KI News

More effective treatment of the most common form of ovarian cancer: this is the aim of the EU-funded HERCULES project, which will be studying ovarian tumours at an unprecedented level of detail.  The mortality rate of ovarian cancer is high; more than 40,000 women die of the disease in Europe every year. “The survival odds for women with high-grade serious ovarian cancer, the most common type of ovarian cancer, has not markedly improved over the past twenty years,” says Jussi Taipale, professor of medical system biology and head of the Swedish part of the HERCULES project. “It’s imperative that we have new innovative solutions if we’re going to understand and treat this form of cancer.”   The HERCULES project recently received EUR 6 million from the EU’s “Horizon 2020 Research and Innovation programme", and scientists in Finland, Italy, France and Sweden are now readying themselves for the start of the project on 1 January 2016. The HERCULES project will spend five years focusing on the most common and hardest to treat form of ovarian cancer, high-grade serious ovarian cancer, in order to identify the constituent cell types, how these cells respond to therapy, and what makes them resistant to treatment. Jussi Taipale and his research group at the Department of Biosciences and Nutrition will be involved in the characterisation of the different tumor cell types, which will entail charting their genetic information and ascertaining which genes are active. Each gene has a regulatory region containing the instructions that control where and when it is to be used, and by studying these regions, the researchers hope to discover the mechanisms responsible for drug resistance. Press release about the HERCULES project Text: Jenny Ryltenius

In two separate studies published in the same issue of the journal Nature Biotechnology, researchers at Karolinska Institutet and their Austrian and American colleagues have managed to combine two methods of potentially analysing and mapping all the brain’s cell types at single-cell level. The new ‘Patch-seq’ combination method makes it possible for scientists to identify new and previously unknown neuronal types in the brain and to gain an understanding of their particular function in relation to specific behaviours. The first study was a collaboration between Rickard Sandberg, professor at Karolinska Institutet’s Department of Cell and Molecular Biology and also affiliated to the Ludwig Cancer Research, and Dr Andreas Tolias at Baylor College of Medicine, USA. The second study was a collaboration between Sten Linnarsson, professor at Karolinska Institutet’s Department of Medical Biochemistry and Biophysics, and Tibor Harkany, professor at the same department, and also at MedUni Vienna in Austria. Previous studies, in which the more recent of the two techniques was presented, have been published in several journals, including Science and Nature Methods. In these two new studies in Nature Biothechnology, the researchers have managed for the first time to bring the two methods together into a novel combination. The first method is electrophysiology, a classic technique that has long been the standard means of classifying nerve cells in the brain and that involves the insertion of a very narrow pipette into individual nerve cells for the purpose of measuring their electrical properties. The second method is single-cell RNA sequencing, which allows scientists to measure which genes are active in a specific cell, and thus determine its molecular identity. In the present studies, the researchers took the electrophysiological measurements of a single cell before sucking out its entire contents through the pipette in order to analyse which genes are active in that particular cell. Valuable to brain research “The combination method can prove very valuable to brain research,” says Professor Linnarsson. “The method allows us to find out which cells communicate with each other in the neural networks of the brain by taking electrophysiological measurements, and which cell types make up these networks.” Another possible area of application is the study of brain diseases where information is available on which genes are involved. The combination of techniques also makes it possible to link the genetic and electrophysiological properties of single cells to better understand the types of cell that are involved in different disorders. The two studies were conducted independently of each other and financed with grants from several sources, including the Swedish Research Council, the Swedish Foundation for Strategic Research, the European Research Council, the EU’s Seventh Framework Programme and the Swedish Brain Fund. View a press release from MedUni Vienna View a press release from Baylor College of Medicine Publications ‘Morphological, electrophysiological and transcriptomic profiling of single neurons using Patch-seq’, Cathryn R. Cadwell , Athanasia Palasantza, Xiaolong Jiang, Philipp Berens1, Qiaolin Deng, Marlene Yilmaz, Jacob Reimer, Shan Shen, Matthias Bethge, Kimberley F. Tolias, Rickard Sandberg, and Andreas S. Tolias, Nature Biotechnology, online 21 December 2015, doi: 10.1038/nbt.3445. ‘Integration of electrophysiological recordings with single-cell RNA-seq data identifies neuronal subtypes’, Janos Fuzik, Amit Zeisel, Zoltán Máté, Daniela Calvigioni, Yuchio Yanagawa, Gábor Szabó, Sten Linnarsson, and Tibor Harkany, Nature Biotechnology, online 21 December 2015, doi:  10.1038/nbt.3443.

Extremely premature babies run a much higher risk of developing autism in later childhood, and even during the neonate period differences are seen in the brains of those who do. This according to a new study by researchers from Karolinska Institutet and Karolinska University Hospital in Sweden. The findings, which are published in the journal Cerebral Cortex, suggest that environmental factors can lead to autism Extremely preterm neonates survive at increasingly early gestation periods thanks to the advances made in intensive care in the past decades. However, babies born more than 13 weeks prematurely run a serious risk of brain damage, autism, ADHD and learning difficulties. They are exposed to numerous stress factors during a period critical to brain development, and it is possible that this plays a key part in the development of autism spectrum disorder (ASD). In this present study, the researchers examined over 100 babies who had been born extremely prematurely (i.e. before week 27, the beginning of the third trimester). With the parents’ permission they studied the growth of the babies’ brains using magnetic resonance imaging during the neonate period, and then screened the children for autistic features when they had reached the age of six. “We were surprised by how many – almost 30 per cent – of the extremely preterm-born children had developed ASD symptoms,” says Ulrika Ådén, researcher at the Department of Women’s and Children’s Health at Karolinska Institutet and neonatologist at the Neonatology clinic at Karolinska University Hospital in Sweden. “Amongst children born after full term pregnancy, the corresponding figure is 1 per cent.” The researchers found that it was more common in the group of children who had developed ASD for there to have been complications during the neonate period, such as surgery, than it was amongst their prematurely born peers who had not developed ASD. Already in the neonatal period, long before the children had manifested signs of autism, differences could be observed between the extremely preterm babies who went on to develop ASD and those who did not, with diminished growth of the parts of the brain involved in social contact, empathy and language acquisition – functions that are impaired in autistic children. Autism is generally attributed to genetic factors, even if no specific autism gene has been identified. This new study supports previous findings indicating that birth weight and complications can increase the risk of autism. “Our study shows that environmental factors can also cause autism,” says Dr Ådén. “The brain grows best in the womb, and if the developmental environment changes too early to a life in the atmosphere, it can disrupt the organisation of cerebral networks. With new therapeutic regimes to stimulate the development of such babies and avoid stress, maybe we can reduce the risk of their developing ASD.” The study was funded by grants from several sources, including the Swedish Research Council, the Regional Agreement on Medical Training and Clinical Research (ALF), the Marianne and Marcus Wallenberg Foundation and the EU Seventh Framework Programme. Publication: ‘Poor Brain Growth in Extremely Preterm Neonates Long Before the Onset of Autism Spectrum Disorder Symptoms’, Nelly Padilla, Eva Eklöf, Gustaf E. Mårtensson, Sven Bölte, Hugo Lagercrantz and Ulrika Ådén, Cerebral Cortex, online 21 December 2015, doi: 10.1093/cercor/bhv300

While all the more is being talked about innovation, the fact is that researchers at Swedish universities could know a great deal more about how to commercialise their ideas. For example, you do not have to state if you have applied for or received a patent. When doctoral students Charlotta Dahlborg and Danielle Lewensohn from the Bioentrepreneurship Unit at KI’s Department of Learning, Informatics, Management and Ethics (LIME) present their theses next year, they hope to fill this knowledge gap, at least when it comes to the innovative powers of the university’s own researchers. “There have been no statistics on the inventions and innovations being made at Swedish universities, which makes it hard for them to assert themselves globally,” says Ms Lewensohn. At a seminar held at the Widerström Building, the doctoral students presented a review of all patents that have been granted in the past fifteen years to KI scientists. Their efforts have resulted in the Karolinska Institutet Intellectual Property (KIIP) database, which also contains details of the patents’ lifetimes and who currently owns them. There is general consensus that research is to have some sort of societal significance, rather than be merely a matter for the individual scientist or university. “Tax payers pump huge sums of money into research but have no idea what they get for it in terms of inventions, enterprises and jobs,” says Ms Dahlborg. “This we can now find out by measuring patenting.” To discover just how good KI scientists are at commercialising their research, they searched for employees’ names in databases between 1995 and 2010. The fruits of their labours gave 437 researchers and over 700 inventions. Since 7,110 researchers were employed over the same period, this equates to just over 6 per cent of the staff. “This isn’t an unusual figure and is on a par with other universities around the world,” says Ms Dahlborg. Another review by other researchers shows that patenting does not occur at the expense of publication. What is clear, however, is that the same people are behind many of the patents. “35 researchers account for half of the inventions,” says Ms Lewensohn. “We obviously have a patent elite here.” Ms Lewensohn believes that individual researchers need stronger incentives to put their energies into innovation: “There’s a pressure on you to churn out your thesis quickly and to produce articles. Most people aren’t against commercialisation – it’s just that you have to decide what to concentrate your efforts on as a researcher.” Text: Maja Lundbäck Photo: Ulf Sirborn How the Karolinska Institutet Intellectual Property (KIIP) can be used: “Innovation support can use these data to ascertain which research groups at KI are responsible for patented inventions and which have founded hive-off companies,” says Ms Lewensohn. It can also reveal which groups need more innovation support. “You can also develop reward systems for innovative research groups,” says Ms Dahlborg. They hope that their method will eventually be used at more of the country’s universities.

In recent decades much hope was based on the development of personalised drug treatments, in which genetic tests determine the choice and optimal dose of medication for each individual patient. However, the real breakthrough is still to be seen, and now researchers at Karolinska Institutet show in two separate scientific papers that many more gene variants affect how a person responds to medication than previously thought – and thus that today’s analytical tools are too coarse. “For the individual patient, the tests used today don’t give enough information, which means that if we’re to provide real personalized drug treatment we need to characterise the entire genetic variability of the patient,” says Magnus Ingelman-Sundberg, Professor of Molecular Toxicology and Principal Investigator at Karolinska Institutet’s Department of Physiology and Pharmacology. “These comprehensive analyses are still costly and need to be further developed, but as the techniques become cheaper and better and the amount of genetic data increases, they should be of value in the future.” The great variation between people in regards to effects and side-effects of drugs have been a problem since the early days of science-based medicine. Today we know that one main reason why people react so differently to different medicines and treatments is genetic variation. In both the EU and USA, vast sums are invested on identification of new biomedical discoveries providing doctors with new tools for personalised treatment. Many drugs have been given 'pharmacogenomic labels' indicating whether genetic tests need to be conducted, or are recommended, in order to determine the choice and dose of drug for the individual patient. These labels are based mainly on the most common genetic variants with particular significance for drug metabolism, transport and target interaction. Gene sequence databases In two recent articles, published in Pharmacogenetics and Genomics and Trends in Pharmacological Sciences, Magnus Ingelman-Sundberg and his colleagues used material from two large gene sequence databases (the 1000 Genomes Project and the Exome Sequencing Project) to examine genes that encode the most important drug metabolising enzymes, the CYP450-enzymes, and found over 6,000 mutations, over half of which were new and over 90 per cent rare. It was found that every individual of European decent has on average 94.6 unique variants of these mutations, of which 24.6 are presumed to affect the function of the corresponding gene product. According to the researchers this means that the total number of genetic variants able to affect an individual’s response to medication is probably several thousand – many more than was previously assumed. They thus note that the genetic tests currently performed in connection with drug development and personalised treatments only cover a fraction of the relevant genetic variations. “In other words, today’s analyses do not accurately identify the true inter-individual variability in pharmacologically important genes, nor do they sufficiently investigate tumour-specific mutations that determine the optimal cancer therapy,” says Volker Lauschke, postdoctoral researcher at the Department of Physiology and Pharmacology and co-author of both articles. “What’s now needed is also software that can analyse all genetic information more efficiently and predict which of the patient’s mutations will impact on the treatment outcomes.” The study was conducted in association with Kobe University in Japan and was funded by grants from the Swedish Research Council and the EU’s Seventh Framework Programme. View our press release about this research Publications 'Genetic variation in the human cytochrome P450 supergene family', Kohei Fujikura, Magnus Ingelman-Sundberg and Volker M. Lauschke, Pharmacogenetics and Genomics,  2015 Dec;25(12):584-94, e-pub ahead of print 3 September 2015, doi: 10.1097/FPC.0000000000000172. 'Precision medicine and rare genetic variants', Volker M. Lauschke and Magnus Ingelman-Sundberg, Trends in Pharmacological Sciences, online 15 December 2015, doi: http://dx.doi.org/10.1016/j.tips.2015.10.006.

Researchers at Karolinska Institutet, and the Sahlgrenska Academy at Gothenburg University in Sweden have identified a gene variant linked to psychotic symptoms and cognitive impairment in people with bipolar disorder. The study, which is published in the journal Molecular Psychiatry, describes a possible mechanism for how the gene variant produces clinical symptoms by affecting levels of specific proteins in the brain. “We’ve identified a gene variant linked to specific psychotic symptoms and cognitive impairment in people with bipolar disorder,” says Mikael Landén, researcher at Karolinska Institutet’s Department of Medical Epidemiology and Biostatistics and the Sahlgrenska Academy’s Department of Neuroscience and Physiology. “The link to cognitive symptoms is particularly interesting, since there are no treatments currently available to improve problems with attention, memory and concentration, which impact heavily on functional outcome and recoverability.” Bipolar disorder and schizophrenia can largely be attributed to inherited factors. In recent years, scientists have identified specific gene variants that increase the risk of these diseases, but these risk variants only go some way to explaining why some people are afflicted by the disease and others are not. We currently do not know how these genetic risk factors affect the chemistry of the brain and cause specific symptoms, so it is not yet possible for scientists to design drugs to relieve symptoms shown by people with a particular genetic variant. To link, at a molecular level, a gene variant with biochemical changes and clinical symptoms related to a heritable psychiatric disorder, as in this present study, is therefore something of a breakthrough. The St. Göran project The study involved people with bipolar disorder from the St. Göran project being run in Stockholm and Gothenburg. Besides carefully mapping the participants’ specific symptoms, the scientists also tested their cognitive abilities and measured levels of different proteins in their blood and CSF, a fluid that surrounds the brain and that thus gives a good indication of its chemistry. On performing a genome-wide association study (GWAS), they found that a genetic variant of the SNX7 gene was associated with both the levels of a protein in the CSF, known as kynurenic acid, and the disease symptoms. “We then conducted a series of supplementary experiments to identify a probable signal pathway, from the occurrence of the genetic risk variant to clinical symptoms in the form of psychosis and cognitive impairment,” says Professor Landén. “The pathway mainly involves signalling via the brains’ immune cells, and thus differs from how today’s drugs operate. What we’re hoping, therefore, is that the new mechanisms we’ve discovered will help in the development of more targeted drugs, where existing immune-modulating drugs can also be of interest.” Although the study participants all suffer from bipolar disorder, the researchers behind the study think that the mechanisms also apply to other psychotic disorders, such as schizophrenia. The study was financed with grants from several bodies, including the Swedish Research Council, the Swedish Foundation for Strategic Research and the Swedish Brain Fund. Our press release about this study Publication A genome-wide association study of kynurenic acid in cerebrospinal fluid: implications for psychosis and cognitive impairment in bipolar disorder Carl M. Sellgren, Magdalena E. Kegel, Sarah E. Bergen, Carl Johan Ekman, Sara Olsson, Markus Larsson, Marquis P. Vawter, Lena Backlund, Patrick F. Sullivan, Pamela Sklar, Jordan W. Smoller, Patrik K.E. Magnusson, Christina M. Hultman, Lilian Walther-Jallow, Camilla I. Svensson, Paul Lichtenstein, Martin Schalling, Göran Engberg, Sophie Erhardt, Mikael Landén Molecular Psychiatry, online 15 December 2015, doi: 10.1038/MP.2015.186

Pregnancy does not increase the risk of relapse among women successfully treated for Hodgkin lymphoma. This according to a new study from Karolinska Institutet published in The Journal of Clinical Oncology. Hodgkin lymphoma is a cancer that originates in the lymphocytes (white blood cells). It affects 160 people in Sweden every year. Unlike other types of lymphoma, a high proportion of patients develop Hodgkin lymphoma in their 20s and 30s. Many women wish to become pregnant following treatment. Prognosis is very good; a previous study from the same research group at Karolinska Institutet estimated that 5-year relative survival for women diagnosed up to age 50 in Sweden was close to 95 percent. The present study included 449 women between the ages of 18 and 40 diagnosed with Hodgkin lymphoma between 1992 and 2009. The study investigated whether women who had responded successfully to treatment and subsequently became pregnant ran a higher risk of relapse than women who did not become pregnant. The study was conducted to alleviate concerns expressed by patients and some doctors and midwives, since the topic had not previously been rigorously examined. “We know that a suppressed immune system or certain inflammatory conditions increase the risk of developing Hodgkin lymphoma,” says researcher Caroline Weibull, biostatistician and doctoral student at Karolinska Institutet’s Department of Medical Epidemiology and Biostatistics, “and since pregnancy affects the immune system, we wanted to see if there was a statistical correlation between pregnancy and risk of relapse.” Within five years of giving birth Among the 449 women in the study, 144 women gave birth during the follow-up period. In total, 47 women had a relapse but only one woman experienced a relapse within five years of giving birth. The results of this study therefore provide no evidence that pregnancy increases the risk of relapse in women who have been successfully treated for Hodgkin lymphoma. “The risk of relapse is at its highest during the first two or three years of diagnosis,” says Dr Ingrid Glimelius, oncologist at Akademiska Hospital in Uppsala and a researcher affiliated to both Karolinska Institutet’s Department of Medicine (Solna) and the Department of Immunology, Genetics and Pathology at Uppsala University. “At the same time, treatment of the primary disease and a possible relapse can cause premature menopause and, at worst, infertility. Survivors of Hodgkin lymphoma need to consider a range of factors when deciding about future reproduction. However, given the results of this study, the risk of pregnancy-associated relapse does not need to be considered. The study was financed with grants from the Swedish Cancer Society, Karolinska Institutet’s strategic research area in epidemiology (SfoEpi), the Swedish Society of Medicine and the Swedish Society for Medical Research. Our press release about this study Publication Pregnancy and the risk of relapse in patients diagnosed with Hodgkin lymphoma Weibull CE, Eloranta S, Ekström-Smedby K, Björkholm M, Kristinsson SY, Johansson ALV, Dickman P*, Glimelius I* Journal of Clinical Oncology, online 14 December 2015, doi:10.1200/JCO.2015.63.3446

The number of articles citing the lyrics of Bob Dylan in the biomedical literature has increased exponentially since 1990, according to a new study from Karolinska Institutet. The results are being published in the special Christmas issue of The BMJ. In 2014, the staff magazine KI Bladet revealed that a group of scientist at Karolinska Institutet had been sneaking the lyrics of Bob Dylan into their papers as part of a long-running bet. The Story quickly went viral, spreading from the local Swedish press to internationalmedia such as the Guardian and Washington Post. As a result another group of researchers also decided to investigate how the lyrics of Bob Dylan are cited in the titles of published biomedical papers in general. A search of all his song and album titles was conducted in May 2015. A selection of the most popular Dylan songs was also searched to find modified titles. In all, 213 of 727 references were classified as unequivocally citing Bob Dylan and were included in the subsequent analysis. According to the search, the first Dylan-citing article appeared in 1970 in Journal of Practical Nursing, eight years after his debut album was released. Interestingly, the researchers note that, after a handful of citations during Bob Dylan’s heyday in the first half of the 1970s, very few articles in the biomedical sciences cited Bob Dylan until 1990. Has increased exponentially However, since then, the number of cited articles has increased exponentially. The two most cited Dylan songs are The Times They Are A-Changin’ (135 articles) and Blowin’ In The Wind (36 articles). The search also revealed the use of other popular titles such as All Along The Watchtower, Knockin' On Heaven's Door, and Like A Rolling Stone. Some journals have a greater preponderance of Dylan-citing articles than others; for instance, no less than six articles citing Dylan songs were found in Nature. However, citing Bob Dylan in a paper doesn’t appear to generate more attention in the research community, say the authors. They point to several possible explanations to the phenomena of citing Bob Dylan in biomedical research, but conclude that “it is clear that Bob Dylan’s rich song catalogue has provided a source of inspiration for medical scientists.”   The researchers behind this study are affiliated to the Karolinska Institutet University Library and the Institute of Environmental Medicine. This news article is an edited version of a press release from The BMJ. The biomedical Dylan favorite on YouTube Publication Freewheelin’ scientists: citing Bob Dylan in the biomedical literature Carl Gornitzki, Agne Larsson, Bengt Fadeel The BMJ, online 14 December 2015, doi: 10.1136/bmj.h6505

This year’s Nobel laureates in physiology or medicine received a very warm welcome from the audience at the Nobel Lecture at Karolinska Institutet on 7 December. Their discoveries have saved millions of lives from fatal and crippling parasite diseases. There were many people who wanted to come to KI to listen to the 2015 Nobel laureates in physiology or medicine Satoshi Ōmura, William Campbell and Youyou Tu, and those seeking a place at the head of the queue waited for hours outside Aula Medica in glorious December sunshine. Following Vice-Chancellor Anders Hamsten’s welcome address, the packed auditorium was given a presentation of this year’s prize winners by Nobel Committee member Professor Jan Andersson. According to Prof. Andersson, while Nobel prizes have been awarded over the years for important discoveries on infection diseases, this year’s is the first to reward the treatment of parasite diseases. Satoshi Ōmura and William Campbell receive their prize for their discovery of avermectin (later modified to ivermectin), which is used against parasitic worms, and Youyou Tu for her discovery of the anti-malaria drug artemisinin. Ōmura’s sample the sole source The first laureate to speak was Professor Satoshi Ōmura, who talked about his work cultivating and identifying previously unknown microbe strains in the hunt for species with interesting bioactive properties. The discoveries he made at the Kitasato Institute have given rise to a large number of new drugs, the most important of which is without doubt avermectin/ivermectin, developed by Merck from bacteria supplied by Ōmura. Despite decades of searching the globe, Satoshi Ōmura explained that the microbe has never been discovered again, and that their sample is the only source for all industrial production of avermectin. Although avermectin/ivermectin treatments have saved many millions of people from river blindness and elephantitis, Ōmura – born 1935 – does not want to call it a day. “I shall continue to search for more and more [substances] that can bring health and socioeconomic benefits to communities around the world and encourage new generations of scientists to do the same.” A bizarre but simple principle After Ōmura’s lecture, Professor William Campbell took to the podium – which seemed a rather fitting reflection of their collaboration, in which Ōmura sent a large number of microbe strains to Campbell at Merck in the USA for evaluation. Given what we are taught about science, with its well-regulated system and emphasis on measurement, one might find Merck’s methods a little dubious, suggested Campbell. “The underlying principle was simple,” he explained. “It was bizarre, but it was simple. And I have described it this way: you line up a series of infected mice. You treat each mouse with an unknown amount of an unknown substance that might not be there. And then you check to see if it worked.” This too, he hastened to add, is well-regulated science. In May 1975, the method gave results: a mouse became completely healthy, which led to the discovery of avermectin. Eventually Campbell travelled to Japan to meet his colleague Satoshi Ōmura, and inadvertently showing the audience a private photo from 1990 of the then 55-year old Ōmura as proof, he joked, “You can see that he has not changed at all!” Campbell lectured with humour as well as gravity, recounting that ivermectin was initially developed for veterinarian use, but that Merck soon realised that it could also be used on humans. Trials showed that avermectin could prevent both river blindness and elephantitis, and since the diseases mainly exist in poor countries that would not be able to afford the drug, Merck decided to donate it. Part of a confidential military project The final speaker was Professor Youyou Tu, whose speech was translated from Mandarin to English and projected onto the large screen behind her. She described the discovery of artemisinin in China in the early 1970s – an exciting story that long remained unheard of in the west. Tu was part of the secret military project 523, where she was entrusted with developing antimalarial drugs from Chinese medicine using modern techniques. “No doubt, traditional Chinese medicine provides a rich resource,” said Tu, who is trained in both traditional and modern medicine. “Nevertheless it requires our thoughtful consideration to explore and improve.” After lengthy and thorough detective work, Tu had collected 2,000 traditional prescriptions and recipes, many of which were then assayed using modern methods. Her breakthrough came in October 1971, when research using wormwood (qinghao) extract proved highly effective on mice. It was then less than a year before trials were done on humans, but in order to proceed quickly without compromising patient safety, the research team began by testing the extract on themselves. Their successes led to the discovery of the substance artemisinin, which has saved many millions of people from malaria, halving the number of fatalities since 2000. However, Youyou Tu warned about the growing resistance to the substance, and strongly urged medical compliance with the recommendations laid out in the Global Plan for Artemisinin Resistance Containment. Tu made reference in her speech to icons of Western culture and science, such as Shakespeare and Pasteur, and closed with a poem by Wang Zhihuan (688–742 CE) “On the Stork Tower”: The sun along the mountain bows, The Yellow River seawards flows. You will enjoy a grander sight, By climbing to a greater height. Text: Anders Nilsson Photo: Erik Cronberg

A recently published study from the Institute of Environmental Medicine (IMM) at Karolinska Institutet shows that exposure to noise during pregnancy can damage the child’s hearing, with an 80 percent increase in risk in occupational environments with particularly high decibel levels. The results strongly indicate that pregnant women should not be exposed to loud noise. Whereas it was previously assumed that fetuses were well insulated from external noise, several studies have shown that noise, especially low-frequency noise, is physically conducted to the fetus. A link between noise exposure during pregnancy and hearing impairment is also corroborated by animal experiments. All in all, the available evidence shows that women should not be exposed to high levels of noise during pregnancy. “The Swedish Work Environment Authority recommendation is that pregnant women should avoid noise levels of over 80 dBA, but unfortunately this recommendation is not always followed,” says Jenny Selander, researcher at the IMM. “Our study shows how imperative it is for employers to observe this recommendation. Even if pregnant women themselves use ear protectors in noisy environments, the babies they’re carrying remain unprotected.” The study, which is being published in the journal Environmental Health Perspectives, comprised over 1.4 million children born in Sweden between 1986 and 2008, and sourced its data on the mothers, such as occupation, smoking habits and presence at work during pregnancy, from the National Board of Health and Welfare’s medical birth register and national central registers kept by Statistics Sweden and Försäkringskassan (the Swedish Social Insurance Agency). Occupation data were used to code exposure to noise at work during pregnancy into three classes: low (< 75 dBA); medium (75-84 dBA) and high (≥85 dBA). Data on hearing dysfunction (sensorineural hearing loss or tinnitus) were taken from the National Board of Health and Welfare’s patient registry, which is based on diagnoses made by specialists. Medium noise exposure Some 290,000 mothers had worked in occupations with medium noise exposure while pregnant, and another 6,000 in occupations with high noise exposure. Hearing dysfunctions serious enough to warrant specialist examination was present in approximately 1 percent of the children. For the women who had worked in high-level noise environments (over 85 dBA), the risk of hearing dysfunction in their children was 80 percent higher than for the women who had worked in low-exposure environments. This increase was statistically significant and adjusted for differences in smoking habits, age, bodyweight, level of education, nationality, and the birth year, sex and birth order of the children. Amongst part-time workers in high-exposure environments, the researchers found a 25 percent increase in risk that was not statistically significant. In the medium-exposure group, there was no statistically significant increase in the number of hearing-dysfunction diagnoses, but the possibility of a higher risk there as well cannot be ruled out. The results will be incorporated into the advice given to pregnant women and in the information we distribute to midwives at maternity clinics. The study was conducted by the Institute of Environmental Medicine (IMM) at Karolinska Institutet, the Stockholm County Council’s Centre for Occupational and Environmental Medicine (CAMM), Occupational and Environmental Medicine at Lund University and Karolinska University Hospital, with financial support the Swedish Research Council for Health, Working Life and Welfare (FORTE). Project manager has been Professor Per Gustavsson, MD, PhD at the Institute of Environmental Medicine.  Our press release about this study Publication Maternal occupational exposure to noise during pregnancy and hearing dysfunction in children – a nationwide prospective cohort study in Sweden Jenny Selander, Maria Albin, Ulf Rosenhall, Lars Rylander, Marie Lewné, and Per Gustavsson Environmental Health Perspectives, online 8 December 2015

Children born to mothers with polycystic ovarian syndrome, PCOS, are at an increased risk of developing autism spectrum disorders, according to a new epidemiological study from Karolinska Institutet. The findings, which are published in the journal Molecular Psychiatry, support the notion that exposure to sex hormones early in life may be important for the development of autism in both sexes. The new study is the first report that demonstrates a link between maternal polycystic ovarian syndrome, PCOS, and autism spectrum disorders, ASD, in children. ASD represent a range of neurodevelopmental disorders characterised by impairments in language and social interaction, as well as stereotypic, repetitive behaviours. The underlying causes are not entirely clear, but there are several lines of evidence that indicate that exposure to certain sex hormones early in life may play a role in the development of ASD. These sex hormones, known as androgens, are responsible for development of male-typical characteristics. Androgens also affect the development of the brain and central nervous system. Since women with PCOS have increased levels of androgens even during pregnancy, the investigators hypothesised that the disorder might affect the risk of ASD in the children. 5–15 per cent of women of child-bearing age are affected by PCOS, making it one of the most common endocrine disorders. The researchers used the extensive nationwide Swedish health and population register databases and studied all children aged 4–17 who were born in Sweden from 1984 to 2007. The researchers used an anonymised dataset where all personal identifiers had been removed. They identified around 24 000 ASD cases and compared them to 200 000 controls. “We found that a maternal diagnosis of PCOS increased the risk of ASD in the offspring by 59 per cent”, says Kyriaki Kosidou, lead researcher on the study, at the Department of Public Health Sciences. “The risk was further increased among mothers with both PCOS and obesity, a condition common to PCOS that is related to more severely increased androgens.” No observed differences in risk  ASD are about four times more common in boys than girls, but there were no observed differences in risk between boys and girls in the study. The mechanisms that explain the association between maternal PCOS and ASD in the children were not explored in this epidemiological study. In addition to increased exposure to maternal androgens, other possibilities are that shared genetic influences between the two conditions, or other metabolic problems common to PCOS, might partly explain the relationship. Further studies are necessary to explore and replicate the finding. “It is too early to make specific recommendations to clinicians in terms of care for pregnant women with PCOS, though increased awareness of this relationship might facilitate earlier detection of ASD in children whose mothers have been diagnosed with PCOS”, says Renee Gardner, senior investigator on the study, also at the Department of Public Health Sciences. Several of the investigators are also affiliated to the Stockholm County Council (SLL) Centre for Epidemiology and Community Medicine. This work was financially supported by Autism Speaks, the Stiftelsen Sunnerdahls Handikappfond Foundation, the Swedish Regional agreement on medical training and clinical research (ALF), and the Swedish Research Council. Our press release about this study Publication Maternal polycystic ovary syndrome and the risk of autism spectrum disorders in the offspring: A population-based nationwide study in Sweden Kyriaki Kosidou, Christina Dalman, Linnea Widman, Stefan Arver, Brian K. Lee, Cecilia Magnusson, Renee M. Gardner Molecular Psychiatry, online 8 December 2015, doi: org/10.1038/MP.2015.183

EurocanPlatform, an EU-funded network coordinated by Karolinska Institutet, held its last meeting in Brussels in November. The outcome was new collaborative ventures between cancer centres in Europe designed to transfer scientific discoveries from lab to clinic. Five years ago, 28 leading European cancer research institutions and cancer organisations came together in an EU-funded venture called the EurocanPlatform project in order to advance both research into and the treatment of the disease by coordinating European cancer research, sharing infrastructure and participating in joint projects. EurocanPlatform coordinator, Professor Ulrik Ringborg at Karolinska Institutet, says that the partnership has been a vital one: “EurocanPlatform has created a multidisciplinary environment to structure collaborations between basic pre-clinical and clinical cancer centres for translational research focusing on individualised cancer care. We’re delighted that EurocanPlatform has managed to deliver important, viable results that will enhance Europe’s ability to revitalise cancer research.”  The EurocanPlatform project, which is now coming to a close, has produced several important results that can ultimately affect the survival of cancer patients. One such is Cancer Core Europe, a consortium of six leading cancer research centres, including Karolinska Institutet, that has been formed to create a virtual “E-hospital” combining European resources and expertise able to translate pre-clinical discoveries into improved cancer care. Another joint project is Cancer Prevention Europe, which focuses on the early discovery of cancer and prophylactic measures.

Karl Deisseroth is a professor at Stanford, where his group has developed two spectacular scientific techniques – optogenetics and Clarity. He has also been working since 2013 at Karolinska Institutet, which has just invested in a Clarity facility. Neurons activated and deactivated by laser. Transparent brains that can be studied without sectioning. Neuroscientist and psychiatrist Karl Deisseroth has an eye for spectacular innovations, and when he gets mentioned in the media he is often hailed as a potential Nobel laureate. Both the techniques developed by his lab – optogenetics and Clarity – are used today at KI, providing valuable tools for scientists examining neuronal structures. But what is more important still, as head of the Department of Neuroscience Sandra Ceccatelli stresses, is that KI has managed to bring Deisseroth on board as a foreign adjunct professor. “It’s a privilege to have such an esteemed scientist pay us regular visits, share his expertise, lecture to doctoral students and discuss matters with colleagues,” she says. Technique in its infancy KI’s Clarity facility was ready for use just a couple of months ago. The technique is used on prepared (dead) tissue to render it transparent, making it possible, for example, to study cerebral structures without cutting up the brain tissue. “There are two parts to the method,” explains Ole Kiehn, professor of neuroscience at KI. “Firstly there’s the chemical process of making the tissue transparent, and secondly the digital imaging, which requires advanced microscopes, a lot of time, and a lot of storage capacity.” Clarity is a very promising technique, but is in its infancy and needs to develop, he explains. “You get great pictures, but we’ve got to get more out of it than that. For one thing, there has to be more software development in the field.” Clarity, which is only a couple of years old, is not the first research tool that Professor Deisseroth’s group has launched. In an article published in 2005 they laid the foundation for optogenetics – a now widespread method that is used by several groups at KI. Put simply, optogenetics is about fitting a switch to individual cells in the brain and spinal cord, enabling them to be turned on and off in an instant. “The method has provided us with an unprecedented opportunity to determine the function of different cells,” says Marie Carlén, researcher at the Department of Neuroscience. “Most revolutionary is the time-scale: we can switch these cells on and off with millisecond precision. In just a few years, optogenetics has given rise to a great deal of new knowledge about which cells do what in the brain. We’ve started to understand how different behaviour, from locomotion to decision-making, is created and executed, and to grasp the basis of phenomena such as attention, memory, fear, hunger, sleep and drug dependency.” Introduced to KI and Sweden in 2007 Professor Kiehn and Dr Carlén are two relative veterans of optogenetics. Kiehn introduced the technique to KI and Sweden in 2007, the same year as Carlén, then doing postdoc research, began using it at the Massachusetts Institute of Technology. It was not until a few years later that the technique saw its true breakthrough. “In our first five years with optogenetics, we sweated away in the lab to solve a whole load of problems,” says Professor Deisseroth. “It was only later, around 2009, that it became an important, widespread method. It seems to me the way Clarity is developing is not unlike the first years of optogenetics – although actually things might be moving a little quicker. There have already been several interesting Clarity articles, including ones from KI.” What is about KI that attracts you? “KI’s neuroscience has a strong tradition in imaging, physiology, genetics and anatomy,” says Professor Deisseroth. “There are people here who are fascinating to talk to. I also feel a strong bond with Sweden since my mother’s father was Swedish – Olof Lundberg, who emigrated to New York in the early 1900s.” Text: Anders Nilsson Photo: Gustav Mårtensson   CLARITY at KI The new CLARITY facility is jointly run by the Department of Neuroscience and CLICK (the Centre for Live Imaging of Cells at Karolinska Institutet), but can also be used by other research groups. The technique works with most of the body’s organs.

KI Professor Abdel El Manira has been elected member of The Royal Swedish Academy of Sciences in the Academy's Class for biosciences. Abdel El Manira is a professor at the Department of Neuroscience at Karolinska Institutet since 2005. At the Academy's general meeting on 11 November El Manira was one of three new elected members. Read more on the KVA website.

The stem cell researcher Dr. Petter Woll was today appointed Wallenberg Academy Fellow at Karolinska Institutet. He receives SEK 8,1 millon over five years to examine the sick stem cells that drive the blood cancer called myelodysplastic syndrome. The long-term aim is to find a treatment that can specifically destroy these stem cells and thus cure the patient. Myelodysplastic syndrome is a blood cancer that often affects people aged 60-75. Each year more than 300 cases are diagnosed in Sweden, and many people with the disease die within a few years due to lack of effective and curative treatments. In his examination of the disease, Dr. Petter Woll, recently recruited to Karolinska Institutet from University of Oxford, has shown that myelodysplastic syndrome develops from a unique group of blood-forming stem cells in the bone marrow. One problem appears to be that the sick cells have changes in genes that govern mRNA splicing. This is a fundamental process in the cell in which copies of genes, known as messenger RNA, are made ready for translation when the gene copy is used as a template for creating functional proteins in the cell. To find a cure for myelodysplastic syndrome, Petter Woll will study how changes to mRNA splicing may lead to cancer. He will investigate how the cancer-driving stem cells work in mouse models of the disease, as well as in affected patients. As a Wallenberg Academy Fellow, Petter Woll will be based at Karolinska Institutet. “It’s a fantastic opportunity for me to be able to this research at Karolinska Institutet” says Dr. Petter Woll. “The long-term aim is to find a way to specifically destroy the cancer cells and spare the healthy cells, so that the patients are cured. “ The programme Wallenberg Academy Fellows was established by the Knut and Alice Wallenberg Foundation in close cooperation with five royal academies and 16 Swedish universities. The universities nominate researchers for the programme, the academies evaluate the candidates and present the most promising researchers to the Wallenberg Foundation, which then makes the final selection. After this, the universities take long-term responsibility for the selected researchers’ activities. “We are truly grateful that Karolinska Institutet to such extent and over so many years receives generous research funding from the Knut and Alice Wallenberg Foundation” says vice-chancellor Anders Hamsten. “The support is very important to our university and to the researchers selected by the foundation.” Read more about the programme and the research of the Wallenberg Academy Fellows Knut and Alice Walleberg Foundation Wallenberg Academy Fellows

A novel study from Karolinska Institutet and University of Michigan in the U.S. shows that gaining weight from one pregnancy to the next can increase the risk that women will face stillbirth or lose their second babies within the first year of life. The findings are being published in The Lancet and build on data from more than 450,000 women in Sweden. “These tragic events are still very rare among infants of mothers with high weight gain. However, as many women gain weight between pregnancies, our results are very important from a public health perspective”, says principal investigator Sven Cnattingius, professor of reproductive epidemiology at Karolinska Institutet.   In their study, researchers reviewed data from the first two pregnancies of nearly 457,000 women who gave birth in Sweden from 1992 to 2012. The women’s information was recorded in the Swedish Medical Birth Register, which since 1973 has collected information on about 98 percent of all births in that country.  Weight was assessed at the beginning of each pregnancy. The results show that stillbirth risk rose with larger gains in body mass index (BMI) from first to second pregnancy. Compared with women who kept their weight, women whose BMI increased more than four units had a 50 percent increased risk of stillbirth. Among women of normal weight in first pregnancy, high weight gain also increased the risk of infant mortality: when their BMI increased by 4 units or more, risk of infant mortality increased by 60 percent. On the other hand, the results also point to the opposite situation. Women who were overweight by their first pregnancy, defined as a BMI of 25 or more (corresponding to at least 70 kg of women with average height), but who lost weight before the second pregnancy, reduced their risk of infant mortality. Rare events in Sweden Every fifth women in the study material gained so much weight that it influenced risks of stillbirth and infant mortality (i.e. at least 2 BMI units, corresponding to 5.5 kg). However, the researchers point out that stillbirth and infant mortality are very rare events in Sweden, and only 2.4 per 1000 births resulted in a stillbirth and 2.1/1000 in infant mortality. There are annually around 100,000 births in Sweden. “Previously, we have published that risks of stillbirth, infant mortality and morbidity increase with maternal weight, and in this new study we find that find that weight gain influence mortality risks. Taken together, our results support the conclusion that mother’s weight per see may influence infant chances of survival”, says Dr Cnattingius. “Still, the explanation for the findings is still speculative. We cannot differentiate from the data whether it is the weight gain during the pregnancy or in between pregnancies that is of significance”. Financial support was provided by the Swedish Research Council for Health, Working Life and Welfare, and a Karolinska Institutet Distinguished Professor Award to Sven Cnattingius.  Our press release about this study Publication Weight gain between successive pregnancies and risks of stillbirth and infant mortality: a nation-wide cohort study Cnattingius S, Villamor E. The Lancet, online 2 December 2015, http://dx.doi.org/10.1016/S0140-6736(15)00990-3

An international collaboration between scientists in Sweden, Russia, and the United States has resulted in the successful engineering of new diaphragm tissue in rats using a mixture of stem cells and a 3D scaffold. When transplanted, it has regrown with the same complex mechanical properties of diaphragm muscle. The study is published in the journal Biomaterials, and offers hope of a cure for a common birth defect and possible future heart muscle repairs. The multidisciplinary team behind the current study includes world-renowned researchers in the field of regenerative medicine and tissue engineering; Paolo Macchiarini, MD, PhD, Director of the Advanced Center for Regenerative Medicine and senior scientist at Karolinska Institutet; Doris Taylor, PhD, Regenerative Medicine Research Director at the Texas Heart Institute; and Mark Holterman, MD, PhD, Professor of Surgery and Pediatrics at the University of Illinois College of Medicine in Peoria, working in collaboration with a research team at the Kuban State Medical University in Russia.  The diaphragm is a sheet of muscle that has to contract and relax constantly to allow breathing. It is also important in swallowing, and acts as a barrier between the chest cavity and the abdomen. Malformations or holes in the diaphragm are found in 1 in 2,500 babies and can cause extreme, often fatal, symptoms.    At the moment, surgical repair of large defects like these involves using an artificial patch, which will not grow with the infant and does not provide any contraction to assist with breathing. The new technique presented in Biomaterials could instead allow such replacements to be grown especially for babies from their own cells, which would provide all the function of diaphragm tissue and would grow with them.   The success of this study also offers hope for the possibility of regenerating heart tissue, which undergoes similar pressure as it contracts and relaxes with every beat.    “So far, attempts to grow and transplant such new tissues have been conducted in the relatively simple organs of the bladder, windpipe and esophagus. The diaphragm, with its need for constant muscle contraction and relaxation puts complex demands on any 3D scaffold; until now, no one knew whether it would be possible to engineer,” said Dr. Doris Taylor.  Dr. Paolo Macchiarini adds, "This bioengineered muscle tissue is a truly exciting step in our journey towards regenerating whole and complex organs. You can see the muscle contracting and doing its job as well as any naturally-grown tissue - there can be no argument that these replacements are truly regenerated, and the possibilities that this opens up for the future are enormous."  The field of tissue engineering involves 'growing' new tissues or organs from stem cells on three dimensional 'scaffolds,' which give both structural support and shape to the new tissue and guide the differentiation and proliferation of the stem cells.  Engineered new tissues can not only help patients avoid the need for an organ donation, but also the need for the recipient to take immunosuppressant drugs.  In the current study, the researchers took diaphragm tissue from donor rats and removed all the living cells from it using a series of chemical treatments. This process removes anything that might cause an immune response in the recipient animals, while keeping all the connective tissue – or extracellular matrix – which gives tissues their structure and mechanical properties. When tested in vitro, these diaphragm scaffolds at first appeared to have lost their important rubber-like ability to be continually stretched and contracted for long periods of time. However, once seeded with bone marrow derived alloegenic stem cells and then transplanted into the animals, the diaphragm scaffolds began to function as well as undamaged organs. The method must now be tested on larger animals before it can be tried in humans, but the hope is that tissue-engineered repairs for congenital diaphragm malformations will be at least as effective as current surgical options with the added benefit of growing with children throughout their lives.   The study was supported and financed by Bioengineering of Tracheal Tissue and the Government of the Russian Federation Grant. Publication Orthotopic transplantation of a tissue engineered diaphragm in rats. Gubareva E, Sjöqvist S, Gilevich I, Sotnichenko A, Kuevda E, Lim M, et al Biomaterials 2015 Nov;77():320-335 About the universities Kuban State Medical University Texas Heart® Institute University of Illinois College of Medicine in Peoria (UICOMP)

Experiencing a traumatic event can cause life-long anxiety problems, called posttraumatic stress disorder. Researchers from Uppsala University and Karolinska Institutet now show that people with posttraumatic stress disorder, PTSD, have an imbalance between two neurochemical systems in the brain, serotonin and substance P. The greater the imbalance, the more serious the symptoms patients have. Many people experience traumatic events in life, e.g. robbery, warfare, a serious accident or sexual assault. Approximately 10 percent of people subjected to trauma suffer long-lasting symptoms in the form of disturbing flashbacks, insomnia, hyperarousal and anxiety. If these problems lead to impairment, the person is said to suffer from PTSD. It has previously been shown that people with PTSD have altered brain anatomy and function. The current study, which is being published in the journal Molecular Psychiatry, shows that shows that people with PTSD have an imbalance between two neurochemical signalling systems of the brain, serotonin and substance P. By using a PET scanner, researchers were able to measure the relationship between these systems. Design improved treatments The study also shows that it is the imbalance between the two signalling systems which determines the severity of the symptoms suffered by the individual rather than the degree of change in a single system. Others have previously speculated that the biological basis of psychiatric disorders such as PTSD includes a shift in the balance between different signalling systems in the brain but none has yet proved it. According to the research team, the study results are a great leap forward in our understanding of PTSD. It will contribute new knowledge which can be used to design improved treatments for traumatised individuals. The study was supervised by Mats Fredrikson, affiliated to both the Department of Psychology at Uppsala University and the Department of Clinical Neuroscience at Karolinska Institutet. The project was supported financially by the Swedish Research Council; the Swedish Brain Foundation; Riksbankens Jubileumsfond—the Swedish Foundation for Humanities and Social Sciences; and the Swedish Research Council for Health, Working Life and Welfare. Read more in a press release from Uppsala University Publikation Overlapping expression of serotonin transporters and neurokinin-1 receptors in posttraumatic stress disorder: a multi-tracer PET study Frick, A., Åhs, F., Michelgård Palmquist, Å., Pissiota, A., Wallenquist, U., Fernandez, M., Jonasson, M., Appel, L., Frans, Ö., Lubberink, M., Furmark, T., von Knorring, L., Fredrikson, M. Molecular Psychiatry advance online publication 1 December 2015; doi: 10.1038/mp.2015.180

Artemisinin and Avermectin/Ivermectin – the discoveries that were awarded this year’s Nobel Prize in Medicine or Physiology – have saved millions of lives from malaria, river-blindness and elephantiasis. The fight against the diseases continues – here in Karolinska Institutet’s laboratories too. A large percentage of the annual 500,000 estimated victims of malaria are babies; older children and adults in malaria-ridden areas have had time to build up an immunity to the disease. Professor Anna Färnert is studying this immunity. “We’ve shown that people continuously infected with several parasite strains have better immunity against the disease. This suggests that a future malaria vaccine should contain several components if it is to provide decent protection.” Färnet’s clinical research in Sweden has changed the medical view of immunity to severe malaria. It is not, as once though, permanent. “Patients originally from Africa but who have lived for a long time in other parts of the world lose this protection,” she says. Ambitious moves against malaria Senior professor Anders Björkman has been researching malaria since the 1980s. One of his research tracks is Zanzibar, off the coast of Tanzania, where ambitious moves against malaria have long been in progress. “We’re dealing with a combination of Artemisinin, impregnated mosquito net and other measures,” he says. “One and a half million people live on these islands and these efforts have reduced the incidence of malaria by 97 per cent.” Professor Akira Kaneko is also interested in islands, and has managed to make and keep the Pacific island of Aneityum, with its 700-strong population, entirely malaria-free. He now intends to repeat her successes in Lake Victoria. “We’re looking at four islands and part of the mainland,” he says. “We’ll be launching a pilot study on a small island in January with a combination of measures, including drug therapy, for all 60,000 people in the area. Population mobility will bring new cases into the area, but we hope our strategy will bring the incidence of the disease down from 30 per cent to less than 1 per cent in four years.” Resistence a serious concern All these malaria researchers share a serious concern about the growing resistance to artemisinin. Pedro Gil is one of many devoting his research to this threat. “We’re researching the molecular mechanisms behind resistance in order to find optimal combinations of drugs for this,” he says. “We hope to find combinations of components that the parasite won’t be able to develop comprehensive resistance to; in other words, to put it in a Catch 22 situation – develop a resistance to A and be attacked by B, or vice versa. We’re planning clinical trials in Mali for next year.” Another way of dealing with the effects of resistance is to develop new drugs. “We’ve produced a candidate called Sevuparin, which operates according to a new principle: blocking a receptor to prevent the parasite from entering the red blood cells,” explains Professor Mats Wahlgren. “We’ve recently completed a phase I/II study and have just sent the results in for publishing.” Countries will be free from the diseases Resistance can also become a problem for the antiparasitic drug Ivermectin, says researcher Susanne Nylén. “There are no clear indications of resistant parasites in humans yet, but there are in livestock,” she says. “But then again, Ivermectin is used much more for animals, so the pressure to develop resistance has been much greater there.” So far, she notes, Ivermectin has been a very successful weapon in the battle against river blindness and lymphatic filariasis (elephantiasis): many countries are, or will soon be, free from the diseases, which might eventually be eradicated completely. Malaria, however, is much harder to combat. “We aim to have completely eradicated the disease by 2050, which is an enormous undertaking,” says Professor Mats Wahlgren. Text: Anders Nilsson  

Nobel Week is soon to come, bringing together all the Nobel Laureates in Stockholm. One of them, Tomas Lindahl, one of this year's three Nobel Laureates in Chemistry, made many of his pioneering discoveries at Karolinska Institutet. It was here, in a basement laboratory in the 1970s, where he shows that DNA is not as stable as once thought and describes a mechanism for how cells repair genetic damage. His colleagues at the time describe a generous, thoughtful person. Tomas Lindahl himself recalls his time at KI as stimulating and stresses the importance of a good laboratory atmosphere. “I remember him sitting there in the lab holding a paper chromatogram. ‘Why this…this is uracil!’ We knew it didn’t fit in with what he was looking for, but had no idea just how far the find would take us,” says Stefan Söderhäll, one of Tomas Lindahl’s first doctoral students. It’s the early 1970s. The ground floor of the then chemistry block, where daylight filters down from the ceiling windows, is where Tomas Lindahl has his lab. He has recently arrived at KI. He has studied medicine and holds a PhD but his doctoral thesis was partly written at Princeton University in the USA, after which he did his postdoctoral research at Rockefeller University. “His time in the US gave him top publications and training in advanced research techniques,” says Professor Emeritus Peter Reichard from KI’s Department of Medical Biochemistry and Biophysics. “I was the medical representative on the Swedish Natural Science Research Council back then, and thought Sweden would benefit greatly from his remaining at KI. Tomas applied for a research post on my advice and had it located here.” The relationship between a researcher and a lab assistant was different back then. At this time, science assumes the DNA molecule, which is the basis of all life, to be extremely durable. Anything else would be unthinkable. But during his postdoc period in the US, Tomas Lindahl discovered that RNA, the molecular cousin of DNA, is easily broken down by heat. This made him wonder if DNA was really so stable as everyone thought. Three years later, as an independent researcher at KI, he starts to search for an answer. In the early days there is just Tomas Lindahl and his lab assistant Barbro Burt (then Nyberg). Together they build up the little lab. “The relationship between a researcher and a lab assistant was different back then,” she recalls. “Not as free-spoken as it is today. He was the one who called the shots, but he was modest and great in that role.” She remembers Tomas Lindahl as being a man who although strict in his manner showed through his gestures that he cared about his co-workers. “He helped me to get a raise, for example. Wrote letters to KI telling them that I was a good worker and woefully underpaid. Not everyone does that! He was considerate and generous.” Barbro Burt can often be found standing wrapped in furs in the refrigeration room cleaning enzymes from slaughter tissue. DNA is new to her, but Tomas Lindahl teaches her and tells her what his work is all about. The job is varied and enjoyable. On a couple of the first articles en route to the now prizewinning DNA repair mechanism, she and Tomas Lindahl are listed as the sole authors. “It wasn’t common for the lab assistant to be listed in a paper,” she says. “I didn’t think back then what significance the results could have, but now I realise that a lot of what I worked with is still relevant.” Tomas could have demanded to be included on the list of authors since he was my supervisor. The first doctoral students gradually arrive. Stefan Söderhäll joins them in 1971. “Tomas left us pretty much alone,” he says. “He was there, accessible, helped in the planning and was interested in our results, but he was never on our backs. But, sure, we worked hard.” Tomas Lindahl often arrives at ten and remains after everyone else has left the lab, which at first doubles up as his scriptorium. Stefan Söderhäll describes him as pensive, friendly and generous. His generosity is evident in the way he promotes his co-workers. One of Stefan Söderhäll’s research papers was accepted by the prestigious journal Nature. While the practical work he had done himself, Tomas Lindahl had advised him and helped with the writing: “Tomas could have demanded to be included on the list of authors since he was my supervisor. The kind of generosity Tomas showed in doing that is rare, both then and now.” He continues: “I was overjoyed when I heard he’d been awarded a Nobel Prize. Not just because I know him, but because he’s made an impact without being academically pushy. Without trying to ruthlessly secure resources at someone else’s expense and by more or less fair means. It pleases me that sheer competence is enough.” I set up my methods and got down to it. He provided the main framework and did so pedagogically. Siv Ljungquist joins Tomas Lindahl in 1971 with her honours degree project. She likes it there and stays on to do her PhD. “We worked very independently,” she says. “I set up my methods and got down to it. He provided the main framework and did so pedagogically. After that it was up to me to use my own head and read a lot.” Tomas Lindahl was rather reticent and absorbed in his research, recalls Siv Ljungquist, but there was also a twinkle in his eye. She also sees him as being considerate to his co-workers – publication successes are celebrated with a bottle of wine and every Christmas the group has dinner in town or at his home: “We’d also go out to the island of Utö. We’d swim, eat, the kids were there too. It was really nice and relaxed. His personal side tended to come out more when we were outside the lab.” When Siv Ljungquist is a relatively new doctoral student, Tomas Lindahl gets invited to hold a lecture at a DNA repair meeting in Prague. He is prevented from going, however, and asks her to take his place. Once there, she finds out that she is also required to be a session moderator. “I was a nervous wreck,” she says. “No one had told me. I guess they thought I’d take it for granted. You had to be assertive, that was all there was to it. Tomas raised us to take initiative.” All I had to do was try to come up with something new. Over the phone from the fashionable north London borough of Highgate Tomas Lindahl reminisces about his time at KI 40 years ago: “I had an excellent group at KI. Barbro, Siv and Stefan were also extremely helpful and lovely people. It was a good time. I had a little teaching and no real pressure on me to produce. All I had to do was try to come up with something new.” And he did. In 1972 he and Barbro Burt show that DNA is not as stable as previously thought, but disintegrates naturally at a rate that should have made evolution on earth impossible. He shows that the nitrogen base cytosine in DNA easily loses an amino group to become the base uracil. If the flaw remains, a mutation will appear the next time DNA replicates. Tomas Lindahl concludes that cells must be able to counteract such damage. In a study published in 1974 he identified the enzyme uracil-DNA glycosylase in e. coli, which finds and removes the faulty uracil base. It is in this paper that he outlines the fundamental concept for the now Nobel prizewinning repair mechanism, base excision repair, which he goes on to describe later. “It was thrilling,” he says. “I can’t pinpoint when, but it gradually dawned on me that we’d found something new and deeply significant.” Successful publications are celebrated with a bottle of wine or champagne. Everyone involved is to feel proud of the achievement, and everyone is acknowledged for their part in it; this is important to Tomas Lindahl. “Barbro Nyberg was extremely good at doing research. It’s very important to be as meticulous as she was, and perfectly fair that she is listed on the papers,” he says. Being generous to his co-workers and helping them up the career ladder is also behind his strategy of sending doctoral students out to conferences as soon as they are ready. Whoever has done something good must show it to the wider scientific community. It is the same with co-authorship. “Back then, doctoral students needed papers on which they appeared as sole authors in order to get their own research posts. Since I had such good students it would’ve been bad form to put my name to each article. And I still did OK, anyway.” Tomas Lindahl is often portrayed as methodical and determined in his research. He recognises this picture of himself but adds that it is also important to be open to unexpected outcomes. “That’s sometimes the most stimulating thing about research,” he says. “That you don’t just routinely churn out data but have to look at what you produce and think to yourself, ‘Does this tell me anything, am I wrong?’” We knew that he was doing good research, but perhaps not that it would be this big. Arne Holmgren, professor at the Department of Medical Biochemistry and Biophysics at KI, was leading a group in the same block as Tomas Lindahl at the time, and shared some of the equipment. He describes Tomas Lindahl as amicable, easy to work with and a respected scientist. “We knew that he was doing good research, but perhaps not that it would be this big,” he says. At KI, Tomas Lindahl is driven by the idea of working in an exciting field and with stimulating senior colleagues. His great role model is Peter Reichard, who was a professor at the same department and subsequently head of the biochemistry section of the Medical Nobel Institute at KI. “He built up an extraordinarily fine department, had excellent co-workers and solved scientific problems that I’m a bit disappointed he hasn’t been awarded a Nobel Prize for,” he says. “He inspired me greatly and I tried to emulate him in my own research.” In what way? “He had interesting novel ideas and an authority in the lab. He was a very skilled researcher. When you hear a great musician play their instrument, you know that that is how it’s done. I got the same feeling with his research.” Like today, research funding was difficult to obtain. Tomas Lindahl says he got by on his research salary, but his group remained small: “I’d wanted to grow it a bit, but there was rivalry within the department and the researcher I competed with was an enterprising administrator and good at securing funds, much better than I was.” Nine years later, in 1978, he leaves KI. A professorship in medical and physiological chemistry has been advertised at Gothenburg University and Tomas Lindahl says that the research position gave him no choice but to apply. Four years later he moves to London, where he establishes the successful Clare Hall Laboratories. What did you take with you from your time at KI? “That you need a friendly and helpful atmosphere in the lab. If you’ve got that, a lot of other stuff comes naturally.” How do you create a good atmosphere? “By having luck, backing the right people and setting an example. It’s important to be generous. There are examples of the opposite – tyrants who have produced great results by applying the whip to their co-workers. That’s not how I want to go about things.”   Text: Sara Nilsson Photo: Gustav Mårtensson © The author and KI Bladet/KI News.   The discovery of DNA repair leads to new cancer treatment. The 2015 Nobel Prize in chemistry was awarded jointly to Tomas Lindahl, Paul Modrich and Aziz Sancar for having mapped, at a molecular level, how cells repair damaged DNA and safeguard the genetic information. Tomas Lindahl’s contribution concerned the discovery of a molecular mechanism, base excision repair, that repairs DNA when a nitrogen base in the molecule has been damaged. Firstly, an enzyme called glycosylase finds the flaw and cuts away the damaged base. A couple of other enzymes then remove the residue, the gap is filled with a correct base and the strand is glued together by yet other enzymes. The discoveries have provided fundamental insight into how cells operate, knowledge that can help scientists understand the ageing process and develop new cancer therapies. One drug that is based on Tomas Lindahl’s discovery is olaparib, developed by Professor Thomas Helleday at KI’s Department of Medical Biochemistry and Biophysics. The drug kills tumour cells by blocking one of their DNA repair enzymes and has been approved for the treatment of ovarian cancer. Emeritus group leader at the Francis Crick Institute. Name: Tomas Lindahl. Age: 77. Home: Highgate, north London. “It’s a pleasant area full of old houses. Not unlike Bromma, where I grew up as a child.” Family: Two children, both living in the USA, and grandchildren. Has been the partner of tumour virologist Beverly Griffin for the past 35 years. Positions: Emeritus group leader at the Francis Crick Institute, which is under construction in central London, and emeritus head of Cancer Research UK at Clare Hall Laboratory, outside London. He is also senior scientific advisor for IFOM, a research institution for molecular oncology in Milan. Free time: Music. “London has an exceptionally rich concert scene. I like to listen to chamber music at the Wigmore Hall, for example. I’m also interested in wine. I did a little wine-tasting when I was at KI with some colleagues and wrote reviews.” Featured in the article were: Barbro Burt (then Nyberg), 68. Laboratory assistant in Tomas Lindahl’s group at the Department of Medical Chemistry II 1969–1978. Stefan Söderhäll, 67. Paediatric oncologist and researcher at the Department of Women’s and Children’s Health at KI. Doctoral student in Tomas Lindahl’s group at the Department of Medical Chemistry II 1971–1976. Graduated with a PhD in 1976. Siv Ljungquist, 67. Researcher in Tomas Lindahl’s group at the Department of Medical Chemistry II 1971–1977. Firstly for an honours degree project, then as a doctoral student. Graduated with a PhD in 1977. Peter Reichard, 90. Professor emeritus, Department of Medical Biochemistry and Biophysics at KI. Was a professor at the same department as Tomas Lindahl, but left in 1970 to lead the biochemistry section of the Medical Nobel Institute at KI. Arne Holmgren, 75. Professor at the Department of Medical Biochemistry and Biophysics at KI.  Led a research group at the Department of Medical Chemistry I and shared certain equipment with Tomas Lindahl (1973–1978).   Important papers published during Tomas Lindahl’s time at KI (1969–1978) *Lindahl, T. and B. Nyberg, Rate of depurination of native deoxyribonucleic acid. Biochemistry, 1972. 11(19): s. 3610-8. *Lindahl, T. and A. Andersson, Rate of chain breakage at apurinic sites in double-stranded deoxyribonucleic acid. Biochemistry, 1972. 11(19): s. 3618-23. *Lindahl, T. and B. Nyberg, Heat-induced deamination of cytosine residues in deoxyribonucleic acid. Biochemistry, 1974. 13(16): s. 3405-10. *Lindahl, T., An N-glycosidase from Escherichia coli that releases free uracil from DNA containing deaminated cytosine residues. Proc Natl Acad Sci U S A, 1974. 71(9): s. 3649-53. *Lindahl, T., New class of enzymes acting on damaged DNA. Nature, 1976. 259 (5538): s. 64-6.