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    Making sense of cell fate

    Despite the proliferation of novel therapies such as immunotherapy or targeted therapies, radiation and chemotherapy remain the frontline treatment for cancer patients. About half of all patients still receive radiation and 60-80 percent receive chemotherapy.

    Both radiation and chemotherapy work by damaging DNA, taking advantage of a vulnerability specific to cancer cells. Healthy cells are more likely to survive radiation and chemotherapy since their mechanisms for identifying and repairing DNA damage are intact. In cancer cells, these repair mechanisms are compromised by mutations. When cancer cells cannot adequately respond to the DNA damage caused by radiation and chemotherapy, ideally, they undergo apoptosis or die by other means.

    However, there is another fate for cells after DNA damage: senescence — a state where cells survive, but stop dividing. Senescent cells’ DNA has not been damaged enough to induce apoptosis but is too damaged to support cell division. While senescent cancer cells themselves are unable to proliferate and spread, they are bad actors in the fight against cancer because they seem to enable other cancer cells to develop more aggressively. Although a cancer cell’s fate is not apparent until a few days after treatment, the decision to survive, die, or enter senescence is made much earlier. But, precisely when and how that decision is made has not been well understood.

    In an open-access study of ovarian and osteosarcoma cancer cells appearing July 19 in Cell Systems, MIT researchers show that cell signaling proteins commonly associated with cell proliferation and apoptosis instead commit cancer cells to senescence within 12 hours of treatment with low doses of certain kinds of chemotherapy.

    “When it comes to treating cancer, this study underscores that it’s important not to think too linearly about cell signaling,” says Michael Yaffe, who is a David H. Koch Professor of Science at MIT, the director of the MIT Center for Precision Cancer Medicine, a member of MIT’s Koch Institute for Integrative Cancer Research, and the senior author of the study. “If you assume that a particular treatment will always affect cancer cell signaling in the same way — you may be setting yourself up for many surprises, and treating cancers with the wrong combination of drugs.”

    Using a combination of experiments with cancer cells and computational modeling, the team investigated the cell signaling mechanisms that prompt cancer cells to enter senescence after treatment with a commonly used anti-cancer agent. Their efforts singled out two protein kinases and a component of the AP-1 transcription factor complex as highly associated with the induction of senescence after DNA damage, despite the well-established roles for all of these molecules in promoting cell proliferation in cancer.

    The researchers treated cancer cells with low and high doses of doxorubicin, a chemotherapy that interferes with the function with topoisomerase II, an enzyme that breaks and then repairs DNA strands during replication to fix tangles and other topological problems.

    By measuring the effects of DNA damage on single cells at several time points ranging from six hours to four days after the initial exposure, the team created two datasets. In one dataset, the researchers tracked cell fate over time. For the second set, researchers measured relative cell signaling activity levels across a variety of proteins associated with responses to DNA damage or cellular stress, determination of cell fate, and progress through cell growth and division.

    The two datasets were used to build a computational model that identifies correlations between time, dosage, signal, and cell fate. The model identified the activities of the MAP kinases Erk and JNK, and the transcription factor c-Jun as key components of the AP-1 protein likewise understood to involved in the induction of senescence. The researchers then validated these computational findings by showing that inhibition of JNK and Erk after DNA damage successfully prevented cells from entering senescence.

    The researchers leveraged JNK and Erk inhibition to pinpoint exactly when cells made the decision to enter senescence. Surprisingly, they found that the decision to enter senescence was made within 12 hours of DNA damage, even though it took days to actually see the senescent cells accumulate. The team also found that with the passage of more time, these MAP kinases took on a different function: promoting the secretion of proinflammatory proteins called cytokines that are responsible for making other cancer cells proliferate and develop resistance to chemotherapy.

    “Proteins like cytokines encourage ‘bad behavior’ in neighboring tumor cells that lead to more aggressive cancer progression,” says Tatiana Netterfield, a graduate student in the Yaffe lab and the lead author of the study. “Because of this, it is thought that senescent cells that stay near the tumor for long periods of time are detrimental to treating cancer.”

    This study’s findings apply to cancer cells treated with a commonly used type of chemotherapy that stalls DNA replication after repair. But more broadly, the study emphasizes that “when treating cancer, it’s extremely important to understand the molecular characteristics of cancer cells and the contextual factors such as time and dosing that determine cell fate,” explains Netterfield.

    The study, however, has more immediate implications for treatments that are already in use. One class of Erk inhibitors, MEK inhibitors, are used in the clinic with the expectation that they will curb cancer growth.

    “We must be cautious about administering MEK inhibitors together with chemotherapies,” says Yaffe. “The combination may have the unintended effect of driving cells into proliferation, rather than senescence.”

    In future work, the team will perform studies to understand how and why individual cells choose to proliferate instead of enter senescence. Additionally, the team is employing next-generation sequencing to understand which genes c-Jun is regulating in order to push cells toward senescence.

    This study was funded, in part, by the Charles and Marjorie Holloway Foundation and the MIT Center for Precision Cancer Medicine. More

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    Novo Nordisk to support MIT postdocs working at the intersection of AI and life sciences

    MIT’s School of Engineering and global health care company Novo Nordisk has announced the launch of a multi-year program to support postdoctoral fellows conducting research at the intersection of artificial intelligence and data science with life sciences. The MIT-Novo Nordisk Artificial Intelligence Postdoctoral Fellows Program will welcome its first cohort of up to 10 postdocs for a two-year term this fall. The program will provide up to $10 million for an annual cohort of up to 10 postdoc for two-year terms.

    “The research being conducted at the intersection of AI and life sciences has the potential to transform health care as we know it,” says Anantha Chandrakasan, dean of the School of Engineering and Vannevar Bush Professor of Electrical Engineering and Computer Science. “I am thrilled that the MIT-Novo Nordisk Program will support early-career researchers who work in this space.”

    The launch of the MIT-Novo Nordisk Program coincides with the 100th anniversary celebration of Novo Nordisk. The company was founded in 1923 and treated its first patients with insulin, which had recently been discovered in March of that year.

    “The use of AI in the health care industry presents a massive opportunity to improve the lives of people living with chronic diseases,” says Thomas Senderovitz, senior vice president for data science at Novo Nordisk. “Novo Nordisk is committed to the development of new, innovative solutions, and MIT hosts some of the most outstanding researchers in the field. We are therefore excited to support postdocs working on the cutting edge of AI and life sciences.”

    The MIT-Novo Nordisk Program will support postdocs advancing the use of AI in life science and health. Postdocs will join an annual cohort that participates in frequent events and gatherings. The cohort will meet regularly to exchange ideas about their work and discuss ways to amplify their impact.

    “We are excited to welcome postdocs working on AI, data science, health, and life sciences — research areas of strategic importance across MIT,” adds Chandrakasan.

    A central focus of the program will be offering postdocs professional development and mentorship opportunities. Fellows will be invited to entrepreneurship-focused workshops that enable them to learn from company founders, venture capitalists, and other entrepreneurial leaders. Fellows will also have the opportunity to receive mentorship from experts in life sciences and data science.

    “MIT is always exploring opportunities to innovate and enhance the postdoctoral experience,” adds MIT Provost Cynthia Barnhart. “The MIT-Novo Nordisk Program has been thoughtfully designed to introduce fellows to a wealth of experiences, skill sets, and perspectives that support their professional growth while prioritizing a sense of community with their cohort.”

    Angela Belcher, head of the Department of Biological Engineering, the James Mason Crafts Professor of Biological Engineering and Materials Science, and member of the Koch Institute for Integrative Cancer Research, and Asu Ozdaglar, deputy dean of academics for the MIT Schwarzman College of Computing and head of the Department of Electrical Engineering and Computer Science, will serve as co-faculty leads for the program.

    The new program complements a separate postdoctoral fellowship program at MIT supported by the Novo Nordisk Foundation that focuses on enabling interdisciplinary research. More

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    J-WAFS announces 2023 seed grant recipients

    Today, the Abdul Latif Jameel Water and Food Systems Lab (J-WAFS) announced its ninth round of seed grants to support innovative research projects at MIT. The grants are designed to fund research efforts that tackle challenges related to water and food for human use, with the ultimate goal of creating meaningful impact as the world population continues to grow and the planet undergoes significant climate and environmental changes.Ten new projects led by 15 researchers from seven different departments will be supported this year. The projects address a range of challenges by employing advanced materials, technology innovations, and new approaches to resource management. The new projects aim to remove harmful chemicals from water sources, develop monitoring and other systems to help manage various aquaculture industries, optimize water purification materials, and more.“The seed grant program is J-WAFS’ flagship grant initiative,” says J-WAFS executive director Renee J. Robins. “The funding is intended to spur groundbreaking MIT research addressing complex issues that are challenging our water and food systems. The 10 projects selected this year show great promise, and we look forward to the progress and accomplishments these talented researchers will make,” she adds.The 2023 J-WAFS seed grant researchers and their projects are:Sara Beery, an assistant professor in the Department of Electrical Engineering and Computer Science (EECS), is building the first completely automated system to estimate the size of salmon populations in the Pacific Northwest (PNW).Salmon are a keystone species in the PNW, feeding human populations for the last 7,500 years at least. However, overfishing, habitat loss, and climate change threaten extinction of salmon populations across the region. Accurate salmon counts during their seasonal migration to their natal river to spawn are essential for fisheries’ regulation and management but are limited by human capacity. Fish population monitoring is a widespread challenge in the United States and worldwide. Beery and her team are working to build a system that will provide a detailed picture of the state of salmon populations in unprecedented, spatial, and temporal resolution by combining sonar sensors and computer vision and machine learning (CVML) techniques. The sonar will capture individual fish as they swim upstream and CVML will train accurate algorithms to interpret the sonar video for detecting, tracking, and counting fish automatically while adapting to changing river conditions and fish densities.Another aquaculture project is being led by Michael Triantafyllou, the Henry L. and Grace Doherty Professor in Ocean Science and Engineering in the Department of Mechanical Engineering, and Robert Vincent, the assistant director at MIT’s Sea Grant Program. They are working with Otto Cordero, an associate professor in the Department of Civil and Environmental Engineering, to control harmful bacteria blooms in aquaculture algae feed production.

    Aquaculture in the United States represents a $1.5 billion industry annually and helps support 1.7 million jobs, yet many American hatcheries are not able to keep up with demand. One barrier to aquaculture production is the high degree of variability in survival rates, most likely caused by a poorly controlled microbiome that leads to bacterial infections and sub-optimal feed efficiency. Triantafyllou, Vincent, and Cordero plan to monitor the microbiome composition of a shellfish hatchery in order to identify possible causing agents of mortality, as well as beneficial microbes. They hope to pair microbe data with detail phenotypic information about the animal population to generate rapid diagnostic tests and explore the potential for microbiome therapies to protect larvae and prevent future outbreaks. The researchers plan to transfer their findings and technology to the local and regional aquaculture community to ensure healthy aquaculture production that will support the expansion of the U.S. aquaculture industry.

    David Des Marais is the Cecil and Ida Green Career Development Professor in the Department of Civil and Environmental Engineering. His 2023 J-WAFS project seeks to understand plant growth responses to elevated carbon dioxide (CO2) in the atmosphere, in the hopes of identifying breeding strategies that maximize crop yield under future CO2 scenarios.Today’s crop plants experience higher atmospheric CO2 than 20 or 30 years ago. Crops such as wheat, oat, barley, and rice typically increase their growth rate and biomass when grown at experimentally elevated atmospheric CO2. This is known as the so-called “CO2 fertilization effect.” However, not all plant species respond to rising atmospheric CO2 with increased growth, and for the ones that do, increased growth doesn’t necessarily correspond to increased crop yield. Using specially built plant growth chambers that can control the concentration of CO2, Des Marais will explore how CO2 availability impacts the development of tillers (branches) in the grass species Brachypodium. He will study how gene expression controls tiller development, and whether this is affected by the growing environment. The tillering response refers to how many branches a plant produces, which sets a limit on how much grain it can yield. Therefore, optimizing the tillering response to elevated CO2 could greatly increase yield. Des Marais will also look at the complete genome sequence of Brachypodium, wheat, oat, and barley to help identify genes relevant for branch growth.Darcy McRose, an assistant professor in the Department of Civil and Environmental Engineering, is researching whether a combination of plant metabolites and soil bacteria can be used to make mineral-associated phosphorus more bioavailable.The nutrient phosphorus is essential for agricultural plant growth, but when added as a fertilizer, phosphorus sticks to the surface of soil minerals, decreasing bioavailability, limiting plant growth, and accumulating residual phosphorus. Heavily fertilized agricultural soils often harbor large reservoirs of this type of mineral-associated “legacy” phosphorus. Redox transformations are one chemical process that can liberate mineral-associated phosphorus. However, this needs to be carefully controlled, as overly mobile phosphorus can lead to runoff and pollution of natural waters. Ideally, phosphorus would be made bioavailable when plants need it and immobile when they don’t. Many plants make small metabolites called coumarins that might be able to solubilize mineral-adsorbed phosphorus and be activated and inactivated under different conditions. McRose will use laboratory experiments to determine whether a combination of plant metabolites and soil bacteria can be used as a highly efficient and tunable system for phosphorus solubilization. She also aims to develop an imaging platform to investigate exchanges of phosphorus between plants and soil microbes.Many of the 2023 seed grants will support innovative technologies to monitor, quantify, and remediate various kinds of pollutants found in water. Two of the new projects address the problem of per- and polyfluoroalkyl substances (PFAS), human-made chemicals that have recently emerged as a global health threat. Known as “forever chemicals,” PFAS are used in many manufacturing processes. These chemicals are known to cause significant health issues including cancer, and they have become pervasive in soil, dust, air, groundwater, and drinking water. Unfortunately, the physical and chemical properties of PFAS render them difficult to detect and remove.Aristide Gumyusenge, the Merton C. Assistant Professor of Materials Science and Engineering, is using metal-organic frameworks for low-cost sensing and capture of PFAS. Most metal-organic frameworks (MOFs) are synthesized as particles, which complicates their high accuracy sensing performance due to defects such as intergranular boundaries. Thin, film-based electronic devices could enable the use of MOFs for many applications, especially chemical sensing. Gumyusenge’s project aims to design test kits based on two-dimensional conductive MOF films for detecting PFAS in drinking water. In early demonstrations, Gumyusenge and his team showed that these MOF films can sense PFAS at low concentrations. They will continue to iterate using a computation-guided approach to tune sensitivity and selectivity of the kits with the goal of deploying them in real-world scenarios.Carlos Portela, the Brit (1961) and Alex (1949) d’Arbeloff Career Development Professor in the Department of Mechanical Engineering, and Ariel Furst, the Cook Career Development Professor in the Department of Chemical Engineering, are building novel architected materials to act as filters for the removal of PFAS from water. Portela and Furst will design and fabricate nanoscale materials that use activated carbon and porous polymers to create a physical adsorption system. They will engineer the materials to have tunable porosities and morphologies that can maximize interactions between contaminated water and functionalized surfaces, while providing a mechanically robust system.Rohit Karnik is a Tata Professor and interim co-department head of the Department of Mechanical Engineering. He is working on another technology, his based on microbead sensors, to rapidly measure and monitor trace contaminants in water.Water pollution from both biological and chemical contaminants contributes to an estimated 1.36 million deaths annually. Chemical contaminants include pesticides and herbicides, heavy metals like lead, and compounds used in manufacturing. These emerging contaminants can be found throughout the environment, including in water supplies. The Environmental Protection Agency (EPA) in the United States sets recommended water quality standards, but states are responsible for developing their own monitoring criteria and systems, which must be approved by the EPA every three years. However, the availability of data on regulated chemicals and on candidate pollutants is limited by current testing methods that are either insensitive or expensive and laboratory-based, requiring trained scientists and technicians. Karnik’s project proposes a simple, self-contained, portable system for monitoring trace and emerging pollutants in water, making it suitable for field studies. The concept is based on multiplexed microbead-based sensors that use thermal or gravitational actuation to generate a signal. His proposed sandwich assay, a testing format that is appealing for environmental sensing, will enable both single-use and continuous monitoring. The hope is that the bead-based assays will increase the ease and reach of detecting and quantifying trace contaminants in water for both personal and industrial scale applications.Alexander Radosevich, a professor in the Department of Chemistry, and Timothy Swager, the John D. MacArthur Professor of Chemistry, are teaming up to create rapid, cost-effective, and reliable techniques for on-site arsenic detection in water.Arsenic contamination of groundwater is a problem that affects as many as 500 million people worldwide. Arsenic poisoning can lead to a range of severe health problems from cancer to cardiovascular and neurological impacts. Both the EPA and the World Health Organization have established that 10 parts per billion is a practical threshold for arsenic in drinking water, but measuring arsenic in water at such low levels is challenging, especially in resource-limited environments where access to sensitive laboratory equipment may not be readily accessible. Radosevich and Swager plan to develop reaction-based chemical sensors that bind and extract electrons from aqueous arsenic. In this way, they will exploit the inherent reactivity of aqueous arsenic to selectively detect and quantify it. This work will establish the chemical basis for a new method of detecting trace arsenic in drinking water.Rajeev Ram is a professor in the Department of Electrical Engineering and Computer Science. His J-WAFS research will advance a robust technology for monitoring nitrogen-containing pollutants, which threaten over 15,000 bodies of water in the United States alone.Nitrogen in the form of nitrate, nitrite, ammonia, and urea can run off from agricultural fertilizer and lead to harmful algal blooms that jeopardize human health. Unfortunately, monitoring these contaminants in the environment is challenging, as sensors are difficult to maintain and expensive to deploy. Ram and his students will work to establish limits of detection for nitrate, nitrite, ammonia, and urea in environmental, industrial, and agricultural samples using swept-source Raman spectroscopy. Swept-source Raman spectroscopy is a method of detecting the presence of a chemical by using a tunable, single mode laser that illuminates a sample. This method does not require costly, high-power lasers or a spectrometer. Ram will then develop and demonstrate a portable system that is capable of achieving chemical specificity in complex, natural environments. Data generated by such a system should help regulate polluters and guide remediation.Kripa Varanasi, a professor in the Department of Mechanical Engineering, and Angela Belcher, the James Mason Crafts Professor and head of the Department of Biological Engineering, will join forces to develop an affordable water disinfection technology that selectively identifies, adsorbs, and kills “superbugs” in domestic and industrial wastewater.Recent research predicts that antibiotic-resistance bacteria (superbugs) will result in $100 trillion in health care expenses and 10 million deaths annually by 2050. The prevalence of superbugs in our water systems has increased due to corroded pipes, contamination, and climate change. Current drinking water disinfection technologies are designed to kill all types of bacteria before human consumption. However, for certain domestic and industrial applications there is a need to protect the good bacteria required for ecological processes that contribute to soil and plant health. Varanasi and Belcher will combine material, biological, process, and system engineering principles to design a sponge-based water disinfection technology that can identify and destroy harmful bacteria while leaving the good bacteria unharmed. By modifying the sponge surface with specialized nanomaterials, their approach will be able to kill superbugs faster and more efficiently. The sponge filters can be deployed under very low pressure, making them an affordable technology, especially in resource-constrained communities.In addition to the 10 seed grant projects, J-WAFS will also fund a research initiative led by Greg Sixt. Sixt is the research manager for climate and food systems at J-WAFS, and the director of the J-WAFS-led Food and Climate Systems Transformation (FACT) Alliance. His project focuses on the Lake Victoria Basin (LVB) of East Africa. The second-largest freshwater lake in the world, Lake Victoria straddles three countries (Uganda, Tanzania, and Kenya) and has a catchment area that encompasses two more (Rwanda and Burundi). Sixt will collaborate with Michael Hauser of the University of Natural Resources and Life Sciences, Vienna, and Paul Kariuki, of the Lake Victoria Basin Commission.The group will study how to adapt food systems to climate change in the Lake Victoria Basin. The basin is facing a range of climate threats that could significantly impact livelihoods and food systems in the expansive region. For example, extreme weather events like droughts and floods are negatively affecting agricultural production and freshwater resources. Across the LVB, current approaches to land and water management are unsustainable and threaten future food and water security. The Lake Victoria Basin Commission (LVBC), a specialized institution of the East African Community, wants to play a more vital role in coordinating transboundary land and water management to support transitions toward more resilient, sustainable, and equitable food systems. The primary goal of this research will be to support the LVBC’s transboundary land and water management efforts, specifically as they relate to sustainability and climate change adaptation in food systems. The research team will work with key stakeholders in Kenya, Uganda, and Tanzania to identify specific capacity needs to facilitate land and water management transitions. The two-year project will produce actionable recommendations to the LVBC. More

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    MIT community members elected to the National Academy of Engineering for 2023

    Seven MIT researchers are among the 106 new members and 18 international members elected to the National Academy of Engineering (NAE) this week. Fourteen additional MIT alumni, including one member of the MIT Corporation, were also elected as new members.

    One of the highest professional distinctions for engineers, membership to the NAE is given to individuals who have made outstanding contributions to “engineering research, practice, or education, including, where appropriate, significant contributions to the engineering literature” and to “the pioneering of new and developing fields of technology, making major advancements in traditional fields of engineering, or developing/implementing innovative approaches to engineering education.”

    The seven MIT researchers elected this year include:

    Regina Barzilay, the School of Engineering Distinguished Professor for AI and Health in the Department of Electrical Engineering and Computer Science, principal investigator at the Computer Science and Artificial Intelligence Laboratory, and faculty lead for the MIT Abdul Latif Jameel Clinic for Machine Learning in Health, for machine learning models that understand structures in text, molecules, and medical images.

    Markus J. Buehler, the Jerry McAfee (1940) Professor in Engineering from the Department of Civil and Environmental Engineering, for implementing the use of nanomechanics to model and design fracture-resistant bioinspired materials.

    Elfatih A.B. Eltahir SM ’93, ScD ’93, the H.M. King Bhumibol Professor in the Department of Civil and Environmental Engineering, for advancing understanding of how climate and land use impact water availability, environmental and human health, and vector-borne diseases.

    Neil Gershenfeld, director of the Center for Bits and Atoms, for eliminating boundaries between digital and physical worlds, from quantum computing to digital materials to the internet of things.

    Roger D. Kamm SM ’73, PhD ’77, the Cecil and Ida Green Distinguished Professor of Biological and Mechanical Engineering, for contributions to the understanding of mechanics in biology and medicine, and leadership in biomechanics.

    David W. Miller ’82, SM ’85, ScD ’88, the Jerome C. Hunsaker Professor in the Department of Aeronautics and Astronautics, for contributions in control technology for space-based telescope design, and leadership in cross-agency guidance of space technology.

    David Simchi-Levi, professor of civil and environmental engineering, core faculty member in the Institute for Data, Systems, and Society, and principal investigator at the Laboratory for Information and Decision Systems, for contributions using optimization and stochastic modeling to enhance supply chain management and operations.

    Fariborz Maseeh ScD ’90, life member of the MIT Corporation and member of the School of Engineering Dean’s Advisory Council, was also elected as a member for leadership and advances in efficient design, development, and manufacturing of microelectromechanical systems, and for empowering engineering talent through public service.

    Thirteen additional alumni were elected to the National Academy of Engineering this year. They are: Mark George Allen SM ’86, PhD ’89; Shorya Awtar ScD ’04; Inderjit Chopra ScD ’77; David Huang ’85, SM ’89, PhD ’93; Eva Lerner-Lam SM ’78; David F. Merrion SM ’59; Virginia Norwood ’47; Martin Gerard Plys ’80, SM ’81, ScD ’84; Mark Prausnitz PhD ’94; Anil Kumar Sachdev ScD ’77; Christopher Scholz PhD ’67; Melody Ann Swartz PhD ’98; and Elias Towe ’80, SM ’81, PhD ’87.

    “I am delighted that seven members of MIT’s faculty and many members of the wider MIT community were elected to the National Academy of Engineering this year,” says Anantha Chandrakasan, the dean of the MIT School of Engineering and the Vannevar Bush Professor of Electrical Engineering and Computer Science. “My warmest congratulations on this recognition of their many contributions to engineering research and education.”

    Including this year’s inductees, 156 members of the National Academy of Engineering are current or retired members of the MIT faculty and staff, or members of the MIT Corporation. More

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    Neurodegenerative disease can progress in newly identified patterns

    Neurodegenerative diseases — like amyotrophic lateral sclerosis (ALS, or Lou Gehrig’s disease), Alzheimer’s, and Parkinson’s — are complicated, chronic ailments that can present with a variety of symptoms, worsen at different rates, and have many underlying genetic and environmental causes, some of which are unknown. ALS, in particular, affects voluntary muscle movement and is always fatal, but while most people survive for only a few years after diagnosis, others live with the disease for decades. Manifestations of ALS can also vary significantly; often slower disease development correlates with onset in the limbs and affecting fine motor skills, while the more serious, bulbar ALS impacts swallowing, speaking, breathing, and mobility. Therefore, understanding the progression of diseases like ALS is critical to enrollment in clinical trials, analysis of potential interventions, and discovery of root causes.

    However, assessing disease evolution is far from straightforward. Current clinical studies typically assume that health declines on a downward linear trajectory on a symptom rating scale, and use these linear models to evaluate whether drugs are slowing disease progression. However, data indicate that ALS often follows nonlinear trajectories, with periods where symptoms are stable alternating with periods when they are rapidly changing. Since data can be sparse, and health assessments often rely on subjective rating metrics measured at uneven time intervals, comparisons across patient populations are difficult. These heterogenous data and progression, in turn, complicate analyses of invention effectiveness and potentially mask disease origin.

    Now, a new machine-learning method developed by researchers from MIT, IBM Research, and elsewhere aims to better characterize ALS disease progression patterns to inform clinical trial design.

    “There are groups of individuals that share progression patterns. For example, some seem to have really fast-progressing ALS and others that have slow-progressing ALS that varies over time,” says Divya Ramamoorthy PhD ’22, a research specialist at MIT and lead author of a new paper on the work that was published this month in Nature Computational Science. “The question we were asking is: can we use machine learning to identify if, and to what extent, those types of consistent patterns across individuals exist?”

    Their technique, indeed, identified discrete and robust clinical patterns in ALS progression, many of which are non-linear. Further, these disease progression subtypes were consistent across patient populations and disease metrics. The team additionally found that their method can be applied to Alzheimer’s and Parkinson’s diseases as well.

    Joining Ramamoorthy on the paper are MIT-IBM Watson AI Lab members Ernest Fraenkel, a professor in the MIT Department of Biological Engineering; Research Scientist Soumya Ghosh of IBM Research; and Principal Research Scientist Kenney Ng, also of IBM Research. Additional authors include Kristen Severson PhD ’18, a senior researcher at Microsoft Research and former member of the Watson Lab and of IBM Research; Karen Sachs PhD ’06 of Next Generation Analytics; a team of researchers with Answer ALS; Jonathan D. Glass and Christina N. Fournier of the Emory University School of Medicine; the Pooled Resource Open-Access ALS Clinical Trials Consortium; ALS/MND Natural History Consortium; Todd M. Herrington of Massachusetts General Hospital (MGH) and Harvard Medical School; and James D. Berry of MGH.

    Play video

    MIT Professor Ernest Fraenkel describes early stages of his research looking at root causes of amyotrophic lateral sclerosis (ALS).

    Reshaping health decline

    After consulting with clinicians, the team of machine learning researchers and neurologists let the data speak for itself. They designed an unsupervised machine-learning model that employed two methods: Gaussian process regression and Dirichlet process clustering. These inferred the health trajectories directly from patient data and automatically grouped similar trajectories together without prescribing the number of clusters or the shape of the curves, forming ALS progression “subtypes.” Their method incorporated prior clinical knowledge in the way of a bias for negative trajectories — consistent with expectations for neurodegenerative disease progressions — but did not assume any linearity. “We know that linearity is not reflective of what’s actually observed,” says Ng. “The methods and models that we use here were more flexible, in the sense that, they capture what was seen in the data,” without the need for expensive labeled data and prescription of parameters.

    Primarily, they applied the model to five longitudinal datasets from ALS clinical trials and observational studies. These used the gold standard to measure symptom development: the ALS functional rating scale revised (ALSFRS-R), which captures a global picture of patient neurological impairment but can be a bit of a “messy metric.” Additionally, performance on survivability probabilities, forced vital capacity (a measurement of respiratory function), and subscores of ALSFRS-R, which looks at individual bodily functions, were incorporated.

    New regimes of progression and utility

    When their population-level model was trained and tested on these metrics, four dominant patterns of disease popped out of the many trajectories — sigmoidal fast progression, stable slow progression, unstable slow progression, and unstable moderate progression — many with strong nonlinear characteristics. Notably, it captured trajectories where patients experienced a sudden loss of ability, called a functional cliff, which would significantly impact treatments, enrollment in clinical trials, and quality of life.

    The researchers compared their method against other commonly used linear and nonlinear approaches in the field to separate the contribution of clustering and linearity to the model’s accuracy. The new work outperformed them, even patient-specific models, and found that subtype patterns were consistent across measures. Impressively, when data were withheld, the model was able to interpolate missing values, and, critically, could forecast future health measures. The model could also be trained on one ALSFRS-R dataset and predict cluster membership in others, making it robust, generalizable, and accurate with scarce data. So long as 6-12 months of data were available, health trajectories could be inferred with higher confidence than conventional methods.

    The researchers’ approach also provided insights into Alzheimer’s and Parkinson’s diseases, both of which can have a range of symptom presentations and progression. For Alzheimer’s, the new technique could identify distinct disease patterns, in particular variations in the rates of conversion of mild to severe disease. The Parkinson’s analysis demonstrated a relationship between progression trajectories for off-medication scores and disease phenotypes, such as the tremor-dominant or postural instability/gait difficulty forms of Parkinson’s disease.

    The work makes significant strides to find the signal amongst the noise in the time-series of complex neurodegenerative disease. “The patterns that we see are reproducible across studies, which I don’t believe had been shown before, and that may have implications for how we subtype the [ALS] disease,” says Fraenkel. As the FDA has been considering the impact of non-linearity in clinical trial designs, the team notes that their work is particularly pertinent.

    As new ways to understand disease mechanisms come online, this model provides another tool to pick apart illnesses like ALS, Alzheimer’s, and Parkinson’s from a systems biology perspective.

    “We have a lot of molecular data from the same patients, and so our long-term goal is to see whether there are subtypes of the disease,” says Fraenkel, whose lab looks at cellular changes to understand the etiology of diseases and possible targets for cures. “One approach is to start with the symptoms … and see if people with different patterns of disease progression are also different at the molecular level. That might lead you to a therapy. Then there’s the bottom-up approach, where you start with the molecules” and try to reconstruct biological pathways that might be affected. “We’re going [to be tackling this] from both ends … and finding if something meets in the middle.”

    This research was supported, in part, by the MIT-IBM Watson AI Lab, the Muscular Dystrophy Association, Department of Veterans Affairs of Research and Development, the Department of Defense, NSF Gradate Research Fellowship Program, Siebel Scholars Fellowship, Answer ALS, the United States Army Medical Research Acquisition Activity, National Institutes of Health, and the NIH/NINDS. More

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    MIT announces five flagship projects in first-ever Climate Grand Challenges competition

    MIT today announced the five flagship projects selected in its first-ever Climate Grand Challenges competition. These multiyear projects will define a dynamic research agenda focused on unraveling some of the toughest unsolved climate problems and bringing high-impact, science-based solutions to the world on an accelerated basis.

    Representing the most promising concepts to emerge from the two-year competition, the five flagship projects will receive additional funding and resources from MIT and others to develop their ideas and swiftly transform them into practical solutions at scale.

    “Climate Grand Challenges represents a whole-of-MIT drive to develop game-changing advances to confront the escalating climate crisis, in time to make a difference,” says MIT President L. Rafael Reif. “We are inspired by the creativity and boldness of the flagship ideas and by their potential to make a significant contribution to the global climate response. But given the planet-wide scale of the challenge, success depends on partnership. We are eager to work with visionary leaders in every sector to accelerate this impact-oriented research, implement serious solutions at scale, and inspire others to join us in confronting this urgent challenge for humankind.”

    Brief descriptions of the five Climate Grand Challenges flagship projects are provided below.

    Bringing Computation to the Climate Challenge

    This project leverages advances in artificial intelligence, machine learning, and data sciences to improve the accuracy of climate models and make them more useful to a variety of stakeholders — from communities to industry. The team is developing a digital twin of the Earth that harnesses more data than ever before to reduce and quantify uncertainties in climate projections.

    Research leads: Raffaele Ferrari, the Cecil and Ida Green Professor of Oceanography in the Department of Earth, Atmospheric and Planetary Sciences, and director of the Program in Atmospheres, Oceans, and Climate; and Noelle Eckley Selin, director of the Technology and Policy Program and professor with a joint appointment in the Institute for Data, Systems, and Society and the Department of Earth, Atmospheric and Planetary Sciences

    Center for Electrification and Decarbonization of Industry

    This project seeks to reinvent and electrify the processes and materials behind hard-to-decarbonize industries like steel, cement, ammonia, and ethylene production. A new innovation hub will perform targeted fundamental research and engineering with urgency, pushing the technological envelope on electricity-driven chemical transformations.

    Research leads: Yet-Ming Chiang, the Kyocera Professor of Materials Science and Engineering, and Bilge Yıldız, the Breene M. Kerr Professor in the Department of Nuclear Science and Engineering and professor in the Department of Materials Science and Engineering

    Preparing for a new world of weather and climate extremes

    This project addresses key gaps in knowledge about intensifying extreme events such as floods, hurricanes, and heat waves, and quantifies their long-term risk in a changing climate. The team is developing a scalable climate-change adaptation toolkit to help vulnerable communities and low-carbon energy providers prepare for these extreme weather events.

    Research leads: Kerry Emanuel, the Cecil and Ida Green Professor of Atmospheric Science in the Department of Earth, Atmospheric and Planetary Sciences and co-director of the MIT Lorenz Center; Miho Mazereeuw, associate professor of architecture and urbanism in the Department of Architecture and director of the Urban Risk Lab; and Paul O’Gorman, professor in the Program in Atmospheres, Oceans, and Climate in the Department of Earth, Atmospheric and Planetary Sciences

    The Climate Resilience Early Warning System

    The CREWSnet project seeks to reinvent climate change adaptation with a novel forecasting system that empowers underserved communities to interpret local climate risk, proactively plan for their futures incorporating resilience strategies, and minimize losses. CREWSnet will initially be demonstrated in southwestern Bangladesh, serving as a model for similarly threatened regions around the world.

    Research leads: John Aldridge, assistant leader of the Humanitarian Assistance and Disaster Relief Systems Group at MIT Lincoln Laboratory, and Elfatih Eltahir, the H.M. King Bhumibol Professor of Hydrology and Climate in the Department of Civil and Environmental Engineering

    Revolutionizing agriculture with low-emissions, resilient crops

    This project works to revolutionize the agricultural sector with climate-resilient crops and fertilizers that have the ability to dramatically reduce greenhouse gas emissions from food production.

    Research lead: Christopher Voigt, the Daniel I.C. Wang Professor in the Department of Biological Engineering

    “As one of the world’s leading institutions of research and innovation, it is incumbent upon MIT to draw on our depth of knowledge, ingenuity, and ambition to tackle the hard climate problems now confronting the world,” says Richard Lester, MIT associate provost for international activities. “Together with collaborators across industry, finance, community, and government, the Climate Grand Challenges teams are looking to develop and implement high-impact, path-breaking climate solutions rapidly and at a grand scale.”

    The initial call for ideas in 2020 yielded nearly 100 letters of interest from almost 400 faculty members and senior researchers, representing 90 percent of MIT departments. After an extensive evaluation, 27 finalist teams received a total of $2.7 million to develop comprehensive research and innovation plans. The projects address four broad research themes:

    To select the winning projects, research plans were reviewed by panels of international experts representing relevant scientific and technical domains as well as experts in processes and policies for innovation and scalability.

    “In response to climate change, the world really needs to do two things quickly: deploy the solutions we already have much more widely, and develop new solutions that are urgently needed to tackle this intensifying threat,” says Maria Zuber, MIT vice president for research. “These five flagship projects exemplify MIT’s strong determination to bring its knowledge and expertise to bear in generating new ideas and solutions that will help solve the climate problem.”

    “The Climate Grand Challenges flagship projects set a new standard for inclusive climate solutions that can be adapted and implemented across the globe,” says MIT Chancellor Melissa Nobles. “This competition propels the entire MIT research community — faculty, students, postdocs, and staff — to act with urgency around a worsening climate crisis, and I look forward to seeing the difference these projects can make.”

    “MIT’s efforts on climate research amid the climate crisis was a primary reason that I chose to attend MIT, and remains a reason that I view the Institute favorably. MIT has a clear opportunity to be a thought leader in the climate space in our own MIT way, which is why CGC fits in so well,” says senior Megan Xu, who served on the Climate Grand Challenges student committee and is studying ways to make the food system more sustainable.

    The Climate Grand Challenges competition is a key initiative of “Fast Forward: MIT’s Climate Action Plan for the Decade,” which the Institute published in May 2021. Fast Forward outlines MIT’s comprehensive plan for helping the world address the climate crisis. It consists of five broad areas of action: sparking innovation, educating future generations, informing and leveraging government action, reducing MIT’s own climate impact, and uniting and coordinating all of MIT’s climate efforts. More

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    Probing how proteins pair up inside cells

    Despite its minute size, a single cell contains billions of molecules that bustle around and bind to one another, carrying out vital functions. The human genome encodes about 20,000 proteins, most of which interact with partner proteins to mediate upwards of 400,000 distinct interactions. These partners don’t just latch onto one another haphazardly; they only bind to very specific companions that they must recognize inside the crowded cell. If they create the wrong pairings — or even the right pairings at the wrong place or wrong time — cancer or other diseases can ensue. Scientists are hard at work investigating these protein-protein relationships, in order to understand how they work, and potentially create drugs that disrupt or mimic them to treat disease.

    The average human protein is composed of approximately 400 building blocks called amino acids, which are strung together and folded into a complex 3D structure. Within this long string of building blocks, some proteins contain stretches of four to six amino acids called short linear motifs (SLiMs), which mediate protein-protein interactions. Despite their simplicity and small size, SLiMs and their binding partners facilitate key cellular processes. However, it’s been historically difficult to devise experiments to probe how SLiMs recognize their specific binding partners.

    To address this problem, a group led by Theresa Hwang PhD ’21 designed a screening method to understand how SLiMs selectively bind to certain proteins, and even distinguish between those with similar structures. Using the detailed information they gleaned from studying these interactions, the researchers created their own synthetic molecule capable of binding extremely tightly to a protein called ENAH, which is implicated in cancer metastasis. The team shared their findings in a pair of eLife studies, one published on Dec. 2, 2021, and the other published Jan. 25.

    “The ability to test hundreds of thousands of potential SLiMs for binding provides a powerful tool to explore why proteins prefer specific SLiM partners over others,” says Amy Keating, professor of biology and biological engineering and the senior author on both studies. “As we gain an understanding of the tricks that a protein uses to select its partners, we can apply these in protein design to make our own binders to modulate protein function for research or therapeutic purposes.”

    Most existing screens for SLiMs simply select for short, tight binders, while neglecting SLiMs that don’t grip their partner proteins quite as strongly. To survey SLiMs with a wide range of binding affinities, Keating, Hwang, and their colleagues developed their own screen called MassTitr.

    The researchers also suspected that the amino acids on either side of the SLiM’s core four-to-six amino acid sequence might play an underappreciated role in binding. To test their theory, they used MassTitr to screen the human proteome in longer chunks comprised of 36 amino acids, in order to see which “extended” SLiMs would associate with the protein ENAH.

    ENAH, sometimes referred to as Mena, helps cells to move. This ability to migrate is critical for healthy cells, but cancer cells can co-opt it to spread. Scientists have found that reducing the amount of ENAH decreases the cancer cell’s ability to invade other tissues — suggesting that formulating drugs to disrupt this protein and its interactions could treat cancer.

    Thanks to MassTitr, the team identified 33 SLiM-containing proteins that bound to ENAH — 19 of which are potentially novel binding partners. They also discovered three distinct patterns of amino acids flanking core SLiM sequences that helped the SLiMs bind even tighter to ENAH. Of these extended SLiMs, one found in a protein called PCARE bound to ENAH with the highest known affinity of any SLiM to date.

    Next, the researchers combined a computer program called dTERMen with X-ray crystallography in order understand how and why PCARE binds to ENAH over ENAH’s two nearly identical sister proteins (VASP and EVL). Hwang and her colleagues saw that the amino acids flanking PCARE’s core SliM caused ENAH to change shape slightly when the two made contact, allowing the binding sites to latch onto one another. VASP and EVL, by contrast, could not undergo this structural change, so the PCARE SliM did not bind to either of them as tightly.

    Inspired by this unique interaction, Hwang designed her own protein that bound to ENAH with unprecedented affinity and specificity. “It was exciting that we were able to come up with such a specific binder,” she says. “This work lays the foundation for designing synthetic molecules with the potential to disrupt protein-protein interactions that cause disease — or to help scientists learn more about ENAH and other SLiM-binding proteins.”  

    Ylva Ivarsson, a professor of biochemistry at Uppsala University who was not involved with the study, says that understanding how proteins find their binding partners is a question of fundamental importance to cell function and regulation. The two eLife studies, she explains, show that extended SLiMs play an underappreciated role in determining the affinity and specificity of these binding interactions.

    “The studies shed light on the idea that context matters, and provide a screening strategy for a variety of context-dependent binding interactions,” she says. “Hwang and co-authors have created valuable tools for dissecting the cellular function of proteins and their binding partners. Their approach could even inspire ENAH-specific inhibitors for therapeutic purposes.”

    Hwang’s biggest takeaway from the project is that things are not always as they seem: even short, simple protein segments can play complex roles in the cell. As she puts it: “We should really appreciate SLiMs more.” More

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    Meet the 2021-22 Accenture Fellows

    Launched in October of 2020, the MIT and Accenture Convergence Initiative for Industry and Technology underscores the ways in which industry and technology come together to spur innovation. The five-year initiative aims to achieve its mission through research, education, and fellowships. To that end, Accenture has once again awarded five annual fellowships to MIT graduate students working on research in industry and technology convergence who are underrepresented, including by race, ethnicity, and gender.

    This year’s Accenture Fellows work across disciplines including robotics, manufacturing, artificial intelligence, and biomedicine. Their research covers a wide array of subjects, including: advancing manufacturing through computational design, with the potential to benefit global vaccine production; designing low-energy robotics for both consumer electronics and the aerospace industry; developing robotics and machine learning systems that may aid the elderly in their homes; and creating ingestible biomedical devices that can help gather medical data from inside a patient’s body.

    Student nominations from each unit within the School of Engineering, as well as from the four other MIT schools and the MIT Schwarzman College of Computing, were invited as part of the application process. Five exceptional students were selected as fellows in the initiative’s second year.

    Xinming (Lily) Liu is a PhD student in operations research at MIT Sloan School of Management. Her work is focused on behavioral and data-driven operations for social good, incorporating human behaviors into traditional optimization models, designing incentives, and analyzing real-world data. Her current research looks at the convergence of social media, digital platforms, and agriculture, with particular attention to expanding technological equity and economic opportunity in developing countries. Liu earned her BS from Cornell University, with a double major in operations research and computer science.

    Caris Moses is a PhD student in electrical engineering and computer science specializing inartificial intelligence. Moses’ research focuses on using machine learning, optimization, and electromechanical engineering to build robotics systems that are robust, flexible, intelligent, and can learn on the job. The technology she is developing holds promise for industries including flexible, small-batch manufacturing; robots to assist the elderly in their households; and warehouse management and fulfillment. Moses earned her BS in mechanical engineering from Cornell University and her MS in computer science from Northeastern University.

    Sergio Rodriguez Aponte is a PhD student in biological engineering. He is working on the convergence of computational design and manufacturing practices, which have the potential to impact industries such as biopharmaceuticals, food, and wellness/nutrition. His current research aims to develop strategies for applying computational tools, such as multiscale modeling and machine learning, to the design and production of manufacturable and accessible vaccine candidates that could eventually be available globally. Rodriguez Aponte earned his BS in industrial biotechnology from the University of Puerto Rico at Mayaguez.

    Soumya Sudhakar SM ’20 is a PhD student in aeronautics and astronautics. Her work is focused on theco-design of new algorithms and integrated circuits for autonomous low-energy robotics that could have novel applications in aerospace and consumer electronics. Her contributions bring together the emerging robotics industry, integrated circuits industry, aerospace industry, and consumer electronics industry. Sudhakar earned her BSE in mechanical and aerospace engineering from Princeton University and her MS in aeronautics and astronautics from MIT.

    So-Yoon Yang is a PhD student in electrical engineering and computer science. Her work on the development of low-power, wireless, ingestible biomedical devices for health care is at the intersection of the medical device, integrated circuit, artificial intelligence, and pharmaceutical fields. Currently, the majority of wireless biomedical devices can only provide a limited range of medical data measured from outside the body. Ingestible devices hold promise for the next generation of personal health care because they do not require surgical implantation, can be useful for detecting physiological and pathophysiological signals, and can also function as therapeutic alternatives when treatment cannot be done externally. Yang earned her BS in electrical and computer engineering from Seoul National University in South Korea and her MS in electrical engineering from Caltech. More