Health and the Understanding of Metabolism, Aging and Nutrition
HUMAN is a EU-funded research project that started in October 2013 that aims to study the function of genetic risk variant associated to metabolic diseases with the use of mouse models with humanised liver and pancreas.
In the last decade, great research efforts have been devoted to identify the genetic basis of age related diseases, mostly by means of large genome-wide association studies (GWAS). About a thousand GWAS have reported associations of around 4,000 single nucleotide polymorphisms (SNPs) for more than 200 traits/diseases. Despite their highly significant association with the trait of interest, the functional role of these genetic variants is, in most cases, still not yet elucidated, thus frustrating their clinical and pharmaceutical potential application. It has been difficult to fill this gap of knowledge using invertebrate animal models, including nematodes and fruit flies. Indeed, despite being very useful to identify genes and pathways involved in basic biological mechanisms, their evolutionary distance from humans and highly different metabolism, together with the poor knowledge of their pathology, represent a major limitation to provide the functional validation of SNPs involved in human age-related diseases. Even within the vertebrates, the differences observed between mouse and human liver are frequently so disparate that data gained from experimentation with mice are not directly relevant to human liver metabolism, gene regulation or pathology. These considerations apply specifically to metabolic diseases, where, despite the identification of many risk gene variants, their pathogenic effect is still unclear. Over the last decade the prevalence of metabolic diseases has seen a dramatic surge owing to the great increase of life expectancy and cultural transitions in lifestyle and nutrition, with a predicted massive economic burden for the European health systems. To overcome these limitations, HUMAN will generate mouse models highly repopulated with human hepatocytes or carrying pancreatic β-cells from either primary cells (hepatocytes) or induced pluripotent stem cells (iPSCs). This innovative approach offers the unique possibility of studying the function of genetic risk variants associated to metabolic diseases in an integrated living system (the mouse body), but in human-derived organs, i.e. liver and pancreas. A specific strength of the HUMAN project is that the iPSCs used to generate hepatocytes and β-cells derive from patients affected by severe metabolic diseases such as type 2 diabetes (T2D) with or without complications or subjects selected for nearly the complete opposite phenotype, for their nearly complete lack of disease and exceptional longevity (subjects over 105 years and offspring of nonagenarian sibships). HUMAN has selected the most relevant genes amongst those that emerged from GWAS and transcriptomic studies for their association with T2D and metabolic syndrome, and cross-referenced and “filtered” them against genes associated with longevity. This allows us to arrive at the allelic differences for the genes most likely to be associated with a risk for, or protection from, disease. Because of the consortium access to large numbers of individuals, we will select donors who are extensively characterised (clinically and metabolically) and will be fully genotyped for a number of gene variants. The donors will be selected according to the best combination of risk (e.g. T2D patients) or protective (105+ and 90+ sibships) alleles and iPSC will be created and differentiated to hepatocytes and pancreatic β-cells.
Mice with humanised liver and/or pancreatic β-cells will be generated, and the phenotype that results from the risk or protective alleles will be characterised. HUMAN will then develop the humanised mouse model using “extreme human phenotypes” in order to maximise the difference between cases and controls, thus consistently increasing the chance to validate the selected gene variants involved in metabolic diseases (see summary diagram on next page). This model will allow testing of the effect of different nutritional regimes (e.g. high fat diet, caloric restriction), to disentangle the complex circuitry across organs (e.g. the hypothalamus-liver axis) and the impact of endocrine regulations. Since complex diseases such as T2D and metabolic syndrome are not likely to be monogenetic or even completely dependent on the genes selected here, the creation of the risk and protective cell lines and mouse models will provide a platform technology for discovery of genes and metabolic pathways that cooperate with these known risk alleles to manifest the full spectrum of the disease.
The HUMAN consortium associates a core of outstanding basic research institutions to leading European biotech SMEs taking advantage of both academic and SME partners who have the ad hoc facilities. The main goal of HUMAN is to offer European research and industries exclusive tools to tackle the challenge of functional validation of metabolic disease-associated genetic variants by offering: i) innovative and robust humanised animal and cellular models; ii) a portfolio of new and validated therapeutic targets for better understanding of metabolic diseases and healthy aging. HUMAN will generate iPSCs biobanks and comprehensively manage all associated information, including clinical and metabolic profiles of the donors, the phenotypes of iPSCs and of the different humanised mice, using state of the art technologies (proteomics, metabolomics, epigenomics, transcriptomics, glycomics). In sum, the HUMAN consortium is uniquely situated to drive innovation towards a better knowledge of the genetic basis of major human metabolic diseases, thereby contributing to the understanding of healthier aging of European citizens.