KNIMS - The Karolinska Neuroimmunology & Multiple Sclerosis Centre

Interview with Professor Fredrik Piehl and Professor Gonçalo Castelo-Branco

Short interview with Professor Fredrik Piehl (CMM) and Professor Goncalo Castelo-Branco (MBB) regarding the role of single-cell technologies in the current understanding of the human genome in both health and disease with the purpose of eventually applying this knowledge to treat neurodegenerative diseases such as Multiple Sclerosis, and contribute to a better understanding of the key role of myelin in the hallmark events of demyelination and remyelination. Interview moderator Dr Chiara Starvaggi Cucuzza (CMM).

KNIMS Principal Investigator profiles

Katharina Liesa Gabriela Fink

TITLE: Neurologist                        

YEAR OF BIRTH: 1982             

NATIONALITY: German

ACADEMIC DEGREE: MD

YEAR OF PHD THESIS: 2010

RESEARCH EXPERTISE AREA: Clinical research with in neuroimmunology

Background:

Katharina Fink was born in Berlin, Germany in 1982. She received her medical degree at the Charité- University Medicine, Berlin. During her medical studies she spent a year at the Karolinska Institutet. She returned to the Karolinska Institutet in 2008 after finishing her studies in Berlin in order to proceed with her residency in neurology. In 2010 she received her doctor´s degree in psychiatry at the Charité-University Medicine, Berlin for her studies in characterizing an animal model of depression. After moving to Sweden she gained clinical experience by working with patients with multiple sclerosis (MS), joining Professor Jan Hillert’s Neurogenetics Multiple Sclerosis research group at the Department of Clinical Neuroscience, Karolinska Institutet looking at clinical outcome measures for patients with MS. In her current role at the Karolinska University Hospital she leads the multidisciplinary narcolepsy-team and at the Academic Specialist Center she has been given the task to set up a national reference center for women with MS planning pregnancies. She is a member of the drug and MRI committee for the Swedish MS society and founder of the Swedish NMO-registry.

Research interests:

Her research is driven by the contact with her patients, addressing relevant clinical knowledge gaps. Through advocating female patients with MS she is interested in research directed at pregnancy, health and socioeconomic outcomes in mothers with MS as well as their children. For example, she is currently involved in a study investigating the risk profile of women with MS that have been exposed to the drug rituximab around the time of their pregnancy. The study looks at delivery complications, birth defects and adverse birth outcomes in patients´ children, as well as structured long-term outcomes.

Statement:

“As a clinician I am driven to meet my patients’ needs. Through the patient-doctor encounter I receive research questions that feed my research. Vice versa, it is my obligation to introduce the latest research into my clinic and to advertise it to society.”

Robert Adam Harris

TITLE: Professor of Immunotherapy in Neurological Diseases, Vice President Doctoral Education at KI

YEAR OF BIRTH: 1966                                   

NATIONALITY: British/Swedish

ACADEMIC DEGREE: B.Sc Hons Biology

YEAR OF PHD THESIS: 1991

RESEARCH EXPERTISE AREA: Cellular immunology

Background:

Professor Robert A. Harris (Bob) was born in Harpenden in Southern UK in 1966. He conducted a Bsc.Hons undergraduate degree at Portsmouth Polytechnic, majoring in Parasitology in 1987. PhD studies at University College London studying innate immune agglutinins in Schistosoma spp. host snail species culminated with a thesis defence in early 1991. A 2½-year postdoc at the London School of Hygiene & Tropical Medicine ensued with focus on understanding the intracellular fate of Leishmania spp. protozoans in macrophages. Bob was awarded a Wellcome Trust postdoctoral fellowship that permitted his relocation to the Karolinska Institutet (Stockholm, Sweden) in the spring of 1994. A postdoc period was spent studying Trypanosoma spp. protozoan proteins. Bob became an Associate Professor at the Karolinska Institute in 1999, heralding his establishment as a PI. Bob started to work with autoimmune diseases in 1996 and began study of therapy using live parasite infections or parasite molecules. During the most recent years his research group has (i) developed autoantigen-specific vaccines, (ii) defined the effects of post-translational biochemical molecules on autoantigenicity and (iii) developed a macrophage adoptive transfer therapy that prevents pathogenesis in several experimental disease models.

Research interests:

Our current research focus is on myeloid cell biology, and in particular macrophages/microglia. We study the role of these myeloid cells during a range of neurological diseases with primary focus on Multiple Sclerosis, but also including Alzheimers’ Disease, Glioblastoma multiforme brain tumors and Stroke, and we also use a model of melanoma in our myeloid cell therapy program. Our major aim in each of these settings is to modulate myeloid cell functionality at the site of inflammation, and we explore different ways to modulate myeloid cells in these settings. These include: (1) the adoptive transfer of pre-activated myeloid cells (immunosuppressive phenotype transferred in settings of autoimmune disease, pro-inflammatory phenotypes transferred into tumors); (2) novel ways to vaccinate (including a novel delivery system for autoantigens, and a neutrophil depletion model in cancer settings); (3) tissue-specific directed nanoparticles containing silencing RNAs.

Statement:

“The central nervous system is one of the last frontiers for scientific discovery. We not only have an interest but also a duty to use knowledge to make the lives of patients better. If just one person benefits from my research efforts then it has all been worthwhile.”

Maja Jagodic

TITLE: Associate Professor of Experimental Medicine                       

YEAR OF BIRTH: 1974                                   

NATIONALITY: Serbian/Swedish

ACADEMIC DEGREE: MSc Molecular Biology and Physiology

YEAR OF PHD THESIS: 2004

RESEARCH EXPERTISE AREA: Experimental and Functional Genetics

Background:

Associate Professor Maja Jagodic was born in Belgrade (Serbia) in 1974. She completed an MSc degree in 1999 at the University of Belgrade (Serbia) in Molecular Biology and Physiology specializing in Experimental Medicine. After receiving an Swedish Institute scholarship she moved to Sweden where she obtained her PhD degree at the Karolinska Institutet in 2004 studying genetic predisposition to autoimmune diseases in model organisms. After her thesis defense she spent a year at the Karolinska Institutet gaining skills in human genetics (2005-2006). Already towards the end of her PhD thesis Maja became fascinated by the field of epigenetics. Epigenetic mechanisms, which orchestrate genome activity in response to environmental cues, were at that time strongly implicated in the etiology of complex inflammatory diseases but virtually unexplored. Maja was awarded a Wenner-Gren foundation postdoctoral fellowship to study epigenetic mechanisms in cancer at the University of Cambridge, UK (2006-2008). In 2008 she was awarded an Assistant Professor position by the Swedish Research Council and she returned to Sweden to initiate studies of epigenetic mechanisms in chronic inflammatory diseases. She was appointed a group leader position at the Department of Clinical Neuroscience at the Karolinska Institutet in 2012 and she became an Associate Professor in Experimental Medicine in 2014. Her research group continues to utilize functional genetic approaches to study mechanisms underlying chronic inflammation in the brain with a focus on Multiple Sclerosis and its experimental models.

Research interests:

Our current research focus is on understanding how the epigenome integrates instructions from genetic and lifestyle factors to convey altered cellular functionality that leads to chronic inflammation and neuronal loss in the brain. We aim to characterize the epigenetic mechanisms that render pathogenic cells ‘aggressive’ and target cells “vulnerable” in Multiple Sclerosis patients. We utilize unique and high-quality clinical cohorts in combination with state-of-the-art methods to measure DNA methylation and transcription in discrete cell types, followed by functional studies in experimental models. Our goals are to: (1) better understand the cause of disease by identifying epigenetic changes that associate with susceptibility to develop MS and long-term disease outcomes and then to understand their functional consequences, (2) identify epigenetic marks that can serve as sensitive and specific biomarkers, and (3) develop novel therapeutic approaches based on targeting epigenetic changes.

Statement:

“The package is equally important as its contents: this is true for our genes. Isn’t it fascinating that 2 meter-long DNA molecules can fit into our cells and that the packaging of DNA determines the identity and function of every cell? We are driven by a desire to understand how changes in the packaging and utilizing genetic information lead to diseases of the immune system and the brain, and to utilize this knowledge for better disease management.”

Ingrid Kockum

TITLE: Professor in genetic epidemiology specializing in MS    

YEAR OF BIRTH: 1967                                   

NATIONALITY: Swedish

ACADEMIC DEGREE: B.A Natural Sciences

YEAR OF PHD THESIS: 1995

RESEARCH EXPERTISE AREA: Genetic Epidemiology

Background:

Professor Ingrid Kockum was born in in 1967 and grew up in Skåne in Southern Sweden. She completed her undergraduate studies in 1989 at Newnham College, Cambridge, UK, in natural sciences majoring in zoology with focus in molecular biology. She started her PhD studies in immunogenetics of type 1 diabetes at Lund University, Sweden and University of Washington, Seattle, USA, but defended her thesis at Karolinska Insitutet in 1995. She continued her research in the genetics of type 1 diabetes as a postdoc at the Wellcome Trust Center for Human Genetics, Oxford University, UK (1996-1997) and at Karolinska Insitutet, now focusing on the role of genes outside of the MHC region.

Between 2001-2005 she lead the Multifactrorial disease genetics research group at the Department of Molecular Medicine and Surgery at Karolinska Insitutet and studied genetics of type 1 diabetes, atopic dermatitis, bipolar disease and alcoholism. In 2006 she joined the Neuroimmunology Unit at the Department of Clinical Neuroscience and changed the focus of her research to genetic epidemiology of multiple sclerosis, having since 2014 led the Multiple Sclerosis genetic epidemiology research group. In 2007 she became Associate Professor in genetics. During the most recent years her research has focused on (i) identification of novel genetic susceptibility variants for multiple sclerosis conducted with IMSGC and deCODE; (ii) identification of genetic control of severity/progression of MS which also including investigating novel ways of measuring severity of MS (iii) identification of interactions between genetic and lifestyle risk factors for MS; (iv) study of the role of viral infections in MS; and (v) attempting to identify novel protein biomarkers for MS.

Research interests:

We continue our efforts to identify novel genetic risk variants for MS, both in collaboration with IMSGC and more recently together with deCODE. We use both traditional genotyping and next generation sequencing in these studies. Currently more than 200 susceptibility variants have been identified for MS, the major ones being in the HLA region. We are attempting to identify which genes these variants control expression for using RNAseq data from samples from MS patients. We study how genetic MS risk variants interact with MS risk lifestyle exposures such as smoking and viral infections, since this pinpoints which biological processes are acting together to cause MS, and have identified several such interactions. Immune response to viral infections such herpes virus infections (Epstein Barr and Cytomegalovirus) is altered in MS, although it is unclear if this is a consequence of the disease or if these viral infections themselves affect the risk of developing MS. We are trying to address this by comparing genetic risk factors for serological response to these infections and genetic risk factors for MS. We are also investigating molecular mimicry between viral antigens and autoantigens for MS. Because we have access to a uniquely large and well-characterized dataset of MS patients we are now embarking on trying to identify genetic and lifestyle exposure risk factors for progression/severity of MS. This work will be carried out in the MultipleMS project, a Horizon2020 funded project coordinated by Ingrid Kockum and Maja Jagodic. In this project we will also aim to stratify patients based on genetic and lifestyle exposures with the aim of identifying subpopulations of patients that respond differently to different treatments in order to achieve personalized medicine for MS.

Statement:

“Very many risk factors have been identified for multiple sclerosis during the past few years. They do not explain all the risk of developing MS, but more worrying is that we do not understand how most of the risk factors act to cause MS. I hope that the research carried out in our group will help us to understand how these disease risk factors act and that it will in turn lead to better treatment for MS.”

Fredrik Piehl

TITLE: Professor of Neurology                            

YEAR OF BIRTH: 1967                                   

NATIONALITY: Swedish

ACADEMIC DEGREE: MD, PhD

YEAR OF PHD THESIS: 1996

RESEARCH EXPERTISE AREA: Clinical neuroimmunology

Background:

Born in Stockholm, Sweden. Graduated in medicine at Karolinska Institutet (KI) 1993 and defended a PhD experimental neuroscience at the Department of Neuroscience, KI, 1996. Conducted a 6-months period at the Max-Planck Institute of Martinsried, Germany, 1993-94. Internship at St Göran´s Hospital 1995-97. Post-doc in experimental neuroimmunology at the Department of Medcine KI 1997-99 with external post-doc scholarships from Hagelen´s stiftelse and Hjärnfonden. Started a residency in clinical neurology at the Department of Neurology of Karolinska University Hospital in 2000, with 1/3 research funded by Stockholm County. Associate Professor of experimental neurology in 2001. Board certification in clinical neurology 2005. Halftime research position in experimental and clinical neuroimmunology awarded by the Swedish Research Council 2005-2009. Head of the MS clinic at Karolinska 2008-2017 and currently head of research at the Academic Specialist Clinic of Stockholm health Services. Professor of Neurology at KI in 2009. Chairman of the Swedish MS Society 2013-2015. Scientific Secretary of the Swedish Society for Medical Research. PI in >10 clinical trials in MS and myasthenia gravis (MG). Chairman of the IDMC of two international multicenter phase III trials in neuromyelitis optica. Member of the scientific advisor board of the Swedish Medical Products Agency and regularly serve as external expert for the European Medicines Agency in issues related to the treatment of MS.

Research interests:

Starting from a purely experimental interest in the link between inflammation and neurodegeneration the research focus has evolved and now spans from experimental models of neurodegeneration to clinical trials in humans. Many new disease modulatory drugs have been developed for MS during recent years. However, information on long-term benefits and risks are still far from perfect. By using biomarkers reflecting important aspects of the disease, such as inflammation and neurodegeneration, a better understanding of modes of action can be gained. Furthermore, a major grant was recently awarded from the US foundation Pcori, which makes it possible to conduct a very large long-term nationwide outcome study in a real-world population to shed light on the benefit/risk balance of all major MS drugs. In contrast, treatment advances in MG lags behind that in MS, since current treatment guidelines are largely based on clinical experience and not on clinical trial data. We recently started a nationwide multicenter placebo-controlled RCT with rituximab for new onset MG (the Rinomax study) with funding from the Swedish Research Council. Hopefully this study, and other academic initiatives, can help evolve also the treatment landscape of MG in the same way as for MS.

Statement

The challenge with diseases such as MS and MG is to integrate and decipher complex clinical, immunological and genetic information and to translate this to effective treatment strategies with optimized risk-benefit for our patients.

Gonçalo Castelo-Branco

TITLE: Associate Professor of Neurobiology                            

YEAR OF BIRTH: 1976                                   

NATIONALITY: Portuguese & Swedish

ACADEMIC DEGREE: B.Sc. Biochemistry, PhD

YEAR OF PHD THESIS: 2005

RESEARCH EXPERTISE AREA: Myelin, neuroscience and transcriptomic/epigenomics

Background:

Gonçalo Castelo-Branco was born in Cantanhede, Portugal. He is currently an Associate Professor of Neurobiology at the Department of Medical Biochemistry and Biophysics at Karolinska Institutet, Stockholm, Sweden. Dr. Castelo-Branco received his B.Sc. (“Licenciatura”) in Biochemistry at the University of Coimbra Portugal in 1999 and PhD in Medical Biochemistry in 2005, at the Karolinska Institutet, working on development of dopaminergic neurons and neural stem differentiation. He completed post-doctoral fellowships first at the Karolinska Institutet and then at the University of Cambridge, United Kingdom, working in neural and pluripotent stem cells and chromatin.  After receiving an assistant professor grant from the Swedish Research Council, he started his research group in 2012 at Karolinska Institutet, focusing on the epigenetic mechanisms regulating the epigenetic states of oligodendrocyte (OL) lineage cells in the context of multiple sclerosis (MS). Dr. Castelo-Branco has received many prestigious awards and grants, including the 100 years’ Jubileum Prize of the Swedish Society for Medical Research (SSMF), and research grants from the European Research Council and Knut and Alice Wallenberg Foundation, among others.

Research interests:

The main focus of his research group is to investigate how distinct transcriptional and epigenomic states within the oligodendrocyte lineage are established, by identifying key transcription factors, chromatin modifying complexes and non-coding RNAs that are involved in epigenetic transitions. His research group integrates leading-edge transcriptomic and epigenomic technologies and animal models of disease, among other techniques, to study the mouse and human OL lineage biology during development and in MS. His previous studies with single-cell transcriptomics in mouse revealed the dynamics of oligodendrocyte differentiation and maturation, uncoupling them at a transcriptional level and highlighting oligodendrocyte heterogeneity in the CNS. Further single-cell studies in the EAE mouse model of MS allowed the identification of specific OL lineage populations expressing genes involved in antigen processing and presentation via major histocompatibility complex class I and II (MHC-I and -II), but also in immunoprotection, suggesting alternative functions of these cells in a disease context.  His research group also performed single nucleus RNA-Seq in post-mortem human brain samples from MS patients and individuals with no neurological pathology and found that disease-specific oligodendroglia are also present in human MS brains The new identified OL lineage cell states might play a role on the aetiology of MS, which his group is actively investigating, in collaboration for instance with Dr. André Cacais Ortlieb and Professor Tomas Olson, alsoat Karolinska Institutet.

Statement

The long term aim of our research group is to be able to design epigenetic based-therapies to induce regeneration (remyelination) or prevent disease progression in demyelinating diseases, such as multiple sclerosis.

Tobias Granberg

TITLE: Radiologist, Research team leader

DATE OF BIRTH: 1987

NATIONALITY: Swedish

ACADEMIC DEGREE: MD

YEAR OF PHD THESIS: 2015

RESEARCH EXPERTISE AREA: Neuroradiology, MRI

Background:

Tobias Granberg was born in Umeå in the Northern parts of Sweden and grew up in Västerås, about 100 km West of Stockholm. He attended medical school at Karolinska Institutet and graduated in 2012, after which he fulfilled the compulsory clinical internship (Allmäntjänstgöring) in Västerås. He then did a residency in Radiology at Karolinska University Hospital and has since started a sub-specialization in Neuroradiology at the same hospital. He continues to work halftime clinically and is Head of R&D for Neuroradiology at Karolinska University Hospital in Huddinge.

Academically, he found an early research interest in MRI as a medical student, where a summer project focusing on detecting cerebral microbleeds in dementia disorders led him to the path towards a PhD in neuroimaging. His PhD was entitled “Neuroradiological aspects of Multiple Sclerosis: From early signs to late disease stages” which focused on defining the importance of incidental MS-like findings on MRI called Radiologically Isolated Syndrome as well as the role of the corpus callosum atrophy as a quantitative imaging biomarker. For his postdoc, he worked at Massachusetts General Hospital and Harvard Medical School with a continued focus on Multiple Sclerosis (MS). There he used advanced multi-modal imaging techniques such as 7 Tesla, Human Connectom Scanner and ¹¹C-PBR28 PET-MR. Since his return to Stockholm, he leads a neuroradiological research team focusing on neurodegenerative and neuroinflammatory disorders. He is also Co-founder and Chair of the MRI Committee of the Swedish MS Society.

Research interests:

Our research is focused on using neuroimaging such as CT, MRI and PET to improve our ability to diagnose, monitor and predict outcomes for neurodegenerative and -inflammatory disorders. Specifically, we have a special interest in ALS, dementia disorders, leukodystrophies, movement disorders and MS. These disorders share many similarities in terms of the histopathological processes that can be detected with neuroimaging. There is therefore fruitful translation of our findings between these patient groups.

Our research team is well-balanced in terms of demography and represents a broad range of both clinical and scientific expertise. We develop new image acquisition techniques (acceleration techniques, fingerprinting, synthetic MRI, myelin quantification, multi-shell diffusion imaging) as well as image post-processing and image feature extraction, ranging from visual ratings and volumetry to deep learning. After validation, these techniques are applied clinically and quickly translated into state-of-the-art clinical neuroimaging and clinical trials.

Statement:

“Time is brain. This well-known concept in stroke care also applies to MS. Neuroimaging plays a key role in making it possible to diagnose and initiate treatment early in MS, as well as monitor treatment and make it possible to design efficient clinical trials for new treatments. Our challenge is to increase the availability and reliability of imaging further by increasing its speed, making it quantitative and more biologically specific. By doing so, we can optimize treatment and open the door for the discovery of new generations of treatments.”