Professor Takats obtained his PhD from Eötvös Loránd University, Budapest, Hungary. He worked as a post-doctoral research associate at Purdue University, Indiana, USA. After returning to Hungary, he served as Director of the Cell Screen Research Centre and also as Head of Newborn Screening and Metabolic Diagnostic Laboratory at Semmelweis University, Budapest.
Professor Takats was awarded a Starting Grant by the European Research Council in 2008 and he subsequently became a Junior Research Group Leader at Justus Liebig University, Gießen, Germany. He moved to the United Kingdom in 2012 and is currently a Professor of Analytical Chemistry and Director of Mass Spectrometry Research within Division of Computational Systems and Medicine at Imperial College London.
Professor Takats has pursued pioneering research in mass spectrometry and he is one of the founders of the field of ‘Ambient Mass Spectrometry’. He is the primary inventor of six mass spectrometric ionisation techniques, including Desorption Electrospray Ionization and Rapid Evaporative Ionization Mass Spectrometry.
He was the recipient of the prestigious Mattauch-Herzog Award of the German Mass Spectrometry Society and the Hungarian Star Award for Outstanding Innovators. He is the founder of Prosolia Inc, Medimass Ltd and Massprom Ltd, all companies pursuing analytical and medical device development. Professor Takats has published over 100 peer-reviewed articles in the fields of analytical chemistry and translational medicine.
>> Tuesday 14:15 in Mozart 1-5
Inflammatory Stories in Time and Space: Using Mass Spectrometry Imaging, Ion Mobility and High Throughput Lipidomics to Understand Human Disease Jules Griffin Computational and Systems Medicine, Surgery and Cancer, Imperial College London, London and Department of Biochemistry, University of Cambridge, Cambridge, UK
Prof. Jules Griffin is the Professor of Biological Chemistry at Imperial College London. He received his D.Phil in Biochemistry from the University of Oxford in 1997. He then took up a Fellowship in Radiology and Cardiology at Harvard Medical School and Massachusetts General Hospital, Boston, USA. He returned to the UK in 1999 to take up a research associate with Prof. Jeremy Nicholson and then held a Royal Society University Research Fellowship. He moved to the University of Cambridge in 2003 and became the Professor of Metabolism and Nutrition in 2016. During this time, he held a group leader position at the Medical Research Council Human Nutrition Research unit. In 2019 he joined Imperial College London to head the section of Computational and Systems Medicine. He is the current President of the Metabolomics Society, an Agilent Thought Leader, a Fellow of King’s College Cambridge and a Fellow of the Royal Society of Chemistry.
A central aspect of the development of many of the pathologies associated with the metabolic syndrome is a chronic progression of inflammation in the affected tissues. This is in part driven by lipid remodelling in the cell membrane and the production of pro-inflammatory lipid mediators produced from polyunsaturated fatty acids such as arachidonic, docosahexaenoic and eicosapentaenoic acids. To explore lipid remodelling during the development of non-alcoholic fatty liver disease we have applied MALDI-based mass spectrometry imaging (MSI) to examine both human tissue and animal models of the disease progression. Using a combination of high fat feeding and genetic modification (the ob/ob mouse which lacks leptin) to cause hepatic steatosis with and without inflammation, MSI shows that one of the events associated with disease progression is a lipid remodelling of phosphatidylcholines (PCs), and in particular, a reduction in arachidonic acid containing PCs. We have also developed a ultra-high performance liquid chromatography ion mobility mass spectrometry-based method to profile known and novel lipid mediators, using a KNIME workflow to process the data and annotate the detected lipids, in part relying on collision cross-section values for these species to aid assignments. This will be illustrated in following the time course of lipid changes in thrombin activated human platelets.
>> Thursday 16:45 in Mozart 1-3
Donor-derived cell-free DNA as a biomarker in organ transplantation Michael Oellerich Institute for Clinical Pharmacology, University Medicine Göttingen, Germany
Michael Oellerich, MD, HonMD, FAACC, FAMM, FFPath (RCPI), FRCPath, is currently a Distinguished Research Professor at the Department of Clinical Pharmacology, University Medical Center (UMG), Goettingen, Germany. He was Chairman of the Department of Clinical Chemistry at UMG from 1991 to 2012, Dean of the Faculty of Medicine, and President of professional organizations (IATDMCT, DGLM, DGKL, WASPaLM). He currently is Associate Editor of the journal Therapeutic Drug Monitoring (TDM). He was Editor-in-Chief of the TDM journal (2003-2018), Associate Editor of Clinical Biochemistry (1996-2007) and Clinical Chemistry (2007-2013). His current research interests are in the field of cfDNA in cancer and transplantation. He authored more than 460 publications and received various awards (e.g. Ludolf-Krehl Award, IATDMCT Charles Pippenger Award, WASPaLM Medal of Honor, WASPaLM Gold-Headed Cane).
Molecular biomarkers have attracted special attention in solid organ transplantation because of unresolved problems that limit long-term outcome. There is a lack of reliable noninvasive markers. Immunosuppressive drug monitoring mainly indicates potential toxicity, but is a poor biomarker of graft damage. In kidney transplant patients, for example, an increase of plasma creatinine may be also be due to exsiccation, the use of ACE inhibitors, or immunosuppressive drug toxicity. By the time a rejection-related increase in plasma creatinine is evident, a significant degree of tissue damage has already occurred within the kidney. A further limitation of the current standard of care is that rejection episodes can only be confirmed by biopsies. Biomarkers are needed to achieve personalized immunosuppression to reduce premature graft loss. Against this background, a particularly promising new approach for the early detection of acute or chronic rejection or asymptomatic graft injury leading to irreversible damage is based on the determination of donor-derived circulating cell-free DNA (dd-cfDNA). Data on clinical validity have been documented in more than 48 independent studies which have shown that dd-cfDNA detects rejection episodes early, at an actionable stage, and is a more reliable marker of graft injury, compared to conventional tests. dd-cfDNA may also be useful to guide changes in immunosuppression, to monitor immunosuppression minimization (e.g. during tapering), and to prevent immune activation. The high negative predictive value of dd-cfDNA is the reason why this test can be helpful to avoid unnecessary biopsies. It could be shown that dd-cfDNA can be useful to detect subclinical (e.g. clinically unsuspected) graft damage as a result of immune activation triggered by under-immunosuppression. Early diagnosis of subclinical antibody-mediated rejection may improve outcomes after kidney transplantation. In summary, dd-cfDNA monitoring will allow more personalized treatment that shifts emphasis from reaction to prevention.
Imaging the unimaginable with imaging mass cytometry Frits Koning LUMC
Prof. Frits Koning is a staff member in the department of Immunohematology and Blood Transfusion (150 fte) of the Leiden University Medical Centre since 1993. He is the chairman of the scientific advisory board of the LUMC. He is well recognized for his contributions to the field of immune mediated disorders, celiac disease in particular. Through his work it is now well established which gluten fragments are disease causative and how they are recognized by disease-related T cells, providing a molecular basis for the genetic association between HLA-DQ and celiac disease. In his most recent work he uses high dimensional (imaging) mass cytometry to unravel the involvement of the innate and adaptive immune system in the mucosal immune system in health and disease.
The fetus is thought to be protected from exposure to foreign antigens, yet CD45RO+ T cells reside in the fetal intestine. Here we combined functional assays with mass cytometry, single-cell RNA sequencing and high-throughput T cell antigen receptor (TCR) sequencing to characterize the CD4+ T cell compartment in the human fetal intestine. We identified 22 CD4+ T cell clusters, including naive-like, regulatory-like and memory-like subpopulations, which were confirmed and further characterized at the transcriptional level. Memory-like CD4+ T cells had high expression of Ki-67, indicative of cell division, and CD5, a surrogate marker of TCR avidity, and produced the cytokines IFN-? and IL-2. Pathway analysis revealed a differentiation trajectory associated with cellular activation and proinflammatory effector functions, and TCR repertoire analysis indicated clonal expansions, distinct repertoire characteristics and interconnections between subpopulations of memory-like CD4+ T cells. Imaging mass cytometry indicated that memory-like CD4+ T cells colocalized with antigen-presenting cells. Collectively, these results provide evidence for the generation of memory-like CD4+ T cells in the human fetal intestine that is consistent with exposure to foreign antigens.
The development of targeted proteomic assays, attempting to take biomarkers from the research lab to the clinic Kevin Mills University of London
I am an Associate Professor at UCL, an Honorary Clinical Scientist at Great Ormond Street Hospital (GOSH) and Head of the Translational Mass Spectrometry Research Group at the UCL Institute of Child Health. My research group’s aim is to bring together state-of-the-art mass spectrometry with precision and stratified medicine, to find new drug targets, disease mechanisms, identify new biomarkers and develop new and more precise tests for the NHS.We mainly use the techniques of proteomic, metabolomic and lipidomics for hypothesis generating and biomarker discovery research, followed by validation and translation onto triple quadrupole mass spectrometry based platforms. My main research interest involves using these techniques to understand the disease mechanisms underlying neurological and rare inborn errors of metabolism. We work closely with our sister hospital at the UCL National Hospital of Neurology and Neuroscience, to use rare diseases as models of more common diseases and vice versa for e.g. Alzheimer’s disease and Niemann Pick Type C. Our group is composed of a mixture of clinical and non-clinical research fellows working side by side on basic as well as patient-driven, translational research which aims to establish rapid, sensitive methods to study, diagnose and monitor the treatment of patients from Great Ormond Street Hospital and the Queen’s Square National Hospital of Neurology and Neuroscience.
My talk will involve how my lab attempts to bridge the gap between finding a biomarker in a research lab to its validation and potential translation of that test into a clinical setting. I will give several examples of this consisting of finding biomarkers in plasma, urine and CSF followed by their translation into multiplexed tests. The diseases I will cover will include inborn errors of metabolism (Fabry Disease), hypertrophic cardiomyopathy and the neurodegenerative conditions of Alzheimer’s and Parkinson’s disease.
Rethinking sex steroids: Understanding the clinical relevance of 11-oxygenated androgens. Karl Storbeck Stellenbosch University
Karl Storbeck is an Associate Professor in Biochemistry at Stellenbosch University, South Africa and an honorary senior research fellow at the Institute of Metabolism and Systems Research at the University of Birmingham, UK. He was awarded his PhD in Biochemistry by Stellenbosch University in 2008 and was subsequently appointed to faculty in 2012. His research focusses on understanding the role of the overlooked adrenal 11-oxygenated androgens in health and disease. His group has shown that 11-ketotestosterone and 11-ketodihydrotestosterone are bone fide androgens and together with others has implicated 11-oxygenated androgens as important role players in disease states including castration resistant prostate cancer, polycystic ovary syndrome and congenital adrenal hyperplasia. He employs state-of-the-art mass spectrometry based assays including ultra-high performance supercritical fluid tandem mass spectrometry (UHPSFC-MS/MS) in his research and was awarded a Newton Advanced Fellowship by the Academy of Medical Sciences in the UK in 2016. This fellowship has allowed him to work with the team from the Steroid Metabolome Analysis Core at the University of Birmingham to develop new UHPSFC-MS/MS methods for application in the clinical laboratory.
The C19 steroid 11β-hydroxyandrostenedione (11OHA4) is a major product of adrenal steroidogenesis, but was ignored for decades due to an apparent lack of activity. However, recent studies have demonstrated that 11OHA4 is the precursor to the potent 11-oxygenated androgens, 11-ketotestosterone and 11-ketodihydrotestosterone, that bind and activate the human androgen receptor with affinities and potencies similar to that of testosterone and 5α-dihydrotestosterone (DHT), respectively. The significance of these findings becomes apparent when considering androgen dependent diseases such as castration resistant prostate cancer and endocrine conditions associated with androgen excess such as polycystic ovary syndrome and congenital adrenal hyperplasia. Recent findings pertaining to the importance of the overlooked 11-oxygenated androgens will be presented, highlighting the role of 11-oxygenated androgens in disease states and challenging the paradigm that testosterone and DHT are the only clinically relevant androgens.
From Spectrometric Data to Metabolic Networks: An Integrated Quantitative View of Cell Metabolism Oscar Yanes Rovira i Virgili University & IISPV
Oscar Yanes received his Ph.D. degree in Biochemistry (2006) from the Universitat Autonoma de Barcelona. In 2007 he became Research Associate in Gary Siuzdak’s lab at The Scripps Research Institute. Since 2011 he coordinates the Metabolomics Platform of the Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), he is affiliated member at the IRB Barcelona and assistant professor at the Universitat Rovira i Virgili where he also leads his own research group (www.yaneslab.com).He has long experience in developing new technologies and methods, computational tools and applications in LC-MS, GC-MS and NMR-based metabolomics. With >60 publications and >4.000 citations, his lab now focuses on understanding metabolic dysregulations in disease through integrating MS and NMR-based metabolomics with other omic platforms.
INTRODUCTION: Metabolite profiling – or metabolomics – presents a powerful global approach to measure shifts in metabolites as functional readouts of cellular state. Metabolites can complement upstream biochemical information obtained from genes, transcripts, and proteins and advance our understanding of how cells are altered in health and disease. Unfortunately, the great success in the characterization of genes, transcripts and proteins has currently no parallel in metabolites. Metabolomic studies are revealing large numbers of naturally occurring metabolites that cannot be characterized because their chemical structures and spectrometric data are not available. This is preventing metabolomics from evolving as fast as other omic sciences, and thus it is restricting the integration of multiple layers of omic data to gain more insights into the emergence of observed phenotypes.
OBJECTIVES: To fill this gap, new experimental approaches based on mass spectrometry (MS), and innovations in bioinformatics to enable a comprehensive analysis of cellular metabolites are needed.
RESULTS: Here I will present novel computational tools for: 1) identifying and quantifying metabolites from reconstructed GC-MS, LC-MS and MALDI-MS spectral profiles; 2) the structural characterisation of unknown metabolites; and 3) the use of isotopically labeled metabolites to study the flow of chemical moieties through the complex set of metabolic reactions that happen in the cell. Finally, I will show that the integrated analysis of proteomics and metabolomics data through metabolic networks provides a new conceptual structure for an alternative quantitative and predictive description of cell metabolism.