Integrative Molecular Phenotyping
INTEGRATIVE MOLECULAR
PHENOTYPING
WHEELOCK LABORATORY
DEPARTMENT OF MEDICAL
BIOCHEMISTRY AND BIOPHYSICS
WHEELOCK LABORATORY
DEPARTMENT OF MEDICAL
BIOCHEMISTRY AND BIOPHYSICS
WHEELOCK LABORATORY
DEPARTMENT OF MEDICAL
BIOCHEMISTRY AND BIOPHYSICS
WHEELOCK LABORATORY
DEPARTMENT OF MEDICAL
BIOCHEMISTRY AND BIOPHYSICS
WHEELOCK LABORATORY
DEPARTMENT OF MEDICAL
BIOCHEMISTRY AND BIOPHYSICS
WHEELOCK LABORATORY

KI News

Updated: 2 hours 39 min ago

Research on medical abortion and miscarriage may change international routines

Fri, 27/03/2015 - 08:08
Two scientific studies led by researchers at Karolinska Institutet are expected to form the basis of new international recommendations for the treatment of medical abortions and miscarriages – recommendations that may also lead to a change in clinical practice in Sweden. One of the studies, both of which are being published in The Lancet, shows that it is possible to replace the clinical follow-up examinations recommended today with medical abortions that include a home pregnancy test. The other study shows that midwives can safely and effectively treat failed abortions and miscarriages in rural districts of Uganda. The term 'incomplete abortion' is when there is residual tissue in the uterus following a failed abortion treatment or spontaneous abortion (miscarriage). This can result in bleeding and infection and is a potentially life-threatening condition that can effectively be treated with the medicine misoprostol. Misoprostol is a prostaglandin analogue that causes the uterus to contract and empty its contents. Some 20 million abortions are performed illegally, and often unsafely, every year at global level. They lead to around 50,000 deaths making unsafe, illegal abortions one of the most common causes of death among women of fertile age. In Uganda there is a very restrictive policy towards abortions, which means that illegal abortions are common, with a large number of incomplete abortions as the result. With funding from WHO, researchers at Karolinska Institutet and colleagues from Makerere University in Uganda have conducted a study that includes around 1,000 women from rural districts of Uganda. The women had visited the health centres with complications following failed abortions or miscarriages. They were selected at random for treatment with misoprostol from either a midwife or doctor. The women were given a dose of the drug in tablet form at the health centre. Instructed to seek medical attention After a few hours they were sent home with antibiotics, pain-relief tablets and were instructed to seek medical attention if they developed a temperature, or had pain or vaginal discharge. When the women were examined after two weeks, around 95 percent of the treatments had been performed safely and effectively, and the figure was as high for the midwives as it was for the doctors. The women who still had residual tissue in the uterus were given surgical treatment. “The study shows that midwives can safely handle the medicinal treatment of incomplete abortions in rural districts of Uganda with misoprostol”, said Dr. Kristina Gemzell Danielsson, Professor at the Department of Women's and Children's Health at Karolinska Institutet and Chief physician at the Department of Obstetrics and Gynaecology  at Karolinska University Hospital in Stockholm. “As the midwives far outnumber the doctors in Uganda and many other low-income countries, this increases the availability of treatment for incomplete abortions and miscarriages, which saves women's lives. The study will form the basis of new guidelines from the WHO, which will recommend that midwives be allowed to handle the treatment of incomplete abortions.” The other study included some 900 women from Finland, Norway, Sweden and Austria, who sought medicinal abortion treatment up to nine weeks of pregnancy. They were selected at random to either book a follow-up appointment within one to three weeks, which is routine today, or to perform a home pregnancy test which measures levels of hCG in the urine after one to three weeks. When the women were followed up there was no difference between the groups in terms of effectiveness or safety. Possible to simplify the routines  “The study shows that it is possible to simplify the routines for medicinal abortions by allowing women to check the completeness of an abortion by perform a urine test at home. This increases the safety of medicinal abortions, as many women today fail to turn up to the follow-up visit. The study is expected to form the basis of new international recommendations from WHO and a change in clinical practice regarding medical abortions in Sweden and globally,” said Dr. Gemzell Danielsson. This research was funded by the Swedish Research Council, Karolinska Institutet, Stockholm County Council, and Dalarna University, and the WHO provided technical support. First author of one of the current studies has been Marie Klingberg Allvin, researcher at Karolinska Institutet and Associate Professor and Pro Vice-Chancellor at Dalarna University. Find our press release about this research Publications 'Comparison of treatment of incomplete abortion with misoprostol by physicians and midwives at district level in Uganda: a randomised controlled equivalence trial', Marie Klingberg Allvin,  Amanda Cleeve, Susan Atuhairwe, Nazarius Mbona Tumwesigye, Elisabeth Faxelid, Josaphat Byamugisha, and Kristina Gemzell Danielsson, The Lancet, online 27 March 2015.  'Clinical follow-up compared with self-assessment of outcome after medical abortion: a multicentre, non-inferiority, randomised, controlled trial', Kevin Sunde Oppegaard, Erik Qvigstad, Christian Fiala, Oskari Heikinheimo, Lina Benson, and Kristina Gemzell-Danielsson, The Lancet, 2015 Feb 21;385(9969):698-704, doi: 10.1016/S0140-6736(14)61054-0, Epub 2014 Oct 30.

Olli Kallioniemi is the new Director for SciLifeLab

Thu, 26/03/2015 - 09:09
The board of Science for Life Laboratory (SciLifeLab) has appointed Professor Olli Kallioniemi as new Director, starting July 1, 2015. Olli Kallioniemi succeeds Professor Mathias Uhlén. SciLifeLab, a national center for molecular biosciences, has appointed its second Director since the establishment in 2010. SciLifeLab is a collaboration between the four universities: Karolinska Institutet, KTH Royal Institute of Technology, Stockholm University and Uppsala University. The center was appointed a national center by the Swedish government in 2013. Olli Kallioniemi will join SciLifeLab as a professor at Karolinska Institutet and continue as a part-time Research Director of the Institute for Molecular Medicine Finland (FIMM) at the University of Helsinki where he has been the Director since 2007. “It is an exciting opportunity to start as Director for SciLifeLab. I look forward to working with the entire staff and stakeholders of the center to develop new opportunities for science and novel enabling technologies. An excellent base has already been established and will be built on to take SciLifeLab to the absolute global front-line in several fields of life science. There are also many new opportunities for collaborations, both locally in Sweden and internationally.” After receiving his M.D. and Ph.D. at the University of Tampere, Finland, Olli Kallionimei continued his career at UC San Francisco and was appointed faculty at the National Human Genome Research Institute, at the NIH, USA. Subsequently, he founded and developed the Medical Biotechnology group at the University of Turku, together with the VTT Technical Research Centre, Finland. His research spans cancer biology and genomics, molecular pathology and translational research, high-throughput technology development and data analysis. He is also a strong propagator for P4 medicine: Predictive, Preventive, Personalized and Participatory health care. “For Karolinska Institutet this is a spectacular recruitment to a position that is vital to Sweden and Swedish research,” says Professor Hans-Gustaf Ljunggren, dean of research at Karolinska Institutet and member of the SciLifeLab board.  Photo: Veikko Somerpuro  

Recycling histones through transcription

Thu, 26/03/2015 - 09:09
Cells reuse a part of the histones which are used to pack DNA, according to a current study by Karolinska Institutet. The study, which was published in the journal Genome Research, was conducted on yeast cells, but it is likely that similar mechanisms are important for human beings as well. Cells are also involved in energy saving and recycling. In this case it entails histones, the proteins which keep the cell's DNA packed by spinning it around itself like thread around reels of thread. The complex of DNA and histones is referred to as chromatin and it may be packed more hardly or loosely.  The level of packing controls which genes are currently expressed by affecting how easy it is for transcription enzymes, referred to as RNA polymerase, to bind to DNA and read the DNA sequence.  During transcription of active genes, the histones are temporarily removed from the chromatin so that the RNA polymerase can access the DNA. In the current study, researchers studied how gene expression impacts the composition of the chromatin. Previous studies have shown that it is often newly-formed histones which are built into the chromatin during transcription. “Instead we show that continuous transcription results in recycling of old histones,” says Peter Svensson at the Department of Biosciences and Nutrition, one of the researchers behind the study. Chemical markers Histones in the chromatin often have a number of modifications in the form of chemical markers. The modifications differ between the active and quiet closed regions in DNA, and help the cell to remember which genes are not used. “Patterns of these modifications take a long time to create and by recycling the histones the cell can keep the region active. We have also seen that the protein complex FACT is necessary to restore mature histones which are temporarily removed from the chromatin during transcription,” says Peter Svensson. The discovery indicates that transcription of genes has a histone-preservation function and that the cell can efficiently recycle the original histones. In this manner, it can save energy and at the same time preserve a cellular (epigenetic) memory in the chromatin. However, new histones which lack chemical markers or have other modifications than the mature histones are added in the chromatin when the genes move between the quiet and active stage. In the new study yeast cells are used as the model system, while the involved proteins and their functions are largely evolutionarily preserved in human cells, and researchers believe that similar mechanisms probably have a general significance. The work was conducted with support of grants from the Swedish Research Council, the Swedish Cancer Society and Karolinska Institutet. Text: Karin Söderlund Leifler (in translation from English) Publication A nucleosome turnover map reveals that the stability of histone H4 Lys20 methylation depends on histone recycling in transcribed chromatin J Peter Svensson, Manu Shukla, Victoria Menendez-Benito, Ulrika Norman-Axelsson, Pauline Audergon, Indranil Sinha, Jason C Tanny, Robin C Allshire, Karl Ekwall  Genome Research, first online 16 March 2015, doi: 10.1101/gr.188870.114

Anna Wedell appointed Wallenberg Clinical Scholar

Wed, 25/03/2015 - 10:10
The Knut and Alice Wallenberg Foundation invests up to SEK 600 million during a ten-year period in the program Wallenberg Clinical Scholars. Among the first four appointed researchers is Anna Wedell, Professor of Medical Genetics at Karolinska Institutet, and also affiliated to SciLifeLab. The foundations objective is to boost Swedish clinical research by identifying the best clinical researchers and giving them ample opportunities to carry out their work and have their findings impact both science and healthcare. Approximately one in two thousand infants is born with a metabolic disorder that often leads to brain damage. By means of high-tech genetic mapping, Professor Anna Wedell, has discovered the molecular foundations for several of these diseases. In one case, a change of diet improved the patient’s condition. Newborns are always offered a PKU-test – a blood test that can reveal a host of rare diseases. Originally the test was used to diagnose the disease phenylketonuria, an inability in children to break down the amino acid phenylalanine. Removing phenylalanine from the diet leads to normal development. Undertaking large-scale studies  Today, children are tested for 24 different congenital, but treatable diseases. Many metabolic disorders, however, lack effective counter-measures. As Wallenberg Clinical Scholar, Anna Wedell will continue to unravel the mysteries of these diseases. Undertaking large-scale studies of children’s genetics, she has already identified the foundations for several such inborn disorders. On one occasion her work has also resulted in successful therapy; for a girl with serious brain damage, the brain’s white matter began developing when she was treated with ketogenic diet, an extreme type of low-carbohydrate diet. This caused the girl’s condition to improve considerably. Anna Wedell’s mapping of the molecular mechanisms in metabolic diseases may not only lead to therapies preventing brain damage, but will also improve the fundamental understanding of the biochemistry of the metabolism. This, in turn, may lead to insights into the driving forces behind other diseases, such as autism as well as Alzheimer’s and Parkinson’s diseases. The program provides funding for 25 of Sweden's most prominent clinical researchers and will run for ten years. The estimated value of the initiative is SEK 600 million and each researcher obtains SEK 15 million for a period of five years, with possibility of extension for another five years. Read more on: Wallenberg Clinical Scholars The Royal Swedish Academy of Sciences  

New role for methionine in protecting cells from oxidative stress

Fri, 20/03/2015 - 11:11
Reduction systems and protection of cells against oxidative stress are processes not entirely dependent on the electron carrier NADPH as generally believed. Researchers at Karolinska Institutet and Montana State University have now demonstrated how mice that are incapable of using the primary NADPH-dependent systems in their livers cope perfectly, as long as they get the amino acid methionine via their food. This discovery is published in the journal Nature Communications. With each intake of breath, very reactive molecules are formed in our bodies when cells use oxygen. These molecules can damage DNA and other important cell components by oxidising everything in their path, in much the same way as iron rusts when exposed to too much oxygen. To protect themselves, cells have two main 'anti-rust systems', dependent upon glutathione and thioredoxin, which neutralise oxidising molecules by donating electrons. When this happens, glutathione and thioredoxin are oxidised instead and must be restored through an inverse process, i.e. reduction. This is handled by the enzymes glutathione reductase (GR) and thioredoxin reductase (TR), both of which are dependent on the electron carrier NADPH. These systems are also used to synthesise DNA building blocks and for many other cellular processes that require reduction. On glutathione alone In this new study, the researchers looked at mice whose livers completely lack GR and TR. To the researchers’ surprise, the mice were in good health and lived long lives despite not having these NADPH-dependent enzymes. When the researchers tried to work out why this was, they made the unexpected discovery that the mice got by on glutathione alone, which was, furthermore, only used once per molecule as the lack of GR meant that the antioxidant properties of the glutathione could not be restored. Somehow the mice were able to constantly form new glutathione in order to maintain the essential balance between oxygen and anti-oxidation. “Another surprise came when we realised that the cells’ entire glutathione requirement could be maintained by the amino acid methionine in a way that doesn’t use NADPH at all. This was surprising as NADPH is usually considered a universal and essential 'anti-rust agent' in cells”, says Elias Arnér at the Department of Medical Biochemistry and Biophysics at Karolinska Institutet, one of the researchers behind the study. Essential amino acid Methionine is an essential amino acid that we must obtain from our food as the body cannot synthesise new methionine. The result of this study indicate that methionine not only functions as a building block in proteins, or as an intermediate stage in various parts of the metabolism, but also that, of its own accord as a source of glutathione, it is able to maintain the good health and long life of mice who lack the ability to use NADPH-dependent GR and TR. This study was conducted on genetically modified mice, whose livers lack these two very important enzymes. The results of the study cannot be directly translated to human beings and methionine as a dietary supplement. The research was funded by funding bodies including the Swedish Research Council and Karolinska Institutet. Text: Karin Söderlund (in translation from Swedish) View a related news article from Montana State University Publication Dietary methionine can sustain cytosolic redox homeostasis in the mouse liver Sofi Eriksson, Justin R. Prigge, Emily A. Talago, Elias S.J. Arnér & Edward E. Schmidt Nature Communications, online 20 March 2015, doi: doi:10.1038/ncomms7479

KI researchers awarded European Research Council grants

Fri, 20/03/2015 - 09:09
Rickard Sandberg, senior researcher at the Department of Cellular and Molecular Biology, and Per Svenningsson, professor at the Department of Clinical Neuroscience, both at Karolinska Institutet, have been awarded ERC Consolidator Grants from the European Research Council (ERC). Rickard Sandberg, who studies molecular gene regulation, receives 1.9 million Euro. Using technology for single cell gene activity analysis, the group aims to map activity in genes originating from each parent of an individual to properties at the cellular and individual level. ERC Consolidator Grants are awarded to promising young researchers who are in the early stages of their careers. – It is an honour and an acknowledgement to receive this grant. It enables us to pursue our research program and learn about how our genome is regulated in different tissues, says Rickard Sandberg. Per Svenningsson, active in Parkinson's disease research, receives an ERC Consolidator Grant of two million Euro for five years. He is awarded the grant to conduct research on the protective mechanisms of a cell receptor, through the use of animal models and tissue from patients with Parkinson's disease. Hopefully, this research will lead to new treatment strategies and biomarkers for Parkinson's. – The grant means that I will have financial support for venturous research that may prove to be groundbreaking in the long term, says Per Svenningsson.  

New honorary doctors at Karolinska Institutet 2015

Thu, 19/03/2015 - 13:13
The Board of Research at Karolinska Institutet has appointed four new honorary doctors, who will have their doctorates formally conferred at a ceremony in the Stockholm City Hall on 22nd May 2015. Every year, Karolinska Institutet confers honorary doctorates to individuals for their vital scientific achievements or significant contributions to the university or humanity at large. Mariam Claeson, Honorary Doctor of Medicine (MDhc) The title of Honorary Doctor of Medicine has been awarded to Mariam Claeson, Director of the Maternal, Newborn and Child Health at the Bill and Melinda Gates Foundation in Seattle, USA. Mariam Claeson has spent her entire professional career successfully introducing the results of new medical research to those who need them the most – women and children in low-income countries. After graduating from Karolinska Institutet with an MD in 1979, she worked in health and medical care in Bangladesh, Bhutan and Ethiopia. After a brief period in Sweden as a global health consultant she was recruited by the World Health Organisation (WHO) where she remained for 6 years. For the next 18 years she held positions as medical consultant in various senior posts at the World Bank Group, and currently holds a senior post at the Bill and Melinda Gates Foundation.. Barry John Everitt, Honorary Doctor of Medicine (MDhc) The title of Honorary Doctor of Medicine has been awarded to Barry John Everitt, zoology and psychology graduate, and Professor of Behavioural Neuroscience at the University of Cambridge, England. Barry Everitt was one of the first to show how hormones affect the signalling substances in the brain through which they control our sex drive. With the same methods he subsequently also tackled the systems that control drug addiction. Through his studies Barry Everitt has changed our perception of neurobiological and psychological mechanisms in drug addiction and his discovery has also played a key role in developing new treatments for addiction and certain psychiatric illnesses, including post-traumatic stress disorder. Barry Everitt introduced behavioural sciences to Karolinska Institutet and inspired many researchers in this field. He has held a number of positions of responsibility at Karolinska Institutet, has been awarded numerous scientific accolades and has been on a large number of international scientific committees and advisory bodies. Bertil Hållsten, Honorary Doctor of Medicine (MDhc) The title of Honorary Doctor of Medicine has been awarded to Bertil Hållsten, PhD in Finance at the Stockholm School of Economics and later Professor of Economics at the Royal College of Forestry. Following a career in academia, Bertil Hållsten worked as an advisor and portfolio manager handling investments in research-intensive companies in the life science area. In 2003 he founded the Hållsten Research Foundation, and has since then contributed significant funding to Swedish medical research, mainly through the Swedish Brain Foundation.  In 2014, Bertil Hållsten donated additional  funds to enable the inception of four Hållsten Academy Fellows at Karolinska Institutet, where young researchers of particular promise received generous grants for four years. Tak W Mak, Honorary Doctor of Medicine (MDhc) The title of Honorary Doctor of Medicine has been awarded to Tak W Mak, Professor, University of Toronto and Director of the Campbell Family Institute for Breast Cancer Research at Princess Margaret Cancer Centre in Toronto, Canada. Tak W. Mak has made fundamental discoveries in immunology as well as cancer research. In 1984 he discovered the T cell receptor, one of the most important discoveries in immunology in modern times. He was also one of the pioneers of genetically modified mice or "knockout mice", which have made a significant contribution to the development of immunological and biological tumour research all over the world. Tak Mak has helped significantly strengthen Karolinska Institutet's research portfolio with his unparalleled generosity by sharing his model systems.

KI decides on a code of conduct for all co-workers

Wed, 18/03/2015 - 13:13
A code of conduct for KI employees, is it really necessary? Yes, says the management, which is now requiring everyone working at the university to sign the one it has just recently issued. The seven-point document summarises laws and regulations relating to the working environment and KI’s own internal rules and guidelines on such matters as discrimination and conflict of interest. HR manager Mats Engelbrektson calls the code a “clarification” and a pedagogical tool for creating a healthy working climate at the university: “I don’t think everyone reads all the laws and regulations, but these particular points they’ll be signing and demonstrating their readiness to live up to them,” he says. The code focuses on showing consideration and respect and on not causing or contributing to discrimination and harassment. There are also items about reporting offensive or discriminatory behaviour amongst colleagues and declaring a personal COI situation. The decision to introduce a code of conduct at Karolinska Institutet comes after the 2011 employee survey, which revealed a high level of victimisation and harassment. Even though the number of such reports had dropped in 2014 from seven to under four per cent, Mr Engelbrektson insists that more has to be done: “The situation still needs improving,” he says. Why not target the ones who do the bullying? “We do that as well. But the better everyone’s behaviour, the better the results.” Polls by doctoral students a motivator Exit polls completed by doctoral students on graduating have also been a motivator for the code. One sixth of doctoral students claim to have been victimised or discriminated against at KI. Dean of Doctoral Education Anders Gustafsson is one of the driving forces behind the new code. “It’s an important sign to all our students that we take action against harassment and discrimination seriously,” he says. Professor Gustafsson says that a code of conduct is not a magic bullet but one of several important initiatives, including increasing participation on supervisor training programmes and strategy plans to improve departmental environments. For doctoral students, it is often a matter of how they are treated by their supervisors. “It’s an incredibly tough culture at the university, but I think we’ve done a great deal to change it and that we’re now seeing the results. Not revolutionary The doctoral students’ ombudsman, John Steen, who is employed by the Medical Students’ Union at KI, was engaged in the discussions of a new code of conduct, and was quick to explain his standpoint to the drafting committee. “It won’t be revolutionary,” he says. “Managers and supervisors already have to be familiar with work environment laws and regulations. The question is how this document will be used,” he continues, adding that it will now be particularly important not to cancel the systematic work being done to improve the working environment just because the employees have now signed a piece of paper. How will you make sure that the code of conduct is actually observed and not just brushed aside? “It’ll be embarrassing to brush it aside,” says Mr Engelbrektson. “We’ll continue to work on these situations, making it clearer exactly what the code involves. If someone breaks the rules, it can affect anything from their working conditions to their employment contract.” Makes workplace requirements clearer Andreas Nyström, the employees’ SACO (the Swedish Confederation of Professional Associations) representative, looks favourably upon KI’s efforts to clarify workplace requirements. “I don’t think the code of conduct per se will solve any problems, but as part of a larger puzzle in which KI is now making more explicit moves to improve its working environment it’s a good thing,” he says. The last item of the code concerns disciplinary measures and, in extreme cases, dismissal. “Employees are already obliged to comply with certain directives, but it’s good to be clearer about their implications,” says Mr Nyström. “If disciplinary action has to be taken, KI, like all institutes of higher education, has a faculty accountability board to deal with it.”   Text: Madeleine Svärd  

Language of gene switches unchanged across the evolution

Tue, 17/03/2015 - 13:13
The language used in the switches that turn genes on and off has remained the same across millions of years of evolution, according to a new study led by researchers at Karolinska Institutet. The findings, which are published in the scientific journal eLife, indicate that the differences between animals reside in the content and length of the instructions that are written using this conserved language. Tiny fruit flies look very different from humans, but both are descended from a common ancestor that existed over 600 million years ago. Differences between animal species are often caused by the same or similar genes being switched on and off at various times and in different tissues in each species. Each gene has a regulatory region that contains the instructions controlling when and where the gene is expressed. These instructions are written in a language often referred to as the 'gene regulatory code'. This code is read by proteins called transcription factors that bind to specific ‘DNA words’ and either increase or decrease the expression of the associated gene. The gene regulatory regions differ between species. However, until now, it has been unclear if the instructions in these regions are written using the same gene regulatory code, or whether transcription factors found in different animals recognise different DNA words. In the current study, the researchers used high throughput methods to identify the DNA words recognised by more than 240 transcription factors of the fruit fly, and then developed computational tools to compare them with the DNA words of humans. 600 million years of evolution "We observed that, in spite of more than 600 million years of evolution, almost all known DNA words found in humans and mice were recognised by fruit fly transcription factors", says Kazuhiro Nitta at the Department of Biosciences and Nutrition at Karolinska Institutet, first author of the study. The researchers also noted that both fruit flies and humans have a few transcription factors that recognise unique DNA words and confer properties that are specific to each species, such as the fruit fly wing. Likewise, transcription factors that exist only in humans operate in cell types that do not exist in fruit flies. The findings suggest that changes in transcription factor specificities contribute to the formation of new types of cells. The study of fundamental properties of gene switches is important in medicine, as faulty gene switches have been linked to many common diseases, including cancer, diabetes and heart disease. The research was funded by, among others, Center for Innovative Medicine at Karolinska Institutet and Göran Gustafsson Foundation. Study leader has been Jussi Taipale, Professor of Medical System Biology at Karolinska Institutet. Researchers in Finland, Germany and Switzerland also contributed to the study. Our press release about this study More about Jussi Taipale's research group Publication Conservation of transcription factor binding specificities across 600 million years of bilateria evolution Kazuhiro Nitta, Arttu Jolma, Yimeng Yin, Ekaterina Morgunova, Teemu Kivioja, Junaid Akthar, Komeel Hens, Jarkko Toivonen, Bart Deplancke, Eleen Furlong, Jussi Taipale eLife, online 17 March 2015, doi: org/10.7554/eLife.04837

Rare ‘DNA and RNA jitters’ may explain random mutations

Fri, 13/03/2015 - 20:20
In a new study being published in Nature, researchers present a possible explanation to how seemingly random errors are made in the molecular machinery that copies DNA and produces proteins in a living cell. In a flicker of a second, DNA or RNA bases sometimes make the slightest change to mimic a different base. These rare ‘jitters’ seems to appear at about the same frequency as the DNA copying machinery makes mistakes or the ribosome incorporates new amino acids, which might make them the basis of random changes that drive evolution and diseases like cancer. The molecular process to copy DNA in a living cell is amazingly fast and accurate when it comes to pairing up the correct bases – G with C and A with T – into each new double helix. The ribosome is a high-throughput machinery producing proteins based on a RNA triple matching. These machineries work by recognizing the shape of the right base pair combinations, and discarding those that do not fit together correctly. Yet for approximately every 10,000 to 100,000 bases copied, a mistake is made that if uncorrected will be immortalized in the genome as a mutation. For decades, researchers have wondered how these seemingly random errors are made. Sophisticated technique By using a sophisticated technique called NMR relaxation dispersion, a team of researchers from Duke University and Karolinska Institutet could witness DNA bases making the slightest of changes – shifting a single atom from one spot to another or simply getting rid of it altogether – to temporarily mimic the shape of a different base. These ‘quantum jitters’ are exceedingly rare and only flicker into existence for a thousandth of a second, and also appears at about the same frequency that the DNA copying machinery makes mistakes or the ribosome adds the wrong amino acid. According to the researchers, it seems like structure of DNA is inherently tailored to allow mistakes to happen at a certain level. Without these errors life would not have evolved. On the other hand, with too many jitters our genes would mutate out of control.  Participating in this study from Karolinska Institutet did Dr. Katja Petzold, Principal investigator at the Department of Medical Biochemistry and Biophysics. Study leader has been Dr. Hashim Al-Hashimi from Duke University. The investigation was funded by an NIH grant and an Agilent Thought Leader Award. This news article is partly a rewrite from a press release issued by Duke University. Learn more about this research on the Futurity website Publication Visualizing transient Watson–Crick-like mispairs in DNA and RNA duplexes Isaac J. Kimsey, Katja Petzold, Bharathwaj Sathyamoorthy, and Hashim M. Al-Hashimi Nature, online 11 March 2015, doi:10.1038/nature14227

Brain training and healthy lifestyle may slow down cognitive decline

Thu, 12/03/2015 - 10:10
A comprehensive programme providing elderly people at risk of dementia with healthy eating guidance, exercise, brain training, and management of metabolic and vascular risk factors appears to slow down cognitive decline, according to a new randomised controlled trial lead from Karolinska Institutet. The study, which is published in The Lancet, is based on data from 1260 people from Finland and is the largest of its kind ever. In the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) study, Swedish and Finnish scientist assessed the effects on brain function of a comprehensive intervention aimed at addressing some of the most important risk factors for age-related dementia, such as high body-mass index and heart health. 1260 people from across Finland, aged 60–77 years, were included in the study, with half randomly allocated to the intervention group, and half allocated to a control group, who received regular health advice only. All of the study participants were deemed to be at risk of dementia, based on standardised test scores.  The intensive intervention consisted of regular meetings over two years with physicians, nurses, and other health professionals.  Participants were given comprehensive advice on maintaining a healthy diet, exercise programmes including muscle and cardiovascular training, brain training exercises, and management of metabolic and vascular risk factors through regular blood tests, and other means. After two years, study participants’ mental function was scored using a standard test, the Neuropsychological Test Battery (NTB), where a higher score corresponds to better mental functioning. Even more striking Overall test scores in the intervention group were 25 percent higher than in the control group. For some parts of the test, the difference between groups was even more striking; for executive functioning (the brain’s ability to organise and regulate thought processes) scores were 83 percent higher in the intervention group, and processing speed was 150 percent higher.  Based on a pre-specified analysis, the intervention appeared to have no effect on patients’ memory.  However, based on post-hoc analyses, there was a difference in memory scores between the intervention and control groups. The study was led by Professor Miia Kivipelto, MD, PhD, at Karolinska Institutet’s Department of Neurobiology, Care Sciences and Society, also affiliated to the Aging Research Centre in Stockholm as well as the National Institute for Health and Welfare in Helsinki, Finland and University of Eastern Finland. Funding bodies were, amongst others, the Academy of Finland, La Carita Foundation, Alzheimer Association, Alzheimer’s Research and Prevention Foundation, Juho Vainio Foundation, Novo Nordisk Foundation, Finnish Social Insurance Institution, Ministry of Education and Culture, Salama bint Hamdan Al Nahyan Foundation, and Axa Research Fund, EVO grants, Swedish Research Council, Swedish Research Council for Health, Working Life, and Welfare, and af Jochnick Foundation (full list in the article). This news article is based on a press release from The Lancet. Publication  A 2 year multidomain intervention of diet, exercise, cognitive training, and vascular risk monitoring versus control to prevent cognitive decline in at-risk elderly people (FINGER): a randomised controlled trial Tiia Ngandu, Jenni Lehtisalo, Alina Solomon, Esko Levälahti, Satu Ahtiluoto, Riitta Antikainen, Lars Bäckman, Tuomo Hänninen, Antti Jula, Tiina Laatikainen, Jaana Lindström, Francesca Mangialasche, Teemu Paajanen, Satu Pajala, Markku Peltonen, Rainer Rauramaa, Anna Stigsdotter-Neely, Timo Strandberg, Jaakko Tuomilehto, Hilkka Soininen, and Miia Kivipelto The Lancet, Published Online March 12, 2015 http://dx.doi.org/10.1016/ S0140-6736(15)60461-5

Karolinska Institutet launches a MOOC in e-health

Wed, 11/03/2015 - 08:08
Karolinska Institutet is now launching a massive open online course (MOOC) in the subject e-health. The course is being delivered via the international education group edX. Karolinska Institutet has been offering a master's programme in e-health for the past five years and will now also be offering a MOOC in the field of e-health (health informatics). In simple terms, the subject is about building bridges between medicine and technology and making information management in health and social care both safe and effective. The idea of the course is to offer students from all over the world an introduction to the field of e-health and its opportunities and challenges from different perspectives. The MOOC will give students an understanding of what health informatics is, and how it works. “IT projects in the healthcare sector require substantial expertise regarding the needs of the medical sector, as well as an understanding of the strengths and weaknesses of the technology. E-health can improve many aspects of the healthcare sector, but more insight is needed into the inherent problems of this area. We will be providing this knowledge in the course”, says course coordinator Professor Sabine Koch. The e-health MOOC begins on the 22 April 2015. Read more about the MOOC in eHealth.

How blood group O protects against malaria

Tue, 10/03/2015 - 07:07
It has long been known that people with blood type O are protected from dying of severe malaria. In a study published in Nature Medicine, a team of Scandinavian scientists explains the mechanisms behind the protection that blood type O provides, and suggest that the selective pressure imposed by malaria may contribute to the variable global distribution of ABO blood groups in the human population. Malaria is a serious disease that is estimated by the WHO to infect 200 million people a year, 600,000 of whom, primarily children under five, fatally. Malaria, which is most endemic in sub-Saharan Africa, is caused by different kinds of parasites from the plasmodium family, and effectively all cases of severe or fatal malaria come from the species known as Plasmodium falciparum. In severe cases of the disease, the infected red blood cells adhere excessively in the microvasculature and block the blood flow, causing oxygen deficiency and tissue damage that can lead to coma, brain damage and, eventually death. Scientists have therefore been keen to learn more about how this species of parasite makes the infected red blood cells so sticky. It has long been known that people with blood type O are protected against severe malaria, while those with other types, such as A, often fall into a coma and die. Unpacking the mechanisms behind this has been one of the main goals of malaria research. A team of scientists led from Karolinska Institutet in Sweden have now identified a new and important piece of the puzzle by describing the key part played by the RIFIN protein. Using data from different kinds of experiment on cell cultures and animals, they show how the Plasmodium falciparum parasite secretes RIFIN, and how the protein makes its way to the surface of the blood cell, where it acts like glue. The team also demonstrates how it bonds strongly with the surface of type A blood cells, but only weakly to type O. Conceptually simple Principal investigator Mats Wahlgren, a Professor at Karolinska Institutet’s Department of Microbiology, Tumour and Cell Biology, describes the finding as “conceptually simple”. However, since RIFIN is found in many different variants, it has taken the research team a lot of time to isolate exactly which variant is responsible for this mechanism. “Our study ties together previous findings”, said Professor Wahlgren. “We can explain the mechanism behind the protection that blood group O provides against severe malaria, which can, in turn, explain why the blood type is so common in the areas where malaria is common. In Nigeria, for instance, more than half of the population belongs to blood group O, which protects against malaria.” The study was financed by grants from the Swedish Foundation for Strategic Research, the EU, the Swedish Research Council, the Torsten and Ragnar Söderberg Foundation, the Royal Swedish Academy of Sciences, and Karolinska Institutet. Except Karolinska Institutet, co-authors of the study are affiliated to Stockholm University, Lund University, Karolinska University Hospital, and the national research facility SciLifeLab in Sweden, and to the University of Copenhagen in Denmark and University of Helsinki in Finland. Mats Wahlgren is a shareholder and board member of drug company Dilaforette AB, which is working on an anti-malaria drug. The company was founded with support from Karolinska Development AB, which helps innovators with patent-protected discoveries reach the commercial market. Publication RIFINs are Adhesins Implicated in Severe Plasmodium falciparum Malaria Suchi Goel, Mia Palmkvist, Kirsten Moll, Nicolas Joannin, Patricia Lara, Reetesh Akhouri, Nasim Moradi, Karin Öjemalm, Mattias Westman, Davide Angeletti, Hanna Kjellin, Janne Lehtiö, Ola Blixt, Lars Ideström, Carl G Gahmberg, Jill R Storry, Annika K. Hult, Martin L. Olsson, Gunnar von Heijne, IngMarie Nilsson and Mats Wahlgren  Nature Medicine, AOP 9 March 2015, doi: 10.1038/nm.3812

New findings on ‘key players’ in brain inflammation

Fri, 06/03/2015 - 09:09
Inflammation is a natural reaction of the body’s immune system to an aggressor or an injury, but if the inflammatory response is too strong it becomes harmful. Inflammatory processes occur in the brain in conjunction with stroke and neurological diseases such as Alzheimer’s and Parkinson’s disease. Researchers from Lund University and Karolinska Institutet in close collaboration with University of Seville have presented new findings about some of the ‘key players’ in inflammation. In the long term, these findings could lead to new treatments.  One of these key players is a receptor called TLR4. The receptor plays such an important role in the body’s innate immune system that the researchers who discovered it were awarded the 2011 Nobel Prize in Physiology or Medicine. The other key player is a protein called galectin-3, which is absent in healthy brains but present in a brain suffering ongoing inflammation. Researchers have now demonstrated that galectin-3 is secreted by microglial cells, a type of immune cell in the brain. The protein binds to the TLR4 receptor and amplifies the reactions that lead to inflammation. More galectin-3 is produced and binds to the immune cells, and the immune response is further intensified in a self-sustaining process. Various different methods The study, which is published in the journal Cell Reports, demonstrates the importance of the link between the two ‘key players’ using various different methods and in laboratory tests, animal experiments and human trials. The researchers have shown that mice genetically modified to be incapable of synthesising galectin-3 show a lower inflammatory response and less brain damage after model mimicing a heart attack. Mice with a model of Parkinson’s disease also suffer less brain damage if they do not have the gene for galectin-3. Researchers also observed the interaction between galectin-3 and TLR4 in the brains of people who died of a stroke. First study-author Miguel Angel Burguillos is currently working at Queen Mary University of London, but carried out the work on galectin-3 and TLR4 during his time as a postdoctoral fellow at Lund University and Karolinska Institutet. The research in Lund has been led by Tomas Deierborg and at Karolinska Institutet by Bertrand Joseph. The University of Seville also participated in the research. This work has been supported by the A.E. Berger Foundation, the Bergvall Foundation, the Crafoord Foundation, the G & J Kock Foundation, the Gyllenstiernska Krapperup Foundation, Lars Hierta Memorial Foundation, Proyecto de Excelencia from Junta de Andalucia, the Royal Physiographic Society in Lund, Spanish Ministerio de Ciencia y Tecnología, the Swedish Childhood Cancer Society, the Swedish Parkinson Foundation, the Swedish Research Council, the Swedish Strategic Research Area MultiPark at Lund University, the Swedish National Stroke Foundation, and the Wiberg foundation. Read more about the study on the website of Queen Mary University of London Publication Microglia-secreted Galectin-3 acts as a Toll-Like Receptor-4 ligand and contributes to microglial activation  Miguel Burguillos, Martina Svensson, Tim Schulte, Antonio Boza-Serrano, Albert Garcia-Quintanilla, Edel Kavanagh, Martiniano Santiago, Nikenza Viceconte, Maria Jose Oliva-Martin, Ahmed Osman, Emma Salomonsson, Lahouari Amar, Annette Persson, Klas Blomgren, Adnane Achour, Elisabet Englund, Hakon Leffler, Jose Luis Venero, Bertrand Joseph, Tomas Deierborg Cell Report, online 5 March 2015, DOI: http://dx.doi.org/10.1016/j.celrep.2015.02.012  

Helping researchers onto the commercial market

Wed, 04/03/2015 - 09:09
Taking a good idea from the lab to the market can seem an insurmountable task. But help is at hand. Gustaf Öqvist Seimyr and Mattias Nilsson Benfatto at KI’s Marianne Bernadotte Centre have been supported by KI Innovations all the way from the drawing board to a pitch for venture capitalists at SEB. ​“Nervous? No, to be honest, we were so well-prepared,” says Gustaf Öqvist Seimyr. He and Mattias Nilsson Benfatto have developed a method for discovering dyslexia in primary school children. “We felt that we simply had to bring our results out into the schools, which is where they’ll be of benefit,” says Dr Öqvist Seimyr. First of all, they were required to fill out an IDF (invention disclosure form) presenting their idea; then KI Innovations helped them investigate whether it was possible to patent and protect the product. Then followed market research and commercial development with consultant, until it was at last time for the dreaded pitch. A meeting was arranged in November with investors invited by SEB. Five minutes meeting “You get about five minutes and have to follow a set format,” says Dr Öqvist Seimyr. “But it went fine.” According to Åsa Kallas, project manager at KI Innovations, most researchers are not accustomed to launching their ideas as commercial projects. “They’re often focused on lab data to start with, and less on business, of course.” KI Innovations gives them the opportunity to pitch their ideas in a way that investors expect, she adds. “We’ve brought presentations down from 10 minutes to about a minute, even to a 30-second elevator pitch,” says her colleague Christian Krog Jensen, business developer and experienced board member. Work strictly confidentially No one need feel nervous about coming to KI Innovations, he says. “We’re very approachable and good at fishing out the gems,” he says. “We work strictly confidentially and protect the researchers who work with us from dodgy investors.” The entire process can take 18 months, depending on the project. “Can commercialising your research make you rich?” Yes. And no. “Sure, I daresay the odd fortune is made in the end. But most people just want to get their research out to the patients,” says Christian Krog-Jensen.   Text: Jonas Fredén Foto: Gustav Mårtensson

Human gene identified for tolerance to an environmental hazard

Wed, 04/03/2015 - 09:09
Studies conducted at the Karolinska Institutet and Uppsala University in Sweden show that some indigenous groups in the Andes of northern Argentina have increased resistance to arsenic. The researchers also identified the gene that underlies the altered metabolism and protects against exposure to arsenic. This study is the first to show that some humans have genetically adapted to a polluted environment. Arsenic occurs naturally in the bedrock in many places in the world and is one of the most potent carcinogens in our environment. People are exposed mainly through drinking water and food, especially rice and various rice products. People living in the Argentinean Andes have likely been exposed to high levels of arsenic in drinking water for thousands of years. The present study shows that residents who live in this region today have a clearly higher frequency of gene variants that enable the body to efficiently handle arsenic by methylating and excreting a less-toxic arsenic metabolite. By contrast, people who lack the protective gene variant produce a more-toxic arsenic metabolite if they are exposed to arsenic. Other communities in neighboring areas without the same historical arsenic exposure have significantly lower frequencies of the protective gene variant. These researchers have identified changes in the main gene for arsenic metabolism, AS3MT, as the cause of the altered metabolism. Their results suggest that people have adapted to arsenic via an increase in the frequency of protective variants of AS3MT. This study is a striking example of how humans have been able to adapt to local, sometimes harmful, environmental conditions. Those who survived the exposure to arsenic lived longer and had more children; thus, the protective gene variants are very common in some regions of the Andes today. Only a few such examples have previously been described in man. Particularly tolerant to environmental toxicants “Our study shows that there are not only extra-susceptible individuals, but also individuals who are particularly tolerant to environmental toxicants. This phenomenon is probably not unique to arsenic, but also applies to other toxicants in food and the environment, to which humans have been exposed for a long time. The results also highlight the necessity to be observant and not base health risk assessments for chemicals on data from people who may have strong genetic tolerance to the particular chemical", says Karin Broberg, researcher at the Institute of Environmental Medicine at Karolinska Institutet. “Only few other studies have found evidence of local adaptation in humans; for instance adaptation to high altitude conditions and the malaria parasite. This study adds another example of how humans have adapted, in a relatively short time, to tolerate an environmental stressor that they encountered when they settled in a new area", says Carina Schlebusch, researcher at the Department of Ecology and Genetics at Uppsala University. The researchers will now study whether other populations with historical arsenic exposure show an equivalent adaptation, and examine if other toxic substances in the environment can result in increased frequency of genetic variants that provide resistance in humans. This study was supported bySwedish Council for Working Life and Social Research, the Erik Philip Sörensen’s Foundation, EU’s Sixth Framework Programme, the Wenner-Gren Foundations, the Swedish Research Council Formas, and the Swedish Research Council for Science. Genotyping was performed by the SNP&SEQ Technology Platform in Uppsala, which is a part of the national research facility Science for Life Laboratory. Principal investigators are Karin Broberg at Karolinska Institutet, and Mattias Jakobsson at Uppsala University.  Read more about arsenic at IMM’s Risk Web View our press release about this research Publication  Human adaptation to arsenic-rich environments Carina M Schlebusch, Lucie M Gattepaille, Karin Engström, Marie Vahter, Mattias Jakobsson, Karin Broberg Molecular Biology & Evolution, online 3 March 2015, doi: doi: 10.1093/molbev/msv046

Government decides to return human remain

Mon, 02/03/2015 - 12:12
The government has decided to comply with the requests of New Zealand and French Polynesia and return the human crania – three from the former nation and seven from the latter – currently being held by Karolinska Institutet. Now that this decision has been taken, KI can inform the recipients that the crania are to be returned and ask how they would like the handover to be effected. “And then we’ll act accordingly,” says Olof Ljungström at the Unit for medical history and heritage. Karolinska Institutet spent last year preparing the matter of the repatriation of human remains to New Zealand. KI has also been working on drawing up a comprehensive inventory of its collections of non-European material, especially that of indigenous populations over and above the individuals from New Zealand.  Included in the 300-plus non-European individuals are three large collections from Ancient Egypt, pre-conquest Peru and Bronze Age Siberia, as well as a hundred or so crania of various origins. No request has as yet been made for the return of these remains. KI’s cranium collection also contains about 250 Swedish individuals. The remaining 200 or so skulls come from elsewhere in Europe.   More on KI News: "KI debates controversial name"   Read more in a pressrelease from the Swedish Government: "Remains at Karolinska Institutet to be returned"

Bariatric surgery affects risk of pregnancy complications

Thu, 26/02/2015 - 08:08
Bariatric surgery has both a positive and negative influence on the risk of complications during subsequent pregnancy and delivery, concludes a new study from Karolinska Institutet. The results, which are published in the New England Journal of Medicine, indicate that maternal health services should regard such cases as risk pregnancies. Pregnant women with obesity run a higher risk of developing complications during pregnancy and risks of fetal/infant complications are also higher. There has been a sharp rise in the number of women becoming pregnant after bariatric surgery; in 2013 almost 8,000 such operations were performed in Sweden, 80 per cent of which were on women. “The effects of bariatric surgery on health outcomes such as diabetes and cardiovascular disease have been studied, but less is known about the effects on pregnancy and perinatal outcomes,” says the study’s lead author, Kari Johansson, PhD, from the Department of Medicine in Solna. “Therefore we wanted to investigate if the surgery influenced in any way the risk of gestational diabetes, preterm birth, stillbirth, if the baby was small or large for its gestational age, congenital malformations and neonatal death.” Using data from nationwide Swedish health registries, the researchers identified 596 pregnancies to women who had given birth after bariatric surgery between 2006 and 2011. These pregnancies were then compared with 2,356 pregnancies to women who had not been operated upon but who had the same body mass index (BMI, weight divided by height squared) as the first group prior to surgery. Large for gestational age What researchers found was that the women who had undergone surgery were much less likely to develop gestational diabetes – 2% compared to 7% – and give birth to large babies. Just over 22% of women in the comparison group had babies that were large for gestational age, and barely 9% of the operated women. On the other hand, the operated women were twice as likely to give birth to babies who were small for gestational age, and the pregnancies were also of shorter duration. “Since bariatric surgery followed by pregnancy has both positive and negative effects, these women, when expecting, should be regarded as risk pregnancies,” says Dr Johansson. “They ought to be given special care from the maternal health services, such as extra ultrasound scans to monitor fetal growth, detailed dietary advice that includes checking the intake of the necessary post-surgery supplements.” The study was financed by the Swedish Research Council, The Obesity Society, Karolinska Institutet and the Stockholm County Council.  Senior authors of this study are Olof Stephansson and Martin Neovius, both affiliated to the Department of Medicine, Solna.     View our press release about this research Publication Outcomes of Pregnancy in Women with Prior Bariatric Surgery Kari Johansson, Sven Cnattingius, Ingmar Näslund, Nathalie Roos, Ylva Trolle-Lagerros, Fredrik Granath, Olof Stephansson, & Martin Neovius New England Journal of Medicine online 26th February 2015

Junior researcher posts now open to more applicants

Fri, 20/02/2015 - 14:14
Karolinska Institutet is now calling for a second round of applications for junior researcher posts as part of its “career ladder” programme. This time, following criticism from the first round, more people than before will be able to apply. At the start of 2014, the Board of Research announced a career ladder for junior researchers involving three levels of appointment: assistant professor (four years), a two-year extension of existing assistant professorships, and senior researcher (five years). In response to the negative comments that some junior researchers made about how the first round of applications was organised, the Board of Research held discussions with the Junior Faculty, an interest group for postdoc researchers at KI who have not yet been given permanent employment in preparation for this second round. Several amendments to the process have been made: “Firstly, we’ve changed the eligibility criteria,” says Birgitta Henriques Normark, vice dean of recruitment. “Beforehand, applicants were not allowed to be permanently employed at KI. This exclusion condition we’ve now removed. But as regards the four-year assistant professorships, applicants may not already hold that post.” “We consider this a very important improvement that makes it possible for more junior researchers at KI to apply for the posts,” Gonçalo Castelo-Branco, chair of the Junior Faculty. Discussions have also been held since the first round of advertisements on the extended assistant professorships. The Board of Research has decided to advertise this type of post again, a decision that has been welcomed by the Junior Faculty. “In most cases, four years isn’t enough time for assistant professors to amass the experience needed to qualify for the next step in their career and compete for positions with more established researchers,” says Dr Castelo-Branco. There is a possibility that the position of assistant professor might be extended, even if it does not happen this year. “We’re working on it being six years instead,” says Professor Henriques Normark. “We and the Junior Faculty both think that this would be for the better.” On top of this, the Junior Faculty might also want the funding for the positions to be supplemented with proper financial support for the completion of a research programme in order to make the post attractive for top-level national and international junior researchers. But according to Professor Henriques Normark the money is lacking to attach such a financial rucksack to the position. The recruitment drive has been announced to attract leading junior researchers to KI. The advertisements are to be published on 20 February on the KI website, in the journals Science and Nature, and on ResearchGate and universitetsjobb.se. The application deadline is 20 March.   Text: Karin Söderlund Leifler Photo: Gustav Mårtensson   The positions advertised Up to ten assistant professorships, 1 million kronor a year for four years. Up to ten positions of senior researcher (two-year extension of existing assistant professorships), 1 million kronor per year for two years. Up to six positions of senior researcher, 1.2 million a year for five years. Find more about the career positions on ki.se.  

New brain mapping reveals unknown cell types

Fri, 20/02/2015 - 08:08
Using a process known as single cell sequencing, scientists at Karolinska Institutet have produced a detailed map of cortical cell types and the genes active within them. The study, which is published in the journal Science, marks the first time this method of analysis has been used on such a large scale on such complex tissue. The team studied over three thousand cells, one at a time, and even managed to identify a number of hitherto unknown types. “If you compare the brain to a fruit salad, you could say that previous methods were like running the fruit through a blender and seeing what colour juice you got from different parts of the brain,” says Sten Linnarsson, senior researcher at the Department of Medical Biochemistry and Biophysics. “But in recent years we’ve developed much more sensitive methods of analysis that allow us to see which genes are active in individual cells. This is like taking pieces of the fruit salad, examining them one by one and then sorting them into piles to see how many different kinds of fruit it contains, what they’re made up of and how they interrelate.” The knowledge that all living organisms are built up of cells is almost 200 years old. Since the discovery was made by a group of 19th century German scientists, we have also learnt that the nature of a particular body tissue is determined by its constituent cells, which are, in turn, determined by which genes are active in their DNA. However, little is still known about how this happens in detail, especially as regards the brain, the body’s most complex organ. Large-scale single-cell analysis  In the present study, the scientists used large-scale single-cell analysis to answer some of these questions. By studying over three thousand cells from the cerebral cortex in mice, one at a time and in detail, and comparing which of the 20,000 genes were active in each one, they were able to sort the cells into virtual piles. They identified 47 different kinds of cell, including a large proportion of specialised neurons, some blood vessel cells and glial cells, which take care of waste products, protect against infection and supply nerve cells with nutrients. With the help of this detailed map, the scientists were able to identify hitherto unknown cell types, including a nerve cell in the most superficial cortical layer, and six different types of oligodendrocyte, which are cells that form the electrically insulating myelin sheath around the nerve cells. The new knowledge the project has generated can shed more light on diseases that affect the myelin, such as multiple sclerosis (MS). “We could also confirm previous findings, such as that the pyramidal cells of the cerebral cortex are functionally organised in layers,” says Jens Hjerling-Leffler, who co-led the study with Dr Linnarsson. “But above all, we have created a much more detailed map of the cells of the brain that describes each cell type in detail and shows which genes are active in it. This gives science a new tool for studying these cell types in disease models and helps us to understand better how brain cell respond to disease and injury.” Approximately 20 micrometres There are estimated to be 100 million cells in a mouse brain, and 65 billion in a human brain. Nerve cells are approximately 20 micrometres in diameter, glial cells about 10 micrometres. A micrometre is equivalent to a thousandth of a millimetre. The study was carried out by Sten Linnarsson’s and Jens Hjerling-Leffler’s research groups at the Department of Medical biochemistry and Biophysics, in particular by Amit Zeisel and Ana Muños Manchado. It also involved researchers from Karolinska Institutet’s Department of Oncology-Pathology, and Uppsala University. The study was financed with grants from several bodies, including the European Research Council, the Swedish Research Council, the Swedish Cancer Society, the EU’s Seventh Framework Programme, the Swedish Society of Medicine, the Swedish Brain Fund, Karolinska Institutet’s strategic programme for neuroscience (StratNeuro), the Human Frontier Science Program, the Åke Wiberg Foundation and the Clas Groschinsky Memorial Fund. View our press release about this study More about the Linnarsson lab More about the Hjerling-Leffler lab Publication Cell types in the mouse cortex and hippocampus revealed by single-cell RNA-seq Amit Zeisel, Ana B. Muñoz Manchado, Simone Codeluppi, Peter Lönnerberg, Gioele La Manno, Anna Juréus, Sueli Marques, Hermany Munguba, Liqun He, Christer Betsholtz, Charlotte Rolny, Gonçalo Castelo-Branco, Jens Hjerling-Leffler, and Sten Linnarsson Science online 19 February 2015, DOI: 10.1126/science.aaa1934

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