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Epidemiological Study links NDMA to Cancer

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Wilmington Massachusetts is a leafy suburb just north of Boston. With classic New England homes and maple trees it provides an idyllic setting for family life. Nevertheless, in the 1990s, mothers started noticing that many of their children had cancer. When a proper study was done, it was discovered that 24 children out of a town of approximately 18,000 had cancer, which is six times higher than the national average. People living in Wilmington wanted to know what had caused so many cases of childhood cancer in their town, and they turned their attention to their drinking water. Knowing that the Olin chemical company had operated in Wilmington for many years, and that the site was used for many other chemical companies prior to Olin, town members wondered if it was possible that chemical waste had made its way from the Olin site to their drinking water wells.

5Olin Site Outline 300x300When town members went to local officials to express their concern about the safety of their drinking water, their concerns were largely dismissed, and they were told that their water was safe. However, local residents did not give up. Remarkably, residents combed through historic documents trying to figure out if dangerous chemicals could have made their way into their water. They learned that in fact, chemical waste had been dumped into unlined pools and lagoons adjacent to the factory raising the possibility that millions of gallons of waste may have seeped into the earth. With no formal training in chemistry, Debbie Duggan and Suzanne Sullivan started wondering if N-nitrosodimethylamine (NDMA) was in their water. They were worried about NDMA because it was well-established that NDMA is a potent carcinogen in animal models. They insisted that the town well water be tested for the presence of NDMA. When testing was finally done, it was discovered that indeed, NDMA was in the town well water that had been drunk by thousands of people for many years.

Although officials did not necessarily agree that NDMA had been a health problem, the wells were nevertheless closed in 2003. Soon thereafter, concerned about contaminated municipal water, the EPA designated the Olin site as a Superfund site. However, people living in Wilmington wanted more research. They wanted a public health study to be done to determine if NDMA was linked to cancer in their children. The study took quite some time.

Meanwhile, there was a serendipitous event. At a committee meeting at MIT, J. E. From Wilmington mass met John Essigmann, a well-recognized Prof. of toxicology and chemistry. She explained to Prof. Essigmann that people living in Wilmington were worried that a Superfund site was responsible for a childhood cancer cluster. When she said that the primary concern was NDMA, Prof. Essigmann was stunned. NDMA is a chemical that is closely related to other chemicals that he had been studying for more than 20 years. Furthermore, there were nearly half a dozen other faculty at MIT who also were studying chemicals related to NDMA. This gave Prof. Essigmann the idea that perhaps a team could be assembled to address the needs of the community and so he recruited fellow faculty and other leaders to put forth the concept of a new Superfund research program at MIT. At a meeting with William Suk and Michelle Heacock (Director and member of the NIEHS Superfund research program leadership team, respectively), the MIT team was encouraged to apply for a Superfund grant. In 2017, the MIT Superfund research program was created with Prof. Bevin Engelward and Prof. John Essigmann as the director, and codirector of the program. Later, Noelle Selin agreed to contribute as a codirector.

5NDMA 300x200The focus of the MIT Superfund research program is on alkylating agents. These are chemicals that create adducts on DNA, disrupting its structure and thus promoting mutagenesis and toxicity. In particular, the MIT team studies NDMA and polycyclic aromatic hydrocarbons (PAHs). In terms of NDMA, the team has made progress in creating sensors. Dr. Maggie He, member of the swagger lab, created a carbon nanotube sensor for NDMA in air. More recently, Jessica Beard from the Swagger lab has been developing a sensor for NDMA in water. In parallel, biologists applied their skills to study the mutagenic and carcinogenic effects of NDMA, with an emphasis on gene environment interactions that might modulate susceptibility. Jennifer Kay, Joshua Corrigan, and Amanda Armijo (from the Engelward and Essigmann laboratories) made the discovery that a particular DNA repair enzyme has a profound effect on the biological consequences of NDMA. (See https://www.cell.com/cell-reports/fulltext/S2211-1247(21)00178-9) When too low, animals suffer from DNA damage induced mutations in cancer, and when too high, animals suffer from DNA damage induced toxicity. This remarkable discovery paves the way for human studies, wherein the role of this repair enzyme can be studied in terms of its relationship to vulnerability to NDMA exposure.

Meanwhile, the epidemiological study of NDMA performed by the Massachusetts Department of Public Health was finally released some 20 years since the time when NDMA was discovered to be in the town’s drinking water. Town members were both stunned and dismayed to learn that NDMA exposure in utero was associated with an increased risk of childhood cancer, though the presence of other chemicals in the drinking water may have contributed. At the same time, town members felt vindicated having struggled for decades for both cleanup and answers. And at MIT, researchers became even more highly motivated to solve problems related to NDMA exposure. In fact, the team hopes to expand its work not only on NDMA but on related N-nitrosamines that have also been found at Superfund sites. While significant funding is being lined up for cleanup, key decisions with regard to how much cleanup should be done are pending. The MIT team aims to learn more about the biology of NDMA and related N-nitrosamines so as to contribute to informed decisions about the extent to which cleanup should be performed. In addition, MIT biological engineers aim to develop biomarkers that predict the downstream health consequences of NDMA long before disease onset. This is particularly important given that exposure to NDMA takes years to show up as cancer. The MIT team has also recruited new members who have expertise in water remediation. By bringing together a cross disciplinary team the MIT SRP has the potential to make a significant impact on public health by helping to protect people from hazardous chemicals.

Tami Kalplan in the laboratory

Edgerton Award Citation for Desiree Plata

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“Doc Edgerton” was a remarkable innovator and leader, and he was dedicated to the successes of junior faculty. MIT has a special annual award in his memory for junior faculty who have an outstanding record in research, teaching and service. On April 21, it was announced that Desiree Plata is one of the winners of the Edgerton Award for 2021. This is one of the Institute’s highest honors and the granting of the award includes a citation that highlights the award winner’s accomplishments. Dr. Tami Kaplan organizes the Edgerton Award nomination process, and she writes the citation that is read at an Institute Faculty Meeting. Members of the committee in 2021 included Professor Bevin Engelward (Chair), Professor Alessandro Bonatti, Professor Amy Glasmeier, Professor Tim Swager, and Professor TL Taylor.

We thank Dr. Kaplan for her leadership. Her outstanding summary of Desiree Plata’s many contributions is recorded here.

“The Selection Committee is delighted to announce Desirée Plata, Gilbert W. Winslow (1937) Career Development Professor in Civil and Environmental Engineering, as a recipient of the 2020-2021 Harold E. Edgerton Faculty Achievement Award.

Professor Plata received a BS in chemistry from Union College and a PhD in chemical oceanography and environmental chemistry from the MIT and Woods Hole Oceanographic Institution Joint Program. After receiving her doctorate, Professor Plata held positions at Mount Holyoke College, Duke University, and Yale University. She joined the MIT faculty in 2018 as an Assistant Professor in the Department of Civil and Environmental Engineering, and was promoted to Associate Professor without Tenure in 2020. The senior faculty colleague who nominated her wrote: “She is one of the most remarkable individuals I have encountered in my years at MIT, and an exemplary member of our faculty.”

Professor Plata is motivated by the common good, especially with regard to keeping people safe from hazardous chemicals in the environment. She feels particularly strongly that we have a responsibility to serve underprivileged persons who are disproportionately impacted by hazardous chemicals.

In alignment with her passions, she is the global leader in proactive environmental engineering – the development of sustainable practices guided by fundamental science, industrial practicality, and concepts such as “green chemistry”. Her work is leading us away from the clean-up mode of environmental protection and toward smart and sustainable innovation that aims to prevent future negative impacts on the environment. In the area of hydraulic fracturing and unconventional drilling, she has provided perhaps the most complete and best-grounded study of potential water quality impacts from this technology and is publishing geospatially-referenced guidance for avoiding compromising chemical reactions. Professor Plata is also making important contributions to carbon nanotube manufacturing – not only with regard to the mitigation of waste product formation, but also to the enhanced growth of desired carbon nanotube products, and she was a driving force behind two patents related to carbon nanotubes from her doctoral time at MIT.

Recognition for Professor Plata’s work includes an NSF CAREER Award as well as being named a National Academy of Engineering Frontiers of Engineering Fellow and – twice! – a National Academy of Sciences Kavli Frontiers of Science Fellow.

Professor Plata is known as an enthusiastic and energetic teacher who presents material clearly and has a deep commitment to ensuring her students’ success. Her exemplary record as a research mentor is similarly impressive. In addition to her dedication to the professional development of her students, she serves as an inspirational model for them in personal development issues such as work-life balance. A former student commented that she “…leads by example and bestows confidence in those she mentors”. Her excellence in these areas has been recognized by the MIT School of Engineering’s Junior Bose Award for Excellence in Teaching and the Mount Holyoke College Student Government Association Mentoring Award.

Professor Plata’s leadership is also evident through her service. At MIT, she is the incoming Deputy Director of MIT’s Superfund Research Program and has helped in the development of educational materials for the Environmental Solutions Initiative. She is also highly proactive with regard to strengthening diversity and inclusion. Outside the Institute, she is a member of the Commonwealth of Massachusetts Decarbonization Academic Steering Committee, which has been commissioned to inform strategies for 80% emissions reductions by 2050. She is also an Associate Editor of the Royal Society of Chemistry journal Environmental Science: Processes and Impacts, and has served as session chair and organizer for several Gordon Research Conferences on Environmental Nanotechnology and one on Environmental Sciences: Water.

Continuing the legacy of Professor Harold E. Edgerton, this award honors achievement in research, teaching, and service by a non-tenured member of the faculty. The Selection Committee recognizes Professor Desirée Plata for her innovative approach to environmentally sustainable industrial practices; her inspirational teaching and mentoring; and her service to the Institute, the Commonwealth, and her professional community.”

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Chemistry Cleanup: Desirée Plata Devises New Methods for Decontaminating Air, Water

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FOR DESIRÉE PLATA PHD ’09, THE DECISION to become an environmental chemist was inspired not only by an interest in science but also by her personal experience with the health effects of environmental contamination. Growing up in Maine, Plata noticed a spike in disease among people in a neighboring town—including members of her family. Later she learned the illnesses were linked to water contamination caused by years of improper industrial waste disposal.

“It’s not just an abstract idea that something that we make in industry could someday cause an undesirable health impact. It’s a real manifestation that a lot of people around the country are living with,” Plata says.

“To me, having a clean environment is a basic freedom.” Now the Gilbert W. Winslow Career Development Associate Professor of Civil and Environmental Engineering at MIT, Plata—who describes herself as “famously broad” in her research—is using her knowledge of environmental chemistry to protect the environment and make industrial processes more sustainable.

One of Plata’s ongoing projects focuses on methane, a greenhouse gas up to 86 times more potent than CO2 that is having a major impact on climate. Plata and her team are building a system that uses catalysts to capture ambient methane from the atmosphere and convert it into CO2.

While creating more CO2 may seem counterproductive, the process is chemically simpler than alternatives (such as making methanol fuel) and has major environmental benefits, Plata explains. “If you could convert about half of the atmosphere’s methane into carbon dioxide, you could save about 16 percent of the near-term warming—and that buys us a little more time to respond and adapt to the changing climate,” Plata says.

Plata is also exploring groundwater contamination caused by hydraulic fracturing for natural gas extraction. To date, she and her team have collected nearly 500 groundwater samples that they are testing for toxic chemicals that evade traditional water treatment. They are also using sustainable nanomaterials to develop technologies that can purify water after it reaches homes.

“When thinking about sustainability, it’s always best to intervene early, but we have a lot of established technologies where there has already been some environmental damage or the infrastructure is too hard to move,” Plata says. “In those cases, you really need treatment technologies.”

Keeping pace with innovation

A broader focus of Plata’s lab is accelerating the pace of discovery in environmental chemistry by leveraging technologies such as robotics and machine learning. The aim, she says, is to build experimental systems that enable more efficient environmental assessment of chemicals. “Innovation will probably always outpace environmental assessment, so we can’t really do the assessment chemical by chemical,” Plata says. “We have to be faster and smarter.”

Plata first experienced MIT while pursuing her PhD in chemical oceanography in the MIT-Woods Hole Oceanographic Institution Joint Program in Oceanography/Applied Ocean Science and Engineering, where she worked on developing more sustainable carbon nanotubes. She later joined the faculty at MIT, driven by her desire to make the practice of innovation more sustainable.

“MIT is a really unique place in the world; there’s a lot of innovation going on,” she says.

Plata especially appreciates the Institute’s strong connection to industry, which she has experienced in many ways, including through MIT’s Industrial Liaison Program. In the program, Plata uses her expertise to work with companies on making their industrial processes more sustainable.

As part of Plata’s commitment to teaching innovators how to incorporate sustainability into their designs, she also mentors young engineers at MIT. “I want to make sure that students are armed with the right skills to not just invent great products and technologies, but to do it in a way that doesn’t cause environmental damage,” Plata says.

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Leona D. Samson, The Pioneer

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On April 22, 2021, Dr. Leona D. Samson was elected a member of the American Academy of Arts and Sciences. Dr. Samson is exceptionally deserving of this recognition. Her innovative research has truly been groundbreaking, with a consistent string of pioneering work that has not only moved her research field forward, but that has also opened doors to personalized medicine and a deeper understanding of cancer etiology. Her work has consistently focused on aspects of DNA damage and repair. With the knowledge that DNA damage has the potential to lead to mutations, and that accumulated mutations can drive cancer, she set out to discover genes that modulate susceptibility to DNA damage and to uncover their molecular mechanisms. Importantly, and somewhat ironically, DNA damaging agents are also used to treat cancer when they are delivered at a high concentration. As such, her work impacts both our understanding of the causes of cancer and our ability to effectively treat cancer. Here, a subset of her remarkable contributions are summarized.

Dr. Samson started her career working with Dr. John Cairns. As a graduate student, she was tasked with the goal of using E. coli as a way to mimic some aspects of somatic cell behavior. In particular, she set out to study accumulation of mutations in E. coli that were exposed to a DNA damaging agent under long-term low-dose conditions. The idea was that somatic stem cells can persist in the body and accumulate mutations, and that fundamental aspects of this process could be studied in E. coli. For these studies, they used a type of DNA damaging agent that adds methyl groups to the DNA (in other words, carbons are added where they do not belong). It was known at the time that methylated bases could be mutagenic (and toxic). Unexpectedly, Dr. Samson observed that E. coli were resistant to DNA damage-induced mutations. After struggling for many months thinking that something was wrong with the experiment, John Cairns and Dr. Samson had an “aha” moment when they came up with the idea that perhaps the cells were adapting during the long low-dose exposure. Indeed, when cells were exposed to a low dose of a DNA damaging agent prior to receiving a much higher dose, they became remarkably resistant to DNA damage-induced mutations and toxicity. This led to the discovery of several genes that play fundamental roles in sensing, responding to, and repairing DNA damage. Published in Nature, this remarkable discovery both uncovered an important biological process (adaptation) and paved the way for cloning and characterization of the genes responsible for adaptation.

One of Dr. Samson’s breakthrough ideas was that DNA repair could be functional across kingdoms. This is because DNA repair proteins recognize structural changes to DNA, and such changes are present in virtually all cell types. In other words, if a protein can recognize a particular methylated base, such as an adenine with an extra carbon on the N3 position (3-methyladenine), it doesn’t matter which cell type the protein is in. This paradigm-shifting idea led Dr. Samson to clone the first eukaryotic gene that repairs methylation damage. To do this study, her team fragmented DNA from yeast and subcloned it into an E. coli expression vector, thus creating a yeast genomic library. The library was then put into E. coli cells that lacked key DNA repair genes responsible for the repair of toxic 3-methyladenine lesions. After creating plates with thousands of colonies, she recruited the lab to test the colonies one by one for their ability to grow in the presence of a methylating agent. Persistence paid off! One colony out of 15,000 showed resistance to the methylating agent. This led to the discovery of the first eukaryotic gene that defends against methylation damage-induced toxicity. She then extended this approach and used a human cDNA library to clone the first human gene able to defend against methylation damage, and she called this gene the alkyl adenine DNA glycosylase (AAG).

Wanting to understand better what Aag does in mammals, she next set out to knock out the Aag gene in mice. This was at a time when there were very few knockout mice in existence, and there was only one knockout mouse that lacked a DNA repair activity. Boldly moving forward, she teamed up with Jan Hoeijmakers to make the Aag KO mouse. These mice turned out to have fascinating phenotypes some of which are described below. She also went on to create a different knockout mouse, one that is lacking a gene called 06-methylguanine DNA methyltransferase (MGMT) that functions to remove methyl groups from the 06 position of guanine by attaching them to its active site. Through studies of cells from these mice, it became clear that the Mgmt gene protects against not only methylating agents, but also other chemicals that create DNA adducts, including BCNU, a chemotherapeutic agent.

Dr. Samson always has had an eye on the utility of understanding the mechanisms of DNA repair in the context of treating cancer. One of the problems with chemotherapy is that it is not only toxic to the tumor, but it is also toxic to normal healthy cells in the body. In fact, the dose of BCNU that can be used to treat a patient is limited by the fact that it can destroy bone marrow cells, which can be lethal to the patient. After presenting her data showing that DNA methyltransferases can rescue human cells from being annihilated by BCNU, she was approached by a clinician in the audience about ways that they could leverage this new understanding. This led to experiments in an animal model in which the bone marrow was removed and a gene for the DNA repair methyltransferase was inserted into the genome of the bone marrow cells. The cells were then returned to the animal, which rendered them resistant to BCNU toxicity. This was the first example of gene therapy using a DNA repair enzyme and it paved the way for clinical trials where the gene for a DNA methyltransferase is being inserted into the bone marrow of children with childhood cancers.

Another key to Dr. Samson’s remarkable impacts is that she has consistently jumped at the opportunity to use whatever cutting-edge technology was available in order to delve deeper into the mechanisms by which DNA damaging agents cause mutations and toxicity. A great example of this is her work studying the transcriptome. At a time when Affymetrix was still in the development phase in the creation of microarrays used to study the level of expression of thousands of genes at a time, Dr. Samson was able to obtain chips even before they were commercially available. Using the Affymetrix chips, her team uncovered hundreds of genes that are differentially expressed upon exposure to a methylating agent. As such, she pioneered studies of the transcriptome in response to DNA damage. One of her key discoveries was that while any particular gene might not be informative regarding cell behavior, analysis of several genes from the same pathway was effective in discerning the impact of gene expression on cell behavior. In other words, she helped to break open the field of pathway analysis in human cells.

One of the fascinating things about the Aag gene is that it is the first step in a repair pathway. Aag is a glycosylase that removes the damaged base, creating an abasic site that then needs to be repaired by downstream enzymes. An essential step is to cut the backbone so that new DNA can be created to replace the damaged piece. Dr. Samson discovered that if Aag is expressed at a high level in mammalian cells, it can actually be detrimental. And she uncovered the mechanism, which was the toxic accumulation of abasic sites. It later became clear that Aag can not only remove toxic DNA damage, but it can also remove benign DNA damage and even undamaged bases. As such, having extra Aag activity puts pressure on the pathway, and if downstream enzymes cannot keep up, repair intermediates can be highly toxic. Having observed these effects, Dr. Samson next asked what the consequences are for Aag activity in animals. She hypothesized that under some circumstances Aag might be detrimental rather than helpful. Remarkably, she discovered that this is indeed the case. For example, when mice are exposed to a methylating agent, they develop retinal degeneration. If Aag is knocked out, the mice actually become resistant to the methylating agent, showing definitively that under conditions of high levels of DNA damage, a DNA repair activity can do more harm than good. Taking this line of thinking even further, Dr. Samson hypothesized that Aag might actually modulate responses to inflammation, because Aag not only removes methylation damage, but it also removes certain DNA damages that are formed by oxidative stress. To test this, Dr. Samson leveraged models of ischemia reperfusion in mice and she demonstrated that indeed, Aag activity greatly increases ischemia-induced tissue damage in the liver, kidney and brain. In other words, mice without Aag were relatively resistant to ischemia reperfusion. This brought Aag into the spotlight as a key enzyme with broad implications for many physiologically important conditions.

Another aspect of Dr. Samson’s work that is remarkable was her work on studies of the transcriptome in response to environmental chemicals, and one of the questions that she set out to answer was the extent to which a baby in utero might be impacted by exposure to the mother. By obtaining cord blood from mothers who had been exposed to arsenic in their drinking water, she was able to analyze the transcriptional responses of the baby. This work led to the discovery that numerous stress responses are induced in the fetus when mothers were exposed to arsenic, and from these results her team was able to identify a set of just 11 genes that serve as an effective biomarker for arsenic exposure for babies in utero.

Dr. Samson has always had an eye on the possibility that differences in DNA repair capacity among people might affect their susceptibility to cancer and their sensitivity to chemotherapy. For some of her most recent work, she focused on developing high-throughput tools to evaluate DNA repair capacity in human cells. To do this, she took an old-fashioned, rarely used assay for the presence of DNA lesions in transcribed genes and modernized it by exploiting site-specific lesion technology and the ability to rapidly assess the efficiency of transcription using fluorescent proteins. She won a prestigious Pioneer Award to pursue the idea of a modernized “host-cell reactivation assay” wherein DNA repair either turns on or off expression of genes for fluorescent proteins. Through a number of clever tricks, she was able to devise methods that enable parallel analyses of multiple DNA repair pathways in human lymphocytes. Her new assay opens doors to both studies of interindividual variation repair and its relationship to disease susceptibility, as well as applications to personalized medicine to evaluate tumors for their ability to use DNA repair as a way to resist the toxic effects of chemotherapeutic agents.

These are merely highlights from an astounding number of discoveries. Her work has made a significant and lasting impact not only in the field of DNA damage and repair, but more broadly in our ability to understand how cells respond to exposures and how we can leverage our understanding to gain insights that help us to better predict, prevent, and treat disease.

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Celebrating John Essigmann, Winner of the 2021 ACS Founder’s Award in Chemical Toxicology

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It was recently announced that Professor John Essigmann is this year’s winner of the American Chemical Society (ACS) Division of Chemical Toxicology (TOXI) Founder’s Award. Prof. Essigmann is the William R. (1956) and Betsy P. Leitch Professor in Residence of Chemistry in the MIT Department of Chemistry and Professor of Toxicology and Biological Engineering in the MIT Department of Biological Engineering. He is also the Deputy Director of the MIT Center for Environmental Health Sciences and a project and core leader for the MIT Superfund Research Program. Previous winners of this award at MIT include our colleague, Dr. Peter Dedon. The award was established in honor of the founders of the ACS Division of Chemical Toxicology and recognizes scientists whose work exemplifies the founders’ vision for excellence in the field of chemical toxicology.

Professor Essigmann’s research group has specialized in utilizing their ability to chemically synthesize oligonucleotides containing DNA lesions formed by environmental toxins and chemotherapeutic drugs and to introduce these oligos into genomes of viruses and plasmids. Those engineered vectors can then be replicated inside of cells and the progeny can be analyzed for the type, amount and genetic requirements for mutagenesis and toxicity by the specific lesions under investigation. Over 100 DNA lesions of environmental carcinogens and drugs have been characterized over the years. Prof. Essigmann and his laboratory have additionally made significant advancements in applying similar techniques to help our understanding of the mechanisms by which DNA damage caused by anticancer drugs induces cell death. More recently, Prof. Essigmann’s work has been focused on mutation spectra and in particular the types of mutations induced by mycotoxins such as aflatoxin B1 and DNA alkylating agents such as N-nitrosodimethylamine (NDMA). These studies pave the way for future testing of tissues or white blood cells from people in order to discern possible prior exposure to NDMA. Such studies could be particularly relevant if analysis of normal tissue adjacent to a tumor shows evidence of prior aflatoxin or NDMA exposure, thus contributing to our ability to deduce the underlying cause of someone’s cancer. One striking early observation has been that mutational patterns arise early after exposure to the chemical agent, making early cancer detection a formal possibility. As such, Prof. Essigmann’s work on mutation spectra has important implications to public health.

As a pioneer in the field of site-specific mutagenesis and a leader in analysis of mutational fingerprints caused by environmental exposures, Prof. Essigmann is highly deserving of recognition by the ACS. The MIT SRP congratulates Prof. Essigmann on his award.

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Manuscript from the Engelward Lab Demonstrates that the Level of a Key DNA Repair Enzyme acts as a Toggle Between NDMA-Induced Cancer and Toxicity

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Recent work from the Engelward Lab has been published in Cell Reports and featured in the MIT News on March 16, 2021. This research highlights increased concerns of the contaminant, N-nitrosodimethylamine or more commonly known by its abbreviation NDMA. NDMA is a probable carcinogen identified in exceedingly high levels at the Olin Chemical Superfund Site in Wilmington, MA. This chemical is also present in food that is known to be carcinogenic (namely, processed meat), and is sometimes present in heavily chloraminated municipal drinking water. Coincidently, last week the Massachusetts Department of Public Health released its findings from a 20 year study that showed an association between exposure to NDMA in utero and a childhood cancer cluster in Wilmington. Additionally, over the past couple of years several types of drugs were found to be contaminated with NDMA or to contain precursors that break down to form NDMA. Tens of millions of people in the United States alone were exposed to high levels of NDMA from taking Zantac, Metformin and Valsartan. In fact, the public health crisis that has stemmed from NDMA contamination is alarming enough that the FDA held a two-day public workshop focused on addressing this issue this past week. (https://www.fda.gov/drugs/news-events-human-drugs/nitrosamines-impurities-drugs-health-risk-assessment-and-mitigation-public-workshop-03292021).

The Engelward lab’s research project stems from studies by Leona Samson showing the cost-benefit of the DNA repair pathway known as base excision repair (BER), and it brings sophisticated mouse models to bear on understanding the role of BER in the context of NDMA exposure. NDMA is a DNA damaging agent that creates methylated DNA bases, that can be mutagenic. The focus of this most recent study is on the Alkyladenine DNA Glycosylase (AAG), which initiates the BER pathway by removing damaged bases, including those created by NDMA. After removal of damaged bases by AAG, downstream enzymes process the abasic site, and single strand breaks must be created to allow polymerase to replace the damaged base. While removal of the mutagenic lesion helps to prevent cancer, the resulting strand breaks can be toxic.

Led by Dr. Jennifer Kay, Engelward’s team discovered that the AAG plays a pivotal role in response to NDMA, literally creating a “pivot” wherein low levels of AAG lead to cancer and high levels of AAG lead to tissue toxicity.

The underlying mechanism for these observations is that AAG removes potentially mutagenic DNA lesions such as 3-methyladenine (3MeA). Having low amounts of AAG therefore results in increased mutations and cancer. Increasing the level of AAG at first glance appears advantageous, because mutations go down and so does cancer incidence. However, having high levels of AAG is also problematic, because excess activity can create pathway imbalance, which is associated with an increase in BER intermediates, some of which are toxic, like single strand DNA breaks.

This work highlights the importance of gene-environment interactions that dictate disease outcome, raising the possibility that people with low levels of AAG protein may be more susceptible to NDMA-induced cancer. An exciting opportunity for application of this research is that methods developed by the Samson and Engelward Labs, using plasmids and the CometChip platform, respectively, enable monitoring of AAG activity in people, thus potentiating precision prevention. Advanced by the Nagel laboratory promise to make the plasmid-based assay accessible to many labs.

Additionally, the study involved the use of the RaDR mouse model developed in the Engelward Lab, which makes it possible to monitor mutation frequency in tissues via fluorescent imaging. RaDR imaging using a standard epifluorescent microscope provides singly the most high-throughput and least expensive method available for mutation studies, and the results from this work show its utility. In particular, the tight correlation between RaDR mutations and cancer points to the potential for using the RaDR mice to screen conditions that might suppress mutations, identifying leads that can then be explored with a longer term cancer study.

Several MIT Superfund Research Program laboratories contributed in essential ways in collaboration of this study, including the White and Essigmann labs. The research project was led by Jennifer Kay (Engelward Lab) with key contributions from Joshua Corrigan (Engelward Lab), Amanda Armijo (Essigmann Lab), and Ishwar Kohale (White Lab). This is an excellent example of collaborative research made possible by the NIEHS Superfund Research Program, shedding light on some of the molecular processes that drive cancer and the methods our genes use to protect us from environmental contaminants.

Timothy Swager

Timothy Manning Swager, the Inventor

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This blog is to celebrate the accomplishments of Timothy M. Swager on the occasion of his being named a Fellow of the National Academy of Inventors. Tim is the John D. MacArthur Professor of Chemistry and the Director of the MIT Deshpande Center for Technological Innovation. Tim is also a project leader for the MIT Superfund Research Program, a program that is focused on environmental health with an emphasis on serving environmental justice communities.

If there is one thing that stands out about Tim, it is his imagination. He has a flare for the creative design of materials that sense things. He is an ‘outside-the-box’ thinker with a toolbox of materials with different physical characteristics that he manipulates for completely new applications. He is unparalleled when it comes to harnessing chemical phenomena for sensing schemes. Give him a box of chemicals and he will turn it into some sort of clever recognition element.

DiagramDescription automatically generatedA favorite example is his use of tiny droplets as sensors. Who would have thought that tiny micron-scale droplets could be used for their light refraction capabilities as molecular sensors? The way this works is that you start with two oils that don’t mix with water and only mix with each when they are hot. Adding this hot mixture to water, droplets are formed, that after cooling, are made up of two halves, like hemispheres of the earth, or like poke balls! The dense oil droplets sink and so the “Janus” (the two-faced God that Janus is named after) droplets sit flat like little boats floating in water. If you shine a light on them, the light goes straight through, unhindered. While this is already pretty neat, the real innovation comes when you decorate the top half of the droplet by adding stuff that binds super-tightly to target molecules.

If two droplets try to grab the same thing, the top halves tip toward each other in a tug-of-war. The end result is that now light doesn’t go straight through anymore, but instead bounces in other directions. What is really cool is that if you have a field of droplets and they are tugging at each other, you can tell that this is happening using a smart phone. Voila! Now you have a molecular sensor that you can use with your smart phone! The idea is brilliantly simple and broadly useful. The method even has the potential to be useful for home-tests for things around us, or even inside of us (e.g., a test that can be used as a diagnostic using a finger prick of blood).

But this is just one example! There is also “Fido,” named after the dog because dogs have amazing senses of smell. Tim is very passionate about conductive polymers and has used them to amplify signals. Using conductive fluorescent polymers (polymers that glow after having light shined on them), Tim created a mind-bogglingly sensitive detector for trace levels of explosives. The same way scents coming from afar tease our noses, this device can sense wafting tendrils of scents. You can wave the sensor in the air and it can sense plumes in the breeze emitted from explosives far away. It’s even better than a dog!

Tim is also a leader when it comes to carbon nanotube sensors. He figured out ways to sense chemicals associated with food products that are past their prime (food spoilage). The carbon nanotubes are used to create a wireless gas detector that transmits signals to a smart phone. Basically, you start with a small piece of paper and a special printer. After printing ‘wires’ as strips of metal on the paper, you add the special carbon nanotubes between the ends of two wires. If the carbon nanotubes stick to their target, the current changes and this change can be sensed by a smart phone (it is kind of like wireless charging, but in reverse). The end result is a near field communication device that is cheap and easy to distribute.

DiagramDescription automatically generatedIn another exciting application, in his role as Leader of Project 2 for the MIT Superfund Research Program, Tim and postdoc Maggie He created a carbon nanotube sensor for N-nitrosodimethylamine (NDMA). NDMA is a carcinogen that can be found at Superfund Sites, and in drinking water and food. More recently, NDMA has been discovered to be a contaminant of commonly used drugs, such as Zantac, Valsartan, and Metformin.

These are just three of many examples of really cool ways to sense things, whether it be something in the air, something in water or even something inside of you!

Despite his accomplishments, Tim is approachable and unassuming. He loves to bounce ideas with people and is constantly throwing out ideas to his colleagues to see what catches. He also thrives on talking with people who think differently from him, whether it is science or other things. When there is a new kid on the block, he reaches out to welcome them and to muster ideas for collaborations. Tim thrives on in the MIT ecosystem of smart minds ready to run with ideas. If Tim asks a question that someone doesn’t know how to answer, rather than judging, he seeks to understand what they do know about. He is quick to appreciate that everyone has something to offer, so you just need to figure out how to match people with project opportunities. People who work with Tim feel lucky, and the members of his team appreciate that he has an eye on their future. For those headed for independence, he is generous with ideas, leaving room for his academic progeny to thrive. A former postdoctoral scholar in Tim’s lab, Julia Kalow, now an Assistant Professor at Northwestern University, had this to say about Tim, “Tim has the unique ability to apply his synthetic intuition to problems across chemistry, engineering, and physics, designing and building molecules that are both beautiful and functional. He can distill complicated concepts into elegant, clear explanations–a wonderful trait in both a mentor and a collaborator. And another invaluable trait for a mentor and collaborator: his awe-inspiringly fast email response time. I can’t find any examples where I had to wait more than 24 hours for a response, and usually, it’s less than 2!”

Tim also has been an influential scientist and mentor to his fellow faculty at MIT, with Jeremiah Johnson a fellow Professor of Chemistry saying, “Tim is a leading figure in the field of organic materials, and his work has inspired a generation of chemists working at the interface of organic synthesis and polymer chemistry. As my faculty mentor when I began at MIT, Tim always gave (and continues to give) candid, detailed advice with my best interest in mind. I would not be where I am today without him, and I look forward to continuing to learn from him throughout my career.”

Tim didn’t grow up thinking that he’d be an inventor, but rather he grew up thinking he’d be a rancher in Montana. He met his wife working a summer job at a nearby ranch and has always put family first. To Tim, family is the most important thing, above all else. That said, his biggest flaw is that he is addicted to work. He says to his postdocs, “you’d be surprised how well you can do with only 4-5 hours of sleep. Don’t worry, you’ll get used to it. It’s just conditioning, you’ll be fine!”

4 SRP Center Directors

MIT SRP Leaders Share Superfund Advances with Congressional Staff

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A group of Superfund Research Program Center leaders from MIT, Northeastern University, University of Kentucky, and Louisiana State University went to Washington DC to engage with Professional Staff from the House and Senate Appropriations Committees. This was a great opportunity to share the good news about the many strengths of the NIEHS Superfund Research Program with people who play a direct role in deciding which programs to support.

The group was led by Akram Alshawabkeh (Prof. of Engineering, Director of the Northeastern University SRP Center) and included Bevin Engelward (Prof. of Biological Engineering, Director of the MIT SRP Center), Lindell Ormsbee (Prof. of Civil Engineering, Associate Director of the University of Kentucky SRP Center) and Margaret Reams (Prof. of Environmental Sciences and Leader of the Community Engagement Core for the Louisiana State University SRP Center). They met with Professional Staff Members Dr. Kusai Merchant, Kristin Clarkson, Kathryn Solmon, Melissa Zimmerman, and Lucas Agnew.

The objective of the meetings was to share ongoing SRP progress and to discuss its value in advancing research, engaging with the community, and promoting public health. The meetings made it possible to raise the profile of the SRP at the national level to ensure that leadership is aware of and appreciates the immense value of the Superfund Research Program. The team shared with Staffers an overview of the Superfund program with highlights from a few Centers.

The team emphasized many key strengths of the program. For example, they described how the work that is being done is solutions oriented, both in terms of remediation of environmental contamination and in terms of providing concrete steps that people can take to prevent exposure and to offset the risk of disease. As an example of an engineering solution, Akram Alshawabkeh described new filtration systems that his team is developing to remove complex mixtures of contaminants. He emphasized that a key challenge is that filters need to be replaced often, which lowers compliance. To solve this problem, his team is making “self-cleaning filters” by exploiting electrochemical destruction of contaminants. The staffers greatly appreciated the fact that this work could lead to under-sink filtration systems for Environmental Justice communities in Puerto Rico who suffer from high levels of complex mixtures of environmental contaminants in their water. When the SRP team brought up the fact that inventions being created by SRP Centers across the country also help to drive the economy (in part via the SRP SBIR program), the staffers took note.

As an example of working being done by biomedical scientists, the team shared a description of the wonderful work being done by the University of New Mexico. They pointed out that the UNM SRP Center is working with native tribes to do research that guides intervention strategies that protect tribe members from the negative health effects of metals that contaminate their environment.

The team also emphasized that the SRP is unique in the world in that it brings engineers and chemists together with researchers in the life and social sciences to enable synergies that give rise to new technologies and solutions to pressing problems in public health. As an example, Dr. Engelward emphasized that the MIT SRP team is developing sensors for environmental contaminants and that results from the sensors guide the biologists to query cellular responses that may predict disease risk under realistic exposure conditions. The team emphasized that all of the SRP Centers support cross-disciplinary collaborations that give rise to synergistic public health benefits.

Dr. Merchant asked how we are sharing research progress with community members. As the Director of Community Engagement for the Louisiana State University SRP Center, Dr. Reams described the importance of bidirectional engagement. In particular, she emphasized that there is ongoing research at LSU to learn about the efficacy of different methods for reaching the public. They are tracking the impact of communications by assessing the extent to which engagement with one part of a community leads to increased awareness by others. Dr. Ormsbee from the Kentucky SRP Center emphasized that their Community Engagement Core uses interviews, focus groups and polling technology to learn about the efficacy of their bidirectional engagement activities. Dr. Alshawabkeh emphasized the importance of community engagement in Puerto Rico, and in particular the importance of sharing valuable health care information to pregnant mothers to help prevent pre-term births. The team also pointed out that there is a strong emphasis on engagement with Environmental Justice communities and native tribes, where the need is greatest, due to their overrepresentation among people living in close proximity to Superfund sites. They shared the example of MIT’s work with tribes in Maine and emphasized that there is tremendous effort to support EJ communities and indigenous people for all the SRP Centers across the country.

Another point that was raised by the SRP Center leaders is that the progress SRPs make is not just beneficial for people living near Superfund Sites, but rather it also has relevance far more broadly. First, the chemicals of concern at Superfund Sites are often prevalent outside of Superfund Sites. For example, MIT is studying N-nitrosamines, carcinogenic chemicals that not only contaminate groundwater near Superfund Sites, but also chlorine-treated drinking water, food, and even some common daily medications. Similarly, many other Superfund chemicals of concern are prevalent outside of Superfund sites, such as PFAS, PCBs, and phthalates. Furthermore, the knowledge that is gained regarding the mechanisms by which Superfund chemicals cause disease are often generalizable to other exposures. Understanding disease progression then opens doors for developing interventions. Finally, approaches that offset disease caused by environmental exposures are often generalizable beyond their application to people living near Superfund sites. The team cited U. of Kentucky SRP Center’s focus on how diet, nutrition, and exercise can help to offset the effects of exposure, which is an exciting direction in terms of supporting what could be a very broad impact on public health.

Throughout the discussion, the team referred to the great work of the many SRP Centers across the country. With each conversation, the team promoted the unique strengths of the NIEHS Superfund Research Program and the staffers were truly impressed.

The SRP team thanks the Professional Staff for taking time to learn about the many ways that the NIEHS SRP Program contributes to research, training, community engagement and research translation.

20.01.07

NIEHS Superfund Research Program Pioneers FAIR Play in Research

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Under the leadership of Director Dr. William Suk, the NIEHS Superfund Research Program is playing a pioneering role in enabling the development of novel tools for leveraging big data in new and exciting ways. Big data comes in many forms, ranging from life-science based data sets for measuring which genes are turned on and off, to engineering modeling of the spatiotemporal dynamics of contaminants in our environment. Not only are large data sets being created faster and more efficiently, but so are innovative tools for combining data sets. To fully leverage these large data sets, we need to be able to find them, access the data, and manipulate the data. In essence, the goal is to reuse data to gain new and deeper understanding and greater predictive capacity. In recognition of the importance of these activities, the NIEHS SRP is adopting innovative strategies for making data findable, accessible, interoperable, and reusable; in other words, making data FAIR1, 2.

One of the first questions is often “how can FAIR be accomplished?” It turns out that the most important step toward achieving FAIR data is to assign and share effective metadata. Metadata is data about data. Some basic elements of metadata might include the name of the person who generated the data, the date when data was collected, and the place where the experiments were performed. While these are obviously valuable attributes, metadata needs to be much more complete in order to enable FAIR data. As a start, think about what essential attributes you would need to know about data before reusing it. For example, for an experiment where cultured mammalian cells are exposed to a carcinogenic chemical found in Superfund Sites, you need to know what the exposure was exactly, including dose and duration, and you would want to have the instructions that were used for the dosing regimen.

To achieve the goal of creating and storing metadata along with its research datasets, the MIT SRP is adopting and adapting the SEEK3 architecture with support from the NIEHS Superfund Research Program. The most exciting aspect of SEEK is that it structures the data and metadata so that computers can be programmed to find and use submitted data. This combination of structured data and metadata is known as “machine-actionable data” and is accessible via computer programs that can harvest preexisting data sets for novel analyses. These approaches are effective when there are repositories wherein properly structured data and metadata reside. On the other hand, there are cases where data are in a form that are primarily human understandable rather than machine-actionable. In this case, the SEEK architecture can be used to enable users to identify the existence of data sets that might be useful for further transformation and analysis.

SEEK is an online data management platform developed for the purpose of enabling data integration across heterogeneous data types in order to model (and ultimately predict) biological outcomes. Although SEEK was originally developed for the purpose of leveraging data for systems biology, the architecture was designed to accommodate a wide range of data types, making it ideal for all MIT SRP members, including those from the environmental science and engineering projects. In essence, the SEEK platform facilitates data sharing by providing a structure for metadata creation that makes it possible to accurately describe datasets and to link corresponding dataset. Ultimately, this makes it possible for researchers to find relevant data sets. Data are not only findable in SEEK, but the metadata structure also makes access possible. Integration of data into the SEEK architecture allows the key information needed to access data from publicly available repositories to be entered for each dataset. Making data findable and accessible is key to data integration across diverse data sets. In other words, you can answer research questions without collecting a single sample! For dataset creators, the impact of their work can be extended far beyond the normal audience. With appropriate citation, supported by good metadata, they get credit for the datasets they have authored whenever they are re-used.

While the SEEK platform makes it easy to add metadata at the time when someone submits their data into a publicly available repository, to be maximally effective, the SEEK platform needs to be dynamic, enabling creation of metadata as data are generated in real time. This is critical because it often takes years between the time of data creation and the time of data deposition, and by the time data are deposited, important metadata and associated supporting information can be lost. For example, a graduate student might inherit a project from someone who has graduated. When asked for key metadata, such as which protocol was used for analysis, the new student might not know with certainty, especially since protocols evolve over time. At MIT, we are tackling this problem by re-engineering the SEEK architecture to make it easy for people to submit metadata in real time. This exciting advance promises to greatly accelerate research by providing researchers with the essential details that are needed for data reuse.

It is interesting to note that the SEEK architecture is useful for documenting and sharing information within a lab, as well as between labs. For example, someone might want to find samples that had been collected by a former labmate. Historically this has been quite difficult, as one might not know which freezer to search, let alone which box to look in. SEEK makes it easy to link specific samples not only with the data generated, but it also makes it easy to indicate where a sample is located (and equally importantly, whether or not the sample still exists, since often samples are used up).

As more and more Superfund data get uploaded into publicly accessible frameworks, there will in turn be countless opportunities to combine data sources in new and exciting ways. Importantly, this creates an opportunity to integrate data across disciplines. This is a particularly exciting aspect of the program, since Superfund is unique among research programs in the incredible diversity of data, ranging from biological responses to environmental fate and transport data. In fact, with its rich diversity of data types, Superfund is the ideal program to propel data science into new and unknown territory. By combining data in new ways, we will increase our potential to make valuable predictions, such as knowing what the impact of cleanup will be on the health of people living near a particular Superfund Site. Stay tuned as we open our eyes to new ways of reusing and integrating data, enabling better science and thus a greater impact on the world around us!

[1] Wilkinson, M., Dumontier, M., Aalbersberg, I. et al. The FAIR Guiding Principles for scientific data management and stewardship. Sci Data 3, 160018 (2016) doi:10.1038/sdata.2016.18
[2] https://www.go-fair.org/fair-principles/
[3] https://fair-dom.org/platform/seek/

NDMA

All About NDMA

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If you’ve been following MIT-SRP, then you’ve probably heard about the chemical N-dimethylnitrosamine (NDMA), but as a lesser-known contaminant, you may not know what it is or why it’s important. NDMA causes liver, lung, and kidney cancer in rodent models, and it is classified as Group 2A probable carcinogen by the International Agency for Research on Cancer (IARC) (EPA class B2). These class designations basically mean that there is strong evidence for NDMA causing cancer in animal models, but there’s insufficient evidence to say for sure that NDMA causes cancer in humans. Since humans and animals often respond similarly, things that cause cancer in animals are generally thought to be risky to people. I’ve introduced how NDMA causes cancer in the earlier blog entries, so here I’ll describe more about the chemical itself.

NDMA in the environment can come from a variety of sources, such as rubber plants, pesticide manufacturers, tanneries, water treatment plants, some methods of carbon capture, and spilled fuels. It is toxic to animals in ranges down to 5 parts per million and considered dangerous by the WHO as low as 0.1 micrograms per liter. However, there are no health-based federal standards for NDMA levels in drinking water, possibly due to insufficient data about human health risks. That means that even though the EPA considers NDMA a priority contaminant, there’s no set level at which the EPA considers NDMA too dangerous for human exposure. In Massachusetts, there is a guideline of 10 ng/L NDMA in drinking water, but that is based on the limit of detection for most analytical methods rather than health risk. Recently, the EPA determined the screening level for NDMA in tap water to be 0.11 ng/L based on an excess cancer risk of ~1 in a million people. (Note that this screening level is 100 times below the limit of detection for most methods!)

People can be exposed to NDMA not just in the environment or from hazardous waste, but through other sources as well. These include food (such as cured meat), malt beverages, toiletry and cosmetic products, and cigarette smoke. The most common route of exposure is through ingestion (either food or drink), and second most common is inhalation. Even if you don’t live near a Superfund site, there is still the potential for exposure through lifestyle.

In Wilmington, MA, NDMA is found in groundwater surrounding the 53-acre Olin Chemical Superfund site. For Superfund site cleanups, the original polluters (known as Primary Responsible Parties, or PRPs) must pay for a study of the extent of contamination on site and in the surrounding area, and in most cases they must pay for the cleanup and sealing off of chemicals. In this case, the Olin PRPs are Olin Corporation, American Biltrite, Inc., and Stepan Company, since they were the companies using the land from the 1960s until now. While the PRPs have completed many analyses of chemicals in the soil, surface water, groundwater, and sediment on and near the site, there are still major gaps in the data. For example, they still don’t know how far the plume of groundwater chemicals extends beyond the site, creating the potential for many local residents to be unwittingly exposed. Once the remedial investigation studies are complete, the PRPs will identify strategies for cleaning up and/or containing chemicals on and near the site.

Understandably, nearby Wilmington residents are concerned about their health and safety. A group of concerned citizens formed the Wilmington Environmental Restoration Committee (WERC), leading the charge to protect their community from NDMA. They are pushing, along with the EPA, for faster, more effective cleanup of the Olin site, which Olin is resisting. WERC brings more visibility to this important issue and keeps the public apprised of the ongoing fight for cleanup. Community organizations like WERC are often important contributors to achieving environmental cleanups by maintaining relationships with responsible parties. For this reason, the MIT SRP has partnered with WERC to ensure that our research and expertise can reach community members and support their push for public health.

The MIT SRP is approaching NDMA research from a variety of directions. On the engineering front, we have projects dedicated to designing sensors for NDMA in water and air. We aim for these sensors to be usable by regulatory agencies to identify contaminated areas, or by citizens to determine their own exposure risk. On the biological side, we have research projects aimed at identifying the mutations NDMA exposure causes, understanding the potential for genetics to affect cancer risk, and characterizing the short-term cellular responses to NDMA exposure. These studies will enable identification of biomarkers that signify previous or ongoing NDMA exposure, and it is hoped that they will ultimately help to stratify populations into groups of high- and low-risk of cancer.

If you have more questions about NDMA, feel free to contact me at ude.tim@yakej. The MIT SRP prides itself on openness and public engagement, so we hope you will take advantage of us as an environmental health resource.