Genomics
Realising the genome’s potential in the context of the living cell
A decade ago, with the completion of the Human Genome Project (HGP), scientists had the long-awaited sequence of the human genome in hand. Once decoded, this invaluable source of data was anticipated to reveal the pathology underlying a host of diseases and to fill the gaps in our knowledge of normal physiological processes, biochemical pathways and the complex regulatory networks that control cell, tissue and bodily functions.
By Dr Amr Abid W
hile it is true that this bounty of genetic sequence information holds the key to answering many of these questions and to countless future biological and medical discoveries, the past 10 years have clear- ly demonstrated that the link between the human genome sequence and how genes, genetic varia- tion and genetic control systems drive physiology and cell behaviour is not a simple one. It is, in fact, highly complex. That complexity has slowed the pace of discovery, delayed the emergence of the new drug targets and therapies anticipated relatively soon after completion of the HGP and tempered the initial wave of excitement. We have learned, however, that the genome sequence is only the tip of the iceberg and the starting point for the coming revolution in molec- ular medicine, the emergence of cell- and gene- based therapies and the realisation of truly precise treatment strategies. Leveraging the information obtained from the HGP requires understanding of what the genome sequence – and the variations and mutations discovered as the number of genomes sequenced continues to expand – mean in the appropriate biological and physiological context. That context is the living cell. Without correlating genotype to phenotype one cannot begin to understand how changes in nucleotide
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sequence, epigenetic modifications, structural alterations in chromatin and regulatory control mechanisms can affect cell behaviour, morpholo- gy and viability, and impact how a cell interacts with its surroundings.
The next critical phase of the broader ‘omic’ revolution that is driving drug discovery and development lies in developing a precise and com- plete picture of cell function – both normal and abnormal. Only then will it be possible to explore more fully the role of the genome, the epigenome, the metabolome and the other ‘omes’ that drive cell behaviour. The ultimate value of all of this information will only be attained through its inte- gration and interpretation in the context of human cells. By studying and developing accurate models of human liver cells, for example, grown and maintained in surroundings that approximate their natural environments, it becomes possible to screen drug candidates in preclinical testing and achieve truly predictive toxicology. Studying and modelling neurons will enable mapping of neural networks to pinpoint the etiology of neurodegen- erative diseases and identify new drug targets to intervene earlier in disease processes. The develop- ment of cardiomyocytes that can be propagated in large-scale cell culture will foster advances in regenerative therapies and improved cell-based
Drug Discovery World Spring 2013
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