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Two of the four winners of Anders Jahre‘s Awards for Medical Research are researchers at Karolinska Institutet. The awards are among the largest within Nordic biomedical research. Professor Rikard Holmdahl at the Department of Medical Biochemistry and Biophysics and professor Ludvig M. Sollid at the University of Oslo share the Anders Jahre Senior Medical Prize, including a grant of NOK 1,000,000. They receive the award in recognition of their pioneering research in the field of autoimmune diseases. Professor Pernilla Lagergren at the Department of Molecular Medicine and Surgery is awarded Anders Jahre‘s Prize for Young Scientists. She is awarded the prize for her ”groundbreaking research on factors that affect survival and quality of life following cancer surgery”. The grant of NOK 400,000 is shared with dr Kaisa Haglund at the Oslo University Hospital. Anders Jahre‘s Awards for Medical Research honour excellent research in basic and clinical medicine. They are awarded annually by a committee at the University of Oslo.  

An international team of scientists led from Sweden’s Karolinska Institutet has for the first time mapped all the genes that are activated in the first few days of a fertilised human egg. The study, which is being published in the journal Nature Communications, provides an in-depth understanding of early embryonic development in human – and scientists now hope that the results will help finding for example new therapies against infertility. At the start of an individual’s life there is a single fertilised egg cell. One day after fertilisation there are two cells, after two days four, after three days eight and so on, until there are billions of cells at birth. The order in which our genes are activated after fertilisation has remained one of the last uncharted territories of human development. There are approximately 23,000 human genes in total. In the current study, scientists found that only 32 of these genes are switched on two days after fertilization, and by day three there are 129 activated genes. Seven of the genes found and characterised had not been discovered previously. “These genes are the ‘ignition key’ that is needed to turn on human embryonic development. It is like dropping a stone into water and then watching the waves spread across the surface”, says principal investigator Juha Kere, professor at the Department of Biosciences and Nutrition at Karolinska Institutet and also affiliated to the SciLifeLab facility in Stockholm. The researchers had to develop a new way of analysing the results in order to find the new genes. Most genes code for proteins but there are a number of repeated DNA sequences that are often considered to be so-called ‘junk DNA’, but are in fact important in regulating gene expression. Treatment of infertility In the current study, the researchers show that the newly identified genes can interact with the ‘junk DNA’, and that this is essential to the start of development. “Our results provide novel insights into the regulation of early embryonic development in human. We identified novel factors that might be used in reprogramming cells into so-called pluripotent stem cells for possible treatment of a range of diseases, and potentially also in the treatment of infertility”, says Outi Hovatta, professor at Karolinska Institutet’s Department of Clinical Science, Intervention and Technology, and a senior author. The study was a collaboration between three research groups from Sweden and Switzerland that each provided a unique set of skills and expertise. The work was supported by the Karolinska Institutet Distinguished Professor Award, the Swedish Research Council, the Strategic Research Program for Diabetes funding at Karolinska Institutet, Stockholm County, the Jane & Aatos Erkko Foundation, the Instrumentarium Science Foundation, and the Åke Wiberg and Magnus Bergvall foundations. The computations were performed on resources provided by SNIC through Uppsala Multidisciplinary Center for Advanced Computational Science (UPPMAX). View out press release about this study Publication Novel PRD-like homeodomain transcription factors and retrotransposon elements in early human development Virpi Töhönen, Shintaro Katayama, Liselotte Vesterlund, Eeva-Mari Jouhilahti, Mona Sheikhi, Elo Madissoon, Giuditta Filippini-Cattaneo, Marisa Jaconi, Anna Johnsson, Thomas R. Bürglin, Sten Linnarsson, Outi Hovatta and Juha Kere Nature Communications, 3 September 2015, doi: 10.1038/NCOMMS9207

Scientists at Karolinska Institutet and Karolinska University Hospital have discovered a new explanation for severe early infant epilepsy. Mutations in the gene encoding the protein KCC2 can cause the disease, hereby confirming an earlier theory. The findings are being published in the journal Nature Communications. Through large-scale genetic analyses of a family with two affected children at SciLifeLab in Stockholm, mutations were identified in the gene encoding the transport protein KCC2. In a collaboration with scientists at the University College London, another family with children carrying mutations in the same gene was further identified. Two of the children in each family demonstrated similar symptoms that can be connected to a severe variant of infant epilepsy with MPSI (Migrating Partial Seizures of Infancy). “Epilepsy occurs in many different forms. Earlier associations with KCC2 have been observed, such as a downregulation of the protein after brain damage that increases the tendency for seizures, but firm evidence for this disease mechanism has been lacking so far”, says Anna Wedell, senior physician at Karolinska University Hospital and professor at the Department of Molecular Medicine and Surgery at Karolinska Institutet. “Through our discovery we have been able to prove that a defective function of the KCC2 protein causes epilepsy and hence that an imbalance in the brain’s chloride ion regulation system can be the reason behind the disease. The next step is to investigate to which extent this imbalance occurs in more common variants of epilepsy.” KCC2 constitutes a chloride channel specifically localized in the brain and have earlier been shown to play a major role in synaptic inhibition by maintaining a low concentration of chloride ions inside the neurons. Normally the amount of KCC2 increases shortly after birth, causing the signal substance GABA to switch from being stimulating to being inhibitory. GABA remain stimulatory “Mutations in the gene encoding KCC2 prevent this switch which makes GABA remain stimulatory, incapable of inhibiting the signals of the brain”, says Dr. Wedell. “The neurons then discharge at times, when they normally should not, giving rise to epilepsy.” By conducting detailed investigations of cells expressing both the normal and the mutated forms of KCC2, the scientists demonstrated that the identified mutations led to disrupted chloride ion regulation and that an imbalance in this system thus brings about severe infant epilepsy, a potentially treatable disease. “Clinical trials are ongoing with a drug that, if successful, will compensate for the disrupted regulation and ameliorate the disease in small children with epilepsy, says Dr. Wedell.”      First study-author of the current study is Tommy Stödberg, a senior physician at Astrid Lindgren's Childrens Hospital, Karolinska University Hospital, and doctoral student at the Department of Women's and Children's Health, Karolinska Institutet. The study was financed by the Swedish Research Council, Karolinska Institutet, Stockholm County Council, Swedish Brain Foundation, and the Knut and Alice Wallenberg Foundation. Text: Frida Wennerholm View our press release about this study More about Anna Wedell's research Publication Mutations in SLC12A5 in epilepsy of infancy with migrating focal seizures Tommy Stödberg, Amy McTague, Arnaud Ruiz, Hiromi Hirata, Juan Zhen, Philip Long, Irene Farabella, Esther Meyer, Atsuo Kawahara, Grace Vassallo, Stavros Stivaros, Magnus Bjursell, Henrik Stranneheim, Stephanie Tigerschiöld, Bengt Persson, Iftikhar Bangash, Krishna Das, Deborah Hughes, Nicole Lesko, Joakim Lundeberg, Rodney Scott, Annapurna Poduri, Ingrid Scheffer, Holly Smith, Paul Gissen, Stephanie Schorge, Maarten Reith, Maya Topf, Dimitri Kullmann, Robert Harvey, Anna Wedell, and Manju Kurian Nature Communications online 3rd August 2015, doi: 10.1038/NCOMMS9038

Miriam Elfström, previously a doctoral student at the Department of Medical Epidemiology and Biostatistics has received the Dimitris N. Chorafas Prize for 2015 for her dissertation Optimizing cervical cancer prevention through screening and HPV vaccination. In her thesis she describes, among other things, the long term efficacy of different screening strategies and the long term risks associated with HPV infection, the quality of different screening programmes and their organization, as well as the efficacy of different vaccination strategies. The aim of the research is to maximize the benefit of prevention initiatives in Sweden and Europe. As a doctoral student Miriam Elfström was the first author of an article in the British Medical Journal and co-author of an article in the Lancet. After her doctoral studies, Miriam Elfström is working as a postdoctoral researcher at the Department of Laboratory Medicine at Karolinska Institutet and process leader for cancer prevention at the Regional Cancer Centre Stockholm-Gotland region. More about her research. The Dimitris N. Chorafas Foundation was founded in  1992 and since 1996 the Foundation has a collaboration with 23 partner universities, including Karolinska Institutet. The subject area ‘medical science’ focuses on new PhD holders or doctoral students who are in the final phase of their doctoral work. The candidates should not be above 30 years of age during their public defence.

Children with autism spectrum disorder should be given more thorough medical examinations and genetic tests that cover the entire genome as soon as possible after their clinical diagnosis. This will facilitate more exact molecular diagnoses, which can inform families about biological causes of the disorder and help the children obtain better care. This according to a paper by Swedish and Canadian researchers published in the scientific journal JAMA. Autism spectrum disorder (ASD) is an umbrella term for different types of autism of varying degrees of severity, of which all are considered neuropsychiatric functional impairments and are characterised by social communication and interaction difficulties as well as limited interests and stereotypical behaviour. It has long been known that co-morbidity with ASD is high: over 70 per cent of all children with the disorder have one or more other psychiatric or medical diagnoses. A group of Swedish and Canadian researchers now claim that children with ASD should routinely be offered early genetic analyses – chromosomal microarray and whole-exome sequencing – to make a molecular diagnosis by identifying the genetic abnormality causing the functional impairment. Abnormalities in specific genes The present study involved 258 Canadian children given ASD diagnoses between 2008 and 2013. By only examining the children medicinally or by means of a medical examination combined with a search for abnormalities in specific genes, the team was able to make a molecular diagnosis for one in twenty children. However, when they conducted broader genetic analyses, this number increased. The researchers employed two different methods, chromosomal microarray and a more recent technique called whole-exome sequencing, which can analyse the entire genome. Using these methods, the team was able to give almost 16 per cent of the children an exact molecular diagnosis. None of the children had the same genetic disorder, demonstrating the complexity and heterogeneous nature of the factors underlying ASD. “Our data suggests that children with ASD should be offered a genetic examination that covers the entire genome,” says the paper’s lead author Kristiina Tammimies, researcher at the Department of Women's and Children's Health, and affiliated to the Center of Neurodevelopmental Disorders at Karolinska Institutet (KIND). “For families, it can be important to understand the biological reason for the disorder and get guidance of possible increased risk for same disorder in younger siblings. We also know that certain genetic anomalies behind ASD are associated with conditions like obesity or diabetes, so the more we learn the more we will be able to provide care at an individual level.” Whole-exome sequencing techniques About 20 per cent of the 258 children had more than five minor physical abnormalities, such as a single palmar crease, uncommonly low-set ears and/or congenital deformities (e.g. heart defects). In this subgroup of children, the researchers were able, using both chromosomal microarray and whole-exome sequencing techniques, to identify a molecular diagnosis in 40 per cent of the children. “If there is a need to prioritise which children should receive these two genetic diagnostic tests, it would the children with more complex clinical symptoms, by which I mean those who have these physical abnormalities or congenital defects in addition to ASD,” says Dr Tammimies. “As in this group we had the best success on making a molecular diagnosis.” The project was financed with grants from several bodies, including the Swedish Research Council, and was conducted with researchers from the Memorial University of Newfoundland and SickKids Hospital in Toronto, Canada.  View the journal's video about this study Press release from SikKids Hospital More about Karolinska Institutet's collaborations in Canada Publication Molecular Diagnostic Yield of Chromosomal Microarray Analysis and Whole-Exome Sequencing in Children with Autism Spectrum Disorder Kristiina Tammimies, Christian R. Marshall, Susan Walker, Gaganjot Kaur, Bhooma Thiruvahindrapuram, Anath C. Lionel, Ryan K. C. Yuen, Mohammed Uddin, Wendy Roberts, Rosanna Weksberg, Marc Woodbury-Smith, Lonnie Zwaigenbaum, Evdokia Anagnostou, Zhuozhi Wang, John Wei, Jennifer L. Howe, Matthew J. Gazzelone, Lynette Lau, Wilson W. L. Sung, Kathy Whitten, Cathy Vardy, Victoria Crosbie, Brian Tsang, Lia D’Abate, Wai Tong, Sandra Luscombe, Tyna Doyle, Melissa T. Carter, Peter Sztarmari, Susan Stuckless, Daniele Merico, Dimitri Stavropoulos, Stephen W. Scherer and Bridget A. Fernandez JAMA, online September 1, 2015

Oliver Sacks is dead. The world-famous doctor was many things. He was, for example, professor of neurology at the NYU School of Medicine in New York, USA, and the best-selling author of several books, including Awakenings, which was later made into a successful film. In 2003 Oliver Sacks was made honorary doctor of medicine at Karolinska Institutet. Oliver Sacks passed away on Sunday 30 August after a long battle with cancer. He told the New York Times last February that the melanoma in his eye had metastasised and that he had only a few months left to live. By the time he was made honorary doctor of medicine at Karolinska Institutet in 2003 he had written a number of popular books on his neurology patients, his collection of essays on memory loss titled “The Man Who Mistook His Wife for a Hat” being regarded by many as a literary classic. The New York Times has called him “The Poet Laureate of Medicine”. The decision to make Oliver Sacks an honorary doctor of medicine at KI was taken in acknowledgement of the way his works aroused such widespread interest in patients with neurological disorders, such as sleeping sickness, Tourette’s syndrome, acquired colour-blindness, autism and Alzheimer’s disease. “His writings are epoch-making in that they combine immense scientific knowledge with a subjective insight into the patients’ problems,” wrote the Board of Research in 2003 in its announcement. The board also commended him for “combining his clinical skills in neurology with an astute eye and a unique talent for writing and story-telling. In this way, he combines medical science with humanist insight into his patients’ suffering.” When he came to Sweden to receive his doctor’s hat at Karolinska Institutet, he took the opportunity to follow in the footsteps of his childhood heroes, the chemists Scheele and Berzelius, and to lay a wreath at Scheele’s grave in Köping. Oliver Sacks was 82.

After a detailed and lengthy investigation, the Vice-Chancellor of Karolinska Institutet has pronounced his decision on a high-profile case of claimed scientific misconduct. Vice-Chancellor  Anders Hamsten has concluded that while on some points Visiting Professor Paolo Macchiarini did act without due care, it does not qualify as scientific misconduct. “Now that we have examined the allegations of scientific misconduct in all seven indicted articles, we have found that they contain certain flaws but nothing that can be considered scientific misconduct,” says Vice-Chancellor Anders Hamsten. The complaints against Professor Macchiarini were lodged by four physicians at Karolinska University Hospital who were themselves part of the research environment and, in some cases, co-authors of the articles that were reported for scientific misconduct. The complaints were submitted in June, August and September 2014, prompting an inquiry by Karolinska Institutet’s Vice-Chancellor in accordance with the provisions of the Higher Education Ordinance and the university’s own rules for dealing with cases of alleged scientific misconduct. Concerns were raised The first paper describes the manufacture of a synthetic oesophageal prosthesis and its functionality on transplantation into a rat. The concerns raised by the complainants include the conclusions of the functionality of this prosthesis and the interpretation of CT scans.  The six other papers describe transplantations of a synthetic tracheal prosthesis in humans, namely three patients with tracheal diseases who were beyond the help of conventional surgery and who were given synthetic trachea coated with their own bone-marrow derived stem cells at Karolinska University Hospital. Here, the complainants pointed out that the results concerning the patients’ clinical progress as expressed in the papers did not match the patients’ medical records as kept at Karolinska University Hospital, and that there was no evidence that a synthetic tracheal transplant can develop into a functional airway. They also questioned the claim that the first patient had suffered a relapse of his tracheal cancer and that surgery was therefore necessary. A statement of opinion was requested As part of the inquiry, a statement of opinion was requested from Professor emeritus Bengt Gerdin, who, on examining the documents and information included in the complaint, Professor Macchiarini’s initial response and the medical records from Karolinska University Hospital, submitted his conclusion in mid-May that the accused was indeed guilty of scientific misconduct. Following the detailed report submitted by Professor Gerdin, Professor Macchiarini and his co-authors submitted over 1,000 pages of comments and documents, including medical records from the first patient’s doctors in Iceland, showing that on the crucial points, the description of his condition given in the articles is correct. “Bengt Gerdin’s examination was extremely valuable for the inquiry, but the documents to which he had access lacked significant data on the pre- and postoperative status of two of the patients,” says Professor Hamsten. “The comments sent in by Professor Macchiarini and his co-authors have had a significant influence on how the case has been assessed. Now that we have all the relevant material on hand, we have a much clearer picture of what happened.” In their complaint, the four physicians also criticised Professor Macchiarini for not having obtained a permit from the regional Ethical Review Board and the Swedish Medical Products Agency before the operation. However, Karolinska Institutet did not examine this issue in its inquiry since the Swedish Research Council’s definition of scientific misconduct does not cover breaches of the Ethical Review Act and the Medicinal Products Act. At the same time, Karolinska Institutet concluded that a decision to perform the three operations was taken by the hospital. “Karolinska University Hospital made the decision to operate following a transparent process and in what it saw as the absence of alternative therapeutic solutions,” says Professor Hamsten. “These decisions did not address research aspects.” Interaction between hospital and university needs improvements The inquiry shows that the interaction between Karolinska Institutet and Karolinska University Hospital has not functioned satisfactorily, and the Vice-Chancellor’s decision promises improvements to procedures, regulations and support structures for clinical trials and clinical therapy research. The line between clinical application and research when it comes to experimental therapy will need to be better defined, and clearer guidelines for academic research and academic healthcare will be drafted. Professor Macchiarini has also been instructed to submit errata to the journals that published some of the scientific papers to clarify and rectify the failings that the inquiry has brought to light. “Some aspects of Paolo Macchiarini’s research do not meet our high quality standards,” says Professor Hamsten. “We will now be remedying the deficiencies our inquiry uncovered with him, the heads of his department and representatives from Karolinska University Hospital.”  

An international study presented in Science Magazine questions the reproducibility of much of the published findings in psychology journals. Researchers tried to replicate 100 studies from three prominent journals, and found that regardless of the analytic method or criteria used fewer than half of their replications produced the same findings as the original study. “A failure to reproduce does not necessarily mean that the original report was incorrect, but this shows the challenges of reproducing research findings”, says study co-author Gustav Nilsonne, MD, PhD, affiliated to the Stress Research Institute at Stockholm University, and to Karolinska Institutet. “Scientific evidence should not depend on trusting the person that made the discovery, rather on credibility accumulating through independent replication and the elaboration of ideas and evidence.” The so-called Reproducibility Project: Psychology was launched in 2011, and has since resulted in similar efforts within other research areas. The current study is the largest systematic investigation of reproducibility ever made in any research field. The team behind it consists of 270 researchers from all over the world, who have contributed through crowdsourcing, which is unique in itself. “In the present academic culture, scientists’ main incentive is to publish as many scientific papers in high impact journals as possible”, says Gustav Nilsonne. "Research presenting new and surprising findings is more likely to be published, even at the cost of reproducibility of the findings. However, what is good for science and what is good for scientists, is not always the same thing, and vice versa. Therefore, we need more transparency and openness about methods and research data, so that independent review and replication is possible.” Press release from the Center for Open Science Editorial comment about the findings News article in The Atlantic Publication Estimating the reproducibility of psychological science – Open Science Collaboration  Science 28 August 2015: Vol. 349 no. 6251, DOI: 10.1126/science.aac4716

Mobility between different physical environments in the cell nucleus regulates the daily oscillations in the activity of genes that are controlled by the internal biological clock, according to a study that is published in the journal Molecular Cell. Eventually, these findings may lead to novel therapeutic strategies for the treatment of diseases linked with disrupted circadian rhythm. So called clock-controlled – or circadian – genes are part of the internal biological clock, allowing humans and other light-sensitive organisms to adjust their daily activity to the cycle of daylight and darkness. In the current study, investigators at Karolinska Institutet found that daily changes in the spatial localisation of clock-controlled genes in the cell nucleus regulates fluctuations in their activity with a 24-hour period length. “We have uncovered a novel principle of circadian transcriptional regulation that involves a so-far unexpected dynamics in the sub-nuclear positioning of circadian genes”, says principal investigator Anita Göndör at the Department of Microbiology, Tumor and Cell Biology at Karolinska Institutet. Follows a pattern The genetic material is packaged in a structure called chromatin in the cell nucleus. It has been established that the 3-dimensional distribution of chromatin in the nucleus follows a pattern. Open chromatin containing active genes tends to occupy the central parts, whereas chromatin containing genes that are not active tends to localise to the peripheral parts of the nucleus – an environment rich in factors that promote gene silencing. Researchers investigated physical meetings between regions that are located far apart from each other on the linear chromatin fibre or reside on different chromosomes. By studying such encounters in the 3-dimensional space of the nucleus, they discovered a network of contacts between clock-controlled genes and domains of gene-poor, repressed chromatin in the periphery of the nucleus. They identified two proteins that bring the genes to bed and help them go to sleep at the periphery of the cell nucleus every day: poly(ADP-ribose) polymerase 1 (PARP1), a well-known regulator of DNA repair and gene expression, and the transcription factor CTCF. The researchers thus found that PARP1 and CTCF promote the diurnal recruitment of circadian genes to the nuclear periphery to attenuate their expression. They were then released from the periphery in a silent, ‘sleeping’ state to start a new cycle. Multifactorial diseases The internal biological clock regulates, among other things, body temperature, metabolism and the levels of several hormones. Disruption of circadian rhythm has been linked to predisposition to multifactorial diseases, such as diabetes mellitus, metabolic syndrome, psychiatric disorders and cancer. The new knowledge may lead up to new strategies for treatment of diseases that are affected by deregulated circadian rhythm. The research was supported by the Swedish Research Council, the Swedish Pediatric Cancer Foundation, the Swedish Cancer Foundation, the Lundberg Foundation, Karolinska Institutet, and the KA Wallenberg Foundation. Researchers from SciLifeLab, and University of Pécs in Hungary also contributed to the current study. View our press release about this study More about Anita Göndör´s research group Publication PARP1- and CTCF-Mediated Interactions between Active and Repressed Chromatin  at the Lamina Promote Oscillating Transcription Honglei Zhao, Emmanouil G. Sifakis, Noriyuki Sumida, Lluís Millán-Ariño, Barbara A. Scholz, J. Peter Svensson, Xingqi Chen, Anna L. Ronnegren, Carolina Diettrich Mallet de Lima, Farzaneh Shahin Varnoosfaderani, Chengxi Shi, Olga Loseva, Samer Yammine, Maria Israelsson, Li-Sophie Rathje, Balázs Németi, Erik Fredlund, Thomas Helleday, Márta P. Imreh, and Anita Göndör Molecular Cell, publishing in the 17 September, 2015 paper issue, online 27 August 2015

The 2015 Ethics Prize at Karolinska Institutet is being awarded to Lena Marions, associate professor in obstetrics and gynaecology and senior lecturer at the Department of Clinical Research and Education, Södersjukhuset (KI SÖS).  The Karolinska Institutet Ethics Prize is awarded annually to a person or group engaged at Karolinska Institutet that has been involved in a special initiative to promote ethics at the University. The prizewinner is chosen by the Karolinska Institutet Ethics Council. Lena Marions' research deals primarily with sexual and reproductive health, which includes methods for family planning and abortion as well as gynaecological cancers and sexually transmitted infections. Her research projects have also been conducted in Bangladesh, Iran, Laos and Ukraine. A tangible result of one of Lena Marions' doctoral projects in Laos is that women are now increasingly being offered a gynaecological examination to screen for early signs of cervical cancer. She has previously worked for the World Health Organization (WHO) with the development of safe abortion methods and is currently also a member of WHO's expert panel for the recommendation of safe and effective contraceptive methods. “Lena Marions stands up for woman, especially in the issue of abortion rights,” says Niels Lynöe, Chair of the Ethics Council at Karolinska Institutet. “She has also highlighted a number of important ethical issues in the public debate, for example, the issue of prescribing contraception for young women.“ ”In addition, she has worked actively to integrate ethics education in the medical programme with gynaecology, pediatrics and clinical genetics.”  The aim of the prize is to increase ethical awareness and to acknowledge worthy role models. The prize is awarded at Karolinska Institutet's installation ceremony in Aula Medica on 15 October 2015. More on the Ethics Prize at Karolinska Institutet.

The Ministry for Foreign Affairs are visiting Karolinska Institutet during Wednesday. This is the first time that the Ministry for Foreign Affairs will address KI as one entity. The visit will include 160 heads of departments and ambassadors and there is a solid program on offer, including the topic global health. The Ministry's work includes promoting Swedish research. Fredrik Jörgensen, Director-General for Administrative Affairs at the Ministry for Foreign Affairs says that this is one of the reasons that they are visiting KI at this time: “KI is one of the world's leading medical universities with a large international network and we would like our ambassadors to join this network. But we're of course also interested in seeing the beautiful building Aula Medica and to find out more about the Nobel Prize. Many of our ambassadors host workshops and other activities during Nobel Week”. And there will certainly be a little bit of everything. The program at KI is introduced by Pro-Vice-Chancellor Kerstin Tham after lunch and will continue until the evening. The day will be moderated by Professor Martin Ingvar who is the Deputy-Vice-Chancellor for the Coordination of Matters Relating to Future Healthcare at Karolinska Institutet. There will be highlights from KI's international activities: Professor Göran Tomson will talk about global health and Professor Gunilla Karlsson Hedestam about KI's collaboration with the US. KI has previously established a vibrant partnership with the embassy in Washington. On the agenda there is also an item on KI's fund-raising activities and the campaign Breakthroughs for life (Genombrott för livet) which was conducted in 2006–2010. And there will be examples of research at KI on the topic ‘How can we achieve a sustainable health care sector?’ Fredrik Jörgensen is looking forward to it all: “We are very happy and grateful for the program on offer and we are excited about meeting the many excellent speakers. We want to find out which research areas are of most interest currently, and we are particularly interested in global health and the researchers' contacts. This all ties in well with the work at the Ministry of Foreign Affairs”. Text: Madeleine Svärd Huss Photo: Erik Cronberg  

A study by researchers at Karolinska Institutet is the first to suggest that cells in the tumour blood vessels contribute to a local environment that protects the cancer cells from tumour-killing immune cells. The results, which are being published in the Journal of the National Cancer Institute, can contribute to the development of better immune-based cancer therapies. Immune-based antitumour therapies, that strengthen the body´s own ability to fight cancer, have attracted great attention in recent years and achieved interesting success rates, especially in malignant melanoma. However, many patients still do not respond to immune-based therapies. The results from the current study imply that tumour pericytes, a cell that is part of the tumour blood vessels, critically manipulate the tumour environment, helping the cancer cells escape immune surveillance. “Understanding the interplay between tumour pericytes, malignant cells, and the immune system might help in designing more personalised and effective therapeutic approaches”, says Principal Investigator Guillem Genové at the Department of Medical Biochemistry and Biophysics at Karolinska Institutet. Tumours evade the immune system by a variety of mechanisms, one of them being the recruitment of so called ‘myeloid-derived suppressor cells’ (MDSC). MDSCs suppress the ability of killer T-cells to destroy cancer cells. It is known that the more MDSCs present, the worse the prognosis or therapy response of the patient. Tumours secrete signal molecules such as interleukin-6 (IL-6) that help in recruiting MDSCs, but the mechanisms behind IL-6 tumour secretion are quite unknown. The number of pericytes The researchers found that the higher the number of pericytes, the more 'normal' the tumour environment looked like. On the contrary, diminished pericyte numbers altered the microenvironment and correlated to higher IL-6 expression from the malignant cells and more MDSCs. They also identified a subset of breast cancer patients who had fewer pericytes and increased MDSCs, correlating to a worse prognosis and more aggressive characteristics of the tumour. “Our work suggests that ways to increase the numbers of pericytes could potentially decrease IL-6 expression. This could improve cytotoxic T-cell activity and result in better antitumour effect”, says Dr Genové. The research was supported by grants from, among others, the Swedish Cancer Foundation, the Strategic Cancer Research Program (StratCan) and BRECT Breast Cancer Theme Centrum at Karolinska Institutet, and the Swedish Research Council–supported STARGET Linneus Center of Excellence. Our press release about these findings View a scientific commentary  Publication Tumor pericytes regulate myeloid-derived suppressor cell recruitment via IL-6 JongWook Hong, Nicholas P. Tobin, Helene Rundqvist, Tian Li, Marion Lavergne, Yaiza García-Ibáñez, Hanyu Qin, Janna Paulsson, Manuel Zeitelhofer, Milena Z. Adzemovic, Ingrid Nilsson, Pernilla Roswall, Johan Hartman, Randall S. Johnson, Arne Östman, Jonas Bergh, Mirjana Poljakovic, and Guillem Genové Journal of the National Cancer Institute, first published online August 21, 2015 , doi:10.1093/jnci/djv209 

Erik Norberg at the Institute of Environmental Medicine, Karolinska Institutet, is awarded the Malin and Lennart Philipson Foundation prize 2015 for his “interesting and creative studies of alternations in the metabolism in cancer cells”. The prize is awarded in alternate years at Uppsala University and Karolinska Institutet respectively. Erik Norberg receives a grant sum of SEK 1 million per year for two years, including a personal prize during the first year of SEK 50,000. Apart from the researcher’s scientific merits, the award also recognises the ability as a leader to establish a strong research group. After receiving his Ph.D. in Medical Sciences from Karolinska Institutet in 2011, Erik Norberg joined the Dana-Farber Cancer Institute, Harvard Medical School in the USA, for his Postdoctoral studies. In 2014, he returned to Sweden and Karolinska Institutet to establish his own independent research group. His research focuses on identifying and targeting tumor specific alterations in metabolism. Read more on the Malin and Lennart Philipson Foundation website and on ki.se.  

The 2015 Academic Ranking of World Universities, the Shanghai ranking, shows that Karolinska Institutet remains well placed, this year as number 48, ranking the highest among the Swedish universities. The five most highly ranked universities are Harvard University, Stanford University and Massachusetts Institute of Technology. In the field of Clinical Medicine and Pharmacy KI is number 12 in the world and number 3 in Europe.  shanghairanking.com More about rankings at ki.se      

The risk of completed suicide is high among people with previous attempts, particularly during the first few years after the attempt. In a study, researchers at Karolinska Institutet have shown how the method used for the attempt plays a role in the risk of a subsequent suicide death. Some psychiatric diagnoses also entail an increased risk. The study is published in the Journal of Clinical Psychiatry. Using the Swedish Board of Health and Welfare's Inpatient Register, researchers have identified 34,219 people who received care as hospital in-patients for at least one day for deliberate self-harm between 2000 and 2005. The patients were monitored until 2009 via the Board of Health and Welfare's causes of death register, i.e. between three and nine years after the suicide attempt. In 2009, 1,182 of the people in the study had died from suicide. The researchers studied the psychiatric diagnoses that patients had at the time of making their suicide attempt. They also took a closer look at the methods they used and, using this information, identified which patients with a previous suicide attempt ran the highest risk of a completed suicide. The study has yielded several clear results: attempters who used another method than poisoning, such as hanging, strangulation, asphyxiation, drowning, using a firearm, knife or other sharp instrument or jumping from a great height, ran a much higher risk of taking their own lives in the near future. Certain differences between genders were observed, particularly when it came to the use of firearms. The risk of subsequent suicide was higher among men with a previous attempt than women. The risk of subsquent suicide was also much higher in people who had been diagnosed with bipolar disorder, depression or psychosis at the time of the attempt. This applied to both men and women. Bipolar disorder was formerly called manic depression, a condition where the person shifts between depressiveness and feelings of elation. Examples of psychoses include schizophrenia, paranoid psychosis and other conditions that alter your perception of reality. When the researchers weighed these parameters together, it turned out that one in five, or 20.4 percent, of bipolar disorder patients who chose a different method to attempt suicide than poisoning had died from suicide by the end of 2009. For patients who had some form of psychosis, the corresponding figure was 15.6 percent, while for those with depression the figure was 13.9 percent. The results confirm the findings of previous long-term studies. Those studies, however, did not include patients who were treated with today's psychiatric methods. Those in the previous studies had received care for attempted suicide further back in time. The study currently being published therefore provides an up-to-date picture of patient groups. “There is a high risk of suicide after an attempt has been made, but the risk is particularly high for certain people. These patients should be treated adequately according to their underlying illness and they should be offered psychosocial support, especially in the period immediately following a suicide attempt. Mobile emergency teams are one example of this type of support. There is also reason to believe that the psychosis and bipolar treatment centres that exist or are being built in most county councils can play a significant role in reducing the suicide rate in these groups,” says Bo Runeson, Chief Physician in Psychiatry and Professor at the Department of Clinical Neuroscience at Karolinska Institutet. The research is funded by Stockholm County Council, Karolinska Institutet, Söderström-Königska Foundation and the Foundation for Professor Bror Gadelius' Memorial Fund. Publication Suicide after previous non-fatal self-harm: National cohort study 2000 – 2008 Bo Runeson, Axel Haglund, Paul Lichtenstein and Dag Tidemalm, Journal of Clinical Psychiatry, 4 August, DOI:10.4088/JSC.14m09453

According to a new study from Karolinska Institutet which is being published in the journal Autophagy, the body's own defence system can be strengthened with existing medicines used for treating tuberculosis. The results suggest a new treatment principle for infectious diseases that can strengthen the effect of traditional antibiotic treatments and reduce the risk of developing a resistance. Widespread resistance to antibiotics requires new, expensive medicines with various side-effects to be used against tubercle bacteria. However, many affected countries lack access to such medicines. Researchers are therefore trying to develop new strategies for  effective treatment of tuberculosis, which continues to be a major worldwide problem. The researchers behind the new study are investigating how to activate the body's own antibiotics, antimicrobial peptides, which form a part of the innate immune defence system. The peptides are produced in all mucus membranes and also in granulocytes and macrophages, two types of white blood cells that are recruited to the site of infection. “We have focused particularly on increasing the body's production of the body's own peptides with the help of existing drugs. LL-37, a human antimicrobial peptide that we discovered in 1995, is highly effective against TB bacteria,” says Birgitta Agerberth at the Department of Laboratory Medicine at Karolinska Institutet, one of the researchers who has led the study. Researchers have already shown that the drugs vitamin D and phenylbutyrate increase the production of LL-37. They have now demonstrated that LL-37 plays a key role in the manner in which these drugs kill the TB bacteria. It is already known that vitamin D can trigger a process known as autophagy which is important for killing pathogenic bacteria  inside macrophages and other cells. In this study, researchers have shown that phenylbutyrate also activates autophagy   and that  vitamin D and phenylbutyrate  work even more effectively when used in combination. In addition,  the underlying mechanism of the activation has been clarified. In an another study from the same research group it is  shown that supplementary treatment with phenylbutyrate and vitamin D had positive results when combined with standard antibiotics in the treatment of newly diagnosed tuberculosis patients in Dhaka, Bangladesh. “The results show that we can thus strengthen the body's defence against serious infections such as tuberculosis by increasing the production of antimicrobial peptides. Both these studies provide combined support for a new treatment principle for infectious diseases with the activation of the body's own defence system combined with traditional antibiotic treatments. This new treatment strategy as we name “Host-Directed Therapy” has many advantages: it minimise the risk of developing resistance, it strengthens the effect of regular antibiotics and controls the often damaging inflammation that occurs commonly in different infections,” says Birgitta Agerberth. The research is funded by the Swedish Foundation for Strategic Research, Swedish Heart-Lung Foundation, the Swedish Research Council and SIDA, among others. Publication Phenylbutyrate induces LL-37-dependent autophagy and intracellular killing of Mycobacterium tuberculosis in human macrophages Rokeya Sultana Rekha, SSV Jagadeeswararao Muvva, Min Wan, Rubhana Raqib, Peter Bergman, Susanna Brighenti, Gudmundur H. Gudmundsson, Birgitta Agerberth Autophagy, online 29 July 2015, doi:10.1080/15548627.2015.1075110

A study that included more than 4,000 Swedish 60-year-olds, showed that high levels of polyunsaturated fats in the blood are linked to increased longevity and decreased risk of cardiovascular disease. The study was a collaboration between Karolinska Institutet and Uppsala University and was published in the medical journal Circulation.  In most studies that investigate the correlation between food and longevity, the subjects report what they have eaten, and this may be inaccurate. In the current study, the level of polyunsaturated fats in the blood of the subjects was measured. This has previously been shown to be a good indicator of intake of these fats that are abundant in oily fishes such as salmon and herring, as well as in walnuts, avocado and olives. “This is the world's largest study in the area as far as we know, and one of its strengths is that both men and women were evaluated at the same time”, says Professor Mai-Lis Hellénius at the Department of Medicine, Solna, Karolinska Institutet, one of the researchers in this study. The results show that high levels of polyunsaturated fats in the blood are associated with decreased overall mortality in both men and women. In women, polyunsaturated fat intake was also linked to a decreased risk of cardiovascular disease. When the results were calculated, other important lifestyle factors, such as exercise alcohol and smoking, were also taken into account. ­“The findings are clinically relevant and support current dietary guidelines that advise us to shift from saturated to unsaturated fats”, says Mai-Lis Hellénius. Publication Polyunsaturated Fat Intake Estimated by Circulating Biomarkers and Risk of Cardiovascular Disease and All-Cause Mortality in a Population-Based Cohort of 60-Year-Old Men and Women Marklund M, Leander K, Vikström M, Laguzzi F, Gigante B, Sjögren P, Cederholm T, de Faire U, Hellénius ML, Risérus U Circulation 17 June 2015, doi: 10.1161/CIRCULATIONAHA.115.015607 Text: Jenny Tollet

People diagnosed with a personality disorder may find it difficult to function in society due to difficulties in regulating emotions – but also healthy individuals differ in how often they become irritated, angry or sad. Scientists from Karolinska Institutet have published a study in the medical journal Social Cognitive and Affective Neuroscience, where they show that the affected brain areas in people with a clinical diagnosis are also affected in healthy individuals. We all vary in how often we become happy, sad or angry, and also in how strongly these emotions are expressed. This variability is a part of our personality and can be seen as a positive aspect that increases diversity in society. However, there are people that find it so difficult to regulate their emotions that it has a serious impact on their work, family and social life. These individuals may be given an emotional instability diagnosis such as borderline personality disorder or antisocial personality disorder.  Previous studies have shown that people diagnosed with emotional instability disorders exhibit a decrease in the volume of certain brain areas. The scientists wanted to know if these areas are also associated with the variability in the ability to regulate emotions that can be seen in healthy individuals. In the current study, 87 healthy subjects were given a clinical questionnaire and asked to rate to what degree they have problems with regulating emotions in their everyday lives. The brains of the subjects were then scanned with MRI. The scientists found that an area in the lower frontal lobe, the so-called orbitofrontal cortex, exhibited smaller volumes in the healthy individuals that reported that they have problems with regulating emotions. The greater the problems, the smaller the volume detected. The same area is known to have a smaller volume in patients with borderline personality disorder and antisocial personality disorder. Similar findings were also seen in other areas of the brain that are known for being important in emotional regulation. ­“The results support the idea that there is a continuum in our ability to regulate emotions, and if you are at the extreme end of the spectrum, you are likely to have problems with functioning in society and this leads to a psychiatric diagnosis”, says Associate Professor Predrag Petrovic, first author of the study and researcher at the Department of Clinical Neuroscience, Karolinska Institutet. “According to this idea, such disorders should not be seen as categorical, that you either have the condition or not. It should rather be seen as an extreme variant in the normal variability of the population”. Publication Significant grey matter changes in a region of the orbitofrontal cortex in healthy participants predicts emotional dysregulation Predrag Petrovic, Carl Johan Ekman, Johanna Klahr, Lars Tigerström, Göran Rydén, Anette G. M. Johansson, Carl Sellgren, Armita Golkar, Andreas Olsson, Arne Öhman, Martin Ingvar and Mikael Landén Social Cognitive and Affective Neuroscience, online: 15 juni 2015, doi: 10.1093/scan/nsv072. Text: Jenny Tollet

Set up a lab, deal with finances, plan, execute and analyze science and in an interesting way communicate the results. This is what students from Karolinska Institutet are dealing with this summer. The International Genetically Engineered Machines (iGEM) is a contest that will prepare the participants early on for a future career in science. A Stockholm team is now battling for the title in The International Genetically Engineered Machines competition (iGEM), a contest where students within the field of synthetic biology will construct their own biological system and in different ways incorporate them into living cells. iGEM, which started in 2004, this year includes a record of 281 teams worldwide. Different components such as science, innovation and scientific communication are all part of the competition. The initiative was founded at Massachusetts Institute of Technology and has now become a part of the education for engaged students at Karolinska Institutet. Felix Richter is hopeful because his 18-person team with students from KI and KTH Royal Institute of Technology in Stockholm have developed a system that will allow cells to show when they are exposed to an antigen, i.e., something that will trigger an immunological reaction. “In our project, Affibody-Based Bacterial Biomarker Assay, we use bacteria that sense the antigen and then mass produce a light signal. Now all team members have learned the techniques and next week we will see if our system really works.” The competition lasts all summer and the winners are presented at a science conference in Boston later this fall, but until then there is a lot of activity. This weekend KI students, together with students from Uppsala, are hosting a conference with the Nordic teams present. “The possibility to “take over a lab” and work on our own is invaluable in itself, but then there is also a lot of practice in communication, primarily within the teams but also between the teams, which increases the individual social competence and helps in getting new perspectives. As of today we have fruitful collaborations with teams from, e.g., Germany, France, Finland, Israel and Taiwan.” Felix Richter points out that his team is developed and run by the students themselves. Supervisors are in place but it is this young generation of scientists-to-be that get all the responsibility, from the primary idea all the way to the presentation in Boston. “We take responsibility both in success as well as failure. This is a step in the right direction for modern education and I hope it will be a permanent feature for interested students at KI.” The students have gotten financial support from The Board of Research and The Board of Doctoral Education at KI.  “This way, the individual student gets to practice for a future career in science. It is also a good way to increase internationalization, initiate entrepreneurship and stimulate a way of thinking scientifically during the students’ undergraduate studies. We are very proud of these industrious students,” says Maria G. Masucci, Deputy Vice-Chancellor for International Affairs at Karolinska Institutet.  Text: Frida Wennerholm

A novel way of making 3D nanostructures from DNA is described in a study published in the renowned journal Nature. The study was led by researchers at Karolinska Institutet who collaborated with a group at Finland's Aalto University. The new technique makes it possible to synthesize 3D DNA origami structures that are also able to tolerate the low salt concentrations inside the body, which opens the way for completely new biological applications of DNA nanotechnology. The design process is also highly automated, which enables the creation of synthetic DNA nanostructures of remarkable complexity. The team behind the study likens the new approach to a 3D printer for nanoscale structures. The user draws the desired structure, in the form of a polygon object, in 3D software normally used for computer-aided design or animation. Graph-theoretic algorithms and optimization techniques are then used to calculate the DNA sequences needed to produce the structure. When the synthesized DNA sequences are combined in a salt solution, they assemble themselves into the correct structure. One of the big advantages of building nanostructures out of DNA is that the bases bind to each other through base-paring in a predictable fashion. “This new method makes it very easy to design DNA nanostructures and gives more design freedom,” says study leader Björn Högberg from the Department of Medical Biochemistry and Biophysics at Karolinska Institutet. “We can now make structures that were impossible to design previously and we can do it in the same way as one might draw a 3D structure for printing out in macroscopic scale, but instead of making it out of plastic, we print it in DNA at the nanoscale.” Using this technique, the team has built a ball, spiral, rod and bottle-shaped structure, and a DNA printout of the so-called Stanford Bunny, which is a common test model for 3D modelling. Apart from being simpler compared to former ways of making DNA origami, the method – importantly – does not require high concentrations of magnesium salt. “For biological applications, the most crucial difference is that we can now create structures that can be folded in, and remain viable in, physiological salt concentrations that are more suitable for biological applications of DNA nanostructures,” explains Dr Högberg. “An advantage of the automated design process is that one can now deal systematically with even quite complex structures. Advanced computing methods are likely to be a key enabler in the scaling of DNA nanotechnology from fundamental studies towards groundbreaking applications,” says Professor Pekka Orponen, who directed the team at the Aalto University Computer Science Department. The possible applications are many. The team at Karolinska Institutet has previously made a DNA nano-caliper used for studying cell signalling. The new technique makes it possible to conduct similar biological experiments in a way that resembles conditions within cells even more closely. DNA nanostructures have also been used to make targeted capsules able to deliver cancer drugs direct to tumour cells, which can reduce the amount of drugs needed. The study was financed by grants from several bodies, including the Swedish Research Council, the Swedish Foundation for Strategic Research and the Knut and Alice Wallenberg Foundation. View our press release More about the study on BBC News Publication ‘DNA rendering of polyhedral meshes at the nanoscale’ Erik Benson, Abdulmelik Mohammed, Johan Gardell, Sergej Masich, Eugen Czeizler, Pekka Orponen & Björn Högberg Nature, online 23 July 2015, doi: 10.1038/nature14586.