Project 5: Systems Biology
Leveraging systems biology to reveal biomarkers and cellular responses to carcinogens. This project will lead to novel strategies for disease mitigation and treatment.
PROJECT LEADERS: DOUG LAUFFENBURGER, FOREST WHITE
Polycyclic aromatic hydrocarbons (PAHs) and N-nitrosodimethylamine (NDMA) are common environmental pollutants that are known to be carcinogenic and are found in high quantities at Superfund sites, including two in the Mystic River Watershed as well as the former Loring Air Force Base in Maine. Potential adverse health effects of these compounds are concerning to the people in these communities, as NDMA has been detected in well water in Wilmington MA, and the Maine Department of Human Services established a fish advisory stating that weekly consumption of fish from water contaminated by the Loring Air Force Base will lead to an increased risk of cancer.
Unfortunately, beyond genotoxicity, the mechanisms underlying potential adverse health effects associated with either acute exposure or chronic, low-dose exposures to these compounds are poorly characterized; yet it is known that PAHs, for instance, have widespread effects on a variety of different cell types and tissues.
To determine the systemic, molecular network and cellular effects of exposure to these compounds, the researchers are utilizing a systems toxicology approach, comprising cutting-edge mass spectrometry for protein phosphorylation profiling, next-generation sequencing for transcript expression profiling, and computational modeling to integrate molecular network data with cell phenotypic data. In collaboration with other projects and as part of the MIT SRP Center, the research team is assessing the effects of acute and chronic exposure on the lungs and liver of infant and juvenile mice, connecting molecular network effects with DNA mutation signatures and downstream biological effects under different models of genetic susceptibility. As other projects define the concentrations and compositions of NDMA and PAHs at Superfund sites, the researchers in Project 5 are performing in vitro and in vivo studies to assess the combined effects arising from real-world mixtures, assessing the additivity and synergy of these mixtures compared to the individual compounds.
This innovative, integrative strategy provides new information regarding the health risks and mechanisms underlying exposure to the chemical contaminants present at these sites. Moreover, integrating this information into a predictive, quantitative computational model that couples exposure to network response and resulting phenotype enables definition of biomarkers of exposure, a potential starting point for testing human samples for exposure signatures. Further, the model will allow for defining network nodes that govern sensitivity to exposure and therefore potential therapeutic intervention points to abrogate adverse health responses.
Together, the results of this MIT SRP project not only help to define the health risks for communities at risk, but may also provide potential therapeutic strategies to minimize adverse outcomes from exposures at these sites. These deliverables have direct relevance to SRP stakeholders, including the Environmental Protection Agency and the Massachusetts Department of Public Health.
Quantitative DNA damage response (DDR) phosphorylation sites altered in response to exposure to NDMA. Altered phosphorylation within the network at early time points following exposure is predictive of oncogenic development months later. These sites, and others in the network, thus provide biomarkers of exposure and potential therapeutic intervention points.
Ishwar Kohale, a PhD student in the Biological Engineering program and in the Koch Institute for Integrative Cancer Research, has played a critical role in experimental design, data acquisition, and computational modeling in Project 5.