Johan Trygg: Chemometrics in Metabolomics, Systems biology and Process Analytical Technologies
- CHEMOMETRICS IN METABOLOMICS
High-resolution NMR and GC-MS spectroscopic techniques have been used in conjunction with multivariate statistics to characterize the metabolic profiles of biofluids with the aim of further understanding the mechanism of pathogenesis and uncovering potential biomarkers of disease progression.A chemometric approach in metabolomics consists of four steps: (1) definition of the aim, (2) selection of objects or samples, (3) sample preparation and characterization, and (4) evaluation of the collected data. Hence, chemometrics constitutes an integral part of the metabolomic technology by providing organized multivariate statistical approaches for modelling and interpreting changes in these metabolic profiles.
- SYSTEMS BIOLOGY IN PLANT BIOLOGY
Systems biology makes use of a multidisciplinary approach, integrating the fields of biology, mathematics, chemistry, physics, informatics, engineering and others to enhance understanding of biological processes. However the complexity of these systems requires further research to develop strategies and systems informatics tools. The aim of this project is to develop and apply a systems biology approach to study growth and development in Poplar trees (the tree model) and Arabidopsis (the universal plant model) - all this in collaboration with Umeå Plant Science Center and Computational Life Science Cluster at Umeå University. We are developing data driven tools and strategies on how to combine, model and predict biological information based on transgenic trees generated from multiple profiling platforms (e.g. NIR, FTIR-imaging, PyMS, metabolomics, enzymology and transcriptomics).
- PROCESS ANALYTICAL TECHNOLOGIES
Within PAT, the Food and Drug Administration (FDA) in the US has reconsidered its procedures for regulatory approval of new drugs. They recognize the need for design of experiments and multivariate techniques to find and evaluate critical parameters. As a result, this will ensure process stability and reduced batch variability and enable prediction of final product quality and safety.
PROJECT: Metabolomics in Rheumatoid Arthritis and other autoimmune diseases
RA is one of the major causes of disability today. The disease is characterized by pain in and swelling of the joints, mainly in the hands and feet, caused by an autoimmune attack on the synovial tissues. Recent years have seen a substantial development in the understanding of disease pathology that has led to significant improvements in the therapy of RA. Unfortunately, the same advances have not been made in the understanding of the development leading to disease, or diagnosis of RA. Existing methods measure a number of peptide compounds related to immune response such as the rheumatoid factor and antibodies against cyclic citrullinated peptides/proteins (ACPAs). From a diagnosis point of view, both are problematic and mainly suffer from low sensitivity (around 75 %). Our approach is based on metabolic profiling and multivariate statistics to find patterns of biomarkers that are highly discriminatory for the perturbation/disease state. An additional advantage of diagnosing patients using a metabolomics strategy is that it can reveal underlying biochemical phenomena associated with the disease, thus providing insights that help researchers to develop a better understanding of the investigated disease in order to :
- monitor the disease and its treatment in patients
- open up completely new possibilities for identifying subgroups of patients for clinical trials
- substantially contribute to the field of personalized medicine.
PROJECT: Metabolomics for diagnosis, therapeutic intervention and novel therapy of Type 1 diabetes (T1D)
Autoantibodies against the pancreatic islet autoantigens GAD65, IA-2, ZnT8 (Arg/Trp/Glu variants) and insulin are currently used to predict T1D and to randomize healthy subjects to T1D prevention trials. The persistent presence of one or several of these autoantibodies is islet autoimmunity, a non-symptomatic forewarning to T1D. However, it is not yet possible to predict when islet autoimmunity appears and why, nor is it possible to predict the conversion from islet autoantibody positivity to T1D. The main goals are therefore to use the metabolomics approach, combined with advanced statistical modeling to identify metabolic biomarkers that predict either the appearance of islet autoantibodies or of T1D in islet autoantibody-positive subjects. The information of specific metabolites that predict either islet autoimmunity or conversion to T1D will be used to identify novel drug targets to prevent the development of islet autoantibodies or T1D.
PROJECT: Ultrasound imaging for functional analysis and dynamics of skeleton muscles
A widespread and fundamental assumption is that muscle function is related to a wide variety of conditions, e.g. pain, ischemic and neurological disorder, exercise and injury. Ultrasound imaging constitute different intensity patterns that relates to the density structure of the tissue and is today capable of high resolution images with high frame rate. Unfortunately, still no method exists that can closely study the dynamics of the skeleton muscle during activity. Hence, our aim is to develop tools to detect, visualise and quantify skeleton muscle dynamics and function based on ultrasound imaging and multivariate image analysis
in sports medicine, neurological disorders and medical rehabilitation and implement results into public and validated software. These tools are currently missing in both the clinic as well as in academic research. In order to succeed, robust, user friendly data modeling methods are required that are available and interpretable for clinicians lacking a statistical background. The strategic significance is very high as it can be applied to
• muscle rehabilitation programmes, including sports medicine
• neurological disorders (e.g. whiplash and fibromyalgi)
• pain related conditions (e.g. back pain)
PROJECT: KIDNEY TRANSPLANT MONITORING OF RENAL FUNCTION
Histological examination of a renal biopsy specimen remains the golden standard in differentiating allograft rejection (kidney tranplant rejection) from CyA nephrotoxicity. CyA nephrotoxicity is inevitable when CyA levels exceed 1000ng/L but can and does occur based on individual sensitivity or additional renal damage. Histologically, CyA nephrotoxicity is characterised by a tubular toxicity that produces region specific abnormalities such as inclusion bodies (giant mitochondria) in cortical tubular epithelial cells of the convoluted part of the proximal tubule, or isometric vacuolization and microcalcification in the thick descending limb of the loop of Henle. In this project, a metabolomics approach is used to provide a means to monitor graft failure at an early stage so as to optimise post-transplantation therapy and maximise the chances of transplantation success. One of the outcomes is the identification of novel urinary markers of graft dysfunction and be able to monitor the dynamic (real-time) biochemical changes following transplantation (this is not possible histopathologically).
PROJECT: FUNCTIONAL FOODS
Nutrition-associated chronic diseases, such as the metabolic syndrome, have increased at an alarming rate in affluent nations over the last decades. Several epidemiology studies supports that even moderate overweight significantly elevates the risk of contracting cardiovascular disease (CVD). Apart from non-regulated foodstuffs, a number of products with specific health claims have been placed on the international market, over the last decade. They are commonly referred to as Functional Foods. In consultation with the NFA and the National Board for Consumer Policies, the Swedish food industry has prepared a program of action where claims of health claim between foodstuffs and health must consist of two parts: details on an established diet-health relationship entailed to product compositional information and a scientific documentation of product-specific physiological health claims. Traditionally, health effects of specific diets are assessed by epidemiology, whereas clinical trial studies are most important for the understanding of impacts resulting from pharmacological intervention.
The objective with this project is to develop a holistic response method using metabolomics including NMR and MS spectroscopy to detect and understand the chemical, biological and physiological effect of different foodstuffs.