrgruppen KI/SLL för Odontologisk Forskning (the KI/SLL steering group for dental research, SOF), KI KID-funding, and the Ruth and Richard Julin Foundation. Publication ”Enrichment of Oral Microbiota in Early Cystic Precursors to Invasive Pancreatic Cancer”. Rogier Aäron Gaiser, Asif Halimi, Hassan Alkharaan, Liyan Lu, Haleh Davanian, Katie Healy, Luisa W Hugerth, Zeeshan Ateeb, Roberto Valente, Carlos Férnandez Moro, Marco del Chiaro, Margaret Sällberg Chen. Gut, online 14 mars 2019.

A Swedish delegation led by H.E. Lena Hallengren, Minister for Health and Social Affairs, visited India in late February with the purpose to strengthen Swedish-Indian health collaboration. KI's Vice-Rector Anders Gustafsson was one of the participants in the delegation. “It was very valuable for Karolinska Institutet, as the only Swedish university, to accompany the Minister for Health and Social Affairs' delegation trip to India. Many new contacts were made and old contacts strengthened“, says Anders Gustafsson, Academic vice president of research at KI. Other participants were representatives from The National Board of Health and Welfare, the Public Health Agency of Sweden, the Swedish Medical Products Agency, Karolinska University Hospital, Region Uppsala and Swecare, which is a foundation that works for enhanced export and internationalization of Swedish health care and life science, with several of their member companies. Within KI, an annual KI-India seminar is held, where researchers who are involved in collaborative projects with colleagues in India gather, present ongoing projects and discuss future opportunities. Researchers, teachers, PhD students and interested are invited to this year's KI-India Seminar which takes place Tuesday 21 May 2019. 

PhD student Sara Causevic and researcher Helena Nordenstedt at the Department of Public Health Sciences and student Wiebke Mohr at the Department of Learning, Informatics, Management and Ethics started the Women in Global Health Sweden Chapter as a response to the Call to Action on Gender Equality. What is the Women in Global Health Sweden Chapter? This chapter aims to enhance the visibility of women working in global health in Sweden or that are coming from Sweden, intensify mutual support, advocate for gender equal representation on panels and conferences, establish mentoring programs, promote women's health and support further countries to start a WGH chapter. We came into contact with the global organization called Women in Global Health (WGH) and got support to organize a WGH chapter in Sweden through the Swedish Institute for Global Health Transformation (SIGHT) at the Royal Swedish Academy of Sciences. WGH in Europe consists of three chapters: Germany, Sweden, and Norway. Why did you take this initiative? The status of women in global health calls for improvement, especially in the field of global health governance where women have not been advancing in their roles or have not been present at all. There are significant gender disparities in career choices, such that women account for up to 75% of the health workforce in many countries. Much work is needed to reach gender parity in leadership across high-level positions in Global Health, academia, non-governmental institutions and private sector institutions related to global health. If we want to achieve the Sustainable Development Goals (SDGs), we need to have a diverse, gender-balanced leadership. Whom do you want to reach and influence? We want to influence the global health field where we can strengthen the position of human resources, and we can connect and advocate for gender equality within UN organizations, aid and development agencies, academia, public and private sectors. What results do you hope for? We hope this initiative will help reduce the pay gap, leadership gap and advance women's position in Sweden, but also offer opportunities to share the lessons learned abroad. What will happen next?  Actively spreading and distributing a recently produced booklet consisting of 100 biographies of women working in global health in Sweden and Swedish women working in global health abroad. This booklet is to help identify women for leadership positions in the field of global health, to connect existing female talent to conference circuits in Europe and worldwide and to propose them for conferences in different thematic areas where global health is also an issue enhancing multidisciplinary cooperation and knowledge transfer. We hope to develop a database for enhanced networking and support. Also, we plan to have open discussion thematic meetings on subjects that have been identified as national priorities, for example increasing opportunities for education and training and transforming unpaid care and informal work into decent jobs. Looking globally, we are collaborating with the other two chapters in Europe to support the development of a South Eastern Europe chapter, so we are going beyond our countries and region.

Karolinska Institutet now facilitates for all educational programs to use digital examinations. Digital examinations are legally secure and efficient as well as allows for new possibilties for teachers and course administrators to develop the education programs. Examinations are an incredibly important tool since it defines what students focus on in a course, says Annika Östman Wernerson, Academic vice president of education at KI. — To be able to conduct the examinations digitally opens the door to new possibilities, where questions can be put into a context, for example a clinical context, with the help of pictures, films or web-based tools. This makes the teachers’ jobs easier and in compliance with the rule of law.  — It can sometimes be difficult to interpret handwritten answers, and it becomes easier to provide comments and feedback. Some of the questions can also be corrected automatically, which gives the teachers more time to correct other questions. I hope that it will also stimulate the teachers to further develop the examinations. The system makes it easy to visualise and analyse the examination statistically, says Annika Östman Wernerson. Ultimately this will benefit the health care system. — If our students undergo exams in a way that stimulates understanding and in-depth learning it will benefit future patients, says Annika Östman Wernerson. Computer equipped examination rooms The examination rooms in BZ at Campus Solna and in Neo at Campus Flemingsberg have been equipped with 250 respectively 175 computers for examination, which opens the door to larger courses to take examinations. It is the result of a venture that has been ongoing since January 2018 in collaboration between several parts of KI, among others the university library, the facilities office, the IT department and the Committee for Education, which is also financing the project. The work has focused on two aspects: acquiring the correct equipment and creating the conditions needed in the rooms to be able to conduct digital examinations. to create a management organisation that can conduct digital examinations in the future with issues surrounding law, technology and pedagogy, an organisation that is under construction. The selection process of computers began with an investigation. — We rather quickly found that in order to guarantee legal security and uniform exams together with secure computer operations we needed permanently installed equipment owned by KI, explains the project leaders from the university library, Joakim Jedholt and Bodil Moberg. The computers have been equipped with software in order for digital examinations to be conducted at KI. — In an exam, only those who are taking the exam have access to the exam plus applications on the computer allowed for the exam, like for example a calculator or pharmaceutical information. The answers are stored in the cloud, not in the computer, so that if there is a power failure everything is saved, says Bodil Moberg Decreasing the risk of cheating Minimizing the risk of cheating has been a top priority — We have ensured that all computers are equipped with secrecy filters and confidentiality protection. The questions can be arranged in individual order in the program, so that everyone is not working on the same questions at the same time, which is considerably harder with traditional paper exams, says Joakim Jedholt. The project leaders have also studied how other universities work with digital examinations. — In particular, we have been impressed by the work done at Oslo University, where the number of e-exams have skyrocketed and there is an efficient organisation that manages all examinations. We have also conducted study visits at Stockholm, Uppsala and Gothenburg universities, says Joakim Jedholt. The first digital examination in the new examination rooms will be held in the end of February-beginning of March, with no lack of tension felt by the two project leaders. — It feels kind of like getting up on stage for the first time. But we are convinced that it is going to work out well, says Bodil Moberg. Three advantages to digital examinations Offers more opportunities for students to demonstrate their knowledge. ​The teachers can better assess the students’ answers and their own exams. Increased compliance with the rule of law since the risk of cheating and misinterpretations of answers decreases. Quality and the compliance to the rule of law — We teachers will be saving loads of time in correcting the exams, time that we can use to prepare questions and analyse the results.  It will also make it easier to keep track of examination data and store questions. It also feels good from a sustainability perspective to stop handing out stacks of paper to the enormous amount of students who are taking the examinations, says Marie Dahlin, Course Coordinator and moderator for Clinical Medicine with an emphasis on neurology, senses and psyche at the Medical Program KI.

By applying gene analysis to individual cells from early mouse embryos, researchers at Karolinska Institutet in Sweden have discovered previously unknown cellular stages of fetal development from fertilised egg to living being. The study is published in the scientific journal Cell Reports. All over the world, researchers are trying to find all the pieces of the puzzle describing how a fertilised egg develops into a healthy being, in order to gain a detailed understanding of the differentiation process from the totipotent stem cell. This knowledge is essential to understanding the mechanisms behind congenital diseases and fetal malformation, and eventually, how to treat diseases using stem cells. “Being able to follow the differentiation process of every cell is the Holy Grail of developmental biology.” says Qiaolin Deng, researcher at the Department of Physiology and Pharmacology, Karolinska Institutet, and Karolinska University Hospital, Sweden. Dr Deng has led the study, which has revealed new details of the critical phase between the attachment of the embryo to the uterus and the formation of the first anatomical axis, at which point the embryonic cells begin their journey towards creating a body, with a front and a back. “It’s a critical period when the whole anatomical plane is created,” she says. “If it doesn’t go smoothly, it can cause fetal malformation or death.” However, the developmental states of the cells that take part in the process is not always the same. In order to map what happens in individual cells, the researchers used single-cell RNA sequencing on a total of 1,724 cells from 28 mouse embryos in four early stages of development (5.25 to 6.5 days old). An average of 8,577 genes were expressed in each cell. Using bioinformatic analysis, the cells were then sorted into different cell types on the basis of which genes were active or inactive, allowing the researchers to see the order in which the genes were switched on. The result was a molecular road-map of the events that control cell differentiation. Previously unknown details “The study has revealed previously unknown details about what happens before the early embryo gains its first spatial orientation, and shown that the cells along the future head-tail axis have different differentiation potential,” says Dr Deng. At the same time as the anatomical axis starts to form, another process gets underway in the female embryo, which contains two X chromosomes, one from each biological parent. Previous studies on mice have shown that the paternal X chromosome is first switched off completely in the embryo so that female embryos do not have twice the genetic activity as male. The paternal X chromosome copy remains switched off in the cells that form the placenta and the yolk sack, but is reactivated in the embryo’s cells. Then a random inactivation of the maternal or paternal X chromosome occurs. Female embryos therefore comprise a “mosaic” of cells, in which either the maternal or paternal X chromosome is active. The new study shows that the first inactivation of the paternal X copy does not happen to the extent previously believed. “What’s interesting, molecule-wise, is that the paternal X chromosomes that are reactivated never have been completely switched off. The random inactivation also takes place at different rates in the embryo’s cells.” New light on the early development The results of the study shed new light on the early development of the embryo in animals, humans included. “Knowledge of the events and factors that govern the development of the early embryo is indispensable for understanding miscarriages and congenital disease,” says Dr Deng. “Around three in every 100 babies are born with fetal malformation caused by faulty cellular differentiation.” The study was conducted in collaboration with researchers at the University of Chinese Academy of Sciences, Shanghai Tech University, Tongji University (Shanghai) and the University of Sydney (Australia). It was financed with grants from the Swedish Research Council, SSMF, the Åke Wiberg foundation, the KID foundation, KI faculty-funded career grant and the Jeansson foundation. Publication “Single-cell RNA-seq reveals cellular heterogeneity of pluripotency transition and X-chromosome dynamics during early mouse development” Shangli Cheng, Yu Pei, Liqun He, Guangdun Peng, Björn Reinius, Patrick P L Tam, Naihe Jing, Qiaolin Deng Cell Reports, online 5 March 2019, doi: 10.1016/j.celrep.2019.02.031

In a paper published in the journal Nature, an international research team led by researchers at Karolinska Institutet in Sweden report that bone growth in mice takes place in accordance with the same principles as when new cells are constantly produced in blood, skin and other tissue. This contradicts the previous understanding that bone growth depends on a finite number of gradually consumed progenitor cells. If the new findings also apply to humans, they could make an important contribution to the treatment of children with growth disorders. The growth of children’s bones depends on growth plates (physes) situated close to the end of all long bones in the body. These plates consist of cartilage cells, chondrocytes, that form a kind of scaffold supporting the formation of new bone tissue, and that are themselves generated from stem-cell like progenitor cells called chondroprogenitors. For long bones to grow properly, chondrocytes must be generated constantly throughout the growth period. The general view in the field has been that there is a limited number of progenitor cells that are formed during embryonic development and then consumed for bone growth until they run out and we stop growing. In an attempt to ascertain whether or not this is true, researchers at Karolinska Institutet decided to study the formation of chondrocytes in mice. “What we found was that small ‘clones’ of cells were generated from the same progenitor cells during embryonic development, which is in line with the current view,” says research group leader Andrei Chagin, docent at the Department of Physiology and Pharmacology, Karolinska Institutet. “But after birth there were dramatic changes in cell dynamics and large, stable clones were formed that proved to be a consequence of how the chondroprogenitors had acquired the ability to regenerate.” Progenitor cell situated in stem cell niche Such progenitor cell behaviour is typical for tissue that constantly produces many new cells, such as skin, blood and intestine. For such tissue types, it has been shown that the progenitor cells are situated in a very specific micro-environment, a stem cell niche, which helps to generate the necessary cells (e.g. skin and blood cells) but also enables the progenitor cells to renew themselves. If the niche is disrupted or dysfunctional, the progenitor cells become depleted and the tissue is damaged. The researchers have now shown that there is a stem cell niche in growth plates too, at least in mice, and that bone growth ceases if this local micro-environment is disrupted, implying that bone growth follows a completely different principle to what was once thought. “If it turns out that humans also have this growth mechanism, it could lead to a significant reassessment of numerous therapeutic approaches used for children with growth disorders,” says Dr Chagin. “The mechanism could also explain some previously puzzling phenomena, such as the unlimited growth seen in patients with certain genetic mutations.” The study was financed by the Swedish Research Council, StratRegen (Karolinska Institutet), the King Gustaf V 80-year Foundation, the Swedish Cancer Society, the Swiss National Science Foundation, EMBO, the Frimurare Barnhuset (Masonic children’s home) Foundation, the Foundation for Child Care and the Grant Agency of the Czech Republic. Publication “A radical switch in clonality reveals a stem cell niche in the epiphyseal growth plate”. Phillip T Newton, Lei Li, Baoyi Zhou, Christoph Schweingruber, Maria Hovorakova, Meng Xie, Xiaoyan Sun, Lakshmi Sandhow, Artem V Artemov, Evgeny Ivashkin, Simon Suter, Vyacheslav Dyachuk, Maha El Shahawy, Amel Gritli-Linde, Thibault Bouderlique, Julian Petersen, Annelie Mollbrink, Joakim Lundeberg, Grigori Enikolopov, Hong Qian, Kaj Fried, Maria Kasper, Eva Hedlund, Igor Adameyko, Lars Sävendahl, Andrei S Chagin. Nature, online 27 February 2019, doi: 10.1038/s41586-019-0989-6.

Researchers at Karolinska Institutet in Sweden have discovered a new and rare skeletal disease. In a study published in the journal Nature Medicine they describe the molecular mechanism of the disease, in which small RNA molecules play a role that has never before been observed in a congenital human disease. The results are important for affected patients but can also help scientists to understand other rare diagnoses. The newly identified skeletal disease was first observed in a parent and a child from a Swedish family. “They came to my clinic,” says the study’s lead author Giedre Grigelioniene, physician and associate professor at the Department of Molecular Medicine and Surgery, Karolinska Institutet. “They’d received a different diagnosis previously, but it didn’t fit with what we were seeing in the X-rays. I was convinced that we were looking at a new diagnosis that had not been described before.” A long, arduous process then began to examine the finding further. The results of these efforts are now published in a study in Nature Medicine, in which Giedre Grigelioniene and her colleagues describe the new skeletal disease – a type of skeletal dysplasia – and its mechanism. Mutation identified Together with Fulya Taylan, assistant professor at the same department at Karolinska Institutet, the disease causing mutation in a gene called MIR140 was identified. The gene does not give rise to a protein but to a so-called micro-RNA (miR-140), a small RNA molecule that regulates other genes. Working alongside with Tatsuya Kobayashi, associate professor at Massachusetts General Hospital, Harvard Medical School in Boston, USA, the researchers produced a mouse model of the disease, using the CRISPR-Cas9 “molecular scissors” technique to create a strain carrying the identified mutation. They subsequently observed that the animals’ skeletons displayed the same aberrations as the three patients in the study. The researchers also show that the identified mutation leads to an abnormal expression of several important genes in the cartilaginous growth plates and the ends of the long tubular bones. These studies were done in collaboration with Hiroshi Suzuki, researcher at the Massachusetts Institute of Technology in the lab of Phillip Sharp, Nobel laureate in medicine. Some genes that are normally suppressed by miR-140 are expressed, while others are down-regulated. “This causes a change in skeletal growth, deformed joints and the delayed maturation of cartilage cells in the patients, who have short stature, small hands and feet and joint pain,” says Dr Grigelioniene. Normal function knocked out The identified mutation knocks out a normal function of the micro-RNA, which is replaced by a different function. The mechanism is called neomorphic and has never before been described involving small RNAs in human congenital disease. A similar mechanism in cancer cells was described last year in a paper in Nature Genetics by researchers who were also involved in the present study. According to Dr Grigelioniene, the results now published are important both for patients with the disease and for scientists interested in how small regulatory RNA molecules are involved in the development of human congenital disease. “We plan to examine whether similar mechanisms with mutations in small RNA genes are involved in the development of other rare congenital disorders,” she says. “As for patients who already have this disease, the results mean that they can choose to use prenatal fetal diagnostic, in order not to pass the disease on to their children”. The study was financed by grants from Stockholm County Council, the National Institutes of Health, the Swedish Research Council, the European Society for Paediatric Endocrinology (a programme financed by pharmaceutical company Eli Lilly), the Fernström Foundation, Karolinska Institutet, the Swedish Society of Medicine, the Promobilia Foundation, Frimurare Barnhuset (Masonic children’s home), the Samariten Foundation for Paediatric Research, the Uehara Memorial Foundation and the Osamu Hayaishi Memorial Scholarship. One of the co-authors works at Emedgene Technologies and one is a director of Syros Pharmaceuticals. Publication "Gain-of-function mutation of microRNA-140 in human skeletal dysplasia” Giedre Grigelioniene, Hiroshi I. Suzuki, Fulya Taylan, Fatemeh Mirzamohammadi, Zvi U. Borochowitz, Ugur M. Ayturk, Shay Tzur, Eva Horemuzova, Anna Lindstrand, Mary Ann Weis, Gintautas Grigelionis, Anna Hammarsjö, Elin Marsk, Ann Nordgren, Magnus Nordenskjöld, David R. Eyre, Matthew L. Warman, Gen Nishimura, Phillip A. Sharp, Tatsuya Kobayashi. Nature Medicine, online 25 February 2019

This year, the Swedish medical university Karolinska Institutet for the forst time awards a research prize in memory of Professor Dan Grandér, who passed away in 2017. The receiver of the Dan Grandér Memorial Prize for best doctoral thesis in the area of cancer research at Karolinska Institutet is Dr Nicholas Valerie, Department of Oncology-Pathology. Nicholas Valerie defended his thesis titled “Roles of NUDT5 and NUDT15 beyond oxidized nucleotide sanitation and their potential as therapeutic targets” in April 2018. In this thesis, he demonstrates novel functions of the two enzymes NUDT5 and NUDT15 in oxidized nucleotide metabolism. Furthermore he shows that NUDT5 is an important regulator of hormone signalling, and that it could block thiopurine-based chemotherapies to reduce their efficacy as cancer therapeutic agents. This led to the development of targeted NUDT5 inhibitors which might be used to potentiate cancer therapy. Professor Dan Grandér was a prominent researcher and physician in the field of cancer, and at the time for his death also Head at the Department of Oncology-Pathology at Karolinska Institutet. He passed away in 2017 at the age of 53 years, himself the victim of cancer disease. The research prize in his memory is awarded on Friday, 22 February 2019 at the BioClinicum Cancer Research Meeting in Stockholm, Sweden. The awardee receives SEK 50,000 and a diploma.