Research ThemesA major goal of the CEHS is to bring the great strengths in basic science and engineering research at MIT to bear on problems in EHS and toxicology. How the CEHS merges the wide range of disciplines is well illustrated in the figure below that breaks down CEHS research into at least seven levels of enquiry virtually all of which are pursued in our five Research Themes (described below). CEHS members study exposures to environmental chemical, physical and biological agents at the following levels of scale and complexity: (1) the molecular level, including fate and transport of molecules through the environment, analytical chemistry, analytical, enzymatic and structural biochemistry of proteins, RNA, DNA, carbohydrates, lipids and other biomolecules; (2) environmentally relevant molecules are studied in the context of individual biochemical pathways and their components, interacting pathways and global regulatory networks, leading the CEHS during the last funding period into the realms of systems biology; (3) the pathways and interacting networks operate in the context of living cells that make up tissues, and the sub-cellular architecture of cells plus the three dimensional architecture of tissues are both very much in focus for many CEHS researchers; (4) molecules, cells and tissues are assembled into organs that are the focus of understanding the pathophysiology of environmentally induced disease, and this includes diseases that affect the brain, colon, stomach, gut, liver, pancreas, lungs, skin, eyes etc., plus quasi-organs like blood and bone marrow; (5) environmental exposures can lead to organ failures that affect the health of the whole organism and these failures manifest in a myriad of different ways, including cancer, heart disease, neurological disease, metabolic disease, premature aging, etc.; endpoints such as these are studied using mouse models exposed to environmental agents, and environmentally induced human disease is studied through epidemiological studies at the population level; (6) each individual experiences a unique set of lifetime exposures according to lifestyle, occupational and other factors, and in addition each individual has a unique armory of gene products to deal with those exposures; CEHS researchers are engaged in studying gene-environment interactions in human populations and understanding inter-individual differences responses to environmental agents; (7) finally, CEHS members study various aspects of environmental exposures around the world in collaboration with EH scientists and engineers in Thailand, Vietnam, Bangladesh, and Singapore, and are planning collaborative research in India and possibly China.
The Center’s research can be sorted into five Research Themes, namely: DNA Damage, DNA Repair and Mutagenesis; Inflammation Chemistry and Biology; Microbes and Disease Susceptibility; Bioengineering for Toxicology; and Exposure and Responses. In the table below, the engagement of CEHS members with each research theme is shown and it is obvious from this table that many of our members are engaged with more than one Research Theme.
DNA Damage, DNA Repair and Mutagenesis: The CEHS has had a very long and history studying the chemistry of environmental DNA damaging agents, the DNA damages they induce, the discovery of DNA repair pathways, elucidation of mutagenic and cytotoxic mechanisms and how these contribute to the induction of cancer and other diseases. A classic exemplar of such CEHS research was the identification of the chemical Aflatoxin B1 as the mutagenic toxin produced by Aspergillus flavus growing on peanuts, identification of the Aflatoxin B1-induced DNA adduct at the N7 position of guanine, demonstration that it leads to G:C to T:A mutations in p53 and other genes elevating risk of liver cancer in Chinese and other populations consuming contaminated peanuts. Collectively this research reached from the Angstrom level of chemical and molecular structures to the global level of human populations. This paradigm shifting series of studies involved Gerald Wogan, John Essigmann (both current CEHS members) plus John Groopman and Thomas Kensler (both members of the John Hopkins Center for Urban Environmental Health) who are currently collaborating with a number of MIT CEHS members.
Inflammation Chemistry and Biology: It has been estimated that a large fraction of the global cancer burden occurs in individuals suffering chronic inflammatory responses, and chronic inflammation has become accepted as an important contributor to the etiology of many different tumor types. An estimated 18% of the global cancer burden can be attributed to infectious agents, most of which activate the innate immune response in the host. Hepatitis B and C viruses that predispose to liver cancer and Helicobacter pylori that predisposes to gastric cancer, each elicit chronic inflammation and together these agents account for 10% of the global cancer burden. These numbers underestimate the fraction of cancers with inflammation as a component in their etiology, as inflammation-related cancer is not always linked to infectious agents. Idiopathic inflammatory bowel diseases like ulcerative colitis (UC) and Crohn’s disease predispose to colorectal cancer; asbestos related respiratory inflammation sensitizes to mesotheliomas and bronchiomas; and chronic acid reflux disease leads to Barrett’s esophagus, a metaplastic disorder associated with chronic inflammation and an enormous predisposition to esophageal cancer. Factors associated with inflammation can be linked to every stage of cancer development, and in recent years the CEHS has made many contributions to dissecting the role that the release of reactive oxygen and nitrogen species (RONS) by macrophages and neutrophils play in cancer etiology.
Microbes and Disease Susceptibility: Advances over the past decade have mandated a broader view of environment-health linkages, in which genomics and ecology play an increasingly prominent and important role. Future advances require better understanding of evolution, gene flow, and ecosystem processes. Gene flow, for example, can affect the distribution of pathogenicity, or the acquisition of antibiotic resistance or biodegradative capability in microbial communities. Ecosystem processes govern the nature of coexisting populations at scales from that of the gut flora to that of continents, with direct effects on humans at all scales. Examples of projects ongoing as part of this Research Theme include: population dynamics of pathogenic and non-pathogenic Vibrio species in natural waters, the ecology of the lower gut and how that influences cancer susceptibility, the ecology and evolution of microorganisms in nature.
Bioengineering for Toxicology: The studies in this Research Theme are aimed at developing new experimental tools and analytical methods spanning the molecular level to the systems level, for exploring biological responses to environmental exposures. The experimental tools include the following: tissue engineered physiological microreactors that bridge the gap between cell culture, animal models, and humans; developing genomic and proteomic approaches for systematic measurements; applying state-of-the-art mechanical engineering to devise new ways of monitoring biological events and single molecule biochemical events; multiphoton imaging methods that allow in situ quantification of events such as single cell apoptosis and DNA recombination; mathematical modeling at the systems biology level of cellular events such as apoptosis; analytical methods using statistical (Bayesian) and deterministic models of signal transduction networks and computational models of protein interactions in the context of different cell compartments. Given the nature of these studies, major progress has so far been made at the molecular, pathways and networks, and cellular and tissue levels.
Exposure and Response: This research theme is deliberately broad to capture the many science and engineering research projects that do not neatly fit into the other four Research Themes, but which are important to the Center because they do perfectly fit into our overall mission, namely to study the biological effects of, and processes of exposure to, chemical, physical and biological environmental agents with the goals of understanding and predicting how such exposures affect human health.