A new systems approach to combat arsenic induced carcinogenesis.

Sir,

As human exposure to arsenic through groundwater is getting widespread in parts of the Indian subcontinent, its long-term effects such as carcinogenesis need to be studied in detail. Systems biomedicine is a new approach that could be used to understand arsenic-induced carcinogenesis at multiple levels. For understanding interindividual variations in terms of individual risks and mechanisms of developing cancer, a heath informatics system may be developed as a proactive medical approach toward prevention and therapy.

Human exposure to toxic levels of arsenic through drinking water is a major public health issue in the Indian subcontinent, particularly in West Bengal in India and Bangladesh, and reports suggest that the problem is getting more serious. For instance, the recent identification of severe arsenic related health effects in the gold-bearing Mangalur greenstone belt of Karnataka, a state in south-west India, is of major concern[1] Scientists have studied arsenicosis and associated problems in their specific domains for decades. However, not much coordinated effort to address it as a unified systems level challenge has been made. Not surprisingly therefore, components of chronic arsenic exposure that have somewhat latent or longer-term consequences, such as carcinogenesis, have received relatively limited attention in translational research. In recent years, discovery of various mechanisms of arsenic-induced carcinogenesis has brought to light a rich and complex landscape of mechanisms that can lead to cancers of skin, lung, liver, kidney, bladder, colon and prostate (see recent review[2] and references therein).

In this new light, it may be useful to consider some of the emerging models of biomedical research that are capable of addressing issues of complexity and heterogeneity. One such approach, Systems Biomedicine, seeks to understand diseases as states that result from the perturbation of biological systems, often modeled as multi-level networks that can propagate effects from single molecules to entire mechanisms and specimens, caused by different pathological factors such as, in this case, an environmental carcinogen as an environmental carcinogen. Thus we can test the effects of lower level or early stage modulation of developmental and pathological processes in terms of outcomes that are measurable higher up or at later stage in the system. For instance, even prenatal arsenic exposure can influence regulation of major pathways such as oxidative stress and apoptosis.[3] In fact, an arsenic-specific tumor suppressorome could hold the key for epigenetic silencing in human cancers.[4]

High-throughput “omic” platforms such as global epigenomics and metabolomics can shed light on the systems biology of arsenic induced carcinogenesis. Studies of the unexplored epigenetic landscape can reveal stochastic spatio-temporal progressions to disease states through an individual's genomic instabilities, diet and co-carcinogenic interactions, intermediate metabolism, signaling transformations, etc., in the process. For instance, arsenic may allow survival selection of stem cells, thus creating an overabundance of cancer stem cells during in vitro malignant transformation,[5] a finding that could have serious implications for human oncogenesis.

Finally, the arsenic problem may be a major public health issue but the devastating cost borne by an affected individual and his/her family should not be lost upon us. Interindividual variability in human arsenic metabolism can not only yield distinct determinants of the disease but also have translational implications for individual patients.[6] Unlike traditional medicine that is reactive in nature, systems medicine seeks to be proactive in predicting and preventing a transition from healthy to disease states within an individual. Using digital disease monitoring and surveillance systems based on a knowledge-base of clinicopathological information on individual attributes, health informatic algorithms could be developed and deployed for rapid, cost-effective decision-making on applications ranging from prevention to therapy. For constructing a comprehensive database of clinically insightful variations using an integrated systems biological approach, multiple cohorts with different levels of exposure and socio-economic status may be studied, thus calling for international and interdisciplinary collaboration, possibly via a consortium model. Importantly, such an integrative and collective approach may serve as a template for tackling of other environmental challenges in the subcontinent as well.