KI News

The Swedish Higher Education Authority (UKÄ) has now reviewed all twenty-two specialist nursing programmes that had been previously faulted for lacking in quality, including nine specialist nursing degrees at Karolinska Institutet. The UKÄ considers the problems now resolved, which means that the programmes may retain their degree-awarding powers. In 2014, nine specialisations on Karolinska Institutet’s specialist nursing programmes were judged to be lacking in quality, while the master’s programme in nursing received a high-quality rating. KI has since taken action to rectify the flaws that the programmes were deemed to have, and they are no longer contested. This means that all of KI’s evaluated degree programmes now have UKÄ approval. “What we’ve learned from the evaluations is proving very useful now that we’re devising a quality system for KI’s programmes,” says Dean of Education Annika Östman Wernerson.

The HPV vaccine is most effective against high-grade cervical lesions if given before the age of 17, according to a new register-based study from Karolinska Institutet and the Public Health Agency of Sweden. The results, which are published in the International Journal of Cancer, show that the vaccine is effective at preventing high-grade lesions. There are over 100 strains of the human papillomavirus (HPV). They are spread through physical contact, such as via sexual intercourse, and are highly infectious. At some point during our lives, most of us are infected with one or more HPV types, at least twelve of which are classed as high risk, since infection can cause cancer. Earlier population studies show that HPV vaccination is effective against both condyloma (an STD) and cervical lesions. Cervical cancer is caused by HPV infection, with HPV types 16 and 18 responsible for some 70 per cent of cases. The same viral types are also behind a high proportion of cervical lesions, which can develop into an invasive cancer if left untreated. HPV types 16 and 18 are included in the HPV vaccine that has been used in Sweden since 2007. In 2012, an HPV vaccine was included in the national childhood vaccination programme, and girls between the ages of 10 and 12 are offered free vaccination through the school health service. The researchers behind this new study have examined the effect of the HPV vaccine on high-grade lesions, with a particular focus on grade 2 and 3 cervical intraepithelial neoplasia (CIN), which can be a prodrome of cancer. The study included all females, 1.4 million individuals all told, between the ages of 13 and 29 living in Sweden at some point during 2006–2013, of whom just over 236,000 had been vaccinated. Details on vaccination, histologically confirmed high-grade lesions (CIN2 and CIN3) and other such data were collected using national healthcare registries. Before the age of 17 Comparing the risk of high-grade lesions between the vaccinated and unvaccinated women, the researchers discovered that in those who were vaccinated before the age of 17, the effectiveness of the vaccine against high-grade lesions was 75 per cent. The protective effect dropped to 46 per cent for those vaccinated between the ages of 17 and 19, and again to 22 per cent for those vaccinated at or after the age of 20. “Our conclusion is that the vaccine protects against serious prodromes of cervical cancer, with the greatest effect being when it’s given before the age of 16,” says principal investigator Lisen Arnheim Dahlström at Karolinska Institutet’s Department of Medical Epidemiology and Biostatistics. The researchers will continue to study the effects of HPV vaccination on the population in the long term. One important line of inquiry is whether the vaccination programme has the expected effect against cervical cancer. The high-grade lesions examined in this new study can eventually develop into cancer, but it will be some years before the researchers can study the protection provided against cervical cancer. The study was financed with grants from the Swedish Foundation for Strategic Research and the Strategic Research Area (SFO) in Epidemiology, Karolinska Institutet. Text: Karin Söderlund Leifler (in translation from Swedish) Our press release about this study Publication Quadrivalent HPV vaccine effectiveness against high-grade cervical lesions by age at vaccination: A population-based study Eva Herweijer, Karin Sundström, Alexander Ploner, Ingrid Uhnoo, Pär Sparén, Lisen Arnheim-Dahlström International Journal of Cancer, version of record online 9 March 2016, doi: 10.1002/ijc.30035

Researchers at Karolinska Institutet have developed a nanoparticle technology that can be used to stabilise membrane proteins so that their structure can be studied in a lipid environment. The method, described in Nature Methods, makes it possible to access drug targets that previously could not be investigated and therefore potentially allows for the development of novel drugs, therapeutic antibodies and vaccines. "Our technology, termed Salipro, may offer a wide range of potential applications, ranging from structural biology to the discovery of new pharmacological agents, as well as the therapeutic delivery of protein-based therapeutics and vaccines", says first author Jens Frauenfeld, who was working at the Department of Medical Biochemistry and Biophysics at Karolinska Institutet when the study was performed. Membrane proteins are the targets of more than 60 per cent of drugs in clinical use. In addition, the membrane proteins of viruses are the key functional unit in commercial vaccines. Thus, membrane proteins are very important in biology, drug discovery and vaccination. The problem that researchers face is that these proteins are very unstable and therefore hard to investigate. They are embedded in membranes that are made up of different kinds of lipids. Most often, detergents are used to extract the membrane proteins. However, detergents are associated with protein instability and poor compatibility with structural and biophysical studies. Moreover, detergents do not provide a lipid environment, which is important for membrane proteins. Small cellular protein  The investigators behind the new study worked around that problem by using the small cellular protein saposin. Usually, saposin shuttles lipids from one place to another within the cell. Since saposin is known to bind to lipids, the researchers evaluated whether it would be possible to develop a method to make stable saposin-based lipid nanoparticles. They then expanded the method so that it is possible to also embed fragile membrane proteins into those lipid nanoparticles and stabilise them. The investigators demonstrate that the method facilitates high-resolution 3-dimensional studies of membrane proteins by single-particle electron cryo-microscopy, cryo-EM, an increasingly popular technique among scientists who want to study proteins at atomic resolution. They also present a method to extract and stabilise fragile membrane proteins from the HIV virus membrane. "To our knowledge, the HIV spike protein preparation presented in the study using the Salipro system represents the first approach that allows the stabilisation of the HIV-1 spike, including the important membrane domains, in a soluble and functional state", says Professor Pär Nordlund at the Department of Oncology-Pathology. Other viral envelope proteins The authors believe that the technology may also be applicable to other viral envelope proteins such as influenza virus haemagglutinin, ebola virus G-protein or hepatitis C virus E protein. Taken together, the researchers  apply the method on three different membrane protein targets for structural and functional studies. The work was performed in Professor Pär Nordlund's group at Karolinska Institutet, in collaboration with researchers at the Department of Biosciences and Nutrition at Karolinska Institutet, University of California San Fransisco and European Molecular Biology Laboratory, EMBL. The project was financially supported by, among others, the European Molecular Biology Organization (EMBO), the Swedish Research Council, the Knut and Alice Wallenberg foundation, the Swedish Cancer Society and the Swedish Childhood Cancer Foundation. Jens Frauenfeld has founded the company Salipro Biotech AB, and three of the researchers have filed patent applications related to the work. Text: Karin Söderlund Leifler View our press release about this study Publication A Saposin lipoprotein nanoparticle system for membrane proteins Jens Frauenfeld, Robin Löving, Jean-Paul Armache, Andreas Sonnen, Fatma Guettou, Per Moberg, Lin Zhu, Caroline Jegerschöld, Ali Flayhan, John A.G. Briggs, Henrik Garoff, Christian Löw, Yifan Cheng, Pär Nordlund Nature Methods, published online 07 March 2016, doi: 10.1038/nmeth.3801

According to a major Swedish cohort study from researchers at Karolinska Institutet and Imperial College London, a surgeon who operates on oesophageal cancer must have performed 60 operations to prevent any lack of experience adversely affecting the long-term survival of the patients. The finding, which is published in the Journal of Clinical Oncology, has potential significance for clinical practice. While it is well known that patient survival after oesophagectomy is related to the surgeon’s experience of the procedure, no figure has been put on how many operations are needed for the surgeon to attain the competence needed for achieving optimal results as regards patient survival. The new study is the first to examine the surgeon’s learning curve in relation to short and long-term fatality rates. “What the study shows us is that a surgeon needs to perform 15 operations to obtain stable results as regards survival during the first months following the operation, and a full 60 before he or she achieves optimal results on long-term survival,” says the chief investigator Jesper Lagergren at Karolinska Institutet’s Department of Molecular Medicine and Surgery, and also affiliated to the Division of Cancer Studies at King’s College London. “What surprised me was that the learning curve for optimising the long-term prognosis for tumour relapse was so long and the effect so pronounced.” Jesper Lagergren’s research team has in collaboration with colleagues at Imperial College London examined a Swedish cohort of 1,821 patients operated on for oesophageal cancer in Sweden between 1987 and 2010 by 139 different surgeons. Experienced with other procedures Using data on which surgeons performed which operations, the researchers studied their learning curves and found that even though the surgeons were experienced with other procedures when starting to perform oesophagectomies, the turning point for their learning curves for a stable 5-year fatality rate was at 60 operations. The form of surgery studied is relatively uncommon with some 150 such operations performed a year in Sweden. The new finding indicates that it is worth concentrating oesophageal cancer operations to a small number of surgeons with a particular interest in this kind of surgery. “Our results can guide clinical practice and indicate that a properly organised mentorship and training programme should be introduced for oesophageal cancer surgery,” adds Professor Lagergren, who is himself an oesophageal cancer surgeon. “Surgeons who start operating on oesophageal cancer should perform many operations together with a more experienced oesophageal cancer surgeon before they begin to operate independently.” The study was financed with grants from the Swedish Research Council and the Swedish Cancer Society. Text: Karin Söderlund Leifler (in translation from Swedish) Our press release about this study Publication Surgical Proficiency Gain and Survival Following Esophagectomy for Cancer Sheraz R. Markar, Hugh Mackenzie, Pernilla Lagergren, George B. Hanna, Jesper Lagergren Journal of Clinical Oncology, online 7 March 2016

Researchers at Karolinska Institutet and the University of Oulu in Finland have elucidated gene regulatory mechanisms that can explain how known genetic variants influence prostate cancer risk. The findings, published in the journal Nature Genetics, reveal widespread deregulation of androgen receptor function, a key player in prostate cancer. The vast majority of the three billion base-pairs in the human genome are identical across individuals. Nevertheless, genome sequence variation that does occur in the population has a profound effect on an individual's predisposition for developing various diseases. In the case of prostate cancer, 100 regions of genetic variation have been identified through comparative genetic studies. Each have a small but significant influence on prostate cancer risk. Previous studies have demonstrated an association of these genomic regions with disease, but the molecular processes accounting for the disease association have not yet been uncovered for most of these 100 regions. Using computational and statistical analysis, Thomas Whitington and colleagues at Karolinska Institutet devised a method for analysing the molecular processes at these genomic regions. The researchers identified mechanisms that can explain many of the known associations between genetic variation and prostate cancer risk. These discoveries were validated using molecular techniques by a research team led by Gong-Hong Wei at University of Oulu. "In particular, we discovered that binding of physical complexes involving the androgen receptor, a key transcription factor in prostate cancer, is often disrupted by DNA sequence variation associated with the disease", says Thomas Whitington at the Department of Medical Epidemiology and Biostatistics at Karolinska Institutet, one of the researchers behind the study. Bind to DNA Transcription factors are key molecular components of the cell that bind to DNA and affect the activity of nearby genes. The androgen receptor is a transcription factor that promotes proliferation and survival of prostate cancer cells. In the current study, the investigators found that binding of androgen receptor at these locations of genetic variation was frequently tumor-specific, and not present in normal prostate tissue. "This work refines our understanding of how this molecular machinery is involved in disease processes", says Thomas Whitington. "An improved understanding of androgen receptor binding may in particular prove useful, as it's activity becomes pivotal during the treatment of late stage aggressive prostate cancer." The research was conducted by scientists based at Karolinska Institutet, University of Oulu, and University of Cambridge. The work was co-supervised by Fredrik Wiklund, Johan Lindberg, and Gong-Hong Wei. Thomas Whitington and Ping Gao were co-first authors. It was funded by, among others, Cancer Research UK, the Swedish Cancer Society, Linneaus grant from the Swedish Research Council, and The Academy of Finland. Text: Karin Söderlund Leifler Our press release about this study Publication Gene regulatory mechanisms underpinning prostate cancer susceptibility Thomas Whitington, Ping Gao, Wei Song, Helen Ross-Adams, Alastair Lamb, Yuehong Yang, Ilaria Svezia, Daniel Klevebring, Ian Mills, Robert Karlsson, Silvia Halim, Mark Dunning, Lars Egevad, Anne Warren, David Neal, Henrik Grönberg, Johan Lindberg, Gong-Hong Wei, Fredrik Wiklund Nature Genetics, online 7 March 2016, doi: 10.1038/ng.3523

Depression and anxiety, and not necessarily the use of antidepressant medication, are associated with lower pregnancy and live birth rates following in vitro fertilisation, according to a large register study from Karolinska Institutet. The findings are published in the journal Fertility & Sterility and can be of interest to clinicians treating infertility and for women with depression or anxiety planning to undergo fertility treatment. Treatment with antidepressants has increased both in general and among women of reproductive age in the last few decades. In particular, the use of selective serotonin re-uptake inhibitors, SSRIs, has increased. However, little is known about the effect of antidepressants on fertility and the ability to conceive.  The new study, including more than 23,000 women, is the largest so far assessing the association between depression, anxiety and antidepressants and the outcome of in vitro fertilisation, IVF. The investigators used anonymized data on all IVF procedures performed in Sweden from 2007 and onwards, extracted from the Swedish Quality Register of Assisted Reproduction. They linked it to information on depression, anxiety and antidepressant prescription dispensations from the nationwide Swedish Patient and Prescribed Drug Registers. Two years before the start of their IVF cycle Of all women in the study, 4.4 per cent had a depression or anxiety diagnosis in the two years before the start of their IVF cycle and/or an antidepressant dispensation in the six months prior to the cycle start. The researchers compared the rates of pregnancy, live birth and miscarriage in these women to rates in women without a diagnosis or antidepressant dispensation. "We found that women undergoing their first IVF treatment who either had been diagnosed with depression or anxiety or had dispensed an antidepressant had lower rates of pregnancy and live birth rates compared to women who did not suffer from these conditions or take antidepressants before beginning their IVF treatment", says first author Carolyn Cesta, doctoral student at the Department of Medical Epidemiology and Biostatistics. "Importantly, we found that women with a depression or anxiety diagnosis without a prescription of antidepressants had an even lower chance of becoming pregnant or having a live birth." SSRIs are the most common type of antidepressant prescribed in Sweden. In the large group of women in the current study taking SSRIs, there was no difference in pregnancy or live birth rates following IVF treatment. However, the small group of women taking antidepressants other than SSRIs, who had more complex cases of depression and anxiety, had reduced odds of pregnancy and live birth as well as an increased risk for miscarriage following their IVF treatment. The underlying factor "Taken together, these results indicate that the depression and anxiety diagnoses may be the underlying factor leading to lower pregnancy and live birth rates in these women", says the study´s principal investigator Anastasia Nyman Iliadou, associate professor at the Department of Medical Epidemiology and Biostatistics. However, she cautions that since the study was not randomised the results could also be explained by unmeasured lifestyle and/or genetic factors associated with depression and anxiety. The research was financially supported by the EU-FP7 Health program, the Swedish Research Council, the Strategic Research Program in Epidemiology Young Scholar Awards, Karolinska Institutet and the European Society of Contraception and Reproductive Health. Text: Karin Söderlund Leifler Publication Depression, Anxiety, and Antidepressant Treatment in Women: Association with In-vitro Fertilization Outcome Carolyn E Cesta, Alexander Viktorin, Henrik Olsson, Viktoria Johansson, Arvid Sjölander, Christina Bergh,  Alikistis Skalkidou, Karl-Gösta Nygren, Sven Cnattingius, Anastasia N Iliadou Fertility & Sterility, published online 23 February 2016, doi:10.1016/j.fertnstert.2016.01.036

Yesterday the acting vice-chancellor and the university director met with the Ethics Council. Recent events have accentuated that there is a need to clarify and revitalise work with research ethics at KI. There was a general agreement that the council’s role should be reviewed and perhaps extended. As soon as the future tasks for the council have been decided it will be necessary to review the competences that will be needed for the Ethics Council’s future work. “Karolinska Institutet is a university where ethical issues are of central importance. Recent events have accentuated the importance of KI’s work with ethical questions and fundamental values”, says acting vice-chancellor Karin Dahlman-Wright. Within a couple of weeks I anticipate to have appointed the person to review the council’s role with the aim of having a final proposal for a new organization before the summer. In association with appointing a new Ethics Council, the present council members will be asked whether they are available to potentially serve in a future organization for ethical questions at KI.

Drinking around six cups of coffee – more than 900 ml – every day is linked to a reduced risk of multiple sclerosis (MS), according to a new study lead from the Institute of Environmental Medicine at Karolinska Institutet. The findings are being published online in the Journal of Neurology Neurosurgery & Psychiatry.  Caffeine, a central nervous system stimulant, has neuroprotective properties and can suppress the production of chemicals involved in the inflammatory response, which may explain the association found, suggest the researchers behind the current study. They base their findings on two representative population studies: one in Sweden comprising 1620 adults with MS and a comparison group of 2788, matched for age and sex; and a US study comprising 1159 people with MS and 1172 healthy people. In both studies, participants were quizzed about their coffee drinking. The results showed that the risk of MS was consistently higher among those drinking fewer cups of coffee every day in both studies, even after taking account of potentially important influential factors, such as smoking, and weight during the teenage years. In the Swedish study, coffee consumption was associated with a reduced risk of MS both at the start of symptoms and 5 and 10 years beforehand, with a 28-30% lower risk among those drinking more than six cups (900 ml+) every day. Similar results were found in the US study, with a 26-31% lower risk among those drinking more than 948 ml daily at least five years beforehand and at the start of symptoms compared with those who never drank coffee. An observational study The higher the quantity of coffee drunk, the lower the risk of MS, the results showed. However, the researchers point out that this is an observational study, so no firm conclusions can be drawn about cause and effect. Changes in coffee consumption between an MS diagnosis and data collection as well as inaccurate recall of coffee consumption could have influenced the results. There are previous animal studies of MS and coffee to back up the current results, but the researchers do not rule out that there could be other chemical components of coffee than the caffeine that may be responsible for the beneficial effect. The study was led by Anna Hedström and Lars Alfredsson at the Institute of Environmental Medicine, and supported by grants from the Swedish Research Council; the Swedish Research Council for Health, Working Life and Welfare, Knut and Alice Wallenberg foundation, the AFA foundation, the Swedish Brain foundation, the Swedish Association for Persons with Neurological Disabilities.This news article is an edited version of a press release from BMJ Publishing. Also view and editorial commentray in the same journal Publication High consumption of coffee is associated with decreased multiple sclerosis risk: results from two independent studies A K Hedström, E M Mowry, M A Gianfrancesco, X Shao, C A Schaefer, L Shen,T Olsson, L F Barcellos, L Alfredsson Journal of Neurology Neurosurgery & Psychiatry, online 3 March 2016, doi: 10.1136/jnnp-2015-312176

The government has announced its decision today, 3 March, to task a nomination committee with submitting proposals for new members of the Karolinska Institutet University Board. The government is to appoint former university chancellor Lars Haikola onto the nomination committee, which will be submitting a list of proposed external candidates to recruit onto the KI University Board. Press realese from the government (in Swedish).  

Monday 22 February the Professors' Collegium, an discussion forum open for all of KI's professors, met for the first time for quite some time. One of the main purposes of the meeting was to discuss how the Professors’ Collegium can contribute to restoring trust in KI. Three questions to.... Nancy Pedersen, professor at the Department of medical epidemiology and biostatistics, who was one of the arrangers of a meeting for the Professors’ Collegium, a discussion forum for all of KI’s professors, on 22 February. How was the atmosphere at the meeting with the Professor’s Collegium? Enthusiasm was great, some 180 were registered but we got the feeling more than 200 professors turned up. It was very pleasing to see that so many were in for this and the atmosphere was quite responsive. The overall feeling is that we are an important resource prepared to contribute to and take our responsibility in the change KI needs to go through.   Which was the most important issue? We focused on how and what we can learn from the Macchiarini matter that has led to the current crisis. Apart from discussing how to attend lessons learned, there were also some concrete suggestions brought to the table, for instance that some kind of faculty senate, providing advice and support to the KI management, should be established. Further we discussed the process of recruiting a new permanent vice-chancellor –many sound views and advice were expressed.  What were the conclusions of the meeting? We agreed that the Professors’ Collegium should meet more often and the next meeting was set to 11 April. The meeting was something of a new start for us as we have not met in a long time. Some commented upon the need for us to improve our communication, how we can reach out and what channels we could use. We also discussed our work within our research groups and our departments and how this could be improved. It was emphasized that we should have an atmosphere guided by ethics, common values, a communicative leadership and transparency. At the next meeting our acting vice chancellor will be present and I look forward to a discussion of more hands-on issues and measures. Text: Maja Lundbäck

Following the relevations concerning the researcher and surgeon Paolo Macchiarini's actions, a number of investigations and other measures have been initiated. .…at Karolinska Institutet The inquiry into scientific misconduct is being reopened. Following fresh information, including new details about the first patient, whose case forms the bases of some of Paolo Macchiarini's articles, KI intends to reopen the inquiry into scientific misconduct. This will involve obtaining an official statement from the Central Ethical Review Board’s expert group for misconduct in research. An external inquiry is to be conducted into Karolinska Institutet’s handling of the Macchiarini case.The inquiry will be led by lawyer Sten Hecksher, assisted by journalist and author Ingrid Carlberg and Professor Carl Gahmberg. Read more on the inquiry here. The rules for extra-mural occupations are to be reviewed.To make it especially clear that all extra-occupational activities conducted abroad must comply with the same ethical rules that apply to corresponding work at KI, the process by which such occupations are reported at KI will now be subject to review. The risks of the damage that such activities may cause to confidence in KI will be compiled, analysed and presented to the University Board. The recruitment process is to be reviewed. Employment procedures are to be complemented with special procedures for the recruitment of researchers lacking a distinct base at a specific university. Researchers who present a particular identifiable risk will have the verification of their CV given special close attention. Read more here. The vice-chancellor’s delegation rules are to be reviewed. There is to be a review of the vice-chancellor decision-making and delegation rules and the allocation of responsibility to different executives in the departments. The distribution of responsibilities shall be clarified when necessary. …at Karolinska Institutet and Karolinska University Hospital KI and Karolinska University Hospital have mounted a common review of the boundary between healthcare and research. This review was initiated by KI and the hospital executive following the inquiry into scientific misconduct against  Paolo Macchiarini. The aim is to define the boundary between clinical application and research as regards experimental therapy and to draw up clear guidelines for academic healthcare and the university. The review is expected to be concluded before the summer. …at Karolinska University Hospital The hospital is to mount an external investigation into the circumstances surrounding the tracheal operations performed by Paolo Macchiarini on three patients at Karolinska University Hospital in 2011 and 2012. The inquiry is to be led by Kjell Asplund, professor emeritus of medicine and chair of the Swedish National Council on Medical Ethics. The inquiry is expected to be concluded in August. …at other public authorities The Health and Social Care Inspectorate (IVO) The transplantation of synthetic tracheas at Karolinska University Hospital was reported to the IVO to ascertain if the hospital had acted wrongly. In order to have the nature of Macchiarini’s work established as healthcare or research, the IVO, in turn, passes the matter on to the police and public prosecutor. The Medical Products Agency (LMV). The operations were reported to the LMV as a breach of the medical products act, as no permit had been issued for the transplantation of synthetic trachea. To better understand the legal nature of the matter, the LMV has filed a report with the police and public prosecutor.  Police and public prosecutor. Both the IVO and LMV have referred the operations to the police and public prosecutor. The Swedish Higher Education Authority (UKÄ). On 10 February, UKÄ announced that it had received a report against Karolinska Institutet. UKÄ now demands to be sent the findings of the University Board’s forthcoming investigation as soon they are ready as well as a report from Karolinska Institutet on the measures that the investigation will entail. A decision on how the matter will be handled by UKÄ will be taken after it has received the documentation requested. …in the Government An inquiry into misconduct proceedings. The minister of higher education and research, Helene Hellmark Knutsson, has appointed a special investigator to look into the need to revise how matters of scientific misconduct are handled and to submit proposals for ensuring clear and legally secure misconduct proceedings. Her report is expected to be submitted on 25 November 2016. KI will be one of the consultative bodies. … at the Royal Swedish Academy of Sciences in association with the Swedish Society of Medicine The Royal Swedish Academy of Sciences has announced its decisions on a raft or measures to deal with shortcomings in the handling of scientific misconduct and clinical research in connection with Paolo Macchiarini’s research. The academy will also be mounting an investigation with the Swedish Society of Medicine in order to propose recommendations for clinicians and researchers working at the crossroads between clinical research and healthcare.              …at the Swedish National Council on Medical Ethics The Swedish National Council on Medical Ethics is running a project on so-called clinical innovation regarding clinical development work that straddles both clinical research and established healthcare. The project will analyse the problems that can arise and whether clear regulations or guidelines are needed in the field.

Misrecruitment, scientific fraud and failing implants that should never have been implanted in patients – serious allegations have been levelled for a long time against visiting professor Paolo Macchiarini and KI’s conduct in connection with his activities. Following SVT’s documentary series Experimenten the flood of criticism has resulted in a crisis of confidence in the university, the resignation of the vice-chancellor and new investigations into the mistakes that have been made. Here is a brief history of the case so far. Autumn 2010 / Paolo Macchiarini is recruited by Karolinska Institutet (KI) as a visiting professor conducting basic research in the field of regenerative medicine/stem cell biology. At the same time, he is employed on a part-time contract as a consultant and surgeon at Karolinska University Hospital. 2011-2012 / Paolo Macchiarini performs three transplantations of synthetic tracheas coated with stem cells at Karolinska University Hospital. The hospital decides to perform the operations as care interventions on the basis of a so-called vital indication (i.e. as an attempt to save the patients’ lives). 2012 / One of the patients operated on at Karolinska University Hospital dies a few months after the operation, the second survives for two and a half years, while the third is alive but still in hospital in the USA. 2013 / Karolinska University Hospital decides to stop all future operations with syntethic trachea and not to extend Paolo Macchiarini’s contract as surgeon. December 2013/ Paolo Macchiarini commences clinical studies in Krasnodar, Russia, where patients are to be operated on for research purposes. Macchiarini informs KI that he has an extra-mural occupation at Kuban Medical State University (KMSU) and the extra-mural occupation is approved by Paolo Macchiarini’s department at KI. June 2014 / A Belgian researcher reports Paolo Macchiarini for scientific misconduct. The case is investigated by KI’s Ethics Council, which clears him of the allegations. Ethics Council’s statement. June-August 2014 / Two separate reports of scientific misconduct are filed against Paolo Macchiarini by four doctors at Karolinska University Hospital, according to whom research results have been described in overly positive terms in seven of Paolo Macchiarini’s scientific papers, which they argue incorrectly describe the postoperative status of the patients and the functionality of the implants. The four doctors are also researchers at KI and three of them are co-authors on some of the papers. August 2014 / Paolo Macchiarini submits his response to the first complaint, which relates to an article in Nature Communications. November 2014 / KI assignes Bengt Gerdin, professor emeritus at Uppsala University, to examine the material and issuing a statement. April 2015 / Paolo Macchiarini submits his response to the second complaint, which relates to six different articles. April 2015 / KI clears Paolo Macchiarini of scientific misconduct in the case of the complaint levelled against him by the Belgian researcher. KI’s Ethics Council also pronounces on the matter May 2015 / Bengt Gerdin submits his official statement of opinion to Karolinska Institutet. He concludes that many of the points constitute scientific misconduct. June 2015 / Paolo Macchiarini and his co-authors submit their comments on the content of Bengt Gerdin’s statement of opinion. August 2015 / KI issues its overall verdict acquitting Paolo Macchiarini of all allegations of scientific misconduct, but states that his research fails to meet the standards of quality set by KI and the scientific community. KI’s judgement on the matter is made with reference to the new information that has emerged from the comments submitted by Paolo Macchiarini and his co-authors on Bengt Gerdin’s official statement of opinion. A summary of the differences between Bengt Gerdin’s conclusions and KI’s decision can be found here. November 2015 / Paolo Macchiarini has his contract extended with KI as a researcher up until 30 November. December 2015 / Bengt Gerdin stands by his conclusion after having, on his own initiative, reviewed KI’s acquittal and the material that arrived in after he had submitted his own report. Gerdin emails his conclusions to Vice-Chancellor Anders Hamsten. January 2016 / Vanity Fair publishes an article in which Paolo Macchiarini is accused of having lied on his CV. KI opens an inquiry into the veracity of the CV with which Paolo Macchiarini furnished KI in connection with his employment. 13, 20 and 27 January 2016 / The 3-part documentary series Experimenten is broadcast on SVT. The documentaries, which closely track Paolo Macchiarini and his work, show how patients have suffered and died in connection with failed operations, and raise numerous issues concerning care and research ethics. The fierce public response to the series causes a crisis of confidence in KI. Anders Hamsten’s comments can be found here. See also Karolinska University Hospital’s comments on the documentaries. 1 February 2016 / KI’s first investigation into Paolo Macchiarini’s CV concludes that it contains several falsehoods, although none so serious as to justify his dismissal or resignation. The definitive examination is yet to be concluded. 4 February 2016 / Vice-Chancellor Anders Hamsten decides that Paolo Macchiarini’s contract with Karolinska Institutet will not be extended. 4 February 2016 / An external inquiry is mounted by the Karolinska Institutet University Board into Karolinska Institutet’s handling of the entire case, from Paolo Macchiarini’s recruitment to the present. It is to be led by lawyer Sten Hecksher. The University Board also decides to give Vice-Chancellor Anders Hamsten their continuing confidence for the duration of the inquiry.  7 February 2016 / Urban Lendahl, secretary of the Nobel Committee at Karolinska Institutet announces that he is resigning from his post at his own request. He cites “concern for the Nobel Prize” as his reason, as he understands that he will be part of the external investigation.  13 February 2016 / Vice-Chancellor Anders Hamsten announces his resignation and that KI will be mounting a new inquiry into scientific misconduct against Paolo Macchiarini after having received information that presents a different account of the first patient from Iceland, whose case forms the basis of some of Macchiarini’s articles. 13 February 2016 / Pro-Vice-Chancellor Karin Dahlman-Wright takes up office as stand-in Vice-Chancellor. 13 February 2016 / Four professors from the Nobel Assembly at Karolinska Institutet decline to participate in the work of the assembly while the Macchiarini case is being investigated since they themselves will be under examination: former vice-chancellor Anders Hamsten, Dean of Research Hans-Gustaf Ljunggren, Katarina Le Blanc and Urban Lendahl. 17 February / The KI University Board decides to request the government to appoint Karin Dahlman-Wright as stand-in vice-chancellor for Karolinska Institutet after Anders Hamsten. 18 February / The government decides to appoint Karin Dahlman-Wright as stand-in vice-chancellor of Karolinska Institutet. Dahlman-Wright was made pro-vice-chancellor on 1 January 2016 and has been a professor of molecular endocrinology since 2009. 22 February / Dean Hans-Gustaf Ljunggren requests to step down from his position as Dean of Research. This article will be kept updated.  

Diabetes researchers at Karolinska Institutet have developed a novel technique that makes it possible to monitor insulin resistance in a non-invasive manner over time in mice. The new method, presented in the journal Scientific Reports, can be used to assess insulin resistance during progression and intervention of metabolic diseases. Insulin resistance is a key contributing factor to a variety of metabolic diseases, including cardio-vascular disease, the metabolic syndrome and diabetes type 2. A major challenge in the field of insulin resistance is to be able to monitor this process dynamically in individual cell types of insulin target tissues, such as fat, liver, brain, kidney or pancreatic islets in the living organism. The researchers behind the new study have previously shown that the insulin-secreting beta-cell, situated in the pancreatic islet of Langerhans, not only produces the hormone insulin but is also a target for insulin signaling. Consequently, beta-cell insulin resistance can contribute to the development and progression of type 2 diabetes. “The problem is that the islets are embedded in the pancreas and therefore not accessible for direct monitoring", says first study-author Meike Paschen, doctoral student at the Rolf Luft Research Center for Diabetes and Endocrinology, Department of Molecular Medicine and Surgery at Karolinska Institutet. "However, by equipping beta-cells with a fluorescent biosensor that reports on insulin resistance and transplanting these reporter islets into the anterior chamber of the eyes of mice, we are now able to study beta-cell insulin sensitivity over months in the living mouse.” The anterior chamber of the eye This novel technique utilizes the cornea as a natural body-window to allow the investigators to non-invasively monitor insulin resistance in islet of Langerhans transplanted to the anterior chamber of the eye. The biosensor expressed by the engrafted islets makes it possible for the researchers to differentiate insulin-resistant cells from those that have a normal response to insulin. The biosensor signal is measured non-invasively by fluorescence microscopy at single-cell resolution in the living animal.  "This technique allows monitoring of cell type specific insulin sensitivity or resistance in real-time in the context of whole body insulin resistance during progression and intervention of disease", says Professor Per-Olof Berggren, who led the current study together with Associate Professor Ingo Leibiger at the Rolf Luft Research Center for Diabetes and Endocrinology. The research was financially supported by, among others, the Swedish Research Council, the Family Erling-Persson Foundation, the Novo Nordisk Foundation and Karolinska Institutet (KID Programme). Our press release about this study Publication Non-invasive cell type selective in vivo monitoring of insulin resistance dynamics Meike Paschen, Tilo Moede, Barbara Leibiger, Stefan Jacob, Galyna Bryzgalova, Ingo B. Leibiger, Per-Olof Berggren Scientific Reports, published online 22 Feb 2016

On 18 February, the government decided to appoint Karin Dahlman-Wright as Acting Vice-Chancellor at Karolinska Institutet, replacing Anders Hamsten, who stepped down from his assignment as Vice-Chancellor 13 February. Karin Dahlman-Wright has been Professor of Molecular Endocrinology since 2009. Her research focuses on studies of estrogen signaling, with specific focus on type 2 diabetes and breast cancer. Karin Dahlman-Wright was appointed Pro-Vice-Chancellor on 1 January 2016.

Muhammad Nasir, Indonesia’s minister of research, technology and education, is paying a visit to Karolinska Institutet today. The minister is in Sweden on a courtesy visit, during which he will sign a letter of intent with the Swedish Department of Education on greater collaboration on research and education. Accompanying Muhammad Nasir to KI are Indonesia’s ambassador to Sweden and Sweden’s ambassador in Jakarta. Their visit is hosted by Maria Masucci, deputy vice-chancellor for international affairs at KI. “We see that the scientific world is becoming more and more international, so we’re eager to establish relations with other universities and other countries,” says Ms Masucci. “We hope this will promote mobility, both to and from KI.” Also taking part in the visit is assistant dean Gunnar Nilsson and two other deans at Karolinska Institutet, Hans-Gustaf Ljunggren and Anders Gustafsson. The visiting delegation will be given a general presentation of KI’s education and research activities. A few months ago, Karolinska Institutet entered a partnership with the Indonesia Empowerment Fund for Education (LPDP), and last autumn signed a Memorandum of Understanding, whereby the two parties will examine and develop different forms of collaboration and the LPDP will support Master’s and doctoral students wishing to study at Karolinska Institutet. This year, 45 Indonesian students have applied for KI’s Master’s programme, compared with 16 last year. The KI management hopes that the ministerial visit will eventually help to make this figure rise even further while creating new opportunities for greater collaboration on doctoral education and research. “Indonesia is South-East Asia’s largest economy and has enjoyed substantial growth this past decade,” says Ms Masucci. “The country also shows considerable interest in international relations to promote development in education and research, especially in the technological and biomedical sectors. This is something we’re delighted to see.” Text: Lisa Kirsebom

A relatively newly discovered group of immune cells known as ILCs have been examined in detail in a new study published in the journal Nature Immunology. By analysing the gene expression in individual tonsil cells, scientists at Karolinska Institutet have found three previously unknown subgroups of ILCs, and revealed more about how these cells function in the human body. Innate lymphoid cells (ILCs) are a group of immune cells that have only relatively recently been discovered in humans. Most of current knowledge about ILCs stems from animal studies of e.g. inflammation or infection in the gastrointestinal tract. There is therefore an urgent need to learn more about these cells in humans. Previous studies have shown that ILCs are important for maintaining the barrier function of the mucosa, which serves as a first line of defence against microorganisms in the lungs, intestines and elsewhere. However, while there is growing evidence to suggest that ILCs are involved in diseases such as inflammatory bowel disease, asthma and intestinal cancer, basic research still needs to be done to ascertain exactly what part they play. Two research groups, led by Rickard Sandberg and Jenny Mjösberg, collaborated on a study of ILCs from human tonsils. To date, three main groups of human ILCs are characterized. In this present study, the teams used a novel approach that enabled them to sort individual tonsil cells and measure their expression across thousands of  genes. This way, the researchers managed to categorise hundreds of cells, one by one, to define the types of ILCs found in the human tonsils. Unique gene expression profiles “We used cluster analyses to demonstrate that ILCs congregate into ILC1, ILC2, ILC3 and NK cells, based on their unique gene expression profiles,” says Professor Sandberg at Karolinska Institutet’s Department of Cell and Molecular Biology, and the Stockholm branch of Ludwig Cancer Research. “Our analyses also discovered the expression of numerous genes of previously unknown function in ILCs, highlighting that these cells are likely doing more than what we previously knew.”  By analysing the gene expression profiles (or transcriptome) of individual cells, the researchers found that one of the formerly known main groups could be subdivided. “We’ve identified three new subgroups of ILC3s that evince different gene expression patterns and that differ in how they react to signalling molecules and in their ability to secrete proteins,” says Dr Mjösberg at Karolinska Institutet’s Department of Medicine in Huddinge, South Stockholm. “All in all, our study has taught us a lot about this relatively uncharacterised family of cells and our data will serve as an important resource for other researchers.” The study was financed by grants from a number of bodies, including the Swedish Research Council, the Swedish Cancer Society, the EU Framework Programme for Research and Innovation, the Swedish Society for Medical Research, the Swedish Foundation for Strategic Research and Karolinska Institutet. Our press release about this study Publication The heterogeneity of human CD127+ innate lymphoid cells revealed by single-cell RNA sequencing Åsa K. Björklund, Marianne Forkel, Simone Picelli, Viktoria Konya, Jakob Theorell, Danielle Friberg, Rickard Sandberg, Jenny Mjösberg Nature Immunology, online 15 February 2016, doi:10.1038/ni.3368

Professor Anders Hamsten steps down from his assignment as Vice-Chancellor of Karolinska Institutet. He declares his resignation in a debate article in the daily newspaper Dagens Nyheter today, Saturday. At the same time Karolinska Instutet’s investigation into scientific misconduct by Paolo Macchiarini will be re-opened. ”Following the criticism on the so called Macchiarini affair at KI I conclude it will be hard for me to serve as Vice-Chancellor with the strength and credibility this university needs. I will therefore leave office”, says Anders Hamsten. Anders Hamsten holds a degree in medicine from Karolinska Institutet in 1978, he finished his PhD in 1986 and did specialist training in heart disease and internal medicine at Danderyd Hospital from 1982 to 1986. He became Docent (associate professor) in 1990 and professor in 1999. He was appointed as Vice-Chancellor at Karolinska Institutet on 1 January 2013. ”I want to thank Anders Hamsten for his three years as Vice-Chancellor at KI,” says chairman of the University Board Lars Leijonborg. “Over these years he has contributed to many important decisions. I especially want to highlight our Strategy 2018, which is a concrete plan to make KI an even better university. When he was elected he was strongly supported by teachers, researchers and students, and in office he continued to be appreciated. The recent period has been difficult for both KI and him. I have the deepest respect for his decision to resign.” A new Vice-Chancellor will be appointed by the Government based on a proposal from the University Board. Meanwhile, Pro-Vice-Chancellor Karin Dahlman-Wright will serve as Vice-Chancellor. ”I wish Karin Dahlman-Wright all the best as Vice-Chancellor. I assume the board will start the process of looking for a successor to Anders Hamsten at its meeting next Wednesday, which very well might be Dahlman-Wright,” says Lars Leijonborg. “We also need to appoint a new Pro-Vice-Chancellor.” The external investigation into KI’s handling of the “Macchiarini case” lead by Sten Heckscher will go on as decided last Thursday, adds Lars Leijonborg. KI will also re-open the investigation into scientific misconduct concerning Paolo Macchiarini. Over the last couple of days the university has received new information which gives a different picture of the time after the operation of the first patient on whose case some of Macchiarini’s articles are based upon. ”We have now analysed the images shown in the documentary by Swedish Television (SVT) and this brings us a whole new picture of the process after the surgery on the patient” says Jan Carlstedt-Duke, Professor and Adviser to the Vice-Chancellor at Karolinska Institutet. “This strengthens the suspicions of scientific misconduct by Paolo Macchiarini. KI has also received a new report of scientific misconduct in two of Machiarini’s articles on research on rats. “When looking at images in those articles several of them seem to be very similar. That leads us to clearly suspect that data published in those publications are incorrect” says Jan Carlstedt-Duke. “We will now investigate this thoroughly and get an independent review of this data.”  

Long-term use of liraglutide, a substance that helps to lower blood sugar levels in patients with type 2 diabetes, can have a deteriorating effect on insulin-producing beta cells, leading to an increase in blood sugar levels. This according to a study on mice implanted with human insulin-producing cells conducted by a team of scientists from Karolinska Institutet, and the University of Miami, USA. The researchers flag the possible consequences of this popular form of therapy in Cell Metabolism. Blood-sugar suppressors in the form of analogues of the incretin hormone GLP-1 are commonly used in the treatment of type 2 diabetes, since they stimulate the glucose response of the pancreatic beta cells to make them secrete more insulin. There is now compelling evidence that liraglutide therapy is efficacious at least in the short term, since it produces an initial reduction in blood sugar. However, many patients do not respond to the treatment and some even display adverse reactions such as nausea, vomiting and diarrhoea. To study the long-term effects of incretin therapy, which has never previously been assayed, researchers at Karolinska Institutet and the University of Miami worked with humanised mice, generated by transplanting human insulin-producing cells into the anterior chamber of the eye. The mice were given daily doses of liraglutide for more than 250 days, during which time the researchers were able to monitor how the pancreatic beta cells were affected. The results showed an initial improvement in the insulin-producing cells, followed by a gradual exhaustion, with reduced secretion of insulin as a response to glucose. This, they say, was unexpected. Long-term treatment regimens “Given the lack of clinical studies on the long-term effect of these drugs in diabetes patients, this is a very important discovery,” says Midhat Abdulreda, researcher at the Diabetes Research Institute, University of Miami Miller School of Medicine. “We also need to take these results into account before prescribing blood-sugar suppressing GLP-1 analogues when planning long-term treatment regimens for patients,” says Per-Olof Berggren, Professor at the Rolf Luft Research Centre for Diabetes and Endocrinology at Karolinska Institutet’s Department of Molecular Medicine and Surgery. “Our study also shows in general how to carry out in vivo studies of the long-term effects of drugs on human insulin-producing cells, which should be extremely important to the drug industry.” The study was financed by grants from several funding bodies, including the Diabetes Research Institute Foundation (DRIF), the National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases, the Swedish Research Council, the Knut and Alice Wallenberg Foundation, the Family Erling-Persson Foundation, the Stichting af Jochnick Foundation, the European Research Council (ERC) and the Novo Nordisk Foundation. Corporate interests: Per-Olof Berggren is co-founder and CEO of Biocrine, an unlisted biotech company that uses the anterior chamber of the eye as a research tool. Midhat Abdulreda is a consultant for the same company. Our press release about this study Publication Liraglutide compromises pancreatic beta cell function in a humanized mouse model Midhat H. Abdulreda, Rayner Rodriguez-Diaz, Alejandro Caicedo, Per-Olof Berggren Cell Metabolism, online11 February 2016

The Karolinska Institutet University Board (Konsistoriet) has appointed the lawyer who will be conducting the external investigation into KI’s handling of the “Macchiarini case”. This person has appointed two others to assist him in his work. The external investigator is the former president and justice of the Supreme Administrative Court of Sweden Sten Heckscher. Heckscher is 73 years old, and has been president of the Administrative Court of Appeal in Stockholm, national police commissioner, general director of the Swedish Patent and Registration Office, under-secretary of state in the Ministry of Justice and minister of Industry and Employment. He also chaired the board of Stockholm University for nine years. Sten Heckscher has appointed two people to assist him in the investigation. They are: Author Ingrid Carlberg Carlberg is 54 years old and a former journalist of 20 years standing at Dagens Nyheter. She has published several books, including “Pillret” (an account of the pharmaceutical industry, 2008) and “Det står ett rum här och väntar på dig…” (a biography of Raoul Wallenberg, 2012). She has won the August Prize and the Guldspaden award, Sweden’s most respected journalism prize. She is an honorary doctor of medicine at Uppsala University, and has sat on the Broadcasting Commission. Professor Carl Gahmberg Gahmberg is 73 years old and professor of biochemistry at Helsinki University. He is a trained doctor and one of Finland’s most cited researchers. He has worked in the USA and continues as emeritus professor to research at the Gahmberg Lab in Helsinki. He has held several international appointments and received many awards for scientific excellence. He is an overseas member of the Swedish Royal Swedish Academy of Sciences. The investigative team will be furnished with whatever administrative resources are required.

Researchers at Karolinska Institutet have taken a step closer to understanding the mechanism that leads to the fusion of egg and sperm at fertilisation. Using the technique X-ray crystallography, they have determined the 3D structure of Juno, a mammalian egg protein essential for triggering gamete fusion. Their findings are not only interesting from an evolutionary perspective, but also reveal the shape of a possible target for future non-hormonal contraceptives. The fusion of egg and sperm is an essential step of fertilisation in sexually reproducing organisms and the molecular mechanism behind this event has long been the object of intense research. A breakthrough came in 2014 with the discovery of Juno, a protein receptor found on the egg. Juno, which is tethered to the cell membrane of the egg, binds to sperm surface protein Izumo1 when egg and sperm meet. The discovery of Juno and Izumo1 opened up new possibilities to study the process of fertilisation at the molecular level. The importance of both molecules was demonstrated when experiments showed that mice lacking either of them are infertile. However, how Juno interacts with Izumo1 was unclear, something that Dr Luca Jovine, Professor of Structural Biology at Karolinska Institutet's Department of Biosciences and Nutrition, and affiliated to the Center for Innovative Medicine (CIMED), has worked hard to understand. Juno belongs to a family of proteins called folate (or vitamin B9) receptors. Such receptors are vital to a number of biological processes, including foetal development. In the present study, which is published in the scientific journal Current Biology, the researchers present a high-resolution 3D structure of Juno. This reveals that Juno is similar in shape to the other members of its family, with the exception of the specific region that – in these other proteins – serves as the binding site for vitamin B9. This observation explains why Juno is unable to bind to the vitamin. Binding site for sperm protein The structure also suggests that the same region of Juno instead acts as the binding site for sperm protein Izumo1. Professor Jovine’s group and their collaborators from Cambridge analysed how changes in this part of Juno affect its ability to pair with Izumo1, and produced results indicating that Izumo1 binding involves two specific loops of Juno. “Remarkably, we found that changing these loops either caused Juno to completely lose its ability to bind Izumo1 or altered the species-specificity of the binding,” says Professor Jovine. “Our data thus not only shows how Juno looks like at the atomic level, but also brings us a step closer to understanding how its interaction with Izumo1 mediates the docking between the membranes of gametes”. According to the researchers, the results suggest that modifications of an ancestral vitamin B9 receptor occurred far back in time, which gave rise to a key interaction essential for mammalian reproduction: the attachment of egg and sperm membranes leading to the fusion of gametes. This research was supported by, among other funding bodies, CIMED, the Swedish Research Council, the Göran Gustafsson Foundation for Research in Natural Sciences and Medicine, the Sven and Ebba Christina Hagberg Foundation, an EMBO Young Investigator award, and the European Research Council. Our press release about this study Publication Divergent evolution of vitamin B9 binding underlies Juno-mediated adhesion of mammalian gametes Ling Han, Kaoru Nishimura, Hamed Sadat Al Hosseini, Enrica Bianchi, Gavin J. Wright, and Luca Jovine Current Biology, online 8 February 2016