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Public Interest in Environmental Issues from Massachusetts to Missouri

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Recently I found myself staying in St. Louis, Missouri to attend a conference for researchers who focus on atmospheric science. The conference was located downtown near the river, which gave ample opportunity to check out the St. Louis Arch and the recently dedicated National Park that surrounds it. From here I was able to gaze upon the gushing waters of the Mississippi, watch the sun cast its light on the heartland of America, and listen to the symphony of cicadas that sounds so sweet to someone from the south like me. Needless to say, I was struck by such natural beauty residing in the middle of a bustling urban center. And, in my opinion, I think the residents of St. Louis were as well. I was never alone at the park, there were always crowds lounging on the open grassy spaces or running along the river paths.

Another observation I made about St. Louis was that the people seemed very interested in the research conference I was attending. The mayor had made a formal declaration dedicating the week to the conference, businesses hung signs in their windows welcoming members of the conference, and locals stopped to ask us about our work. This was unusual because, to be frank, my research doesn’t have much crowd appeal. I focus on aerosol particles, which are small pieces of liquid or solid materials suspended in our atmosphere. They are too small to see, but they have huge impacts on our health and climate. These particles are important for the work of the MIT Superfund Research Program (SRP) because harmful chemicals are sometimes found within aerosol particles, affecting the transport and exposure of those chemicals (see this post by fellow MIT SRP researcher Dr. Hélène Angot for more details). The conference was dedicated to aerosol research (literally, called the International Aerosol Conference), so I expected to be talking about it with colleagues. However, when I ended up talking with a local man named Antoine about them, I was rather surprised. He had heard that the conference was about air pollution, and wanted to know which area we studied. We ended up talking about the chemistry that happens in our atmosphere and how that relates to our health. After saying goodbye, I was left wondering, what makes everyone so curious?

Now that I’m back in Boston, I could sing equally elegant praises about the outdoor features of our city. The Charles River and surrounding esplanade constantly draws us out of hectic urban life into the beauty of nature. And here too, in Boston, there is what I consider to be an increased level of interest in environmental issues. I’ve seen this mainly through the MIT SRP’s partnerships with community organizations like the Friends of the Malden River (FoMR) and the Mystic River Watershed Association (MyRWA). These organizations aren’t groups of professionals getting paid for their work, they’re simply residents; teachers, business people, retirees, who want to do what they can for their environment. They organize clean ups for their respective water features, host events to engage the public, and invite speakers to come and increase their understanding of the environment. After seeing all this during my first year of grad school, I am again left wondering, what makes these people care?

Among other reasons, I would propose that maybe having access to natural elements within the city keeps the citizens of St. Louis and Boston in touch with their environment and more concerned about it. Taking this to be true, our work as part of the SRP becomes that much more important. The SRP stems from national efforts to clean up Superfund sites, which are areas of heavy chemical contamination throughout the US. If our research can help remediate these areas and make them safe for public use, then maybe local citizens will have more access to their environment, take a greater interest in the safety of the environment, and take steps to prevent future environmental calamities like Superfund sites. This process may take years to complete, but it certainly motivates my work with the MIT SRP today.

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Transport and Transformation of Chemicals in the Atmosphere

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Have you ever wondered how we can trace the fate of toxic pollutants in the atmosphere and forecast air pollution in a given region? If so, this blog post is for you! We are going to focus on polycyclic aromatic hydrocarbons (PAHs), one of the MIT Superfund Research Program’s chemicals of interest, but keep in mind that the principles discussed here can be applied to other pollutants.

Let’s start with a review of PAHs. What are these compounds, where do they come from, and why are they of concern to public health? PAHs are hydrocarbons (i.e., they only contain carbon and hydrogen atoms) that are composed of fused “aromatic” carbon rings (aromatic is a chemical designation here that describes the ring structure, not a reference to smell). For example, naphthalene has two fused rings, pyrene has four, and benzo[a]pyrene has five. (More info regarding their structure can be found here.)

They are primarily emitted to the atmosphere by combustion of carbon-containing fuels, and can come from industrial, commercial, vehicular, and residential sources, as well as natural sources, like forest fires and volcanoes. Industrial processes produce most atmospheric PAH emissions, but individuals can also directly expose themselves to PAHs from sources like wood stoves, cigarettes, or grilled food. These compounds are potent carcinogens, and the U.S. Environmental Protection Agency (EPA) has established a list of 16 priority PAHs.

So, PAHs are emitted to the atmosphere. Then what? Now is a good time to describe their atmospheric life cycle. PAHs entering the atmosphere can be transported over very long distances (as far as pole-to-pole!) before deposition (through rain, for instance) to environmental surfaces (e.g., soils, vegetation, waters). Upon deposition, they can return to vapor form and re-enter the atmosphere, a process called “re-emission”. PAHs can also react with other atmospheric pollutants (such as ozone, nitrogen oxides, and sulfur dioxides) to form so-called degradation products, which can be even more toxic than the original chemicals. How far a given PAH can travel and how quickly it deposits or is re-emitted depends, among other things, on its volatility (i.e., it tendency to evaporate at ambient temperature). In general, low-weight PAHs (2, 3, or 4 rings) are more volatile and exist mainly in the gas phase, while heavier PAHs occur mainly in the particulate phase (i.e., they adhere to the surface of atmospheric particles) and are deposited more readily. However, the tendency of a given PAH to be in the gas or in the particle phase also depends on temperature: as temperature increases, it is more likely to be found in the gas phase.

As you can see, the atmospheric life cycle of PAHs is rather complex. Now the more pressing question: how can we tell if the atmospheric concentration of PAHs in a given area is of concern? The easiest way to answer that question is to use a sensor to analyze the local concentration, which gives a measurement for a certain place at a certain time. However, concentration is expected to vary with time of year and location, and collecting readings from sensors requires time (and therefore money). As we increase the temporal and spatial resolution of measurements, this approach quickly becomes too expensive. The other (and complementary!) option is to use a chemical transport model.

A chemical transport model is a numerical model used to simulate the fate of compounds in the atmosphere. Using mathematical equations, the model represents the entire cycle for the chemical species of interest, such as transport, production/loss, and deposition. The model is driven by meteorology (e.g., wind speed and direction) to simulate transport. We also rely on emissions inventories, databases that list the amount of PAHs emitted each month or year from each country and sector of activity. The atmosphere is divided into grid boxes, which are like 3D latitude, longitude, altitude boxes that define portions of the atmosphere. The atmospheric concentration of PAHs in a given box depends on the magnitude of local and foreign emissions, the relative importance of deposition and re-emissions, and the local composition of the atmosphere that degrades PAHs. 

If we increase the number of grid boxes for a given area, the size of each box becomes smaller, and the model better represents smaller-scale features (i.e., the horizontal resolution of the model improves). However, it also takes more time to calculate the model results. A compromise between resolution and computation time has to be made! The example below shows three typical horizontal resolutions that can be achieved with one of the most widely used chemical transport models, GEOS-Chem (4×5°, 2×2.5°, and 0.5×0.667°, for the atmospheric scientists out there). In these three simulations, the 48 contiguous states of the U.S. are represented by approximately 70, 290, or 4,325 boxes, respectively, and you can see that fine-scale details become clearer with increased resolution.

Here at the MIT SRP Center, Project 2 is investigating the fate of the EPA’s 16 priority PAHs and their degradation products. Using the chemical transport model GEOS-Chem, we can predict the presence and relative abundance of the various compounds over regions of interest and identify priority species for further exposure studies (such as the biological consequences that will be determined in Projects 3 and 5). Knowing when and where specific chemicals are found allows scientists, environmental groups, and the government to prioritize research and cleanup efforts and helps inform new policies to address air pollution.

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DNA Repair and Cancer

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This month we’re going to discuss why some people are more likely to get cancer than others.

As you may recall from our previous post, Introduction to Mutations and Cancer, cancer generally arises from mutations in the genetic code. Mutations can happen randomly, even in healthy cells, but they become more likely if DNA has been damaged. To prevent DNA damage from causing mutations, every organism has evolved DNA repair mechanisms to fix damage and preserve the genetic sequence. Humans have at least six different DNA repair pathways (depending how you count), each of which is particularly suited to certain types of damage.

Here are (very) simplified descriptions of the major DNA repair pathways and the damage they fix:

  • Mismatch Repair (MMR) happens as DNA is being synthesized, such as during replication. If the incorrect nucleotide is incorporated (e.g., A gets added opposite C), the replication machinery backtracks, removes the newly created mismatch, and synthesis resumes.
  • Direct Reversal (DR) deals with small chemical additions, called adducts, on nucleotide bases. An enzyme or protein directly removes atoms that shouldn’t be on the base, restoring the original structure.
  • Base Excision Repair (BER) also deals with damage to single nucleotides. Rather than removing the lesion on the nucleotide, BER removes the entire base from the DNA strand, and then reads the complementary strand to fill in the gap. BER proteins can also repair breakage of the DNA backbone, provided only one side of the double helix is broken.
  • Nucleotide Excision Repair (NER) repairs damage that causes distortion to the DNA double helix. Very large adducts on nucleotides (e.g., benzo[a]pyrene adduct on guanine) and crosslinks between nucleotides cause the helix to contort. The cell identifies the lesion causing the bend, removes a whole segment of that strand (about 30 nucleotides) containing the distorting lesion, and then uses the complementary strand to fill in the gap.
  • Non-Homologous End Joining (NHEJ) repairs double strand breaks, where both backbones of the double helix are broken. NHEJ takes the two ends of DNA that were once connected and joins them directly back together.
  • Homologous Recombination (HR) also repairs double strand breaks, but only when the cell is preparing to divide. During cell division, when the entire genome has been duplicated for partitioning into the new daughter cells, thereare two identical copies of every chromosome, one for each daughter cell (these duplicate copies are called sister chromatids). A double strand break in one chromatid can be repaired by using the identical sister chromatid to fill in any lost information.

Different types of cells encounter various types of DNA damage to varying degrees, so certain cells and tissues rely more on some DNA repair pathways than others. For example, UV light exposure can cause thymine bases to react and stick together, forming a crosslink that distorts the double helix. Therefore, skin cells rely heavily on NER, and defects in NER increase the likelihood of skin cancer.

In the case of N-nitrosodimethylamine (NDMA), one of MIT SRP’s chemicals of interest, exposure leads to the addition of a carbon and three hydrogens (a “methyl group,” for the chemists out there) to adenine and guanine, producing the structures shown. These little adducts can be disruptive enough to the nucleotide structure that they confuse the cell into incorporating the wrong base, or they block DNA replication altogether.

Importantly, all DNA repair activities are carried out by proteins. Since all proteins are coded in DNA, mutations sometimes occur in the genes that code for DNA repair proteins. If one DNA repair protein becomes mutated, it can cause problems for the entire repair pathway, reducing efficiency and increasing the opportunity for errors. Mutations in DNA repair genes are extremely common in cancer development, at least in part because they facilitate the accumulation of ever more mutations.

Mutations in DNA repair genes can be inherited or arise over time. Inherited deficiencies in DNA repair genes strongly predispose people to developing cancer early in life, since DNA is never properly protected and mutations accumulate more rapidly. For example, inherited mutations in some NER genes cause a 2,000-fold increase in skin cancer susceptibility, and people with these deficiencies must be shielded from all sunlight. Similarly, inherited defects in some HR genes result in vastly increased risk of breast cancer, prompting many women with these mutations to get preventative mastectomies to reduce their cancer risk. There are also nuanced differences in DNA repair capacity among all individuals, as some variants of DNA repair proteins have slightly increased or decreased activity, producing less severe health outcomes.

Aging also facilitates the progressive accumulation of mutations, because every cell division presents the opportunity for new mutations to arise. Taking the skin example, UV-induced DNA damage from sunburns may cause mutations in those skin cells, some of which could occur in NER genes. As we age, those cells continually divide to maintain healthy functional skin, but division of mutant cells leads to entire mutant populations over time. Repeated sunburns compound that effect, both by proliferation of mutant cells and by induction of new mutations. The same logic applies to all dividing cells, which is why aging increases risk for most types of cancer.

Here at the MIT SRP Center, Project 4 is examining how genes involved in repairing NDMA-induced DNA damage impact susceptibility to cancer. Both Direct Reversal and Base Excision Repair are active in fixing NDMA-induced lesions, so the activity of each pathway is likely to impact a person’s susceptibility to NDMA-induced mutations and cancer. To gain some insight about genetic susceptibility, we have animals with “normal” DNA repair activity, animals lacking a major DR protein, animals lacking a major BER protein, and animals with increased BER activity. This will allow us to determine the relative importance of each repair pathway, and also provide insight regarding individuals’ cancer risk based on genetics.

Overall, cancer risk depends on a lot of factors, including the type, timing, and amount of DNA damage (i.e., history of exposure); inherited efficiencies of DNA repair pathways (i.e., genetics); and the random mutations you accumulate over your lifetime (i.e., luck). Since cancer is a product of each of these factors, and you can’t do much about your genetics or luck, I recommend avoiding DNA damage when possible!

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Introduction to Mutations and Cancer

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We have quite a variety of scientists and research projects in our program, so over time you’ll have the chance to hear many different perspectives in this blog. Since I have the privilege of writing the first few posts, I’m going to begin with my specialty, the development of cancer. I want to start this conversation with the basics: where does cancer come from?

This is a HUGE question with lots of facets, more than I can address in one post, so let’s take it one step at a time.

Cancer arises from normal cells misbehaving (proliferating when they’re not supposed to, migrating where they’re not supposed to, surviving when they’re not supposed to, etc.). Such misbehavior can be caused by alterations to the genetic instruction manual that provides the basis of all cellular activity. In fact, many of us in the field consider cancer to be a disease of the genome.

The instructions for all cellular behavior are coded in DNA, comprised of the nucleotide bases adenine (A), thymine (T), cytosine (C), and guanine (G) strung together into long strands (called chromosomes) that get bundled into the cell nucleus. DNA is comprised of two complementary strands that twist around each other, known as a double helix, where A should always pair with T and C should always pair with G (thanks to hydrogen bonding patterns, which is more chemistry than I’m going to get into today). Having the information coded in two complementary strands is sort of like having a backup copy; if there’s a problem on one side of the helix, the other side can be used as a template to correct the issue.

Cells read the sequences of nucleotides in their DNA as instructions for assembling the proteins that perform cellular functions (generally, each DNA sequence that encodes a protein is called a gene). Every cell has a complete copy of the genetic code, but different cell types use different sets of genes to accomplish their particular roles. Broadly speaking, if a gene’s sequence is altered (called a mutation), then the protein may be assembled incorrectly, and that particular function of the cell won’t be executed properly.

As cells divide, they copy their DNA so that the daughter cells are genetically identical. The cell copies both complementary strands, always pairing A with T and C with G to create two identical chromosomes, one for each daughter cell.  Every cell division requires accurate replication of the entire genome, but replication provides opportunities for genetic information to be copied incorrectly (imagine trying to transcribe an entire book without missing a single letter). Once a cell acquires a mutation, every time it divides from then on, all of the daughter cells will contain that mutation as well. As those mutant cells divide, cells within the lineage have more opportunities to acquire new mutations, allowing the accumulation of errors in the genetic code.

Cancer arises when cells accumulate multiple mutations that enable escape from normal behavior. The most common carcinogenic mutations include inactivation of genes that keep behaviors in check (e.g., moderating cell division, regulating migration, inducing programmed death) or improper activation of genes that enable behaviors (e.g., enhancing proliferation, activating migration, resisting programmed death). Mutations enable cancer cells to evolve, continually altering their behavior to enhance growth, escape normal physiological confines, and resist cell death. (By the way, this accelerated evolution is what makes cancer so difficult to treat, since cancer cells are constantly altering themselves to resist chemotherapeutics, but that’s a story for another time.)

Mutations become more likely when the cell’s DNA has undergone damage, such as alterations to the nucleotide structure. If the nucleotide looks wrong, the cell will have difficulty interpreting it properly. (In our book analogy, if the top bar on a capital T is gone, you might incorrectly transcribe it as a lowercase l. Similarly, if the cell doesn’t recognize G as G due to a change in its structure, it won’t know to pair it with C.)

One prominent source of DNA damage is chemical exposures – indeed, many toxic chemicals are carcinogenic precisely because they damage DNA. MIT’s Superfund Research Program is centered around two such DNA-damaging classes of chemicals, N-nitrosamines (e.g., NDMA) and polycyclic aromatic hydrocarbons (PAHs). NDMA causes DNA damage by adding a single methyl group (-CH3) to nucleotides, which in itself can be enough to mask the identity of the base. One mutagenic product of NDMA exposure is O6–methylguanine, which changes guanine’s hydrogen bonding pattern and can confuse the cell into pairing it with T. Then, during replication, one of the strands ends up with A-T where a G-C should have gone.

PAHs create large adducts on DNA, and it’s easy to see how a giant lesion could obscure the identity of the nucleotide or block cellular machinery from copying the DNA altogether. Cells have evolved various mechanisms to fix different types of DNA damage, and we refer to these as DNA repair pathways. DNA repair is absolutely essential for every organism, and when there are deficiencies in DNA repair, mutations become a whole lot more common.

Two of our research projects are specifically aimed at studying the genetic impacts of exposures to NDMA and PAHs. Project 3 will determine the unique patterns of mutations that occur when animals are exposed to these chemicals, and Project 4 will study how the inability to repair DNA damage impacts cancer susceptibility.

In our next entry, we’ll dive into how DNA repair pathways help protect against mutations and discuss why some people are more likely to get cancer than others.

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Introduction to MIT’s Superfund Research Program

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Welcome to the MIT Superfund Blog!

We will be using this platform to share perspectives from our research team, whose work focuses on the impact of environmental exposures on health, in terms that are accessible to a broad audience. Our goal is to explain big picture concepts with minimal jargon and technicalities.

I am Jenny Kay, director of the MIT Superfund Research Program’s Research Translation Core. My job is to share the insights and progress of our research projects with anyone and everyone who might possibly be interested, including government agencies, community groups and individuals, other research institutions, and… well, you! This blog will be one of our lay-language outlets, where trainees and I will describe our research for non-scientists. Follow us on Twitter (@MIT_SRP) for updates, including blog posts, research news, and more perspectives on environmental health.

Let’s start off this blog series with an introduction to Superfund and MIT’s SRP Center.

In 1980, Congress passed the Comprehensive Environmental Response, Compensation, and Liability Act (CERCLA), which created the Superfund Cleanup Program to be run by the US Environmental Protection Agency (EPA). The mission of the EPA Superfund is to clean up sites that are heavily contaminated with hazardous substances, typically from inadequately contained industrial waste. There are currently over 1300 active Superfund sites in the country.

In 1987, the National Institute of Environmental Health Sciences (NIEHS) started the Superfund Research Program (SRP) to help inform Superfund Cleanup efforts. The NIEHS funds academic institutions to research Superfund contaminants in terms of environmental presence and transport (e.g., measuring chemicals in soil, air, and water and predicting routes of exposure to humans) as well as the biological consequences of exposures (e.g., cancer, neurological defects, birth-related complications). The NIEHS currently funds 23 multi-project research centers, comprising the collaborative efforts of 120 institutions.

In August 2017, a dedicated group of MIT professors received funding to begin a Superfund Research Program Center, led by Program Director Bevin Engelward and Co-Program Director John Essigmann.

We are studying two classes of carcinogenic chemical contaminants, N-nitrosamines (specifically N-nitrosodimethylamine, NDMA) and polycyclic aromatic hydrocarbons (PAHs), found at the Olin Chemical, IndustriPlex, Wells G&H, and Loring Air Force Base Superfund sites. Exposures to NDMA and PAHs can lead to cancer, because these chemicals react with DNA, creating lesions that lead to mutations.

We are proud to partner with several community groups who are concerned about potential exposures from these Superfund sites. The Friends of the Malden River (FoMR) and Mystic River Watershed Association (MyRWA) represent communities living near the Olin, IndustriPlex, and Wells G&H sites. We are also honored to partner with the Tribal Nations of Maine, some of whom live and rely on land and water near the former Loring USAFB.

Our Center integrates research from nine different laboratories, comprising five Research Projects:

Project 1: The labs of Professors Harry Hemond and Tim Swager are designing sensors to measure and models to predict the presence and movement of NDMA and PAHs in water.

Project 2: The labs of Professors Jesse Kroll, Noelle Selin, and Tim Swager are creating tools to measure and predict the atmospheric presence and movement of NDMA, PAHs, and their chemical breakdown products.

Project 3: Professor John Essigmann’s lab is determining the unique patterns of mutations caused by exposures to NDMA and PAHs.

Project 4: The labs of Professors Bevin Engelward and Leona Samson will examine how genetics impact one’s susceptibility to developing cancer after NDMA exposure.

Project 5: The labs of Professors Doug Lauffenburger and Forest White are analyzing the immediate cellular responses to NDMA and PAH exposures.

Together, Projects 1 and 2 will provide a clearer understanding of where and how people are exposed to NDMA and PAHs, and Projects 3 through 5 will examine the biological effects of exposures.

Since I have the privilege of starting this blog, my next post will be an introduction to cancer, my personal field of expertise.

Stay tuned, and thanks for reading!