Integrative Molecular Phenotyping

KI News

Updated: 1 hour 23 min ago

Nobel prize-winning discovery – a research area that is developing rapidly

Tue, 02/10/2018 - 16:45
This year’s Nobel Prize in Physiology or Medicine recognizes the discovery that it is possible to treat cancer by inhibiting the brakes on the immune system. Behind their discovery lies a bold idea and eager basic research, which has led to an entirely new principle for cancer therapy and new medicines that have already been approved. Many factors contribute to rapid developments in this field—in particular, current research at Karolinska Institutet. Before motion cameras and rows of seats filled with journalists from all over the world, it was announced that the 2018 Nobel Prize in Physiology or Medicine will be shared by the researchers James P. Allison and Tasuku Honjo. “For their discovery of cancer therapy by inhibition of negative immune regulation,” Secretary to the Nobel Assembly and the Nobel Committee at Karolinska Institutet Thomas Perlmann proclaimed. This year’s Prize is a recognition of the discovery that it is possible to unleash the body’s native ability to attack tumor cells by blocking mechanisms that function as a brake on the immune system By inhibiting proteins that impede the immune system’s T-cells, the T-cells can instead be activated and create an immune response to the cancer cells. New concept for cancer treatment “The discoveries made by these two researchers have led to an entirely new principle for cancer therapy,” Chair of the Nobel Committee at Karolinska Institutet Anna Wedell remarks. “Because this new cancer therapy exploits the immune system’s innate ability to attack cancer cells more broadly, this ends up being a general form of cancer therapy; not one used only on specific tumors. It will be effective in treating types of cancer we haven’t been able to treat, and provide healing to patient groups we haven’t been able to help,” Anna Wedell says. During the 1990s, James P. Allison, one of the two laureates, studied the CTLA-4 protein that is found on the surface of T-cells. The protein had earlier been found to have a suppressing function on T-cells, thus inhibiting activation of the immune system. But while other researchers tried to exploit this mechanism to treat auto-immune diseases, James P. Allison explored the alternative. Rather than seeking to inhibit activation of the immune system, Allison tried instead to block the CTLA-4 “brake” using an antibody. This freed the T-cells to attack cancer cells. “It was his idea. He was creative and bold, driving his research forward to achieve this result,” Anna Wedell says. Immune therapy inhibition In December 1994, James Allison and his colleagues completed an experimental critical to his later discovery in which an antibody to CTLA-4 was tested on mice with cancer. The result was spectacular: Nobel Committee member Klas Kärre remarked. “The mice who were treated with the antibody were cured of cancer, while the control group of mice developed large tumors. That was the beginning of a whole new field within immunotherapy, today often called “Immune Therapy Inhibition,” he says. On the basis of these results, James Allison wanted to take next steps toward human trials but was turned down by several pharmaceutical companies. Finally, a small company responded and in 2010 he published a study that showed positive results in patients with advanced skin cancer. In several of the patients, the cancer appeared to have disappeared; this result had never been seen before. In 2011, the medicine was approved by the Federal Drug Administration (FDA). The second Nobel laureate, Tasuko Honjo, had, several years before James P. Allison’s discovery, discovered another protein which also was found on the surface of T-cells. He called this protein, PD-1, and started an ambitious research program to identify its function. “This is a great example of how curiosity drives foundational research which in turn provides a significant clinical benefit. Tasuko was curious about the new molecule he had discovered, this drove his efforts to gain an understanding of its function,” Anna Wedell says. It turned out that PD-1 also functions as a brake on the immune system, but with a different mode of action than CTLA-4. Here too antibodies develop that inhibit the protein. During 2012 clinical studies showed very good results after treatment of several different cancer types. In 2014, the therapy was approved for skin cancer and in 2015 for lung cancer and kidney cancer. PD-1 inhibition is a growing field with other PD-1 inhibitors shown to be effective in treating additional forms of cancer. Significant importance As with other cancer therapies, this type of treatment can have side effects, but these are in general manageable. All patients do not show a positive effect from checkpoint inhibition, but for those who do, the difference can be significant. For example, a third of patients with skin cancer respond to CTLA-4 inhibition therapy and 20% of this number appear to have been cured when seen in a 10-year perspective. “This can seem like a modest result, but is significant when compared to earlier when all patients died after just a few years. With PD-1 inhibition 40 percent of patients with advanced metastatic melanoma are cured,” Klas Kärre says. After James P. Allison’s and Tasuku Honjo’s discoveries, there has been rapid advancement in this field of research. A large number of clinical studies are currently in progress where checkpoint treatment is being tested on a variety of cancer types. New checkpoint molecules are also being tested as targets for treatment. Attempting to combine different checkpoint inhibitors with each other is also an important way forward that may yield an even better effect—something already seen with skin cancer. Another prospect is to combine checkpoint inhibition therapy with conventional courses of treatment. Karolinska Institutet has, together with other research institutions, been a site for this research. Here researchers have participated in clinical studies to test the effect of checkpoint inhibitors on a number of different cancers. “We both participate in extensive studies run by others and design our own. My research group is planning to start its own study soon to test the effect of adding checkpoint inhibitors to existing therapies for breast cancer,” says Jonas Bergh, Professor at the Institute for Oncology and Pathology at Karolinska Instittutet. Text: Sara Nilsson

KI met high school students during European Researchers' Night

Tue, 02/10/2018 - 15:47
Around 50 researchers from Karolinska Iinstitutet met about 4,000 high school students when they participated in European Researchers' Night on the 28 September. The students participated in interactive activities, shows, lectures and research dialogues and more. In addition to KI, researchers from KTH and Stockholm University and others participated in the exhibition, which was performed at Alba Nova University Center at KTH. During the day Researchers’ Grand Prix was also held, where scientists compete in presenting their research as entertaining and informative as possible during four minutes. The audience of approximately 260 students voted together with a jury for the winner. In this year's competition, researchers Tobias Alfvén and Charlotte Skoglund from KI participated and finished in an honorary second and third place. The EU-event European Researchers' Night in Stockholm is organized by Vetenskapens hus. Co-organizers are Karolinska Institutet, KTH and Stockholm University. It has been organized since 2006.

New knowledge on how neurons talk to muscles

Tue, 02/10/2018 - 10:12
Researchers at Karolinska Institutet have discovered a new way in which nerve cells can control movement. In a study on zebrafish published in the journal PNAS they show that the contact between neurons and muscles is more dynamic than previously thought. The results can open up new avenues to treating spinal cord injury and certain neurological diseases. The ability to move deliberately is essential to the survival of all animal life, and is based on an interaction between the muscles and the brain. The site where motor neurons and muscle cells communicate with each other is called the neuromuscular junction. This is where the neurons transfer signal substances that can be taken up by the muscle cells to make them contract. This point of contact – the synapse – has long been described as a relatively simple system in adult vertebrates, with the molecule acetylcholine as the most important neurotransmitter. Despite this, knowledge is lacking on how the communication is actually effected and how adult motor neurons can respond to damage or environmental change. Fine motor adjustment Researchers at Karolinska Institutet have now generated new knowledge about how the neuromuscular junction works. Their results show that it is a more dynamic system than previously believed. “Our study shows that the function of the neuromuscular synapses can change under certain conditions and in certain diseases in order to fine-tune movements, which was a completely unexpected finding,” says assistant professor Konstantinos Ampatzis at the Department of Neuroscience, Karolinska Institutet, who led the study. The study was conducted on zebrafish, which is a common model system in neurobiological research. The researchers show that changes in the form of an increase in physical activity and spinal damage can cause certain adult motor neurons to switch from producing acetylcholine to producing another neurotransmitter – glutamate. The researchers believe that this is to control movements better. New therapeutic potential The results indicate that more detailed studies of the neuromuscular junction are needed, not least in humans. Such knowledge is important because impaired communication between neurons and muscles can cause serious diseases, such as the neuromuscular disease myasthenia gravis. “Our study can open new doors to the treatment of diseases involving reduced neuromuscular transmission,” says Dr Ampatzis. “More detailed knowledge on which neurons express specific neurotransmitters can enable the development of better treatments that restore function to the nervous system.” There is also growing evidence that the neuromuscular junction is involved in the early stages of such diseases as spinal muscular atrophy (SMA) and amyotrophic lateral sclerosis (ALS), which have previously been regarded as diseases of the motor neurons. The study was financed by the Swedish Research Council, the Strategic Research Area Neuroscience, the Swedish Brain Foundation, the Längman Cultural Foundation and Erik and Edith Fernström Foundation. Publication “Adult spinal motoneurons change their neurotransmitter phenotype to control locomotion” Maria Bertuzzi, Weipang Chang, Konstantinos Ampatzis PNAS, online 1 October 2018, doi: 10.1073/pnas.1809050115

More than SEK 100 million to KI researchers from KAW Foundation

Tue, 02/10/2018 - 09:29
The Knut and Alice Wallenberg Foundation (KAW) has awarded a total of SEK 104.2 million to four research projects led from Karolinska Institutet. In all, the Foundation is granting SEK 640 million this year to 22 research projects at Swedish universities. The KAW Foundation is financing research projects in the fields of medicine, science and technology that are considered to offer potential for future scientific breakthroughs. KAW is the largest private research funder in Sweden. “These grants have been awarded to promising and exciting projects at the forefront of international research, comments KAW chairperson Peter Wallenberg Jr in a press release. “The Foundation supports long-term basic research that benefits Sweden, and gives researchers complete freedom to formulate and test their hypotheses. Funding applications are evaluated by the foremost international researchers in each field,” Some other examples of project goals are: better cancer therapies, new knowledge about carbon dioxide in the atmosphere, how our seas may be impacted by future environmental changes, increasing fiber-optic capacity, and clues about how the brain can repair itself. Unveil the dynamics of cell turnover in heart and brain Project:  Cell turnover in human health and disease Grant: SEK 40,600,000 over five years Principal investigator: Professor Jonas Frisén, Department of Cell and Molecular Biology, Karolinska Institutet. Partners: Henrik Druid, Karolinska Institutet, Joakim Lundberg, KTH, and Göran Possnert, Uppsala University. Short summary: By combining a retrospective birth-dating by analysis of 14C, derived from nuclear bomb tests, with phylogeny by single-cell DNA sequencing, the researchers aim to unveil the dynamics of cell turnover, the origin of new cells and how turnover and cell lineages are altered in pathology in humans. This fundamental knowledge is needed to understand human tissue homeostasis and pathology, and to devise regenerative strategies. Destructive interaction on the way to type 2 diabetes Project: Tissue-crosstalk and metabolic regulation of type 2 diabetes Grant: SEK 18,000,000 over three years, with the possibility of a two year extension. Principal investigator: Professor Juleen Zierath, Department of Molecular Medicine and Surgery, Karolinska Institutet. Partners: Per-Olof Berggren, Carsten Daub, Anna Krook, Erik Näslund och Mikael Rydén, all at Karolinska Institutet, and Thomas Moritz, Swedish University of Agricultural Sciences.  Short summary:  Metabolism in adipose tissue, liver and skeletal muscle plays a major role in the onset of type 2 diabetes, and low-grade chronic inflammation is common in people who develop the disease.  So, how do these organs interact with each other in an inflammatory environment, and how are the insulin-producing beta cells affected? This is what the researchers in the current project will investigate and try to explain. The researchers aim to show which proteins and metabolites that are secreted from adipose tissue, liver and skeletal muscle in inflammation, how these substances affect the interaction between these organs – and how this in turn affects the insulin-producing beta cells. Walk or run – how do muscles get their commands about speed? Project: Decoding the logic of the neural circuits for motor actions Grant: SEK 16,200,000 over five years Principal investigator: Professor Abdel El Manira, Department of Neuroscience, Karolinska Institutet. Short summary: Whether moving slowly to approach a prey or quickly to escape from a predator, it is vital that our muscles move with the right timing and at the appropriate speed – but how is this achieved within neural circuits in our brain? This will be investigated in this project using both optogenetics and advanced electrophysiological approaches to map the dynamic connectivity scheme of circuits for motor actions in zebrafish. The project is expected to provide novel insights into the rules governing the organization and function of the neural circuits controlling our movements. Capturing the riddle of conception on picture Project: Integrative structural biology of mammalian fertilization: Unveiling the beginning of life from gametes to atoms Grant: SEK 29,400,000 over five years Principal investigator: Professor Luca Jovine, Department of Biosciences and Nutrition, Karolinska Institutet Partners: Alexey Amunts, Stockholm University, and Linda Sandblad, Umeå University, both also at SciLifeLab. Short summary: The goal of the project is to visualize in three dimensions how egg and sperm interact with each other and eventually fuse at the molecular level. The researchers will study different stages of mammalian fertilization and, by combining X-ray crystallography with single-particle cryo-electron microscopy as well as focused ion beam milling coupled to cryo-electron tomography, obtain information at different levels of organization – from single molecules to sections of whole gametes frozen in in near-native conditions.

Full house when KI opened Biomediucm to the public

Mon, 01/10/2018 - 16:09
Nearly 1,500 people spent their Saturday in Biomedicum, when Karolinska Institutet held an open house for the public. Visitors could attend exhibitions, activities and lectures with KI researchers in the newly opened laboratory and learn more about stem cells, physical activity, pain, intestinal flora and much more.

The Nobel Prize in Physiology or Medicine 2018 to James P. Allison and Tasuku Honjo

Mon, 01/10/2018 - 11:34
The Nobel Assembly at Karolinska Institutet has today decided to award the 2018 Nobel Prize in Physiology or Medicine jointly to James P. Allison and Tasuku Honjo for their discovery of cancer therapy by inhibition of negative immune regulation. Cancer kills millions of people every year and is one of humanity’s greatest health challenges. By stimulating the inherent ability of our immune system to attack tumor cells this year’s Nobel Laureates have established an entirely new principle for cancer therapy. James P. Allison studied a known protein that functions as a brake on the immune system. He realized the potential of releasing the brake and thereby unleashing our immune cells to attack tumors. He then developed this concept into a brand new approach for treating patients. In parallel, Tasuku Honjo discovered a protein on immune cells and, after careful exploration of its function, eventually revealed that it also operates as a brake, but with a different mechanism of action. Therapies based on his discovery proved to be strikingly effective in the fight against cancer. Allison and Honjo showed how different strategies for inhibiting the brakes on the immune system can be used in the treatment of cancer. The seminal discoveries by the two Laureates constitute a landmark in our fight against cancer. James P. Allison: Affiliation at the time of the award: University of Texas MD Anderson Cancer Center, Houston, TX, USA , Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA Prize motivation: ”for their discovery of cancer therapy by inhibition of negative immune regulation.” Prize share: 1/2 Tasuku Honjo: Affiliation at the time of the award: Kyoto University, Kyoto, Japan Prize motivation: ”for their discovery of cancer therapy by inhibition of negative immune regulation.” Prize share: 1/2

Bariatric surgery linked to safer childbirth for the mother

Wed, 26/09/2018 - 20:00
Obese mothers who lose weight through bariatric surgery can have safer deliveries. The positive effects are many, including fewer caesarean sections, infections, tears and haemorrhages, and fewer cases of post-term delivery or uterine inertia. This according to an observational study by researchers at Karolinska Institutet in Sweden published in PLOS Medicine. Today, more than one in every three women admitted into prenatal care are either obese or overweight, and statistics from the National Board of Health and Welfare show that this is a rising trend. “We know that obesity and overweight are dangerous in connection with childbirth,” says Dr Olof Stephansson, obstetrician and researcher at Karolinska Institutet’s Department of Medicine in Solna. “Bariatric surgery is by far your best option if you want a lasting weight reduction over time.” The research group to which he belongs has made several studies of how bariatric surgery affects pregnancy and childbirth. This latest study compared deliveries in 1,431 women who had achieved considerable weight loss after bariatric surgery, with those in 4,476 women who had not undergone surgery. The women in the control group had the same BMI during early pregnancy as the experimental group had had before surgery. Comparison was done using registries “The effects were quite salient, and all of those we studied were to the benefit of the women who’d had surgery,” says Dr Stephansson. “There are a lower proportion of C-sections, fewer induced deliveries, a lower proportion of post-term deliveries, less frequent epidurals and fewer cases of uterine inertia, infection, perineal tears and haemorrhaging.” The comparison was done using the Scandinavian Obesity Surgery Registry (SOReg) and the Medical Birth Registry. The positive effect is thought to be attributable to the considerable weight loss that these women have undergone, on average 38 kilos from the time of surgery to the start of pregnancy. At the same time, earlier studies show that women who have bariatric surgery run a slightly greater risk of pre-term delivery and having babies that are small for their gestational age. “It’s therefore not as simple as just advising every woman who’s overweight to have bariatric surgery,” says Dr Stephansson. “But going by the results of this study, it has positive effects for mothers. More studies are needed in which we weigh up outcomes so that we can give a more general recommendation.” Bariatric surgery number is rising The Swedish studies should also be complemented with similar studies in other countries, he says. Internationally, Sweden stands out in terms of the volume of bariatric surgery performed. “Today, one per cent of all babies born in Sweden have mothers who have had bariatric surgery. It might not sound many, but this number is rising. When the women start to lose weight their fertility quickly recovers, so this too is improved by the operation.” The research is patient-centred and conducted by people with different competencies, including obstetricians, nutritionists, surgeons and epidemiologists. “Thanks to the fact that we combine good study design and method with proximity to clinic and patient, we can also conduct really good studies,” says Olof Stephansson. The study was financed with grants from several bodies, including the Swedish Research Council for Health, Working Life and Welfare (FORTE), the Swedish Research Council, Karolinska Institutet and the National Institute of Diabetes and Digestive and Kidney Diseases. Publication  “Delivery outcomes in term births after bariatric surgery: Population-based matched cohort study”. Olof Stephansson, Kari Johansson, Jonas Söderling, Ingmar Näslund and Martin Neovius. PLOS Medicine, online 26 September 2018, doi: 10.1371/journal.pmed.1002656.

EU project aims to increase knowledge on hormone disruptors

Wed, 26/09/2018 - 17:29
Hormone-disrupting chemicals in our environment can affect early neurodevelopment in children, but little is known about the exact mechanisms for this interference. A new EU funded research project, coordinated from Karolinska Institutet, now aims to learn more and to develop better screening and testing tools.     The project called ENDpoiNTs (Novel Testing Strategies for Endocrine Disruptors in the Context of Developmental NeuroToxicity) includes 16 partners in Europe, United States and Australia. Coordinator for the entire project is Dr Joëlle Rüegg, a molecular biologist and associate professor at the Institute of Environmental Medicine (IMM), Karolinska Institutet and also affiliated to the research organisation Swetox. The project is funded through the Horizon2020 framework programme with EUR 6.89 million or about SEK 70 million. The ENDpoiNTs researchers hope to clarify the causal link between hormone-disrupting chemicals and neurodevelopmental injuries by integrating expertise from different, but today largely independent, toxicology communities, and by combining novel experimental technologies with advanced biostatistics on human epidemiological and biomonitoring data. Another important aim is to ensure that the tools developed by the project can successfully be used in society.

Risk-profiling can benefit HIV prevention

Wed, 26/09/2018 - 10:38
That men who have sex with men run a greater risk of HIV than others has been known since the virus was discovered. However a thesis from Karolinska Institutet now shows that it is a small sub-group of these men who account for the greater part of the risk increase. The results are important to preventive efforts against HIV in Sweden. Men who have sex with men (MSM) are disproportionately affected by HIV compared to the general population, and now an increase in other sexually transmitted diseases, such as syphilis and gonorrhoea is also seen. The pattern is similar in large parts of Western Europe and North America. In her research, Kristina Ingemarsdotter-Persson has focused on how to distinguish groups of MSM with different risk profiles and preventive needs in order to better target preventive measures. Those who have many sexual partners and a broader sexual repertoire possibly require more and different kinds of intervention. Receptive for preventive measures “Men who have sex with men, particularly the high risk-takers, are open and receptive for preventive measures,” says Ms Ingemarsdotter-Persson, doctoral student at the Department of Public Health, Karolinska Institutet. “Healthcare providers need to utilise HIV test occasions and other contacts to reach these men with the right messages and offers.” Using both quantitative and qualitative methods, she has examined how Swedish MSM perceive and handle sexual risk-taking. “We found that those with high-risk behaviour often have it both at home and while traveling abroad. They also are better informed about HIV and sexual health than others. It was clear that for many of them, sex was important, but it was equally clear that they care about their own health and that of others.” Can live a long, healthy life In recent years, several studies have shown that someone living with HIV and who has effective medical treatment with undetectable virus levels can live a long, healthy life, and are not infectious when having sex. HIV rapid testing with results delivered within half an hour and prophylactic HIV treatment (PrEP, pre-exposure prophylaxis for HIV) are now made available for Swedish MSM. “Today, HIV should be seen as a chronic infection rather than a fatal disease,” Ms Ingemarsdotter-Persson says. “My research shows, unfortunately, that anxiety about being infected and unawareness about the rapid advances in HIV research still make some people not getting tested, even though the consequences of a positive result are completely different to what they once were. Knowledge about the HIV treatment progress needs to spread. Most importantly, however, we need to continue preventing HIV infection.” Kristina Ingemarsdotter-Persson is due to defend her thesis “Relating to risk: sexual behaviour and risk perception among men who have sex with men” at Karolinska Institutet on 28 September 2018.

People with fibromyalgia have inflammation of the brain

Tue, 25/09/2018 - 12:44
The causes of the difficult-to-treat pain syndrome fibromyalgia are largely unknown. Using PET brain imaging, researchers at Karolinska Institutet and Harvard University have now shown that glial cells – the central nervous system’s immune cells – are activated in the brains of patients with fibromyalgia. The finding which is published in the scientific journal Brain, Behavior, and Immunity opens the way for new therapies. Fibromyalgia is a chronic pain syndrome that causes extensive pain in the muscles and joints, severe fatigue, insomnia and cognitive difficulties. The higher pain sensitivity that is characteristic of the syndrome has been related to functional and structural alterations of brain regions associated with pain processing. In 2012, Eva Kosek’s research group at Karolinska Institutet showed that patients with fibromyalgia had elevated levels of certain inflammatory substances (cytokines) in the cerebrospinal fluid, suggesting inflammation of the central nervous system. Their findings were subsequently corroborated by other researchers, but the source of the inflammation remained unknown. Glial cells are activated Using modern PET (positron-emission topography) brain imaging Eva Kosek’s team has now been able to show that the central nervous system’s immune cells, called glial cells, are activated and thus give rise to inflammation of the brain. “As far as we know, this is the first time it’s been shown that glial cells are involved in the pathogenesis of fibromyalgia,” says Professor Eva Kosek from the Department of Clinical Neuroscience, Karolinska Institutet. The results show that in Swedish and American patients with fibromyalgia, glial cells are activated in large parts of the cerebral cortex, and that the degree of activation was related to the degree of fatigue reported by the patients. Objective aberrations in the brain “The findings may open the way for the development of completely new therapies for this currently difficult-to-treat condition,” says Professor Kosek. “The fact that scientific research is able to demonstrate objective aberrations in the brains of people with fibromyalgia will hopefully mitigate the suspicion with which patients are often treated by the health services and society.” Today, an estimated 200,000 Swedes, mainly women, suffer from fibromyalgia. The brains of people with the condition are known to have an impaired ability to dampen pain signals, which means that things that are normally painless cause considerable discomfort. The study was a collaboration between Eva Kosek’s research group at Karolinska Institutet in Sweden, the PET Centre at Karolinska Institutet and Dr Marco Loggia’s research group at Harvard University, Cambridge, USA. The research in Sweden was financed from several sources, including the EU’s 7th Framework and Programme and a donation from the Lundblad Family. The Swedish part of the project was also funded by Stockholm County Council, the Swedish Research Council, the Swedish Rheumatism Association and the Swedish Fibromyalgia Association. Publication “Brain glial activation in fibromyalgia – A multi-site positron emission tomography investigation” Daniel S. Albrecht1, Anton Forsberg1, Angelica Sandström, Courtney Bergan, Diana Kadetoff, Ekaterina Protsenko, Jon Lampa, Yvonne C. Lee, Caroline Olgart Höglund, Ciprian Catana, Simon Cervenka, Oluwaseun Akeju, Mats Lekander, George Cohen, Christer Halldin, Norman Taylor, Minhae Kim, Jacob M. Hooker, Robert R. Edwards, Vitaly Napadow, Eva Kosek2, Marco L. Loggia2 1Co-first authors, 2Co-senior authors Brain, Behavior, and Immunity, online 14 September 2018, doi: 10.1016/j.bbi.2018.09.018

New drug candidate makes cancer cells more sensitive to radiotherapy

Tue, 25/09/2018 - 11:10
Researchers from Karolinska Institutet and Kancera AB have developed a molecule that makes cancer cells sensitive to radiotherapy. In a study published in Nature Communications, the researchers describe a new way to block cancer cells' ability to repair their DNA and thus stop the survival of cancer cells. Radiotherapy is one of the most common cancer treatments. It damages the DNA, causing cancer cells to stop growing and die if the damage is left unrepaired. Unfortunately, some cancers are resistant to radiotherapy and the treatment also damages the DNA in healthy cells, thus limiting the amount of radiation that can be used with respect to normal tissue damage. In collaboration with the Swedish company Kancera AB, researchers at Karolinska Institutet have discovered a new mechanism that cancer cells use to repair DNA damage. In the current study, the researchers discovered that cancer cells use a protein called PFKFB3 to repair the DNA damage that occurs in radiation therapy. They found that the protein locates to sites of DNA damage in the cell nucleus where the protein regulates the cancer cell's ability to repair its DNA and thus survive. Drug candidate blocks the protein The research groups at Kancera AB and Karolinska Institutet have now developed a new drug candidate which blocks the protein and its ability to repair DNA damage. They demonstrated that cancer cells treated with the drug do not survive upon radiotherapy in laboratory experiments. “It is known that the levels of PFKFB3 is much higher in cancer cells than in healthy cells. However, the discovery that PFKFB3 regulates DNA repair upon radiotherapy is new and very exciting,” says Nina Gustafsson, Assistant Professor and Team Leader in Translational Medicine at the Department of Oncology-Pathology, Karolinska Institutet, who led the study together with Professor Thomas Helleday at the same department. Foundation for a new cancer treatment Since normal, healthy cells are not dependent on PFKFB3 for proper DNA repair, the researchers hope that combination therapy with radiation or chemotherapy will be well tolerated. The goal is now to further develop the drug and lay the foundation for a new cancer treatment with less side effects than the treatments currently available. The study was led by researchers at Karolinska Institutet, operating at SciLifeLab, and Kancera AB, and in collaboration with researchers from Stockholm University, University of Sheffield, Sprint Bioscience, Roma Tre University, Emory University School of Medicine and more. The research has been funded by the Swedish Society for Medical Research, the European Union's Horizon 2020 research and innovation program, together with Torsten Söderberg and Ragnar Söderberg Foundation and more. Publication ”Targeting PFKFB3 radiosensitizes cancer cells and suppresses homologous recombination”. Nina M.S. Gustafsson, Katarina Färnegårdh, Nadilly Bonagas, Anna Huguet Ninou, Petra Groth, Elisee Wiita, Mattias Jönsson, Kenth Hallberg, Jemina Lehto, Rosa Pennisi, Jessica Martinsson, Carina Norström, Jessica Hollers, Johan Schultz, Martin Andersson, Natalia Markova, Petra Marttila, Baek Kim, Martin Norin, Thomas Olin, Thomas Helleday. Nature Communications, online 24 September 2018, doi: 10.1038/s41467-018-06287-x.

KI opens Biomedicum to the general public

Tue, 25/09/2018 - 09:47
On Saturday 29 September Karolinska Institutet invites the general public to an open house at the newly opened research laboratory Biomedicum on Campus Solna. Visitors will get a chance to meet researchers during lectures, exhibitions, interactive activities, scientific activities for children and more. Hi there, Lilian Kisiswa, project leader and postdoc ... why is KI arranging an open house at Biomedicum? "KI organizes this open house because it's important to have an open and vibrant dialogue between researchers and the general public, and we want to give people a chance to find out about the high quality research conducted in the house. I'm very proud of KI, and research is a cornerstone of modern society and the two cannot be separated." What’s on the agenda for the day? "A lot! We’re offering classic lectures, interactive activities, exhibitions and a chance to look at our exciting laboratories and the building’s architecture. People will also get to ask questions direct to the researchers." Who is the open house for? "The event is free and for the general public, with or without an academic background, and there’s something for people of all ages." What’s special about the Biomedicum research building? "Biomedicum is an exciting, modern laboratory to work in and gives us researchers the chance to interact and collaborate. We can also share experiences, ideas and techniques across scientific boundaries, which is vital to research." What are you particularly looking forward to during the event? "We have a fantastic programme and I’ll try to attend all sessions. But if I had to choose one thing, then I’m looking forward to the interactive activities. As a visitor, you’ll get up close to research in an informal atmosphere. From our perspective, this will enable us to show how exciting research can be on an everyday basis and what it means to work as a researcher. To me, it’s a win-win situation."  

President Ole Petter Ottersen held anatomy lecture for medical students

Wed, 19/09/2018 - 10:54
The anatomy of the head was the theme of KI president Ole Petter Ottersen’s first lecture for the university’s students last week. “I get inspired by lecturing and meeting the students,” he says. An important signal about what teaching means, according to Lena Nilsson-Wikmar, chair of KI’s pedagogical committee. The lecture is due to start, and the buzz in KI Campus Solna’s gradually filling Berzelius lecture hall is getting louder. At the front, Karolinska Institutet president Ole Petter Ottersen makes himself ready to hold his lecture on the anatomy of the head for students on the third semester of the medical programme. “I get inspired by lecturing and meeting the students, both as a lecture and a researcher,” he says. “The questions they ask often give me new ideas about and for my own research.” Once he has been introduced by Hugo Zeberg, physician and lecturer in anatomy at the Department of Neuroscience he turns to address the students: “It’s an honour to teach anatomy at Karolinska Institutet – so this is a big day for me.” He then opens the lecture with a picture of the human cranium. “The head and face are packed with different organs, so that a disease in one can easily affect another. To understand this, you must know your anatomy. My very first patient had a sinus infection the cause of which I wouldn’t have seen without such knowledge. But more about that later,” says Professor Ottersen. Invaluable signal having the president teach According to Lena Nilsson-Wikmar, professor of physiotherapy at the Department of Neurobiology, Care Sciences and Society and chair of KI’s Pedagogical Academy , having the president teach sends out an invaluable signal. “It shows that he thinks teaching is important. That the university’s educational mission, and not just its research, is actually incredibly important. If KI’s study programmes and courses are to be even more rooted in research, teaching must not only be done by lecturers but also by professors. That’s not always the case today, so he’s setting a good and vital example,” she says. After long having a subordinate role at KI, Professor Nilsson-Wikmar feels that teaching and education have recently taken on a greater prominence – even if the change is a slow one. She is pleased that these days, since the introduction of the new employment regulations in April, the positions of professor, senior lecturer and lecturer at KI require a ten-week training in academic pedagogy. But the course must not be something that people take for its own sake, she stresses. “If you’ve taken a course on student-centred learning, you have to actually apply it to your teaching. I hope this will be the case, and in that sense the president and those who lead educational activities here at KI present important role models,” she says. An incentive and a requirement for senior researchers to teach Professor Nilsson-Wikmar also thinks that there has to be both an incentive and a requirement for senior researchers to teach, and would eventually like to see more stringent demands on teaching hours when new appointments are made. Professor Nilsson-Wikmar also welcomes the newly established Unit for Education and Learning, of which she is the pro tem director. The idea of the unit is to gather together the university’s pedagogical activities and develop its pedagogical training. In the Solna lecture hall, Professor Ottersen shows a CAT scan of a patient’s head. He asks the students what the picture shows and receives a swift response. An inflammation in a sinus turns out to come from the root of a tooth. “Knowledge of anatomy is vital to understanding how diseases can develop in the patients you’ll be encountering,” he says. "Teaching with a real-life perspective" We break for coffee . In the fourth row sits medical student Marika Rostvall. She is enjoying the lecture, and particularly likes the links he makes to the clinical significance of anatomy. “I often find anatomy boring, learning all those names,” she admits. “But when I feel that I’ll have use for it, it’s more interesting to learn about.” She also thinks it’s good for the president to hold lectures, not only so that the students get to form an impression of him, but also so that he can see how the teaching works. “It sends the signal that he cares about us and about education and not only about the ones who do research or securing their financing,” says Ms Rostvall. Her course-mate Richard Wang is also pleased with the lecturer, whose approach he finds different to that of others. “He reflected a lot on what the anatomy actually looks like, like how thin some things are or how closely together they sit,” he says. “I love that kind of teaching, as textbooks don’t give you that kind of real-life perspective. It’s also great to see the university’s top executives being so engaged in the students.” Professor Ottersen is happy that the students participated so actively in the lecture. The break is soon over and he readies himself for part two. “Teaching is a fascinating and important job for everyone in a scientific position at KI,” he says. “It’s a vital aspect of our work. There are synergies to be gained from linking research to education and it’s the idea of a university to do just that.”

Use of muscle relaxant during general anaesthesia increases risk of pulmonary complications

Tue, 18/09/2018 - 09:32
Muscle relaxants that are used during general anaesthesia increase the risk of pulmonary complications after surgery, according to the European multicentre study POPULAR, in which Karolinska Institutet researchers are involved. The study is published in the journal Lancet Respiratory Medicine. Increasing numbers of people around the world undergo anaesthesia and surgery, and in Sweden over 10 per cent of the population are exposed to anaesthesia every year. In the case of general anaesthesia, in order to reduce the dose of the anaesthetic and morphine-like drugs, so-called neuromuscular blockers are often also administered, thus mitigating the risk of complications. Even if this group of anaesthetic drugs has contributed to safer and more effective anaesthesia, several patient studies and smaller studies on healthy participants indicate that the addition of neuromuscular blockers to anaesthesia increase the risk of respiratory complications. In the current study, the researchers sought to ascertain if the use of these muscle relaxants in combination with anaesthesia and surgery increases the risk of developing post-surgical pulmonary complications, such as infections, respiratory insufficiency or lung collapse. Large European study Data from over 22,800 patients in 28 European countries who had received general anaesthetic, including some 1,200 patients from ten Swedish hospitals, were gathered from between July 2014 to April 2015. “The study shows that the use of neuromuscular blockers significantly increases the risk of pulmonary complications after anaesthesia and surgery,” says Malin Jonsson Fagerlund, consultant and docent at the Department of Physiology and Pharmacology, Karolinska Institutet. “More targeted studies need to be made to find out the underlying mechanisms behind this finding.” The study also shows that neither neuromuscular monitoring nor the use of drugs that reverse the neuromuscular blockade reduce the risk of post-surgical pulmonary complications. The study was financed by the European Society of Anaesthesiology. Publication “Post-anaesthesia Pulmonary Complications after Use of Muscle Relaxants: A Prospective Multicentre Observational Study (POPULAR)” Kirmeier E, Eriksson LI, Lewald H, Jonsson Fagerlund M, Hoeft A, Hollmann M, Meistelman C, Hunter JM, Ulm K, Blobner M and the POPULAR Contributors Lancet Respiratory Medicine, online 14 September 2018, doi: 10.1016/S2213-2600(18)30294-7

Structural map of bacterial toxins raises hopes for new anti-infectives

Mon, 17/09/2018 - 12:05
The bacteria Pseudomonas aeruginosa can cause serious and difficult to treat infections. The infection process involves the activation of toxic substances from the bacteria by a common protein in our cells. Researchers at Karolinska Institutet now show how this happens and that the activation can be stopped with drug-like molecules. The results are presented in Nature Communications. Pseudomonas aeruginosa infections are a common problem in hospitals. Antibiotic-resistant strains of the bacteria can cause life-threatening infections in patients with reduced immunity or large, open wounds. The bacteria also cause infection of the airways, which makes people with respiratory impairment, such as cystic fibrosis, particularly vulnerable. To find new means of treating these infections, researchers at Karolinska Institutet, Umeå University and Yale University have mapped the three-dimensional structure of two toxic proteins that the bacteria use to trigger the infection process. Protected by human protein The researchers have determined the structure of these toxins, called ExoS and ExoT, along with a human protein, called 14-3-3, which is known to be necessary for the toxins to become active. Previously, only little was known of the structure of one of the toxins (ExoS) and how it binds to the human protein. But it was unclear how this contact could give rise to the bacterium’s toxic effects. The team has now found a large, hydrophobic contact interface between the human protein and the bacterial toxins and shown that if this surface is not protected by the human protein, the toxins form inactive clusters in the cell’s water-soluble environment. In other words, the protein makes the bacterial toxins active by acting as a protective “chaperone”. A step towards new anti-infectives This newly identified contact interface presents a possible target for drug molecules. The study identified two small organic molecules that can prevent the infection between the bacterial toxins and the human protein. It also shows that the toxins lose their toxic activity when these molecules are introduced. The effect is weak, but according to the researchers, the results show that the principle works. The previously known contact between the bacterial toxins and the human protein takes place in an area where many other proteins in the cell bind. Affecting this region with drug molecules would probably therefore cause serious adverse effects. The newly discovered surface can prove a more specific target. “Our study shows that it’s possible to block toxin activity with drug-like molecules via an interface where no other proteins have yet been shown to interact,” says principal investigator Herwig Schüler, associate professor of structure biology at the Department of Biosciences and Nutrition, Karolinska Institutet. The study was financed by the Swedish Research Council, The Swedish Foundation for Strategic Research, the Wenner-Gren Foundation and the IngaBritt and Arne Lundberg Research Foundation. Publication “14-3-3 proteins activate Pseudomonas exotoxins-S and -T by chaperoning a hydrophobic surface” Tobias Karlberg, Peter Hornyak, Ana Filipa Pinto, Stefina Milanova, Mahsa Ebrahimi, Mikael Lindberg, Nikolai Püllen, Axel Nordström, Elinor Löverli, Rémi Caraballo, Emily V. Wong, Katja Näreoja, Ann-Gerd Thorsell, Mikael Elofsson, Enrique M. De La Cruz, Camilla Björkegren and Herwig Schüler Nature Communications, online 17 September 2018, doi: 10.1038/s41467-018-06194-1

Discovery of new neurons in the inner ear can lead to new therapies for hearing disorders

Wed, 12/09/2018 - 11:03
Researchers at Karolinska Institutet have identified four types of neurons in the peripheral auditory system, three of which are new to science. The analysis of these cells can lead to new therapies for various kinds of hearing disorders, such as tinnitus and age-related hearing loss. The study is published in Nature Communications. When sound reaches the inner ear, it is converted into electrical signals that are relayed to the brain via the ear’s nerve cells in cochlea. Previously, most of these cells were considered to be of two types: type 1 and type 2 neurons, type 1 transmitting most of the auditory information. A new study by scientists at Karolinska Institutet shows that the type 1 cells actually comprise three very different cell types, which tallies with earlier research showing variations in the electrical properties and sonic response of type 1 cells. Three different routes “We now know that there are three different routes into the central auditory system, instead of just one,” says François Lallemend, research group leader at the Department of Neuroscience, Karolinska Institutet, who led the study. “This makes us better placed to understand the part played by the different neurons in hearing. We’ve also mapped out which genes are active in the individual cell types.” The team conducted their study on mice using the relatively new technique of single-cell RNA sequencing. The result is a catalogue of the genes expressed in the nerve cells, which can give scientists a solid foundation for better understanding the auditory system as well as for devising new therapies and drugs. “Our study can open the way for the development of genetic tools that can be used for new treatments for different kinds of hearing disorders, such as tinnitus,” says Dr Lallemend. “Our mapping can also give rise to different ways of influencing the function of individual nerve cells in the body.” Crucial function The study shows that these three neuron types probably play a part in the decoding of sonic intensity (i.e. volume), a function that is crucial during conversations in a loud environment, which rely on the ability to filter out the background noise. This property is also important in different forms of hearing disorders, such as tinnitus or hyperacusis (oversensitivity to sound). “Once we know which neurons cause hyperacusis we’ll be able to start investigating new therapies to protect or repair them,” explains Dr Lallemend. “The next step is to show what effect these individual nerve cells have on the auditory system, which can lead to the development of better auditory aids such as cochlear implants.” The researchers have also shown through comparative studies on adult mice that these different types of neurons are already present at birth. The study was financed by grants from the Swedish Research Council, the Knut and Alice Wallenberg Foundation (Wallenberg Academy Fellow), the Swedish Brain Fund, Karolinska Institutet, the Ragnar Söderberg Foundation and the Silent School Foundation. Publication ”Neuronal heterogeneity and stereotyped connectivity in the auditory afferent system” Charles Petitpré, Haohao Wu, Anil Sharma, Anna Tokarska, Paula Fontanet, Yiqiao Wang, Françoise Helmbacher, Kevin Yackle, Gilad Silberberg, Saida Hadjab and François Lallemend Nature Communications, online 12 September 2018

New explanation for the cause of MS

Fri, 07/09/2018 - 09:49
In multiple sclerosis (MS), not only the T cells of the immune system, but also its B cells, play an important role. This is shown by researchers at Karolinska Institutet and the University of Zurich in a study published in the journal Cell. The findings explain how a new class of MS drugs works, and can open up for more precise ways of treating the disease. MS is a chronic disease where the body's immune cells attack and damage its own nerve tissue. The disease affects around 2.5 million people worldwide, with a higher risk among women. Now, a key aspect in the development of the disease has been found by researchers at Karolinska Institutet and the University of Zurich. The results are published in the journal Cell. Faiez Al Nimer, researcher at the Department of Clinical Neuroscience at KI, is co-first author of the study. Attack the nerve cells Until recently, MS research has mainly focused on a type of immune cells called T cells. They normally help protecting the body against intruders. In some people, however, they attack the protective layer surrounding the nerve cells – marking the onset of MS. The new study shows that not only T cells, but also B cells of the immune system, play a role in the development of the disease, by activating the T cells. By analysing blood samples, the researchers saw that blood from people with MS contained increased numbers and activation status of T cells known to be important for MS disease activity.  When the B cells were eliminated, the activation status of these disease-driving T cells returned to normal, suggesting that B cells play a crucial role in the activation of autoimmune T cells in MS. Migrate to the brain The team also discovered that these activated T cells detectable in the blood notably included those that also occur in the brain in MS patients during flare-ups of the disease. These T cells were shown to recognise the structures of a protein that is produced by the B cells as well as nerve cells in the brain. The researchers conclude that after being activated in the blood by B cells, the T-cells migrate to the brain, where they destroy the nerve tissue. The study explains the previously unclear mechanism of a new class of MS drugs (rituximab and ocrelizumab) and can, according to researchers, pave the way for more precise ways of treating MS in the future. The research is funded mainly by the European Research Council (ERC Advanced Grant). Further funds come from the University of Zurich, the Swiss Multiple Sclerosis Society, the Swiss National Science Foundation and a number of Swedish funding sources. This news article is based on a press release from the University of Zurich. Publication "Memory B Cells Activate Brain-Homing, Autoreactive CD4 + T Cells in Multiple Sclerosis" Ivan Jelcic, Faiez Al Nimer, Jian Wang, Verena Lentsch, Raquel Planas, Ilijas Jelcic, Aleksandar Madjovski, Sabrina Ruhrmann, Wolfgang Faigle, Katrin Frauenknecht Clemencia Pinilla, Radleigh Santos, Christian Hammer, Yaneth Ortiz, Lennart Opitz, Hans Grönlund, Gerhard Rogler, Onur Boyman, Richard Reynolds, Andreas Lutterotti, Mohsen Khademi, Tomas Olsson, Fredrik Piehl, Mireia Sospedra, and Roland Martin Cell, online 30 August 2018, doi: 10.1016 / j.cell.2018.08.011

President of Karolinska Institutet cleared of misconduct charges

Thu, 06/09/2018 - 18:09
France’s Institut Pasteur’s ethical committee has cleared Karolinska Institutet’s President Ole Petter Ottersen from all suspicions of scientific misconduct, committee chairperson François Rougeon has announced on the conclusion of the investigation. On 19 July this year Karolinska Institutet received a complaint of suspected scientific misconduct against its president, Ole Petter Ottersen. The complaint concerned a scientific paper published in the Journal of Neuroscience almost twenty years ago (1999), of which Professor Ottersen listed as co-author. The case aroused considerable attention in the Swedish and Norwegian media, which connected it with the misconduct verdict that the President announced on 25 June 2018 concerning the so-called Macchiarini affair. The research on which the Journal of Neuroscience article is based was not conducted at KI, which means that the matter cannot be investigated here. The complaint was therefore dismissed. KI contacted the research principal, the Institut Pasteur in Paris, to check if they had considered the article in question and found it to qualify as scientific misconduct. On 5 September 2018, François Rougeon, chairperson of the Institut Pasteur’s ethical committee announced that, following a review of the data published in the article, the investigators found no grounds to bring a verdict of scientific misconduct: ”In our opinion, the analyses of the data does not support the allegation of scientific misconduct”.

Laura Fratiglioni, Håkan Eriksson and Bertil Fredholm awarded Karolinska Institutet’s Grand Silver Medal

Wed, 05/09/2018 - 15:54
Laura Fratiglioni, Håkan Eriksson and Bertil Fredholm are awarded Karolinska Institutet’s Grand Silver Medal 2018. They are given the medal for their great contributions to support KI’s activities. Since 2010, Karolinska Institutet awards medals to people who have made special contributions to support KI. Now this years recipients of the Grand Silver Medal are announced: Laura Fratiglioni, professor, Department of Neurobiology, Care Sciences and Society, KI Laura Fratiglioni is one of the leading international researchers in epidemiology of aging. She is awarded the medal for her outstanding contributions to Karolinska Institutet in science, doctoral education and leadership and innovation. With her strong clinical and scientific background, Laura Fratiglioni is often sought out as an expert in aging and she has strongly contributed to the international profile of KI in this field. Her work has contributed to the use of epidemiologic methods in agin research. Thereto, Laura Fratiglioni is devoted to communicating her research findings to the general public. Bertil Fredholm, professor emeritus, Department of Physiology and Pharmacology, KI Bertil Fredholm is awarded for his outstanding contributions to research and doctoral education in the area of pharmacology. Bertil Fredholm is one of KI’s most internationally acclaimed researchers. His discoveries are related to the molecule adenosine and its receptors, and he was among the first to describe ways in which caffein affects the body. Bertil Fredholm has been a member of the Nobel Committee for eighteen years, including two as its chairperson. He has also devoted a great deal of time to teaching, and was a highly regarded teacher at bot the undergraduate and doctoral levels. Håkan Eriksson, professor emeritus, Department of Women’s and Children’s Health, KI Håkan Eriksson is awarded the medal for his exceptional contributions to KI and to Swedish medical research. Håkan Eriksson is distinguished by a strong and innovative research career within reproduction biology, but also his extensive contributions to KI and to Swedish research policy. For fifteen years he was the Director of Studies at the Department of Medical Chemistry, and a driving force behind efforts to strengthen the clinical connection of the education. His work was of crucial importance, particular during the 1990s, when KI underwent a period of great change. The result of these changes included more efficient processes and higher quality research, education and collaboration throughout KI. The medals will be awarded in conjunction with the installation ceremony in Aula Medica in October.

New project to improve drugs safety in East Africa

Tue, 04/09/2018 - 09:27
In recent years access to drugs and vaccines has been increasing in many African countries, but the systems for monitoring treatment effects and reporting side-effects require further development. Karolinska Institutet will now lead an international collaboration project on pharmacovigilance – drugs safety – in four countries in East Africa. Those taking part in the project, known as PROFORMA, are researchers from Karolinska Institutet, researchers and experts from universities and regulatory authorities in Ethiopia, Kenya, Tanzania and Rwanda, and some regional and international stakeholders in the field of drugs safety. The total project funding is EUR 6 million, of which the major part is provided by the EU Framework Programme for Research and Innovation-Horizon2020, via the European and Developing Countries Clinical Trials Partnership (EDCTP). Among other significant funding bodies is the Swedish International Development Cooperation Agency (SIDA).  “The main aim of this project is to strengthen the national infrastructures for drugs safety monitoring in our partner countries in Africa. This involves developing regulatory capacity for routine surveillance and reporting, and training of staff working in healthcare and medical services and regulatory authorities,” says Dr Eleni Aklillu, senior researcher at the Department of Laboratory Medicine at Karolinska Institutet and scientific coordinator for the project. Right now, she is in Ethiopia attending the national kick-off meeting for PROFORMA. PROFORMA is estimated to last five years. The project also involve training at Master’s and postgraduate level and exchange of knowledge in general between researchers and experts. “The increasing number of clinical trials and different types of mass drug administration and vaccination programmes in African countries underlines the need to strengthen pharmacovigilance infrastructure. One important tool is to improve collaboration between the Medical Universities and regulatory authorities in the countries concerned, and we’ve already made good progress in this area during the few months we’ve been working on the project,” says Eleni Aklillu. Facts about PROFORMA Project title: Pharmacovigilance infrastructure and post-marketing surveillance system capacity building for regional medicine regulatory harmonization in East Africa (PROFORMA) Project funding: EUR 6 million, to be spread over five years, of which approx EUR 3 million will be funded by Horizon2020/EDCTP. Other funding bodies are SIDA, Karolinska Institutet, the Pharmacy and Poisons Board (Kenya), Muhimbili University of Health and Allied Sciences (Tanzania) and the Tanzania Food and Drugs Authority. Project period: 1 March 2018 – 28 February 2023 (60 months) Coordinator: Dr Eleni Aklillu, Associate Professor, Karolinska Institutet.  Website: