KI News

The names of the first six KI researchers to receive grants under the Ming Wai Lau Centre for Reparative Medicine, Karolinska Institutet’s new research centre for regenerative medicine, have now been announced. The recipients are part of the Stockholm part of the centre, the other part being a lab in Hong Kong. This October sees the opening of Karolinska Institutet’s first ever overseas branch – the Ming Wai Lau Centre for Reparative Medicine in Hong Kong. The establishment was made possible after a donation of USD 50 million from businessman Ming Wau Lau, and consists of a node in Hong Kong – a lab with space for up to 50 scientists – and a node at KI in Stockholm. The names have now been announced of the six researchers at KI who are to receive the first of the grants included in the donation. Each so-called Lau Grant is worth SEK 1.6 million for three years, and has been awarded to researchers at the virtual Stockholm part of the new centre. The grants were advertised to research group leaders at KI who are establishing their own research groups in regenerative medicine. The recipients are: Gonçalo Castelo-Branco at the Department of Medical Biochemistry and Biophysics: “Modulating the epigenetic state of oligodendrocyte lineage cells to induce remyelination in multiple sclerosis” Simon Elsässer at the Department of Medical Biochemistry and Biophysics: “Function of short peptides encoded by sORFs (sPEPs)”. Christian Göritz at the Department of Cell and Molecular Biology: “Central Nervous System Scarring and Repair”. Francois Lallemend at the Department of Neurosciewnce : “Genetic control of neuronal survival: implications for new cancer therapies”. Ning Xu Landén at the department of Medicine, Solna: “Regulatory RNAs in wound-edge keratinocytes: new perspectives towards treating chronic wounds”. Fredrik Lanner at the Department of Clinical Science, Intervention and Technology: “Pluripotency, embryonic stem cells and regenerative medicine”.

Heart failure in people with coronary artery disease and simultaneous type 2 diabetes can be prevented with effective treatment. In a large registry study published in The Journal of American College of Cardiology, researchers from Karolinska Institutet show that patients with type2 diabetes who had undergone coronary artery surgery prior to their heart failure diagnosis have better chances of survival in the long term. For people with type 2 diabetes, heart failure is a common condition that has proved more serious than it is for people without diabetes. Often, but not always, the heart failure is attributable to atherosclerotic coronary artery disease (CAD). To improve the blood supply to the heart muscle, people with CAD can be given either a bypass operation or catheter balloon dilation. According to the study, roughly every other person with type 2 diabetes and simultaneous CAD are treated using one of these interventions. The long-term impact of these operations was previously uncertain, but by studying registry data from over 35,000 heart failure patients, over a quarter of whom had type 2 diabetes, the team found that the risk of death within eight years of heart-failure onset was much higher if the patient also had type 2 diabetes, with those who also had CAD showing the worst prognosis. However, the study also shows that the prognosis for long-term survival was better for the patients who had undergone coronary artery surgery before developing heart failure, an observation that held even when controlling for factors such as old age or other diseases, which might have affected the decision to perform revasculising surgery. “Our study indicates that revasculising coronary artery surgery can do much to improve the prognosis,” says Isabelle Johansson, doctoral student at the Department of Medicine. “A decision must be taken as to whether this is possible should be made without delay for all patients with combined type 2 diabetes and heart failure.”  The study also shows that over 90 per cent of the patients with type 2 diabetes have one or more other precursors of heart failure, such as high blood pressure, COPD or atrial fibrillation, diseases to which effective treatments are available that improve the chances of long-term survival. “A greater focus should be put on preventing heart failure in patients with type 2 diabetes,” says Ms Johansson. The results are based on an observational study in which coronary artery surgery was not randomly distributed, giving some uncertainty over when surgery was performed in relation to disease onset. They should therefore be interpreted with a degree of caution and corroborated in future randomised studies. The study was financed with grants from several bodies, including the Heart and Lung Foundation and the Swedish Diabetes Association, and through the ALF agreement between Stockholm County Council and Karolinska Institutet. Publication “Prognostic Implications of Type 2 Diabetes Mellitus in Ischemic and nonischemic Heart Failure” Isabelle Johansson, Ulf Dahlström, Magnus Edner, Per Näsman, Lars Rydén, Anna Norhammar Journal of American College of Cardiology, online September 20 2016, doi: 10.1016/j.jacc.2016.06.061  

Research teams from Karolinska Institutet and Uppsala University have jointly discovered that the usually protective enzyme FBW7 is commonly mutated and inactivated in childhood brain cancers causing tumors to spread and become more difficult to treat. The study, recently published in the scientific journal EMBO Journal, contribute to improving knowledge that is relevant to the development of more effective cancer treatments and future individualized treatment strategies. “We have shown that when FBW7 is functionally inactivated this leads to a block of degradation of the stem cell protein SOX9 which becomes more stable in the brain cancer cells”, said first author Aldwin Suryo Rahmanto at the department of Cell and Molecular Biology. These findings are not unique to childhood brain tumours. "We believe this is a central mechanism for different types of cancer since an independent research team at the Rutgers Cancer Institute of New Jersey, USA, recently published similar results as ours, but instead in colon, skin and lung tumors”, says Fredrik Swartling, research group leader at Uppsala University and one of the principal investigators of the Swedish study. The researchers examined the protein levels of SOX9 in malignant childhood brain tumours from more than 140 patients together with scientists in Germany. They found that tumours with increased levels of SOX9 more easily metastasise. In laboratory experiments the researchers mimicked the way SOX9 is stabilised in brain tumour cells and showed that SOX9 turned on 40 to 50 genes in the tumour to make it more resistant to standard treatment with cytotoxic drugs and more prone to spread. “We also identified a way to de-stabilize the SOX9 protein by treating the brain cancer cells with small molecular drugs, which made them less resistant to chemotherapy again”, says Olle Sangfelt, the other principal investigator of the study and research group leader at Karolinska Institutet. At the molecular level, tumours from different patients are often quite diverge, even though they belong to the same type of cancer. Certain childhood brain tumours have for instance high levels of SOX9 whereas others have relatively low levels. If it would be possible to identify tumours that have an aberrantly stabilised SOX9 protein, the drugs tested in this study could be used to prevent tumour spread in these patients and improve their response to standard chemotherapy. Publication "FBW7 suppression leads to SOX9 stabilization and increased malignancy in medulloblastoma" Aldwin Suryo Rahmanto, Vasil Savov, Andrä Brunner, Sara Bolin, Holger Weishaupt, Alena Malyukova, Gabriela Rosén, Matko Čančer, Sonja Hutter, Anders Sundström, Daisuke Kawauchi, David TW Jones, Charles Spruck, Michael D Taylor, Yoon‐Jae Cho, Stefan M Pfister, Marcel Kool, Andrey Korshunov, Fredrik J Swartling, Olle Sangfelt, EMBO Journal, 13 September 2016, doi:10.15252/embj.201693889

Three questions for Maria Masucci, deputy vice-chancellor for international affairs and chair of the steering committee of the Ming Wai Lau Centre for Reparative Medicine, KI:s first overseas branch. What does the new centre mean to KI? “Scientifically, opening and investing in a reparative medicine research centre in an environment so far ahead in its field opens up fantastic opportunities. At the same time, what we’re doing has never been done before in either KI or Sweden. Having to explain our rules and ensure their compliance in a different environment is an important organisational learning process. If all goes well, we’ll have a good model for how to work with major international projects like this in the future.” “We also see this as an important way in to mainland China, which with its large and growing population is in enormous need of medical innovation.” What are the chances, do you think, of being able to conduct free academic research in Hong Kong? “The signals we get are that high quality research and the standard of research quality that KI represents are interesting to both Hong Kong and mainland China – and this includes scientific freedom and ethical rules. We have strong support from Hong Kong to ensure that the structure we build there will be KI’s and will follow our rules.” “Hong Kong is in a special political situation, but I judge the situation to be stable. It’s in everyone’s interests that Hong Kong remains a strong centre and I feel reassured that we’ll be able to conduct high quality research there.” Donor Ming Wau Lau and his father are involved in the companies in the so-called Panama papers – documents leaked from a law firm in Panama that creates shell corporations in tax havens. His father, an extremely wealthy property magnate, has been convicted of corruption and money laundering in Macau while being the owner of Chinese Estate Holdings Ltd. The same company where Ming Wai Lau has had, and still has leading positions.” Is Ming Wau Lau a suitable donor for KI? “We’ve investigated the donor and as far as we’ve been able to ascertain there’s nothing that makes him unsuitable as regards him personally or his businesses. We cannot comment on his father’s financial affairs. Owning shares in companies that pay little corporate tax is nothing remarkable in Hong Kong, since the tax rate there is so low. His interests in Panama companies were also known by the Hong Kong tax authorities.” “Ming Wau Lau is interested in the field of reparative medicine and is passionate about education at different levels. He also knows Sweden and KI well. His children and their mother have lived here, he’s visited often and even has a summer house in the Stockholm area.” Text: Sara Nilsson

Karolinska Institutet´s (KI) first overseas branch – the Ming Wai Lau Centre for Reparative Medicine in Hong Kong – is due to open in October. The centre represents a solid reinforcement of KI’s research in the field and is expected to open doors for collaborations in Hong Kong and other parts of Asia – but the way there is paved with challenges. Early last year, the Hong Kong-based businessman Ming Wai Lau donated USD 50 million – equivalent to just over SEK 400 million – to KI for the establishment of a research centre in regenerative medicine, with one node in Stockholm and one in Hong Kong, and managed by KI. Basic research on regenerative technologies The Ming Wai Lau Centre will be opening its doors in the Hong Kong Science Park on 7 October. “We’re creating a research embassy in Hong Kong. It’s so exciting! Area-wise it’s like a little Biomedicum section with room for up to 50 researchers,” says Ola Hermanson, scientific director of the new centre and researcher at the Department of Neuroscience. The Lau Centre will focus on basic research concerning technologies of relevance to regenerative medicine, such as RNA technology, singe-cell analysis or genetic engineering.  The aim of regenerative medicine is to replace damaged or lost tissue with new cells or with tissue produced from stem cells. Looking into the future, the research can be relevant to the treatment of diseases such as severe heart failure, liver failure, spinal cord damage and Parkinson’s disease. The recruitment is in the final phase The business in Hong Kong is still being built up, and the research group leaders who will be recruited and who will relocate to the new lab are soon to be announced. The call for applications was targeted at junior researchers from all over the world, with the highest ranking candidates being interviewed in Stockholm. It will also become clear at the end of September which KI researchers will be receiving the first Lau Grants, which are included in the donation and which have been advertised to research group leaders at KI who are busy establishing their own research groups in regenerative medicine. Each grant is worth an annual SEK 1.6 million over three years, with the option of a two-year extension. A maximum of eight grants will be awarded, with the recipients constituting the virtual Stockholm section of the research centre. "The hub of a global research network" The centre represents a solid reinforcement of KI’s research in regenerative medicine, according to Agneta Wallin Levinovitz, the centre’s scientific coordinator. But it also creates valuable opportunities for cooperation between not only KI researchers with Lau Grants and researchers at the Hong Kong node, but also KI researchers and colleagues at other institutions inside and outside Hong Kong. The University of Hong Kong has also received a donation of some SEK 115 million for collaborations with KI in the same field. “The Lau Centre will be the hub of a global research network,” she says. KI’s presence increases the chances of producing groundbreaking research, according to Dr Hermanson. “We believe that the establishment will appeal to people who are skilled in this field. Modern research centres very much on collaboration, especially for newly formed groups. Much of the best stem cell research is being done in China, near Hong Kong, in Japan and elsewhere in Asia. We want to be part of this, but then it can be a bit far from Stockholm,” he says. Focus on the link between the nodes But collaboration presents not only opportunities but also challenges, he adds. An extensive programme of joint doctoral courses, scientific conferences and workshops is being developed to tie the two nodes together. Postdoc exchanges are encouraged and calls for grant applications make clear that applicants are expected to collaborate with the other node and the rest of China. The cost of travel between Stockholm and Hong Kong will be covered by the donation. Doctoral students in the Hong Kong groups must also be registered at KI in Sweden, since Swedish universities may not issue degrees abroad. Dr Hermanson notes that with it British past, the ethical research regulations in Hong Kong are in line with the European, and says that he will be liaising closely with Ronald Li, scientific director of the Hong Kong node and professor of stem cell biology and regenerative medicine at the University of Hong Kong. The Hong Kong centre will be run in KI’s name and must live up to the university’s standards. But as Marie Tell, administrative manager at the centre and deputy university director at KI, points out, one major challenge will be making sure from across the other side of the globe that internal control works as it should: “It’s a matter of recruiting the right local people and giving them a good introduction to KI’s rules and regulations concerning both administration and research. I believe that it’s important to create a feeling of belonging to KI. We, the Swedish KI, must have a presence there.” The first one to establish abroad  At the same time, there must be no breach of local laws, and the establishment of the centre has entailed a lot of work finding out the legal requirements when it comes to recruitment and other matters. “This is the first time a Swedish state-run university has established a branch in another country. Much time is being spent on making sure that we’re going about things properly, and there’s often nothing to guide us,” says Ms Wallin Levinovitz. A great deal of effort was also put into ensuring that KI was actually allowed to set up in Hong Kong in the first place. KI first contacted the education department to apply for a permit and conducted a legal inquiry with the help of a law firm to clear up any legal impediments. Then a new request was sent to the department for a permit to take on local employees abroad. The decision came in August: no action would be taken on the request. An authority is deemed to be itself responsible for ensuring that its activities are conducted in accordance with the prevailing regulations and decisions. “It’s important to us that the government is aware of what we do and that it hasn’t said no. Even if it doesn’t think a permit is needed either,” says Ms Tell. Funded entirely by the donation One decisive factor is that the centre’s costs, including for research, administration and any future wind-down programme, are wholly covered by donated funds. Government appropriations may not be used by institutions to run their own units in other countries. The donation is to cover activities for five years, with an evaluation after year three. “By that time I want to see the groups in Hong Kong maintaining a high degree of quality in their research and interacting well with their Stockholm colleagues. I hope that one day this will be a permanent, autonomous centre not unlike a department at KI,” says Dr Hermanson. Text: Sara Nilson

Researchers at Karolinska Institutet have managed to produce the first molecular map of the genes that are active in the various cells of the human pancreas. They have also revealed differences in genetic activity between people with type 2 diabetes and healthy controls. The study, which is published in Cell Metabolism, was conducted in the AstraZeneca and Karolinska Institutet co-run Integrated Cardio Metabolic Centre, and in association with researchers from AstraZeneca. Although knowledge of what the body looks like and how it operates at a molecular level is still limited, researchers can now examine the organs of the body in a higher resolution than before using a new technique developed by researchers at Karolinska Institutet based on single-cell transcriptomics, which makes it possible to sort out individual cells from complex tissue, study them and analyse the activity of all their genes. Using this technique, scientists can now map out the cells of an organ along with molecular patterns in organs and tissues . “We hope that our atlas of the pancreas will serve as a catalyst for research into the metabolic diseases that affect it,” says Rickard Sandberg, professor at the Department of Cell and Molecular Biolog, who is also a researcher at the Ludwig Institute for Cancer Research and at the Cardio Metabolic Centre. The pancreas is an important organ that regulates the body’s metabolism through hormones that it secretes into the blood from special cells. By studying thousands of individual cells, the team has made up a molecular atlas of the pancreatic cells with a focus on the hormone-producing ones in the Islets of Langerhans. An analysis of data revealed many interesting genes that were active in specific cell types, particularly the delta cells, in which they found unique proteins expressed genes that give these cells a unique ability to operate as signalling centres in the pancreas, where they are able, for example, to gauge the body’s energy balance and hunger through the hormone leptin. To conduct their study, the researchers examined the pancreas of ten deceased individuals, of whom six had been healthy and four had died of type 2 diabetes. Using single-cell transcriptomics, they were able to compare the genetic activity of all cell types while examining the presence of any disease-related changes. “This is the first time someone has compared normal and morbid pancreatic tissue using this technique,” says Professor Sandberg. Carina Ämmälä is a researcher at AstraZeneca and a member of the team working at the Integrated Cardio Metabolic Centre. “Our study indicates that the different endocrinal cells of the pancreas express distinct and unique pattern genes that regulate cellular function, which changes in diabetes,” she says. “It’s now time to start looking for treatments for type 2 diabetes that restore the function of the network of cells that make up the Islets of Langerhans rather than just trying to make the beta cells work harder.” The study was financed by grants from the Swedish Research Council, the European Research Council, the Swedish Foundation for Strategic Research, the Swedish Cancer Society and the Centre for Innovative Medicine. Publication “Single-cell transcriptome profiling of human pancreatic islets in health and type 2 diabetes” Åsa Segerstolpe, Athanasia Palasantza, Pernilla Eliasson, Eva-Marie Andersson, Ann-Christine Andreasson, Xiaoyan Sun, Simone Picelli, Alan Sabirsh, Maryam Clausen, Magnus Bjursell, David M. Smith, Maria Kasper, Carina Ämmälä and Rickard Sandberg Cell Metabolism, online 22 September 2016, doi: 10.1016/j.cmet.2016.08.020

Endurance training changes the activity of thousands of genes and give rise to a multitude of altered DNA-copies, RNA, researchers from Karolinska Institutet report. The study, which also nuances the concept of muscle memory, is published in the journal PLOS Genetics. Regular endurance training is very beneficial to health and wellbeing, and can be used to prevent cardiovascular disease, diabetes, obesity and other such conditions. However, just how this works on a molecular level is not fully known.  Researchers at Karolinska Institutet have now analyzed RNA, the molecular copies of the DNA-sequence, in muscle tissue before and after endurance training. They found approximately 3400 RNA variants, associated with 2600 genes, that changed in response to training. One implication of the study is that training can induce the same gene to increase the production of one RNA variant and reduce that of another. According to the researchers, this can mean that genes can change function as a result of exercise and, for example, start to promote the production of certain protein variants over others. “It has not been previously shown that training changes the expression of genes in this particular way. The study also provides new basic information about how the body adapts to regular endurance training and what role many of our genes play in the adaptation,” says Dr Maléne Lindholm at Karolinska Institutet’s Department of Physiology and Pharmacology. The study began with an exercise programme for 23 individuals that involved working one leg but not the other. Muscle samples were taken before and after the training period. After a nine months rest period, they then exercised both legs in the same way as in the initial period of exercise, with muscle samples taken from both legs. “We were looking for any residual effects of previous training, a kind of muscle memory as it were, and trying to find out if this could influence the response to repeated training.” The changed genetic activity in the previously trained leg was no longer present when exercise resumed. However, the repeated response to training was somewhat different in the trained and previously untrained legs in the second training period, which suggests that the exercise could have left other lasting impacts. According to Dr Lindholm, the study is important above all for the fundamental understanding of how muscles operate and how we adapt to endurance training. “The results can also contribute to the future optimisation of training effects in different individuals,” she says. “In the long run, it is conceivably of some significance to the possibility of preventing cardiovascular disease and the development of new, more precise drugs for people who, for whatever reason, are unable to exercise.” The study was financed by the Swedish National Centre for Research in Sports, Karolinska Institutet and the Knut and Alice Wallenberg Foundation Publication ”The impact of Endurance Training on Human Skeletal Muscle Memory, Global Isoform Expression and Novel Transcripts” Maléne Lindholm, Stefania Giacomello, Beata Werne Solnestam, Helene Fischer, Mikael Huss, Sanela Kjellqvist, Carl Johan Sundberg. PLOS Genetics, published online 22 September, 2016, doi: PGENETICS-D-16-01025

Karolinska Institutet is placed 28th in this year’s Times Higher Education (THE) World University Rankings and 8th in Europe. Almost the same position compared to last year, with the exception that KI then ended up in place 9 in Europe. The subject category of clinical, pre-clinical and health, in which KI is compared with other medical universities, will be published in October. Times Higher Education World University Rankings. KI remains stable in earlier university rankings The 2016 Academic Ranking of World Universities, the Shanghai ranking, published in August, showed that Karolinska Institutet remains stable. KI climbed to number 44 in the world and number 10 in Europe. In the field of Clinical Medicine and Pharmacy KI remained in the same place as last year – number 12 in the world and number 3 in Europe. Shanghai ranking lists.

Statins protect against cardiovascular disease in more ways than previously thought. In a study, rresearchers from Karolinska Institutet are able to show the immunological effects of statins, and present a new hypothesis on why satins are effective at preventing heart attacks. The study is published in The Journal of the American Heart Association. Atherosclerosis can lead to a number of serious medical conditions, such as heart attack, stroke and intermittent claudication. These and other cardiovascular diseases are on the increase around the world, and are the leading causes of death in the west. Johan Frostegård, professor at KI’s Institute of Environmental Medicine, has had a long-standing interest in atherosclerosis and the possible underlying causes of this chronic inflammation. Atherosclerosis is visible on the blood vessel walls as plaque consisting of accumulated dead cells and oxidised (rancid) LDL cholesterol (the so-called “bad” cholesterol) and two types of immune cell, T cells and dendritic cells, which are the key players in this chronic inflammation. Statins are a common class of drug often used to prevent cardiac arrest and other such conditions. Even though it has long been known that statins are anti-inflammatory, it is unclear whether the immune system is more specifically affected, the assumption having been that statins are so effective because they reduce levels of cholesterol in the blood. “We can show how statins can protect against cardiovascular disease through a new, specific immunological mechanism, and I believe that this can explain much of their beneficial effect,” says Johan Frostegård, professor of medicine at Karolinska Institutet’s Institute of Environmental Medicine and consultant at Karolinska University Hospital’s Emergency Clinic. “For the first time, we’re able to show that an immunological treatment for atherosclerosis can actually work.” The researchers studied the interaction between the two most important immune cells in this context, T cells and dendritic cells. By looking at atherosclerotic plaque sourced direct from operations on human patients, they found that oxidised LDL-cholesterol activates inflammatory T cells from plaque via the dendritic cells. The statins block the T cells and stimulate the production of anti-inflammatory T cells (T regulatory cells). The dendritic cells are also affected in a way that renders them anti-inflammatory. When the side-effects of statins are discussed, their possible carcinogenic properties are sometimes addressed. While large-scale metastudies have shown that there is a reduction in most kinds of tumour, in this study it was discovered that statins repress gene activators (microRNA), including a certain kind called let7c, which normally helps to inhibit tumour growth. In this study, let7c was involved in oxidized LDL-induced T cell activation. “Statins severely repressed let7c,” says Professor Frostegård. “If a patient has a tumour in which let7c plays an important part, the statin effect could be adverse. At the same time, statins reduce inflammation and that can lower the risk of cancer, and large metastudies show no general increase in cancer risk.” The research was financed by grants from several bodies, including the Heart and Lung Foundation, the Swedish Research Council, Stockholm County Council (ALF), the King Gustaf V 80-year Foundation, the Swedish Rheumatism Association, Vinnova (The Swedish governmental agency for innovation systems), AFA insurance and the Torsten Söderberg Foundation. Publication “Oxidized Low-Density Lipoprotein (OxLDL) – Treated Dendritic Cells Promote Activation of T Cells in Human Atherosclerotic Plaque and Blood, Which Is Repressed by Statins: microRNA let-7c Is Integral to the Effect”, Johan Frostegård, Yong Zhang, Jitong Sun, Keqiang Yan, Anquan Liu, Journal of the American Heart Association, online 20 September 2016, doi: 10.1161/JAHA.116.003976

An ancient area of the midbrain of all vertebrates called the corpora quadrigemina can independently contol and reorientate the eyes, researchers from Karolinska Institutet report in a study published in the journal eLIFE. There is much going on around us all the time, phenomena that we perceive with our different senses, which send information to the brain. When we walk along the street, for example, we encounter other people that we have to avoid bumping into, or might find our attention drawn to an unexpected object. The brain then has the very difficult task of determining which of these multifarious events we need to respond to. This problem is solved by an ancient part of the midbrain called the corpora quadrigemina, or tectum. This area is found in all vertebrates and [Neil Bett1] contains a complex network of neurons that control the movements of the head and eyes. Information from different parts of the retina project onto different parts of the tectum creating a retina-based map that reflects the information sent by the retina. “You could say there's a spatial sensory map in the tectum, where images from the eye are projected to create signals about where things happen,” says Professor Sten Grillner at Karolinska Institutet's Department of Neuroscience. Different parts of the retinal map can then activate nerve cells that control motor centres for eye and head movements in the brain stem. When a movement is triggered, other parts of the tectum network are disabled and thus other movements of the eyes and head. The study also shows that if an event is registered by two senses (e.g. vision and hearing) from the same point the signals will be merged. If two senses thus supply the tectum with contradictory information, the neurons will become less active, thus reducing the likelihood of a triggered physical event such as eye-movement. The study was conducted on the lamprey, a small, eel-like fish that represents the earliest form of vertebrate, by Sten Grillner along with visiting researchers Andreas Kardamakis and Juan Pérez-Fernández. “It's more primitive than normal fish, but important parts of its nerve system share all their basic features with the more advanced nerve systems of mammals,” says Professor Grillner. Although the study was basic research, it can help scientists understand certain clinical phenomena, such as the morbid impairment of ocular movements caused by Parkinson's disease. The study was financed by the Swedish Research Council, KI's Research Funds, EU FP7 and StratNeuro. Publication “Spatiotemporal interplay between multisensory excitation and recruited inhibition in the lamprey optic tectum” Andreas Kardamakis, Juan Pérez-Fernández and Sten Grillner. eLIFE, published online September 16, 2016, doi: 10.7554/eLife.16472  

The swine flu vaccine, when administered to pregnant women, caused neither fetal injury nor infant death, writes Karolinska Institutet professor Johan F Ludvigsson an opinion piece in Tuesday’s Dagens Nyheter in conjunction with the publication of his research findings in The Annals of Internal Medicine. Jonas F Ludvigsson is a professor at Karolinska Institutet and led this large-scale study on the swine flu vaccine Pandremix and its effects on fetal development. The study, which is the third and final part of a seven-year project, included over 40,000 mothers who were given the flu jab while pregnant. His results show that the vaccine did not increase the risk of child deformity, not even if given in the early stages of pregnancy. Earlier studies have, however, shown that pregnant women often suffer more acutely from influenza than others. A major Norwegian study has also shown that the risk of stillbirth was twice as high as normal if the mother contracted swine flu while pregnant. This, writes Professor Ludvigsson, gives good cause to vaccinate pregnant women. He is also convinced that this knowledge is valuable for the future, especially given the current concerns over the Zika virus, which is associated with microcephaly, the underdevelopment of the brain and head, in babies. If a Zika vaccine becomes available, it can be worth knowing how previous national vaccination programmes have affected pregnant women and their unborn babies. Publication Risk for Congenital Malformation With H1N1 Influenza Vaccine. A Cohort Study With Sibling Analysis Jonas F. Ludvigsson, MD, PhD; Peter Ström, MSc; Cecilia Lundholm, MSc; Sven Cnattingius, MD, PhD; Anders Ekbom, MD, PhD; Åke Örtqvist, MD, PhD; Nils Feltelius, MD, PhD; Fredrik Granath, PhD; and Olof Stephansson, MD, PhD Annals of Internal Medicine, online 20 September 2016, doi:10.7326/M16-0139

Alessandro Furlan, doctoral student at the Department of Medical Biochemistry and Biophysics has received the Dimitris N. Chorafas Prize 2016 for his thesis "Neuronal types and their specification dynamics in the autonomic nervous system". Alessandro Furlan receives the prize for his research aiming to identify molecular mechanisms and signaling pathways that regulate the nervous system, with particular focus on the autonomic nervous system. Alessandro Furlan is first author of an article in EMBO Journal where he describes the role of the transcription factor HMX1 for development of noradrenergic sympathetic neurons. In a subsequent study in Nature Neuroscience, he reports a much greater specificity in the sympathetic system than previously known. He also co-first authored a Science paper describing the emergence of the parasympathetic neurons from stem-like cells. Alessandro Furlan will defend his thesis in November 2016 and will after that start his post-doc training at Cold Spring Harbor Laboratory in New York, USA. About the prize 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.

The government commissioned a nomination committee on 15 September to draw up a list of proposed candidates for the new chairperson and three new members of the Karolinska Institutet University Board (Konsistoriet). Last spring, the government decided to replace some members of the board. Following the recent inquiries into the Paolo Macchiarini case, it has now decided to also replace the other government-appointed members who sat when Macchiarini was working at Karolinska Institutet. In an official statement, Minister for Higher Education and Research Helene Hellmark Knutsson says that this is what is needed to restore confidence in Karolinska Institutet. The current members will remain in office during the nomination period until the government announces its decision.   View government press release (in Swedish). More about the University Board. More about the Macchiarini case.  

The Håkan Mogren Foundation has awarded its 2016 medical scholarship in recognition of – and for the advancement of – efforts for human well-being to district doctor Peter Berggren. Through his work, he has created good conditions for continuity and the safety for patients in rural areas. “Peter Berggren has made pioneering and extremely creative efforts to improve care in rural areas,” says Håkan Mogren. “He has used computers and modern technology to develop new working models, and has helped many patients to receive more accessible, better care.”            Peter Berggren has worked tirelessly for more than 20 years to tackle the challenges posed by long distances and an ageing population in Västerbotten County. Stationed in Storuman, 250 km northwest of Umeå, he is the only doctor providing out-of-hours care for around 12,000 patients at the same time, in an area the size of the provinces of Halland and Skåne put together. “To some extent, working in rural areas involves a different job so we’ve developed what we call rural medicine,” explains Peter Berggren, who is also head of the Rural Medicine Centre, a primary care R&D unit in Västerbotten which he helped to build up. “Today, this is seen as being attractive, interesting and highly technologically advanced.” His work has contributed towards brand new care models being devised using advanced remote technology. For example, patients can meet with a dietician or a CBT practitioner via video conferencing, and doctors can listen to a heartbeat or look down into a patient’s throat remotely thanks to various technological solutions. Many doctors and nurses have completed specialist training in this new way of working that Peter Berggren has helped to draw up. Experiences of remote care work have been shared with twin towns and care centres in Australia and Canada. Continuity and safety are the guiding principles in everything that is done. “Peter Berggren has demonstrated an enormous commitment to the best interests of his patients, and has contributed great patient benefit, not least through patients being able to avoid making long journeys for care,” says Håkan Mogren, emphasising that Peter Berggren is a highly worthy winner of the prize. The foundation’s medicine prize is awarded to individuals who have earned a reputation for caring for their patients with empathy and passion. They should work actively to disseminate their knowledge through lectures and supervision. In other words, they do not necessarily need to be active in research.  “As an ordinary district doctor, it feels fantastic to be recognised in this way,” adds Peter Berggren. “I’ve devoted many years to developing remote care and this work will, of course, continue.” Peter Berggren will receive the SEK 250,000 scholarship at Karolinska Institutet’s Installation Ceremony on 13 October 2016. Text: Pia Hellsing

The results of a new study from Karolinska Institutet, published in the journal Cerebral Cortex, suggest that the brain of preterm children with growth retardation can have underdeveloped functional networks.  The purpose of the present study was to see if restricted growth in preterm babies is linked to differences in the brain’s functional networks, which are important for the development of social awareness, empathy and language. The study included a total of 60 babies, 20 of whom were categorised as preterm with restricted growth, 20 as preterm with good growth,t the age of 26 months old with tests for autism. “Even at the MR stage at the age of one we could see differences in signal strength of the specific brain networks between the preterm, restricted growth group and the preterm, normal growth group,” says Professor Ulrika Ådén at Karolinska Institutet’s Department of Women’s and Children’s Health. There have been great advances made in modern intensive care in the past few decades, which is gradually lowering the age of preterm survival. Extremely preterm babies, however, are more likely to develop brain damage, autism, ADHD and learning difficulties. “Autism is generally taken to be caused by genetic factors, even if no specific gene has been identified. Our study indicates that environmental factors such as premature birth and poor growth could impact on the organisation of cerebral networks and possibly cause autistic behaviour,” says Professor Ådén. At the same time, the researchers say that the results have to be substantiated and complemented with longitudinal follow-up studies. If their results hold, they claim that new therapeutic procedures to stimulate growth could reduce the risk of autism and other such conditions. The study was financed with grants from several bodies, including the Cerebra Foundation for the Brain-Injured Child in Britain, the Thrasher Research Fund in the USA, the Swedish Research Council, the ALF collaboration between KI and Stockholm County Council, the Marianne and Marcus Wallenberg Foundation, the EU’s Seventh Framework Programme, the Swedish Order of Freemasons, the Swedish Society of Medicine, the Swedish Brain Fund, the Foundation for Child Care, the Linnéa and Josef Carlsson Foundation, and Spain’s Fondo de Investigaciones Sanitatias. Publication “Intrinsic functional connectivity in preterm infants with fetal growth restriction evaluated at 12 months corrected age” Nelly Padilla, Peter Fransson, Antonio Donaire, Francesc Figueras, Angela Arranz, Magdalena Sanz-Cortés, Violeta Tenorio, Núria Bargallo, Carme Junqué Hugo Lagercrantz, Ulrika Ådén, Gratacós Eduard. Cerebral Cortex, published online 15 September 2016

A previously unknown gene plays a critical part in the development of the human embryo during the first days of fertilisation, researchers from Karolinska Institutet show. The paper, which is published in the scientific journal Development, describes the molecular mechanisms governing early embryonic development and can help in the understanding of what causes certain kinds of infertility. In 2015, scientists at Karolinska Institutet discovered that a number of previously unknown genes are active in the embryo during the first days of fertilisation of the egg by the sperm. In the present study, they have identified a new variant of one of these genes – called LEUTX – and observed that it is one of the first to be activated in the embryo. LEUTX belongs to a family of genes known for controlling anatomical development during the embryonic stage in humans and other organisms. Scientists have now, for the first time, shown that LEUTX potently activates hundreds of other genes involved in embryonic development during the first three days following fertilisation. The study shows that LEUTX is shut off shortly afterwards and remains dormant, probably until death. “The discoveries provide new information about how the development of the human embryo gets started and how the process is controlled,” says principal investigator Juha Kere, professor at Karolinska Institutet’s Department of Biosciences and Nutrition. “Our results also indicate that LEUTX is one of few genes needed to start the first stages of development.” The researchers also found that the same genes that are activated by LEUTX are inhibited in the embryo just a few days later by another gene called DPRX. This suggests that both genes have opposing roles in the regulation of the embryo’s development in the next phase, LEUTX by starting the process and DPRX by keeping it under control. “The next stage in our research is to examine if these genes can explain the causes of certain kinds of infertility and if they have applications in stem cell biology,” says Professor Kere. The study was a collaborative project by researchers at Karolinska Institutet, the Competence Centre on Health Technologies in Estonia and the University of Basel in Switzerland. It was financed by Karolinska Institutet’s Distinguished Professor Award and the Knut and Alice Wallenberg Foundation along with grants from Karolinska Institutet’s Research Foundations, the Swedish Research Council, the Strategic Research Programme in Diabetes at Karolinska Institutet, the EU Commissions’ SARM project, the ALF partnership between KI and Stockholm County Council, the Ragnar Söderberg Foundation, the Swedish Foundation for Strategic Research, the Åke Wiberg Foundation, the Jane & Aatos Erkko Foundation, the Orion Research Foundation, the Mats Sundin Fellowship in Developmental Health, and the Magnus Bergvall Foundation. Publication “The human PRD-like homeobox gene LEUTX has a central role in embryo genome activation”, Eeva-Mari Jouhilahti, Elo Madissoon, Liselotte Vesterlund, Virpi Töhönen, Kaarel Krjutškov, Alvaro Plaza Reyes, Sophie Petropoulos, Robert Månsson, Sten Linnarsson,Thomas Bürglin, Fredrik Lanner, Outi Hovatta, Shintaro Katayama, Juha Kere, Development, 2016, doi: 10.1242/dev.134510.

Researchers at Karolinska Institutet and the Feinstein Institute for Medical Research have discovered that the human immune system has a hitherto unknown role – blood pressure regulation. Collaborating with colleagues from Canada, they have found that a special kind of immune cell called acetylcholine-producing lymphocytes can regulate blood pressure in laboratory mice. The study, which is published in Nature Biotechnology, could open the way for new forms of treatment for hypertension. High blood pressure, or hypertension, is a crucial risk factor for premature death around the world. Despite this, hypertension often has indeterminable causes, although it has long been known that the neurotransmitter acetylcholine plays an important part in that it causes blood vessels to relax and regulates blood pressure by influencing the production of nitric oxide. By studying laboratory mice lacking a certain kind of immune cell called acetylcholine-producing lymphocytes, a research group at Karolinska Institutet and their colleagues at the Feinstein Institute for Medical Research in New York and the University Health Network in Toronto have discovered that these immune cells have a previously unknown function: to reduce the blood pressure. “These lymphocytes produce acetylcholine that can be delivered to target cells lacking direct contact with nerves,” says lead author Peder Olofsson, researcher at KI’s Department of Medicine in Solna. “It therefore seems that they can transmit signals for regulating the immune system and blood pressure. This is a new piece of the puzzle in our understanding of blood circulation.” Detailed knowledge The discovery is of significance to the understanding of how blood pressure is regulated: “If we’re to develop effective and safe therapies for hypertension, we need more detailed knowledge about its underlying biological mechanisms,” he says. The researchers now hope to find out if acetylcholine-producing lymphocytes play the same key part in regulating blood pressure in humans as well. If this is the case, the next question is whether the immune cells can be made to produce more of this important neurotransmitter so that hypertension can be effectively regulated. These new findings on how this specific immune cell is involved in the regulation of high blood pressure can open the way for new diagnostic and therapeutic methods for hypertension. Since lymphocytes are regulated by the nerve system, the researchers believe that it could one day be possible to control the activity of the immune system through implants that stimulate neuronal signals electronically. Publication ”Blood pressure regulation by CD4+ lymphocytes expressing choline acetyltransferase” Peder S Olofsson, Benjamin E Steinberg, Roozbeh Sobbi, Maureen A Cox, Mohamed N Ahmed, Michaela Oswald, Ferenc Szekeres, William M Hanes, Andrea Introini, Shu Fang Liu, Nichol E Holodick, Thomas L Rothstein, Cecilia Lövdahl, Sangeeta S Chavan, Huan Yang, Valentin A Pavlov, Kristina Broliden, Ulf Andersson, Betty Diamond, Edmund J Miller, Anders Arner, Peter K Gregersen, Peter H Backx, Tak W Mak & Kevin J Tracey, Nature Biotechnology, online 12 September 2016, doi:10.1038/nbt.3663

The fire at the building site of KI’s new research laboratory Biomedicum at Campus Solna last week was caused by polystyrene sheets that caught fire. They had been laid as ground insulation between the facade and ventilation tower.  A fierce fire centre with smoke flared up against the building and the area was evacuated, but no one was injured.  The fire caused glass at the ground level to crack as well as some external non-façade glass sections higher up. There were also some smoke damage on a couple of floors. Akademiska Hus and Skanska are now looking into the cause of the fire and whether it will delay completion of the building. Read more about the fire on internwebben.ki.se.

Glioblastomas exert an influence on the microglia, immune cells of the brain, which causes them to stimulate cancer growth rather than attacking it. In a study published in the journal Nature Immunology, an international research team led from Karolinska Institutet now explains the molecular mechanisms behind this action. Glioblastomas are one of the most malignant forms of brain tumour and are difficult to surgically remove because the tumour cells invade the surrounding healthy brain tissue. Glioblastomas also affect the microglia – immune cells of the brain – in such a way that they stimulate the tumour cells instead of attacking them. The multi-national research group has previously shown that pro-inflammatory activation of microglia is controlled by a group of enzymes called caspases. In the present study, they sought to examine if the way the cancer cells affect microglia also includes similar mechanism. By cultivating microglia and glioblastoma cells together, the researchers were able to show that the cancer cells inhibit caspase-3 activity in the microglia. “We show that it’s the same inhibition of caspase-3 that causes the microglia to stimulate the tumour cells instead of attacking them,” says Bertrand Joseph, Principal Investigator at Karolinska Institutet’s Department of Oncology-Pathology. “When we removed caspase-3 from the microglia in a glioblastoma mouse model, the tumours grew more quickly.” Use a nitric oxide-dependent mechanism According to the study authors, their results demonstrate that the glioma cells use a nitric oxide-dependent mechanism to force microglia to modify caspase-3 to form a tumour-stimulating form of these cells. “Two things surprised us,” says Bertrand Joseph. “First and foremost, that affecting the signalling mechanism between glioblastoma cells and microglia that we discovered has such a major effect on tumour growth. Secondly, that basal caspase-3 activity, which is often considered to be an absence of activity, fulfills essential function in regulating microglia cell behavior.” The lead authors of the study are Xianli Shen and Miguel Burguillos. Researchers from at the Universidad de Sevilla, Spain, Stockholm University, Sweden, and Yale University, USA, and others also contributed to this study. The research was financed with grants from, amongst others, the Swedish Research Council, the Swedish Childhood Cancer Foundation, the Swedish Cancer Society, the Swedish Brain Fund, StratCan, StratNeuro, and agreement with Stockholm County Council, and through the ALF agreement between Karolinska Institutet and the Stockholm County Council. Publication Glioma-induced caspase-3 inhibition in microglia promotes a tumor-supportive phenotype Xianli Shen, Miguel A. Burguillos, Ahmed M. Osman, Jeroen Frijhoff, Alejandro Carrillo-Jiménez, Sachie Kanatani, Martin Augsten, Dalel Saidi, Johanna Rodhe, Edel Kavanagh, Anthony Rongvaux, Vilma Rraklli, Ulrika Nyman, Johan Holmberg, Arne Östman, Richard A. Flavell, Antonio Barragan, Jose Luis Venero, Klas Blomgren and Bertrand Joseph Nature Immunology, online 12 September 2016, 2016, doi: 10.1038/ni.3545

A study by researchers at Karolinska Institutet conducted in collaboration with several other European research centres evaluates a device for measuring sugar levels in the subcutaneous fat of people with type 1 diabetes. The results, published in the journal The Lancet, show that the patients controlled their blood sugar much more often with the new, simpler technique and obtained safer glucose control. The new technique involves the subcutaneous placement of a glucose sensor on the upper arm, enabling patients to easily take readings to monitor their current sugar control and see if the sugar level is stable, rising or falling. They can then preventatively make the necessary adjustments with more insulin or carbohydrates. “The idea is that the new technique will replace normal blood sugar tests,” says principal investigator Jan Bolinder, professor of clinical diabetes research at Karolinska Institutet’s Department of Medicine, Huddinge. The glucose sensor used in the study is called FreeStyle Libre and is already available on the market in Sweden and other European countries. However, this is the first publication where the technique has been evaluated in a randomised controlled study. Higher risk of hypoglycaemia The apparatus was tested on a group with well-controlled insulin-treated (via injection or pump) type 1 diabetes. Such patients run a higher risk of hypoglycaemia (low blood sugar), since the buffer zone between normal and low blood sugar is relatively narrow. A control group continued to use the conventional finger-prick means of checking their blood sugar. Masked sensor readings were also taken on this group for two consecutive weeks after intervals of three and six months to obtain comparative, detailed data on their sugar control over a 24-hour period. “The intervention group were able to use the device continuously for six months as often as they wanted, which immediately tripled the average daily frequency of self-testing” says Professor Bolinder. Increased the number of self-controls The patients randomly assigned to the Libre group immediately increased the number of self-controls from around five or six times a day to around 18. As a result of this, incidences of low blood sugar levels dropped by 38 to 65 per cent, accompanied by a reduction in the number of hypoglycaemic episodes by 33 to 55 per cent. There was also a shortening of the time spent with excessive blood sugar levels, while that spent with optimal sugar control increased. “We also used questionnaires on different aspects of life quality and satisfaction with the treatment, and here too we could see positive results,” says Professor Bolinder. What do you hope will come of your results? “It’s important to evaluate assistive technology that can make life easier for patients with diabetes and help them obtain better and more stable sugar control. I hope that our positive results will help give more patients access to this type of aid.” Have any new issues arisen that you would like to investigate further? “Our study examined well-controlled patients. New research is needed to see if this self-help device can also improve sugar control for patients who don’t attain our treatment targets.” Parts of the study will be presented this week at the European Association for the Study of Diabetes (EASD) conference in Germany. The study was financed by Abbott Diabetes Care. Publication Novel glucose-sensing technology and hypoglycaemia in type 1 diabetes: a multicentre, non-masked, randomised controlled trial Jan Bolinder, Ramiro Antuna, Petronella Geelhoed-Duijvestijn, Jens Kröger, Raimund Weitgasser The Lancet, first online 12 September 2016