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The Board of Research at Karolinska Institutet, Sweden, has appointed three new honorary doctors – Sir Richard Peto, Bob Langer, and Alimuddin Zumla – who will have their doctorates formally conferred at a ceremony in the Stockholm City Hall on 13 May 2016.  Every year, Karolinska Institutet (KI) confers honorary doctorates to individuals for their vital scientific achievements or significant contributions to the university or humanity at large. Sir Richard Peto, Honorary Doctor of Medicine The title of Honorary Doctor of Medicine (MDhc) has been awarded to Sir Richard Peto, Professor of Medical Statistics and Epidemiology at the University of Oxford, United Kingdom. Sir Richard Peto is an epidemiologist who studies the major causes of adult mortality; he is also a clinical trialist who evaluates widely practicable treatments. Throughout the past 40 years he has helped document the massive hazards of smoking, first in developed countries and then in the much greater populations elsewhere, generating big nationwide studies in China to monitor their evolving epidemic of tobacco deaths. In the 1990s he showed that, if worldwide smoking patterns continued, tobacco would cause one billion deaths during the present century, and his predictions helped get the World Health Organisation and World Bank seriously committed to tobacco control.  On disease treatment, he initiated many of the biggest trials in the world in heart disease, stroke, and cancer, and helped originate the science of meta-analyses, which bring together the findings from many different studies. He has created a worldwide collaboration between the breast cancer trialists in many different countries, showing that widely practicable chemo-endocrine treatments reduce by more than half the risk of death from the commonest type of breast cancer. For his achievements in human medicine Sir Richard Peto has gained many international honours, and he continues to collaborate closely with breast cancer researchers from KI. Robert S. Langer, Honorary Doctor of Medicine The title of Honorary Doctor of Medicine (MDhc) has been awarded to Robert S. Langer, Institute Professor, Massachusetts Institute of Technology (MIT), Cambridge, USA. Bob Langer works at the interface between biotechnology and material sciences. He pioneered the development and synthesis of polymers for controlled delivery of drugs. These delivery systems include microspheres, nanospheres, and implants for treating cancer, heart disease, diabetes, and mental health disorders such as schizophrenia, narcotic addiction and alcoholism. Hundreds of millions of individuals every year use controlled drug delivery systems. He has been cited approximately 200,000 times (h-index 222) by other scientists, and has trained a large group of leaders in biotechnology research and in the biotech industry. The research and inventions of Bob Langer have transformed the pharmaceutical industry across the world and improved the life of many patients with chronic diseases. Bob Langer has received more than 220 major awards for his achievements in human medicine and bioengineering. He is one of only four living individuals to have received both the United States National Medal of Science and United States National Medal of Technology and Innovation. He has over the years maintained a close contact with KI, where he has been an inspiring lecturer and teacher at graduate and post-graduate courses. Alimuddin Zumla, Honorary Doctor of Medicine The title of Honorary Doctor of Medicine (MDhc) has been awarded to Alimuddin Zumla, Professor in Infectious Diseases and International Health at University College London, London, United Kingdom. Alimuddin Zumla is distinguished for being one of the few individuals who has combined research excellence with creativity for establishing equitable research partnerships between Europe, USA, Middle East and sub-Saharan Africa, and for effectively aligning them to capacity development and training activities. He has made seminal contributions to the understanding and advancement of knowledge of the epidemiology, transmission, pathogenesis, rapid diagnosis and treatment of respiratory tract infections, particularly tuberculosis and HIV/AIDS, two diseases declared global emergencies by the World Health Organization in 1992. These data have been used for developing new global diagnostic, prevention and treatment guidelines. Alimuddin Zumla has been awarded numerous honors, medals and prizes not only for his scientific excellence, but also for his contributions to international policy development and advancement of public health agenda on infectious diseases with epidemic potential. He has also been a major driving force for training of young developing country physicians, scientists and laboratory personnel. Alimuddin Zumla works closely with KI researchers, co-authoring numerous high impact publications, and jointly with colleagues at KI has established the Host-Directed Therapies network consortium of 64 international partners.   Who may be appointed Honorary Doctor? Academics who have made a palpable difference when it comes to research at Karolinska Institutet by means of scientific achievement or otherwise, may be appointed Honorary Doctors at Karolinska Institutet. It is also possible to confer honorary doctorates to individuals who have not received PhDs by passing formal examinations but who have nevertheless advanced the cause of research and development. However, certain restrictions apply. For example, a Doctor of Medicine at a Swedish University cannot be appointed Honorary Doctor of Medicine at another Swedish university.

Alexander von Gabain, deputy vice-chancellor for innovation and corporate alliances, wants to change attitudes towards innovation at KI. “I don’t mean we should start forcing everyone to start up companies or to give up excellent research and education, only that we should be more open to innovation,” he says. Alexander von Gabain was made KI’s deputy vice-chancellor for innovation over a year and a half ago. When he arrived at KI, he found an innovation system that people found cumbersome and complicated. “Some parts lacked clear roles, people were overlapping each other and weren’t cooperating well,” he says. “On top of this, awareness of innovation was not spread across KI.” This claim was also corroborated by a survey on KI’s innovation climate conducted by an external expert last spring amongst 70 of the university’s researchers, heads of department and research group leaders. A committee to give feedback One of Alexander Von Gabain’s first steps was to put together a committee of people representing important players in the area. This innovation council contains representatives of Karolinska University Hospital, Stockholm County Council, investors and the Dean of Research. The council is directly answerable to KI’s vice-chancellor and is led by Alexander von Gabain. “It’s an important network,” he says. “Not only does it tell all these actors what KI has on its agenda, it also gives us feedback that we’re on the right path with our strategy. But the actual implementation must take place here.” A strategic agenda for innovation gives the current status of the innovation system and what needs to be done to focus resources and create an environment that encourages innovation. KI’s employees get to learn about the innovation agenda through activities and achieved results, explains Alexander von Gabain. Priority to build a common path Work has already begun on structuring the roles the different actors will take in KI’s innovation system. A common operational goal has been set, and meetings are now held more frequently. A priority measure is now to build a clear, common path into the system. The researcher who has an idea or a question should not have to think about whom to contact. “A common portal will be up and running by the early summer,” says Alexander von Gabain. We’ve not got there yet, but we’re in promising discussions. According to the deputy vice-chancellor, many academic researchers underestimate how complex it is to convert an idea into a product or a service. Already at an early developmental stage industrial competence is needed in the form of people who have experience of the process and work with it on a daily basis. One way to reach this competence is through a new type of corporate agreement, such as that with drugs company Johnson & Johnson entered into last year. The company has opened an office in Karolinska Institutet Science Park and is looking to team up with people from KI’s innovation system on projects that can be offered financing for verified studies. Education important aspect The agreement is not exclusive and similar partnerships with more companies are on the cards. The aim is also to establish a proof-of-concept fund – a pot of money from which KI researchers can apply for the financing they need to verify the viability of an idea. “We’ve not got there yet, but we’re in promising discussions with interested investors,” says Alexander von Gabain, who believes that another way to strengthen KI’s innovative muscle is to adopt new attitudes and an openness towards innovation, such as through lectures, exemplary cases and prizes to those who succeed with their innovation. Education is another aspect. An introduction to innovation and entrepreneurship has been introduced as part of the compulsory induction programme for new doctoral students. Some study programmes have a clear innovation component, but such initiatives should be even broader, he says.   Text: Sara Nilsson Translated by: Neil Betteridge Foto: Gustav Mårtensson Note: The article has been published in KI Bladet 2/2016 (in Swedish).

Mabthera, when used outside the intended indications, rheumatoid arthritis and lymphoma, is more effective than one of the more recent drugs for multiple sclerosis. This according to an observation study by researchers from Sweden´s Karolinska Institutet, which is in published in Annals of Neurology. Increasingly efficacious disease modulatory drugs have been developed in recent years against multiple sclerosis (MS) but some of them carry risks of adverse reactions, which limits their usefulness. Tysabri (natalizumab), which is considered one of the most powerful of today’s MS drugs, in about 50 per cent of patients is associated with a greatly increased risk of contracting an opportunistic, potentially fatal viral infection of the brain. A simple blood test is all it takes to assess if someone is at risk of infection. Consequently, patients who have responded well to Tysabri often switch regimens to minimise the risk of this serous side-effect. However, when patients are taken off Tysabri, there is a high chance that their MS will flare up despite the change-over to another MS drug. Compared outcomes In this present observation study, which was conducted in Sweden at the MS clinics at Karolinska University Hospital, Sahlgrenska University Hospital and Umeå University Hospital, researchers compared the outcomes for a total of 256 patients who had switched from Tysabri to either Gilenya or Mabthera. “We found that patients treated with Mabthera ran a much lower risk of their MS flaring up after the change of drugs than those treated with Gilenya,” says principal investigator Fredrik Piehl, professor at Karolinska Institutet’s of Department of Clinical Neuroscience and consultant at Karolinska University Hospital’s neurology clinic. “Those who changed to Mabthera also had a lower risk of developing an adverse reaction to the new drug.” Older drug Mabthera is an older drug mainly used for the treatment of rheumatoid arthritis and lymphoma, and has not been formally approved for the treatment of MS. Nonetheless, a growing number of patients in Sweden have received this treatment as many clinics have found it effective. But since there are no evaluations of its medical efficacy, its use is controversial and has been reported to the Health and Social Care Inspectorate on the grounds that there is no evidence to support it.  “The results we’ve seen in this study provide strong support for the genuine efficacy of Mabthera in the treatment of high-inflammatory MS and for it being a valuable alternative to approved MS drugs for this category of patients,” says Professor Piehl. “It would also bring considerable savings to the healthcare services as it is much cheaper than the regular MS drugs.” The study was financed with grants from the Swedish Research Council and the Stockholm County Council. Publication Rituximab versus Fingolimod after Natalizumab in Multiple Sclerosis Patients Peter Alping, Thomas Frisell, Lenka Novakova, Protik Islam-Jakobsson, Jonatan Salzer, Anna Björck, Markus Axelsson, Clas Malmeström, Katharina Fink, Jan Lycke, Anders Svenningsson, Fredrik Piehl Annals of Neurology, published online 31 March 2016, DOI: 10.1002/ana.24651

Acting Pro-Vice-Chancellor, cancer researcher Henrik Grönberg, is replacing Karin Dahlman-Wright, the permanent pro-vice-chancellor, while she serves as acting vice-chancellor. His main responsibility will be to restore confidence in KI after the Macchiarini case. How much can you actually do in your temporary managerial role and how much authority do you have to change things? “We’ve been given a very strong mandate from the University Board, and feel that we have the full support of the organisation. I’m leading the Fenix project, whose goal is to change and restore confidence in KI.” How will you do that? “Over the next few weeks, we’ll be gathering information. The University Director and I will be visiting all departments and meeting with all of the administrative managers and heads of department. We’ll be explaining how we work, identifying the problems that the departments want to raise, and looking both at what the challenges are and what needs to be prioritised.” How have your meetings with the departments gone so far? “We’ve been welcomed. Most of them talk about how they’ve handled the crisis of confidence at KI, and what they’re now doing in the ‘second phase’, during which many will be addressing key issues.” What can the KI management say about the Macchiarini case today? “Our overall message has been clear: what happened was wrong. We deeply regret the possible involvement of KI researchers in the premature death or unnecessary suffering of patients. Karolinska Institutet takes responsibility for what happened and is working hard to ensure it won’t happen again.” But more specifically? “These issues about where KI has failed are mainly up to the three internal investigations to review, and their reports will probably not be released until after the summer. There’s the external investigation into KI’s handling of the Macchiarini case, Kjell Asplund’s investigation into the hospital’s responsibility for the different operations, and the Central Ethical Review Board’s (CEPN) investigation into the case of scientific misconduct against Macchiarini. Once we receive their reports, we’re prepared to provide our detailed analysis and comment on the matters.” The Ethnics Council at KI has received particular attention in this case and you will oversee its reorganisation – how will you be going about that? “I’ll do the departmental reviews first, and then I intend to meet key people from the Ethics Council. The investigation into the Macchiarini case is about that specific case, but ethical questions in general are totally independent of this, and I think that the Ethics Council’s remit should be broader than it currently is. I’ll also be meeting with other universities. Lund, for instance, is also in the process of setting up an ethics council and is wrestling with the same issues.” What about the Ethics Council in the mean time? “I’ll be overseeing a review of its duties and mandate this spring. All of its activities will be put on hold, which in effect means that the current council has been disbanded. We’ll also be looking at how we handle cases of misconduct internally. In this situation, we’re avoiding internal investigations.” What results do you yourself expect from this year as acting pro-vice-chancellor? “Our changes are relatively small. There’ll be no revolutionary changes. It’ll be mostly about how we handle difficult departmental issues and support the departmental heads. Certain environments work extremely well, have an open culture and share their research results so that others can either be supportive or critical. Having a work environment in which people are happy and show respect for each other means you can be competitive. “Other departments require more support. They’re geographically dispersed or lack an open culture. There are also some isolated environments were people don’t collaborate with colleagues. There are many advantages to be had from sharing our experiences, and we need to have the courage to discuss and address our failures.” Text: Madeleine Svärd Huss Translated by: Neil Betteridge, Sara Aldén Name: Henrik Grönberg. Occupation: Acting pro-vice-chancellor at Karolinska Institutet since 7 March 2016. In charge of leading the work of restoring confidence in KI. Responsible for KI’s involvement in SciLifeLab and the new building work on the Huddinge campus; also participates in the KI/SLL management group discussions. Brief biography: Medical degree from Umeå University in 1987, specialisation in oncology in 1994, and PhD in 1995 from Umeå in prostate cancer epidemiology. Postdoc at Johns Hopkins (1996–1997), professor of oncology at Umeå (2002), and professor of cancer epidemiology at KI (2005). Has held several positions, including head of the Department of Medical Epidemiology and Biostatistics (2008–2013). Why he accepted the job: “It’s obviously a challenge. That was the first reason. Secondly, I’ve had ten very good years at KI, the best of my professional life, so it felt right to do more for KI. I had initial reservations because of my huge research commitments, but my junior colleagues were prepared to take charge of things during this period. I’ve also had to stop seeing patients at Radiumhemmet and take leave of absence.”

The concentration of the hormone prolactin in the blood is controlled by dopamine. However, the system can be thrown off balance by certain drugs, especially antipsychotics, which can result in sexual side effects. A new study from Karolinska Institutet in rats, published in the journal Cell Reports, shows how dopamine can regulate itself and provides new knowledge about how the side effects arise. The researchers behind the study examined a group of dopamine producing neurons that control the secretion of prolactin, a hormone that leads to the production of breast milk, suppresses fertility and stimulates appetite in new mothers. Under most circumstances beyond pregnancy, blood levels of prolactin are usually suppressed by the neurotransmitter dopamine, which serves to inhibit the prolactin cells. Antipsychotics But the inhibitory mechanism can be lost, as is commonly seen in patients on antipsychotics that block dopamine receptors, resulting in sexual and reproductive problems such as impotence, low libido, amenorrhoea and infertility. "Side effects that impair quality of life are fairly common. It’s crucial that the prolactin-regulating system is maintained under strict control so that blood levels of the hormone remain stable and adapted to the body’s needs, such as during pregnancy", says Christian Broberger, docent at Karolinska Institutet’s Department of Neuroscience.  After measuring the electrical activity of neurons and how they behave when they “talk to each other”, the researchers discovered a new feedback regulatory system through which dopamine itself controls the activity of dopamine cells, which continually register the intensity of their own activity. Activity slowed down When they increased the level of dopamine around the cells, the researchers observed that the activity of the dopamine cells slowed down. Their results can lead to a better understanding of how hormone regulation – and thus the side-effects of neuropsychiatric drugs - arises. "The autoregulation we describe makes for a faster system, which can be adjusted to avoid such extreme fluctuations", says Dr Broberger. Was there anything surprising in your results? "We expected to find some kind of regulation, but that the drugs paradoxically completely inhibit the electrical discharge of dopamine cells came as a surprise. We hope that this information will be of use in the development of drugs with fewer side-effects", says Dr Broberger. First author of this study has been Stefanos Stagkourakis, doctoral student at the Department of Neuroscience. The study was conducted with grants from the European Research Council, the Swedish Research Council, and the Karolinska Institutet’s Strategic Research Programme in Diabetes. Publication Dopamine Autoreceptor Regulation of a Hypothalamic Dopaminergic Network Stefanos Stagkourakis, Hoseok Kim, David J. Lyons, Christian Broberger  Cell Reports, online 14 April 2016

Once every year a selection of the best articles are translated into English and collected in an English issue of Medicinsk Vetenskap. Order your issue of Medical Science 2016 and read articles about regenerative medicine, empathy, internet drugs and many other things.  Order your issue here. Browse the 2016 issue of Medical Science.

Infertility and hormonal fertility treatments may influence the amount of dense tissue in the breast, a risk factor for breast cancer, according to a study at Karolinska Institutet published in the open access journal Breast Cancer Research. The researchers selected 43313 women aged between 40 and 69 years, who had mammograms as part of the KARMA project between 2010 and 2013. Out of 8963 women who reported fertility problems, 1576 had undergone controlled ovarian stimulation (COS), 1,429 had had hormonal stimulation without COS and 5,948 had received no fertility treatment. Denser breasts The researchers found that women with a history of infertility had denser breasts than other women. The association was more pronounced in women who had undergone COS, the hormone treatment required for in vitro fertilization. While this may indicate a potential adverse effect of COS on breast density, the researchers point out that the effect may be due to the underlying infertility that motivates the use of a specific treatment, rather than to the treatment itself. Frida Lundberg, doctoral student at the Department of Medical Epidemiology and Biostatistics, and lead author of the study, said: – The results from our study indicate that infertile women, especially those who undergo COS, might represent a group with an increased breast cancer risk. While we believe it is important to continue monitoring these women, the observed difference in breast tissue volume is relatively small and has only been linked to a modest increase in breast cancer risk in previous studies. Breast tissue is composed of two types of tissue: dense, fibroglandular and non-dense, fatty tissue. Women with extremely dense breasts have a four to six fold higher risk of developing breast cancer than women with non-dense breasts, previous research has found. Self-reported information In this study, women with a history of infertility were found to have higher absolute dense volume – that is more dense, fibroglandular breast tissue – than non-infertile women. Among infertile women, those who had undergone COS had higher absolute dense volume than those who had not received any hormone treatment. To assess associations between infertility, hormonal fertility treatments and mammographic density, the researchers first compared mammographic density levels between fertile and infertile women. They then compared infertile women who had never received hormonal fertility treatment to those who had. As this study relied on self-reported information and it was not possible to capture specific diagnoses from the existing KARMA data, there may be a risk of misclassification of fertility and infertility. For example, women reporting a history of infertility may include some fertile women who had an infertile partner. The researchers caution that due to the cross-sectional design of the study, which assessed history of infertility and breast density at the same time, no causal links between hormonal fertility treatment, infertility and breast density could be established. Whether differences in breast density may affect potential breast cancer risk remains unknown. Given the observed, moderate association between infertility, hormonal treatments and breast density, continued monitoring of women undergoing COS is warranted, according to the researchers. Principal investigator has been Anastasia Nyman Iliadou, Associate professor at the vid Department of Medical Epidemiology and Biostatistics. The study has been funded by the EU-FP7 Health Programme, the Swedish Research Council, and Märit and Hans Rausings initiative against breast cancer. This news article is an edited version of a press release from BioMed Central. Publication Association of infertility and fertility treatment with mammographic density in a large screening-based cohort of women: a cross-sectional study Frida E. Lundberg, Anna L. V. Johansson, Kenny Rodriguez-Wallberg, Judith S. Brand, Kamila Czene, Per Hall and Anastasia N. Iliadou Breast Cancer Research 2016 DOI: 10.1186/s13058-016-0693-5 Online 13 April 2016.

Two prominent clinical researchers at Karolinska Institutet have been appointed Wallenberg Clinical Scholars 2016. The individual funding of SEK 15 million from Knut and Alice Wallenberg Foundation provides Miia Kivipelto and Per Svenningsson with the opportunity to deepen their research and disseminate their results in healthcare. In addition, Patrik Ernfors receives a second grant of SEK 15 million within the Wallenberg Scholar programme, to support leading researchers at Swedish universities. Miia Kivipelto, Professor of Clinical Geriatric Epidemiology at the Department of Neurobiology, Care Sciences and Society has made significant contributions to insights into how the development of dementia can be slowed down through the use of lifestyle measures. As a Wallenberg Clinical Scholar she will continue to investigate how best to prevent the disease. Among other things, she will develop a platform for high-quality clinical studies of dementia. Her work also includes developing models for assessing a person’s risk of dementia, investigating which mechanisms drive the disease and how these can be counteracted through a range of measures. Globally, the frequency of Alzheimer’s disease and other dementias is rapidly increasing. In recent decades, a great deal of resources have been put in to developing pharmaceuticals that can prevent the progress of the disease, but this has turned out to be easier said than done. As yet there is no drugs that can prevent the development of dementia.  However, Miia Kivipelto, has shown that it is possible to decrease memory problems with a number of measures: changed diet, physical training, cognitive training and normalising blood pressure and blood lipids.  More reading about Professor Miia Kivipelto   Per Svenningsson, Professor in Neurology at the the Department of Clinical Neuroscience, studies proteins that are central to the development of Parkinson’s disease and investigates pharmaceuticals that may potentially protect brain cells from damage. Every year, around 2,000 Swedes are diagnosed with Parkinson’s disease, in which the brain’s dopamine-producing cells are destroyed. Those affected lose the ability to control their movements; their muscles become stiff and often start to shake involuntarily. Many patients are also affected mentally. There are pharmaceuticals that can lessen the symptoms of Parkinson’s, but there are no treatments that can slow its degenerative progress. Wallenberg Clinical Scholar Per Svenningsson aims to develop treatments that can provide protection from the destructive forces that break down the cells in the brain. The focus of the project is a protein called glucocerebrosidase, which appears to interact with another protein found in the abnormal deposits, Lewy bodies, which form in the brains of people with Parkinson’s disease. Mutations in the gene for glucocerebrosidase lead to a 10-15-fold greater risk of developing Parkinson’s disease. Among other things, Per Svenningson is studying a substance, SapC, that appears to boost the protective effect of glucocerebrosidase. One of several aims is to produce a pharmaceutical that can imitate SapC and that will hopefully help everyone affected by the disease.   About Per Svenningsson's research group   Patrik Ernfors, Professor of Molecular Neurodevelopment at the Department of Medical Biochemistry and Biophysics, was appointed a Wallenberg Scholar in 2010 for his research about the mechanisms behind cell division of stem cells, and the possible ability of the brain to heal itself. Now, that he has received five years of further funding from the Knut and Alice Wallenberg Fundation, he aims to find new ways of treating Glioblastoma multiforme (GBM), the most common and also most aggressive and lethal of all brain tumors. Research over the past decades have provided extensive knowledge on cellular processes of growth factor signaling, apoptosis, autophagy, senescence, cell cycle control, DNA repair which have been instrumental for understanding physiology as well as cancer biology. The identification of such core “driver” pathways in tumor formation has steered drug development to targeted therapies. Despite intense research targeted therapies currently does not exist or work for all cancers. So instead of “correcting errors” causing the cancer, as in most targeted therapies, Patrik Ernfors and his research group will take an entirely new strategy by hypothesizing that the marked cellular changes in cancer cells may lead to acquired vulnerabilities. The idea is simply that acquired vulnerabilities associated with cell transformation can be exploited for development of new therapeutic strategies. The proposal combines highly innovative and systematic approaches to identify the hierarchical cell organization in glioblastoma tumors, gene-regulatory networks governing the different cell states and finally the identification of selective vulnerability of tumor initiating cells. Patrik Ernfors – Wallenberg Scholar 2010   About the research funder The Knut and Alice Wallenberg Foundation (KAW) is one of the largest private financiers of research in Europe. The Foundation grants currently the total of SEK 1.7 billion per year for various projects, mainly at Swedish Universities. KAW grants funding in two main areas; research projects of high scientific potential and individual support of excellent scientists. The funding goes mainly to research within the natural sciences, technology and medicine. The Wallenberg Clinical Scholars programme is managed in collaboration with the Royal Swedish Academy of Sciences (KVA). 

Genotoxins damage the genetic material in cells and can cause mutations and cancer. Some bacteria code for and produce genotoxins. In a new study in mice, published in the journal PLOS Pathogens, researchers from Karolinska Institutet reports the surprising finding that one of them – typhoid toxin –actually increases survival of the infected host and promotes long-term colonization without causing disease in the host. DNA damage caused by bacterial genotoxins has been linked to cancer, but is has been unclear what function genotoxins have in the context of a natural infection is not clear. Teresa Frisan, principal investigator at Karolinska Institute’s Department of Cell and Molecular Biology, and colleagues focused on the typhoid toxin from Salmonella enterica Typhi (S. Typhi), and specifically looked at chronic asymptomatic infection, which is known to increase the risk for tumors. S. Typhi infects only humans, making it difficult to study in in vivo mouse models. To get as close as possibly in an animal model, the researchers developed two Salmonella enterica Typhimurium (S. Typhimurium) strains, which cause systemic typhoid fever-like infection in immunocompetent mice. In contrast to normal S. Typhimurium strains that do not harbor the genotoxin, the two strains were engineered to produce either an active or an inactive typhoid genotoxin. Early stages of infection The researchers infected mice orally with the two bacterial strains and found that mice infected with the strain carrying the intact typhoid toxin had higher survival rates within the first 10 days post infection. None of the surviving mice from either group fell ill at later stages, but the mice infected with the toxigenic strain were more likely to develop chronic infection without disease signs. When looking more closely at the early stages of infection, the researchers found that the mice infected with the intact toxin strain mounted a weaker inflammatory immune response in the intestines than mice infected with the strain lacking the functional genotoxin. At other sites of infection throughout the body, however, the situation was consistently different: outside the intestine, the immune response in mice infected with the toxigenic strain was stronger than the response against the control strain. Since the intestinal microbiota (the community of microorganisms living in the gut) can contribute to the host immune response, the researchers analyzed a total of 35 mouse stool samples collected from uninfected mice and mice infected with the two Salmonella strains. Analyzing bacterial DNA from the stool samples, they found that the presence of typhoid toxin is associated with a different timing and pattern of the changes in the gut microbiome compared with either no infection or infection with the Salmonella strain that lacks the genotoxin. An immune modulator The researchers conclude that their data “collectively highlight a novel aspect of typhoid toxin as an immune modulator, which reduces the intestinal inflammatory response and the clearance of the bacteria”. Commenting on the potential link between genotoxins and cancer, they say “in our experimental conditions, chronic infection was not associated with induction of dysplasia or pre-carcinogenic lesions within the study period”.  This work is supported by grants awarded by the Swedish Research Council, the Swedish Cancer Society, the Danish Council for Independent Research, the Danish Research Council , the Infect-ERA project CINOCA, the Rotary Foundation, Swedish Research Council Formas, and Karolinska Institutet doctoral funding (KID). This news article is an edited version of a press release from PLOS. Publication The Typhoid Toxin Promotes Host Survival and the Establishment of a Persistent Asymptomatic Infection Lisa Del Bel Belluz, Riccardo Guidi , Ioannis S. Pateras, Laura Levi, Boris Mihaljevic, Syed Fazle Rouf, Marie Wrande, Marco Candela, Silvia Turroni, Claudia Nastasi, Clarissa Consolandi, Clelia Peano, Toma Tebaldi, Gabriella Viero, Vassilis G. Gorgoulis, Thorbjørn Krejsgaard, Mikael Rhen, Teresa Frisan  PLoS Pathogens 12(4): e1005528, online 7 April 2016, doi:10.1371/journal.ppat.1005528

One of the researchers behind a recent study in the journal Cell, Sophie Petropoulos, has a scholarship from the Mats Sundin Fellowship Programme (MSF) – a research partnership between Karolinska Institutet and the University of Toronto founded by the former member of the national ice-hockey squad and NHL professional, Mats Sundin. How does it feel to have MSF contribute to the study? “It’s incredibly inspiring that the MSF can show such amazing results so soon after starting up. Sophie’s work shows that with the right partnership, the right type of fundraising and, above all, the right attitude and motivation you can quickly produce great results.”                                   Why are you engaged in the research? “The MSF has given me a fantastic opportunity to give something back to Toronto, where I played hockey for 13 years, and to Stockholm, where I was brought up. Research and elite sport have many similarities and parallels, and that attracted me. After having met some of the skilled scientists working at Karolinska Institutet and the University of Toronto, I decided that this was the right way to give something back.” What do you hope to achieve? “The aim of the MSF is to continue to raise funds so that we can give scientists like Sophie the chance to probe their field more deeply, and develop their research and themselves as scientists. We’re setting up a Canadian foundation, a website, and hope to have everything ready for the next MSF event, which will take place during the 2016 World Cup of Hockey in Toronto this September.” Text: Heléne Almqvist (in translation from Swedish) More reading: "Fresh insights into early human embryo development" MSF postoc Sophie Petropoulos from Toronto and her Swedish PIs Fredrik Lanner and Rickard Sandberg. In a new study in the journal Cell, they show that there are considerable differences in embryonic development between humans and mice.  More about this on KI News

Researchers at Karolinska Institutet and the Ludwig Cancer Research in Stockholm have conducted a detailed molecular analysis of the embryo’s first week of development. Their results show that there are considerable differences in embryonic development between humans and mice, which is the most common organism of study in this field. The new study, which is published in the journal Cell, also shows that genes on the X chromosome are regulated differently. Early human embryonic development is difficult to study, and most of our knowledge comes from mice. During the first seven days of fertilisation, the egg develops from a single cell to a blastocyst, a hollow cluster of some 200 to 300 cells. It is during this time that the first three cell types appear: the trophectoderm, which gives rise to the placenta, the hypoblast, which forms the embryonic endoderm, and the embryonic cells that go to make up the embryo itself. If the embryo is to adhere to the uterus wall and pregnancy commence, all these three cell types must mature properly. However, exactly when and in which order and how the cell types form in humans has not been known. By detecting gene expression in individual cells, from donated human embryos that were not used for IVF treatment, two research groups led by Rickard Sandberg and Fredrik Lanner have managed to identify which genes are used in the embryo’s cells at different times during the first week of development. Mature more simultaneously  The Lanner-Sandberg team found that the first three cell types form later and seem to mature more simultaneously in the human than in the mouse.  “The fundamental knowledge generated by our research doesn’t only help us understand embryonic development better, it also tells us more about how pluripotent cells are formed and regulated in its early stages,” says Fredrik Lanner, assistant professor at the Department of Clinical Science, Intervention and Technology. “This is important for the use of embryonic stem cells in regenerative medicine.” The researchers also found that the expression of genes situated on the X chromosome is subject to an unexpected expression pattern. The X chromosome has a particular gene regulation problem, since women’s cells have two X chromosomes, while men only have a copy (XY). To avoid women having twice the level of expression of all genes on the X chromosome as men, women’s cells must offset the gene expression. In mice, where this process is well-studied, one of the two X chromosomes is simply shut off during the first week. However, it has always been uncertain if this process even begins during the first week of human embryo development. Offset the gene expression “What we’ve been able to demonstrate is that dose balance is gradually attained during day 4 to 7, interestingly through a completely new manner in which the gene expression from both X chromosomes in the female embryo is suppressed,” says Rickard Sandberg, professor at Karolinska Institutet’s Department of Cell and Molecular Biology and the Ludwig Cancer Research. Lead authors of this study are Sophie Petropoulos, Daniel Edsgärd and Björn Reinius. Sophie Petropoulos has a scholarship from the Mats Sundin Fellowship Programme for an exchange between Karolinska Institutet and the University of Toronto. Other funding bodies have been the Swedish Research Council, the Ragnar Söderberg Foundation, the Swedish Foundation for Strategic Research, the European Research Council, the Åke Wiberg Foundation, and the Ludwig Cancer Research. Text: Karin Söderlund Leifler (in translation from Swedish) View our press release about this study Publication Single-cell RNA-seq reveals lineage and X chromosome dynamics in human preimplantation embryos Sophie Petropoulos, Daniel Edsgärd, Björn Reinius, Qiaolin Deng, Sarita Pauliina Panula, Simone Codeluppi, Alvaro Plaza Reyes, Sten Linnarsson, Rickard Sandberg, and Fredrik Lanner Cell, published online 7 April 2016, doi: 10.1016/j.cell.2016.03.023 More reading: "Three questions to ice-hockey champ Mats Sundin…"

KI researcher Magda Bienko has been selected for the Career Development Award 2016 by the international research funding organisation Human Frontier Science Program (HFSP). In a global competition, eight young scientists received this prestigious award, worth around EUR 260 000 spread over three years, to jump-start their first independent laboratory. Among the awardees of 2016, selected from 57 applications, is Magda Bienko, Assistant Professor at Karolinska Institutet's Department of Medical Biochemistry and Biophysics, and also a SciLifeLab Fellow. She receives the grant for the project “Mapping genome organization and expression landscapes in single cells in early embryonic development.”

The government has now received proposals for the members of the KI University Board (konsistoriet) whom it is to appoint. The proposals were submitted by the nomination committee, comprising County Governor Christ Heister, former University Chancellor Lars Haikola and a student representative. The proposal will now be considered by the Government Offices, which will be announcing its decision at the end of April. A new board is to be in place by 1 May. Apart from the government-appointed members, the board consists of the vice-chancellor, pro-vice-chancellor and the university director along with three faculty representatives (appointed internally), three student representatives (appointed by the students’ unions) and three staff representatives. Current government-appointed members: Lars Leijonborg, chair Annika Andersson Dan Andersson Anders Blanck Susana Borrás Eskil Franck Torbjörn Rosdahl Charlotte Strömberg Proposed government-appointed members: Lars Leijonborg, chair, returning Susana Borrás, returning Sofia Heidenberg, new Marianne Lundius, new Jonas Milton, new Torbjörn Rosdahl, returning Lisa Sennerby Forsse, new Charlotte Strömberg, returning   More about the board of Karolinska Institutet

Researchers at Karolinska Institutet and Nanyang Technological University in Singapore have produced a unique method for monitoring the development of insulin-producing cells, which play a key part in regulating blood glucose concentration. The method, which is described in the journal Diabetologia, might prove to be step on the way to one day manufacturing insulin-producing cells in the laboratory. The pancreatic beta cells produce insulin, the hormone that regulates the body’s blood sugar levels, and the partial or total loss of their functionality causes diabetes. To understand how our insulin-producing beta cells are formed, they must be studied in vivo; one of the difficulties with this, however, is that the tissue where they reside is so hard to access. The researchers behind the current study have developed a unique method that is able to circumvent this obstacle by enabling scientists to monitor in detail how the beta cells develop from the embryonic stage to adult, functional cells in mice. In their study, the team shows that tissue from the mouse embryo, when transplanted to the anterior chamber of the eye, quickly establishes itself with a healthy supply of blood vessels. By using the cornea as a natural window into the body and a fluorescing marker for beta cell growth, the researchers are able to non-invasively monitor their development under a microscope. The researchers report that the embryonic tissue develops into fully functional, mature, insulin-secreting cells. A valuable tool “This means that we now have a valuable tool for studying the development of the hormone-secreting part of the pancreas and establishing in detail how this process is regulated at a molecular level,” says study leader Per-Olof Berggren, professor at the Rolf Luft Research Centre for Diabetes and Endocrinology at Karolinska Institutet’s Department of Molecular Medicine and Surgery. “This is highly significant and means that we one day might be able to stimulate the development of fully functional beta cells.” The study was financed with grants from the Swedish Research Council, the Family Erling-Persson Family Foundation, the Novo Nordisk Foundation, the Stichting af Jochnick Foundation, the Swedish Diabetes Association, Karolinska Institutet’s Strategic Research Area in diabetes, Skandia Insurance Company Ltd., Diabetes Wellness Sweden, the Berth von Kantzow Foundation, the European Research Council and the Knut and Alice Wallenberg Foundation. Per-Olof Berggren is co-founder and CEO of Biocrine, an unlisted biotech company that uses the technique as a research method. Another study author, Dr Helena Edlund, is co-founder, part owner and consultant for the unlisted biotech company Betagenon AB. Publication The anterior chamber of the eye is a transplantation site that supports and enables visualisation of beta cell development in mice. Ali Y, Diez J, Selander L, Zheng X, Edlund H, Berggren P Diabetologia 2016 Feb;():

The Nobel Assembly at Karolinska Institutet has appointed Professor Anna Wedell as chair of the Nobel Committee for Physiology or Medicine for 2016. She replaces Professor Thomas Perlmann, who is to become the secretary of both bodies. Anna Wedell was made professor of medical genetics at Karolinska Institutet in 2004. She was voted into the Nobel Assembly in July 2010, was an adjunct member of the committee between 2011 and 2012, becoming a permanent member in 2013. Anna Wedell was also elected as a member of the Royal Swedish Academy of Science’s Class for medical sciences.   The vice-chair of the Nobel Committee is Ole Kiehn, professor of neuroscience at Karolinska Institutet.   The Nobel Assembly has also appointed Thomas Perlmann, professor of molecular developmental biology, secretary of the Nobel Assembly at Karolinska Institutet and the Nobel Committee for Physiology or Medicine, replacing Urban Lendahl.   For further details, visit nobelprizemedicine.org.  

The Staff Disciplinary Board at KI has today decided to relieve Paolo Macchiarini of his duties as a researcher at KI. He is to be informed immediately that his contract has been rescinded. Paolo Macchiarini has engaged in conduct and research that is incompatible with a position of employment at KI. His dismissal is based on numerous reasons, including: PM’s activities at Kuban State Medical University in Krasnodar are in breach of KI’s fundamental values and have damaged KI’s reputation.   PM failed to truthfully and fully report his extra-occupational activities.  PM supplied false or misleading information in the CV he submitted to KI. Paolo Macchiarini demonstrated scientific negligence, according to KI’s investigation in 2015. “It’s impossible for KI to have any kind of collaboration with Paolo Macchiarini any longer,” says HR manager Mats Engelbrektson. “He has acted in a way that has had very tragic consequences for the people affected and their families. His conduct has seriously damaged confidence in KI and for research in general.“  KI has no further comment.

The European Research Council (ERC) has announced the winners of its prestigious ERC Advanced Grants 2015. Among a total of nine grantees from Swedish universities, four are researchers from Karolinska Institutet: Jonas Frisén, Thomas Helleday, Ole Kiehn and Klas Wiman. Jonas Frisén, professor at the Department of Cell and Molecular Biology, KI, receives the grant for the project ”Exploration and promotion of neurogenesis in the adult brain". Thomas Helleday, professor at the Department of Medical Biochemistry and Biophysics, KI, receives the grant for the project ”Targeting oxidative repair proteins for treatment of cancer and inflammation”. Ole Kiehn, professor at the Department of Neuroscience, receives the grant for the project ”Functional deciphering of the integrated brainstem connectome that selects locomotor behavior”. Klas Wiman, professor at the Department of Oncology-Pathology, receives the grant for the project ”Restoration of tumor suppressor function by induction of translational read-through of premature termination codons – a strategy for improved cancer therapy”. The ERC Advanced Grants are designed for established and world leading researchers who strive to pursue ground-breaking research with exceptional scientific ambition. The funding is up to 2.5 million Euros per grant and lasts up to five years.  More on ERC funding.    

Interstitial nephritis, a common cause of kidney failure, has a complex and largely unknown pathogenesis. In a new published paper in The Journal of the American Society of Nephrology (JASN), a team of researchers led from Karolinska Institutet shows how interstitial nephritis can develop from an autoimmune attack on the kidney’s collecting duct. Interstitial nephritis describes a type of morbid lesion often seen in patients with kidney failure that is characterised by tubular atrophy and interstitial scarring. The condition can develop from diverse backgrounds, such as adverse reactions to drugs, hypertension and diabetes; in many patients, however, the underlying cause is never identified. “Our study sheds light on a new pathogenesis of interstitial nephritis and kidney failure,” says researcher Nils Landegren from the Department of Medicine at Karolinska Institutet in Solna. “Our findings suggest that mechanisms similar to those that cause diseases like type 1 diabetes and thyroiditis, in which the immune system targets a specialised type of cell, can also cause interstitial nephritis.” Sometimes, rare diseases present an inroad into understanding common and more complex diseases. In this present study, the researchers studied a monogenic disease called autoimmune polyendocrine type 1 (APS1), which is an important model for the larger group of organ-specific autoimmune diseases. Some people with APS1 develop of interstitial nephritis and kidney failure. The renal tubular system To understand the causes of interstitial nephritis the group focused their investigations on three patients with APS1, all of whom developed kidney failure at an early age, and found that the immune system had attacked their kidneys. The researchers found antibodies that reacted to cells in the collecting ducts, which represent the terminal part of the renal tubular system, and were able to show that the target molecule was a water-channel protein that is only expressed in the collecting duct. All in all, their findings suggest that an autoimmune attack was responsible for the patients’ kidney disease. The researchers do not yet know, however, how common this type of pathogenesis is for kidney failure amongst the general population. The participating researchers work at Karolinska Institutet, Uppsala University, SciLifeLab and Århus University. The study was led by Professor Olle Kämpe at Karolinska Institutet’s Department of Medicine in Solna and financed with grants from the Swedish Research Council, the Torsten and Ragnar Söderberg Foundation, the Swedish Research Council for Environment, Agricultural Sciences and Spatial Planning (Formas), the Novo Nordisk Foundation, the National Organization for Rare Disorders (USA) and the National Institutes of Health (USA). Text: Karin Söderlund Leifler (in translation from Swedish) Publication Autoantibodies targeting a collecting duct-specific water channel in tubulointerstitial nephritis Nils Landegren, Mina Pourmousa Lindberg, Jakob Skov, Åsa Hallgren, Daniel Eriksson, Trine Lisberg Toft-Bertelsen, Nanna MacAulay, Eva Hagforsen, Anne Räisänen-Sokolowski, Heikki Saha, Thomas Nilsson, Gunnel Nordmark, Sophie Ohlsson, Jan Gustafsson, Eystein Husebye, Erik Larsson, Mark Andersson, Jaako Perheentupa, Fredrik Rorsman, Robert Fenton, Olle Kämpe JASN, published online 16 March 2016, doi: 10.1681/ASN.2015101126

A study of 1.3 million people in Sweden found that the risk of being diagnosed with schizophrenia or other psychoses was three times higher in refugees than in the Swedish-born population. The research team from Karolinska Institutet in Sweden and the University College London (UCL), UK, found that more than one in a thousand refugees were diagnosed with schizophrenia or other psychoses every year. For every 10,000 people, there would be approximately 4 new diagnoses among Swedish-born people per year, 8 among non-refugee migrants and 12 among refugees. The study, published in the BMJ, supports the theory that schizophrenia and other psychoses are influenced by life experiences. In the study, refugees were also 66% more likely to be diagnosed with such disorders than other migrants from the same regions. This suggests that the specific experiences of refugees, including traumatic events such as persecution, conflict or natural disasters, may contribute to risk of developing these disorders. “The dramatically increased risk among refugees shows that life events are a significant risk factor for schizophrenia and other psychoses,” explains leads author Dr Anna-Clara Hollander from Karolinska Institutet’s Department of Public Health Sciences. “This illustrates the impact that traumatic experiences can have on serious mental health conditions.” Refugees are already known to be at increased risk of post-traumatic stress disorder (PTSD) and depression, but this is the first study to show an increased risk of psychotic disorders such as schizophrenia. Specialist care and support “We know that refugees are a vulnerable group, facing many social, economic, physical and mental health challenges in their lives,” says co-senior author Dr James Kirkbride from UCL Psychiatry. “Our study shows that such groups also face increased risk of schizophrenia, highlighting the need for specialist care and support. In most countries refugees undergo standard health checks, but mental health issues can be overlooked. Like all people, refugees would benefit from timely and early treatment of any mental health problems.” The research was conducted using Swedish national registry data up until December 2011, so the data does not include recent migrants. However, there is nothing to suggest that people displaced by recent conflicts will be any less vulnerable than those granted refugee status in the past. Co-senior author Dr Christina Dalman, professor of psychiatric epidemiology at Karolinska Institutet, says: “We now know more about how traumatic life events can increase the risk of developing a wide range of mental health conditions, including schizophrenia. This knowledge should be applied to improve mental health care, for example when planning screening processes for migrants and refugees, or checking on people’s mental health following adverse life events.” This study has been supported by FORTE, the Wellcome Trust, the Royal Society, and the Swedish Research Council. Our press release about this paper A scientific editorial in BMJ Video on YouTube Publication Refugee migration and risk of schizophrenia and other non-affective psychoses: a cohort study of 1.3m people in Sweden Anna-Clara Hollander, Henrik Dal, Glyn Lewis, Cecilia Magnusson, James B Kirkbride, Christina Dalman BMJ, online 15 March 2016, doi: 10.1136/bmj.i1030

To meet the challenge of Alzheimer’s disease and other dementias, a concerted effort and long-term economic commitment is needed, according to a new expert report by internationally leading researchers in the field. The journal Lancet Neurology devotes its entire April issue to a detailed overview and recommendations about how patient care, as well as basic and clinical research on Alzheimer’s disease and other dementias should be organised in the future. The report will be presented at a workshop hosted by the European Parliament in Brussels on March 15, during the Brain Awareness Week 2016. The comprehensive report is the work of the Lancet Neurology Commission led by Professor Bengt Winblad, Centre for Alzheimer Research at Karolinska Institutet in Sweden. This commission was initiated by Lancet editors and formed with the aim to provide expert recommendations and information to politicians and policy makers about Alzheimer’s disease and related dementias. More than 30 internationally leading researchers collaborated on the 78 pages long report, which identified a range of challenges that need to be addressed to reduce the burden of dementia. “What we need now is for the politicians to realise that this is a growing problem that already costs society tremendous amounts of money”, says Professor Bengt Winblad. “We need investments of resources in research in all areas involved in this disease, to find better drugs, but also to improve compassionate care and prevention.” Alzheimer’s disease is the most common form of dementia and accounts for approximately 60 percent of the cases. The most important risk factor is high age and as life expectancy increases, the number of persons with dementia is expected to rise. In 2015, almost 47 million persons around the world were estimated to be affected. By 2030, the number is expected to reach 75 million. By 2050, up to 131 million persons are expected to be burdened by the disease. So far no treatment is available that can effectively halt or reverse the disease. Large multinational partnerships The Lancet Neurology Commission report discusses health economics, epidemiology, prevention, genetics, biology, diagnosis, treatment, care and ethics. The commission advocates that public governmental agencies form large multinational partnerships with academic centres and pharmaceutical companies to deploy capital resources and share risk. “To defeat Alzheimer’s disease and other dementias, united actions are needed, not only within research, but also within the political arena on all levels”, says Professor Winblad. “My hope is that our work will stimulate increased national and international collaboration.” The authors of this report are researchers from Sweden, France, UK, Australia, Denmark, Canada, Switzerland, Italy, Luxembourg, the United States, Germany and Netherlands. The report will be presented at a workshop hosted by the Science and Technology Options Assessment (STOA) panel of the European Parliament in Brussels, Belgium, during the international Brain Awareness Week 2016. View our press release Publication Defeating Alzheimer’s disease and other dementias: a priority for European science and society Bengt Winblad, Philippe Amouyel, Sandrine Andrieu et al, Lancet Neurology, 2016;15:455-532, online 14 March 2016