MANUFACTURING
Mathematical Modelling of Gene Expression A toolbox for treatment design targeting modulation of gene networks dynamics Designing efficient therapies to modulate epigenetics is a major challenge of precision medicine. Cells are composed by a plethora of molecular species subjected to randomness and multiple time scales, while dynamically interacting with environment. Application of mathematical methods for control of processes helps on the development of personalised treatment strategies. Alexandre Ferreira Ramos, School of Arts, Sciences and Humanities University of São Paulo, São Paulo Guilherme Giovanini, School of Arts, Sciences and Humanities University of São Paulo, São Paulo
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espite all recent advances of molecular biology and imaging techniques, treatment designs based on pharmaceuticals still need enhancement to improve prognostics of patients while reducing the severity of side effects. The development of DNA sequencing techniques enabled an unprecedented increase of our understanding of genetic diseases such as cancer [1]. Cancer sub-types classification based on specific mutations, such as the mutation of Epidermal Growth Factor Receptor (EGFR) gene related to lung cancer, increased prognostic accuracy while providing the opportunity for early interventions. In some cases, that may even result in pre-disease surgical intervention as it may happen when mutations are detected in BRCA1 and BRCA2 genes as those may be key factors underpinning emergence of breast cancer. Because of
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ISSUE 44 46 - 2021 2022
its stationary character, however, knowledge of the genome of a patient is not sufficient to understand when or how a genetic disease manifests. The effects resulting from interaction with environmental factors and the dynamic character of expression of genetic information require the use of an additional conceptual framework. For that, experimentally validated mathematical models may play an important role. The post-genomic age is characterised by the necessity of knowing not only which genes are inside a cell but also when, where and how many products are synthesised from those genes. That propelled the field of epigenetics and opened a new avenue for designers of treatment strategies. As our understanding of epigenetics advances, treatment may be designed to exploit the coordinated dynamics of a plethora of
chemical components interacting inside the cell. A major goal of such an epigenetic engineering is to reprogram the cellular behaviour to increase chances of treatment success. That reprogramming is achieved by the proper manipulation of either gene networks or signalling pathways by means of genetic techniques that enable one to change the DNA or inputting chemicals that intervene on the amounts of products synthesized from a set of genes. In its simplest representation, a gene network is a set of genes and their products, namely proteins, also termed transcription factors (TF) because of their biological function. TFs bind to the regulatory regions of a gene and either stimulate or repress its expression. If the transcription factor from a gene A binds to the regulatory region of gene B to stimulate or repress its expression, we say that genes A and B interact. The reverse interaction may also happen. One may affect the dynamics of a gene network, EPIGENETICS is the discipline dedicated to the investigation of how the expression of a genome is governed by the multiple environmental inputs that affect the cell behaviour. GENE can be considered as a DNA sequence composed by the region encoding its protein and the regions to which regulatory components bind to modulate the amounts of products expressed from a gene.
