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    Search algorithm reveals nearly 200 new kinds of CRISPR systems

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    Microbial sequence databases contain a wealth of information about enzymes and other molecules that could be adapted for biotechnology. But these databases have grown so large in recent years that they’ve become difficult to search efficiently for enzymes of interest.

    Now, scientists at the McGovern Institute for Brain Research at MIT, the Broad Institute of MIT and Harvard, and the National Center for Biotechnology Information (NCBI) at the National Institutes of Health have developed a new search algorithm that has identified 188 kinds of new rare CRISPR systems in bacterial genomes, encompassing thousands of individual systems. The work appears today in Science.

    The algorithm, which comes from the lab of pioneering CRISPR researcher Professor Feng Zhang, uses big-data clustering approaches to rapidly search massive amounts of genomic data. The team used their algorithm, called Fast Locality-Sensitive Hashing-based clustering (FLSHclust) to mine three major public databases that contain data from a wide range of unusual bacteria, including ones found in coal mines, breweries, Antarctic lakes, and dog saliva. The scientists found a surprising number and diversity of CRISPR systems, including ones that could make edits to DNA in human cells, others that can target RNA, and many with a variety of other functions.

    The new systems could potentially be harnessed to edit mammalian cells with fewer off-target effects than current Cas9 systems. They could also one day be used as diagnostics or serve as molecular records of activity inside cells.

    The researchers say their search highlights an unprecedented level of diversity and flexibility of CRISPR and that there are likely many more rare systems yet to be discovered as databases continue to grow.

    “Biodiversity is such a treasure trove, and as we continue to sequence more genomes and metagenomic samples, there is a growing need for better tools, like FLSHclust, to search that sequence space to find the molecular gems,” says Zhang, a co-senior author on the study and the James and Patricia Poitras Professor of Neuroscience at MIT with joint appointments in the departments of Brain and Cognitive Sciences and Biological Engineering. Zhang is also an investigator at the McGovern Institute for Brain Research at MIT, a core institute member at the Broad, and an investigator at the Howard Hughes Medical Institute. Eugene Koonin, a distinguished investigator at the NCBI, is co-senior author on the study as well.

    Searching for CRISPR

    CRISPR, which stands for clustered regularly interspaced short palindromic repeats, is a bacterial defense system that has been engineered into many tools for genome editing and diagnostics.

    To mine databases of protein and nucleic acid sequences for novel CRISPR systems, the researchers developed an algorithm based on an approach borrowed from the big data community. This technique, called locality-sensitive hashing, clusters together objects that are similar but not exactly identical. Using this approach allowed the team to probe billions of protein and DNA sequences — from the NCBI, its Whole Genome Shotgun database, and the Joint Genome Institute — in weeks, whereas previous methods that look for identical objects would have taken months. They designed their algorithm to look for genes associated with CRISPR.

    “This new algorithm allows us to parse through data in a time frame that’s short enough that we can actually recover results and make biological hypotheses,” says Soumya Kannan PhD ’23, who is a co-first author on the study. Kannan was a graduate student in Zhang’s lab when the study began and is currently a postdoc and Junior Fellow at Harvard University. Han Altae-Tran PhD ’23, a graduate student in Zhang’s lab during the study and currently a postdoc at the University of Washington, was the study’s other co-first author.

    “This is a testament to what you can do when you improve on the methods for exploration and use as much data as possible,” says Altae-Tran. “It’s really exciting to be able to improve the scale at which we search.”

    New systems

    In their analysis, Altae-Tran, Kannan, and their colleagues noticed that the thousands of CRISPR systems they found fell into a few existing and many new categories. They studied several of the new systems in greater detail in the lab.

    They found several new variants of known Type I CRISPR systems, which use a guide RNA that is 32 base pairs long rather than the 20-nucleotide guide of Cas9. Because of their longer guide RNAs, these Type I systems could potentially be used to develop more precise gene-editing technology that is less prone to off-target editing. Zhang’s team showed that two of these systems could make short edits in the DNA of human cells. And because these Type I systems are similar in size to CRISPR-Cas9, they could likely be delivered to cells in animals or humans using the same gene-delivery technologies being used today for CRISPR.

    One of the Type I systems also showed “collateral activity” — broad degradation of nucleic acids after the CRISPR protein binds its target. Scientists have used similar systems to make infectious disease diagnostics such as SHERLOCK, a tool capable of rapidly sensing a single molecule of DNA or RNA. Zhang’s team thinks the new systems could be adapted for diagnostic technologies as well.

    The researchers also uncovered new mechanisms of action for some Type IV CRISPR systems, and a Type VII system that precisely targets RNA, which could potentially be used in RNA editing. Other systems could potentially be used as recording tools — a molecular document of when a gene was expressed — or as sensors of specific activity in a living cell.

    Mining data

    The scientists say their algorithm could aid in the search for other biochemical systems. “This search algorithm could be used by anyone who wants to work with these large databases for studying how proteins evolve or discovering new genes,” Altae-Tran says.

    The researchers add that their findings illustrate not only how diverse CRISPR systems are, but also that most are rare and only found in unusual bacteria. “Some of these microbial systems were exclusively found in water from coal mines,” Kannan says. “If someone hadn’t been interested in that, we may never have seen those systems. Broadening our sampling diversity is really important to continue expanding the diversity of what we can discover.”

    This work was supported by the Howard Hughes Medical Institute; the K. Lisa Yang and Hock E. Tan Molecular Therapeutics Center at MIT; Broad Institute Programmable Therapeutics Gift Donors; The Pershing Square Foundation, William Ackman and Neri Oxman; James and Patricia Poitras; BT Charitable Foundation; Asness Family Foundation; Kenneth C. Griffin; the Phillips family; David Cheng; and Robert Metcalfe. More

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      2023-24 Takeda Fellows: Advancing research at the intersection of AI and health

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      The School of Engineering has selected 13 new Takeda Fellows for the 2023-24 academic year. With support from Takeda, the graduate students will conduct pathbreaking research ranging from remote health monitoring for virtual clinical trials to ingestible devices for at-home, long-term diagnostics.

      Now in its fourth year, the MIT-Takeda Program, a collaboration between MIT’s School of Engineering and Takeda, fuels the development and application of artificial intelligence capabilities to benefit human health and drug development. Part of the Abdul Latif Jameel Clinic for Machine Learning in Health, the program coalesces disparate disciplines, merges theory and practical implementation, combines algorithm and hardware innovations, and creates multidimensional collaborations between academia and industry.

      The 2023-24 Takeda Fellows are:

      Adam Gierlach

      Adam Gierlach is a PhD candidate in the Department of Electrical Engineering and Computer Science. Gierlach’s work combines innovative biotechnology with machine learning to create ingestible devices for advanced diagnostics and delivery of therapeutics. In his previous work, Gierlach developed a non-invasive, ingestible device for long-term gastric recordings in free-moving patients. With the support of a Takeda Fellowship, he will build on this pathbreaking work by developing smart, energy-efficient, ingestible devices powered by application-specific integrated circuits for at-home, long-term diagnostics. These revolutionary devices — capable of identifying, characterizing, and even correcting gastrointestinal diseases — represent the leading edge of biotechnology. Gierlach’s innovative contributions will help to advance fundamental research on the enteric nervous system and help develop a better understanding of gut-brain axis dysfunctions in Parkinson’s disease, autism spectrum disorder, and other prevalent disorders and conditions.

      Vivek Gopalakrishnan

      Vivek Gopalakrishnan is a PhD candidate in the Harvard-MIT Program in Health Sciences and Technology. Gopalakrishnan’s goal is to develop biomedical machine-learning methods to improve the study and treatment of human disease. Specifically, he employs computational modeling to advance new approaches for minimally invasive, image-guided neurosurgery, offering a safe alternative to open brain and spinal procedures. With the support of a Takeda Fellowship, Gopalakrishnan will develop real-time computer vision algorithms that deliver high-quality, 3D intraoperative image guidance by extracting and fusing information from multimodal neuroimaging data. These algorithms could allow surgeons to reconstruct 3D neurovasculature from X-ray angiography, thereby enhancing the precision of device deployment and enabling more accurate localization of healthy versus pathologic anatomy.

      Hao He

      Hao He is a PhD candidate in the Department of Electrical Engineering and Computer Science. His research interests lie at the intersection of generative AI, machine learning, and their applications in medicine and human health, with a particular emphasis on passive, continuous, remote health monitoring to support virtual clinical trials and health-care management. More specifically, He aims to develop trustworthy AI models that promote equitable access and deliver fair performance independent of race, gender, and age. In his past work, He has developed monitoring systems applied in clinical studies of Parkinson’s disease, Alzheimer’s disease, and epilepsy. Supported by a Takeda Fellowship, He will develop a novel technology for the passive monitoring of sleep stages (using radio signaling) that seeks to address existing gaps in performance across different demographic groups. His project will tackle the problem of imbalance in available datasets and account for intrinsic differences across subpopulations, using generative AI and multi-modality/multi-domain learning, with the goal of learning robust features that are invariant to different subpopulations. He’s work holds great promise for delivering advanced, equitable health-care services to all people and could significantly impact health care and AI.

      Chengyi Long

      Chengyi Long is a PhD candidate in the Department of Civil and Environmental Engineering. Long’s interdisciplinary research integrates the methodology of physics, mathematics, and computer science to investigate questions in ecology. Specifically, Long is developing a series of potentially groundbreaking techniques to explain and predict the temporal dynamics of ecological systems, including human microbiota, which are essential subjects in health and medical research. His current work, supported by a Takeda Fellowship, is focused on developing a conceptual, mathematical, and practical framework to understand the interplay between external perturbations and internal community dynamics in microbial systems, which may serve as a key step toward finding bio solutions to health management. A broader perspective of his research is to develop AI-assisted platforms to anticipate the changing behavior of microbial systems, which may help to differentiate between healthy and unhealthy hosts and design probiotics for the prevention and mitigation of pathogen infections. By creating novel methods to address these issues, Long’s research has the potential to offer powerful contributions to medicine and global health.

      Omar Mohd

      Omar Mohd is a PhD candidate in the Department of Electrical Engineering and Computer Science. Mohd’s research is focused on developing new technologies for the spatial profiling of microRNAs, with potentially important applications in cancer research. Through innovative combinations of micro-technologies and AI-enabled image analysis to measure the spatial variations of microRNAs within tissue samples, Mohd hopes to gain new insights into drug resistance in cancer. This work, supported by a Takeda Fellowship, falls within the emerging field of spatial transcriptomics, which seeks to understand cancer and other diseases by examining the relative locations of cells and their contents within tissues. The ultimate goal of Mohd’s current project is to find multidimensional patterns in tissues that may have prognostic value for cancer patients. One valuable component of his work is an open-source AI program developed with collaborators at Beth Israel Deaconess Medical Center and Harvard Medical School to auto-detect cancer epithelial cells from other cell types in a tissue sample and to correlate their abundance with the spatial variations of microRNAs. Through his research, Mohd is making innovative contributions at the interface of microsystem technology, AI-based image analysis, and cancer treatment, which could significantly impact medicine and human health.

      Sanghyun Park

      Sanghyun Park is a PhD candidate in the Department of Mechanical Engineering. Park specializes in the integration of AI and biomedical engineering to address complex challenges in human health. Drawing on his expertise in polymer physics, drug delivery, and rheology, his research focuses on the pioneering field of in-situ forming implants (ISFIs) for drug delivery. Supported by a Takeda Fellowship, Park is currently developing an injectable formulation designed for long-term drug delivery. The primary goal of his research is to unravel the compaction mechanism of drug particles in ISFI formulations through comprehensive modeling and in-vitro characterization studies utilizing advanced AI tools. He aims to gain a thorough understanding of this unique compaction mechanism and apply it to drug microcrystals to achieve properties optimal for long-term drug delivery. Beyond these fundamental studies, Park’s research also focuses on translating this knowledge into practical applications in a clinical setting through animal studies specifically aimed at extending drug release duration and improving mechanical properties. The innovative use of AI in developing advanced drug delivery systems, coupled with Park’s valuable insights into the compaction mechanism, could contribute to improving long-term drug delivery. This work has the potential to pave the way for effective management of chronic diseases, benefiting patients, clinicians, and the pharmaceutical industry.

      Huaiyao Peng

      Huaiyao Peng is a PhD candidate in the Department of Biological Engineering. Peng’s research interests are focused on engineered tissue, microfabrication platforms, cancer metastasis, and the tumor microenvironment. Specifically, she is advancing novel AI techniques for the development of pre-cancer organoid models of high-grade serous ovarian cancer (HGSOC), an especially lethal and difficult-to-treat cancer, with the goal of gaining new insights into progression and effective treatments. Peng’s project, supported by a Takeda Fellowship, will be one of the first to use cells from serous tubal intraepithelial carcinoma lesions found in the fallopian tubes of many HGSOC patients. By examining the cellular and molecular changes that occur in response to treatment with small molecule inhibitors, she hopes to identify potential biomarkers and promising therapeutic targets for HGSOC, including personalized treatment options for HGSOC patients, ultimately improving their clinical outcomes. Peng’s work has the potential to bring about important advances in cancer treatment and spur innovative new applications of AI in health care. 

      Priyanka Raghavan

      Priyanka Raghavan is a PhD candidate in the Department of Chemical Engineering. Raghavan’s research interests lie at the frontier of predictive chemistry, integrating computational and experimental approaches to build powerful new predictive tools for societally important applications, including drug discovery. Specifically, Raghavan is developing novel models to predict small-molecule substrate reactivity and compatibility in regimes where little data is available (the most realistic regimes). A Takeda Fellowship will enable Raghavan to push the boundaries of her research, making innovative use of low-data and multi-task machine learning approaches, synthetic chemistry, and robotic laboratory automation, with the goal of creating an autonomous, closed-loop system for the discovery of high-yielding organic small molecules in the context of underexplored reactions. Raghavan’s work aims to identify new, versatile reactions to broaden a chemist’s synthetic toolbox with novel scaffolds and substrates that could form the basis of essential drugs. Her work has the potential for far-reaching impacts in early-stage, small-molecule discovery and could help make the lengthy drug-discovery process significantly faster and cheaper.

      Zhiye Song

      Zhiye “Zoey” Song is a PhD candidate in the Department of Electrical Engineering and Computer Science. Song’s research integrates cutting-edge approaches in machine learning (ML) and hardware optimization to create next-generation, wearable medical devices. Specifically, Song is developing novel approaches for the energy-efficient implementation of ML computation in low-power medical devices, including a wearable ultrasound “patch” that captures and processes images for real-time decision-making capabilities. Her recent work, conducted in collaboration with clinicians, has centered on bladder volume monitoring; other potential applications include blood pressure monitoring, muscle diagnosis, and neuromodulation. With the support of a Takeda Fellowship, Song will build on that promising work and pursue key improvements to existing wearable device technologies, including developing low-compute and low-memory ML algorithms and low-power chips to enable ML on smart wearable devices. The technologies emerging from Song’s research could offer exciting new capabilities in health care, enabling powerful and cost-effective point-of-care diagnostics and expanding individual access to autonomous and continuous medical monitoring.

      Peiqi Wang

      Peiqi Wang is a PhD candidate in the Department of Electrical Engineering and Computer Science. Wang’s research aims to develop machine learning methods for learning and interpretation from medical images and associated clinical data to support clinical decision-making. He is developing a multimodal representation learning approach that aligns knowledge captured in large amounts of medical image and text data to transfer this knowledge to new tasks and applications. Supported by a Takeda Fellowship, Wang will advance this promising line of work to build robust tools that interpret images, learn from sparse human feedback, and reason like doctors, with potentially major benefits to important stakeholders in health care.

      Oscar Wu

      Haoyang “Oscar” Wu is a PhD candidate in the Department of Chemical Engineering. Wu’s research integrates quantum chemistry and deep learning methods to accelerate the process of small-molecule screening in the development of new drugs. By identifying and automating reliable methods for finding transition state geometries and calculating barrier heights for new reactions, Wu’s work could make it possible to conduct the high-throughput ab initio calculations of reaction rates needed to screen the reactivity of large numbers of active pharmaceutical ingredients (APIs). A Takeda Fellowship will support his current project to: (1) develop open-source software for high-throughput quantum chemistry calculations, focusing on the reactivity of drug-like molecules, and (2) develop deep learning models that can quantitatively predict the oxidative stability of APIs. The tools and insights resulting from Wu’s research could help to transform and accelerate the drug-discovery process, offering significant benefits to the pharmaceutical and medical fields and to patients.

      Soojung Yang

      Soojung Yang is a PhD candidate in the Department of Materials Science and Engineering. Yang’s research applies cutting-edge methods in geometric deep learning and generative modeling, along with atomistic simulations, to better understand and model protein dynamics. Specifically, Yang is developing novel tools in generative AI to explore protein conformational landscapes that offer greater speed and detail than physics-based simulations at a substantially lower cost. With the support of a Takeda Fellowship, she will build upon her successful work on the reverse transformation of coarse-grained proteins to the all-atom resolution, aiming to build machine-learning models that bridge multiple size scales of protein conformation diversity (all-atom, residue-level, and domain-level). Yang’s research holds the potential to provide a powerful and widely applicable new tool for researchers who seek to understand the complex protein functions at work in human diseases and to design drugs to treat and cure those diseases.

      Yuzhe Yang

      Yuzhe Yang is a PhD candidate in the Department of Electrical Engineering and Computer Science. Yang’s research interests lie at the intersection of machine learning and health care. In his past and current work, Yang has developed and applied innovative machine-learning models that address key challenges in disease diagnosis and tracking. His many notable achievements include the creation of one of the first machine learning-based solutions using nocturnal breathing signals to detect Parkinson’s disease (PD), estimate disease severity, and track PD progression. With the support of a Takeda Fellowship, Yang will expand this promising work to develop an AI-based diagnosis model for Alzheimer’s disease (AD) using sleep-breathing data that is significantly more reliable, flexible, and economical than current diagnostic tools. This passive, in-home, contactless monitoring system — resembling a simple home Wi-Fi router — will also enable remote disease assessment and continuous progression tracking. Yang’s groundbreaking work has the potential to advance the diagnosis and treatment of prevalent diseases like PD and AD, and it offers exciting possibilities for addressing many health challenges with reliable, affordable machine-learning tools.  More

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      A more effective experimental design for engineering a cell into a new state

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      A strategy for cellular reprogramming involves using targeted genetic interventions to engineer a cell into a new state. The technique holds great promise in immunotherapy, for instance, where researchers could reprogram a patient’s T-cells so they are more potent cancer killers. Someday, the approach could also help identify life-saving cancer treatments or regenerative therapies that repair disease-ravaged organs.

      But the human body has about 20,000 genes, and a genetic perturbation could be on a combination of genes or on any of the over 1,000 transcription factors that regulate the genes. Because the search space is vast and genetic experiments are costly, scientists often struggle to find the ideal perturbation for their particular application.   

      Researchers from MIT and Harvard University developed a new, computational approach that can efficiently identify optimal genetic perturbations based on a much smaller number of experiments than traditional methods.

      Their algorithmic technique leverages the cause-and-effect relationship between factors in a complex system, such as genome regulation, to prioritize the best intervention in each round of sequential experiments.

      The researchers conducted a rigorous theoretical analysis to determine that their technique did, indeed, identify optimal interventions. With that theoretical framework in place, they applied the algorithms to real biological data designed to mimic a cellular reprogramming experiment. Their algorithms were the most efficient and effective.

      “Too often, large-scale experiments are designed empirically. A careful causal framework for sequential experimentation may allow identifying optimal interventions with fewer trials, thereby reducing experimental costs,” says co-senior author Caroline Uhler, a professor in the Department of Electrical Engineering and Computer Science (EECS) who is also co-director of the Eric and Wendy Schmidt Center at the Broad Institute of MIT and Harvard, and a researcher at MIT’s Laboratory for Information and Decision Systems (LIDS) and Institute for Data, Systems and Society (IDSS).

      Joining Uhler on the paper, which appears today in Nature Machine Intelligence, are lead author Jiaqi Zhang, a graduate student and Eric and Wendy Schmidt Center Fellow; co-senior author Themistoklis P. Sapsis, professor of mechanical and ocean engineering at MIT and a member of IDSS; and others at Harvard and MIT.

      Active learning

      When scientists try to design an effective intervention for a complex system, like in cellular reprogramming, they often perform experiments sequentially. Such settings are ideally suited for the use of a machine-learning approach called active learning. Data samples are collected and used to learn a model of the system that incorporates the knowledge gathered so far. From this model, an acquisition function is designed — an equation that evaluates all potential interventions and picks the best one to test in the next trial.

      This process is repeated until an optimal intervention is identified (or resources to fund subsequent experiments run out).

      “While there are several generic acquisition functions to sequentially design experiments, these are not effective for problems of such complexity, leading to very slow convergence,” Sapsis explains.

      Acquisition functions typically consider correlation between factors, such as which genes are co-expressed. But focusing only on correlation ignores the regulatory relationships or causal structure of the system. For instance, a genetic intervention can only affect the expression of downstream genes, but a correlation-based approach would not be able to distinguish between genes that are upstream or downstream.

      “You can learn some of this causal knowledge from the data and use that to design an intervention more efficiently,” Zhang explains.

      The MIT and Harvard researchers leveraged this underlying causal structure for their technique. First, they carefully constructed an algorithm so it can only learn models of the system that account for causal relationships.

      Then the researchers designed the acquisition function so it automatically evaluates interventions using information on these causal relationships. They crafted this function so it prioritizes the most informative interventions, meaning those most likely to lead to the optimal intervention in subsequent experiments.

      “By considering causal models instead of correlation-based models, we can already rule out certain interventions. Then, whenever you get new data, you can learn a more accurate causal model and thereby further shrink the space of interventions,” Uhler explains.

      This smaller search space, coupled with the acquisition function’s special focus on the most informative interventions, is what makes their approach so efficient.

      The researchers further improved their acquisition function using a technique known as output weighting, inspired by the study of extreme events in complex systems. This method carefully emphasizes interventions that are likely to be closer to the optimal intervention.

      “Essentially, we view an optimal intervention as an ‘extreme event’ within the space of all possible, suboptimal interventions and use some of the ideas we have developed for these problems,” Sapsis says.    

      Enhanced efficiency

      They tested their algorithms using real biological data in a simulated cellular reprogramming experiment. For this test, they sought a genetic perturbation that would result in a desired shift in average gene expression. Their acquisition functions consistently identified better interventions than baseline methods through every step in the multi-stage experiment.

      “If you cut the experiment off at any stage, ours would still be more efficient than the baselines. This means you could run fewer experiments and get the same or better results,” Zhang says.

      The researchers are currently working with experimentalists to apply their technique toward cellular reprogramming in the lab.

      Their approach could also be applied to problems outside genomics, such as identifying optimal prices for consumer products or enabling optimal feedback control in fluid mechanics applications.

      In the future, they plan to enhance their technique for optimizations beyond those that seek to match a desired mean. In addition, their method assumes that scientists already understand the causal relationships in their system, but future work could explore how to use AI to learn that information, as well.

      This work was funded, in part, by the Office of Naval Research, the MIT-IBM Watson AI Lab, the MIT J-Clinic for Machine Learning and Health, the Eric and Wendy Schmidt Center at the Broad Institute, a Simons Investigator Award, the Air Force Office of Scientific Research, and a National Science Foundation Graduate Fellowship. More

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      The tenured engineers of 2023

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      In 2023, MIT granted tenure to nine faculty members across the School of Engineering. This year’s tenured engineers hold appointments in the departments of Biological Engineering, Civil and Environmental Engineering, Electrical Engineering and Computer Science (which reports jointly to the School of Engineering and MIT Schwarzman College of Computing), Materials Science and Engineering, and Mechanical Engineering, as well as the Institute for Medical Engineering and Science (IMES).

      “I am truly inspired by this remarkable group of talented faculty members,” says Anantha Chandrakasan, dean of the School of Engineering and the Vannevar Bush Professor of Electrical Engineering and Computer Science. “The work they are doing, both in the lab and in the classroom, has made a tremendous impact at MIT and in the wider world. Their important research has applications in a diverse range of fields and industries. I am thrilled to congratulate them on the milestone of receiving tenure.”

      This year’s newly tenured engineering faculty include:

      Michael Birnbaum, Class of 1956 Career Development Professor, associate professor of biological engineering, and faculty member at the Koch Institute for Integrative Cancer Research at MIT, works on understanding and manipulating immune recognition in cancer and infections. By using a variety of techniques to study the antigen recognition of T cells, he and his team aim to develop the next generation of immunotherapies.  
      Tamara Broderick, associate professor of electrical engineering and computer science and member of the MIT Laboratory for Information and Decision Systems (LIDS) and the MIT Institute for Data, Systems, and Society (IDSS), works to provide fast and reliable quantification of uncertainty and robustness in modern data analysis procedures. Broderick and her research group develop data analysis tools with applications in fields, including genetics, economics, and assistive technology. 
      Tal Cohen, associate professor of civil and environmental engineering and mechanical engineering, uses nonlinear solid mechanics to understand how materials behave under extreme conditions. By studying material instabilities, extreme dynamic loading conditions, growth, and chemical coupling, Cohen and her team combine theoretical models and experiments to shape our understanding of the observed phenomena and apply those insights in the design and characterization of material systems. 
      Betar Gallant, Class of 1922 Career Development Professor and associate professor of mechanical engineering, develops advanced materials and chemistries for next-generation lithium-ion and lithium primary batteries and electrochemical carbon dioxide mitigation technologies. Her group’s work could lead to higher-energy and more sustainable batteries for electric vehicles, longer-lasting implantable medical devices, and new methods of carbon capture and conversion. 
      Rafael Jaramillo, Thomas Lord Career Development Professor and associate professor of materials science and engineering, studies the synthesis, properties, and applications of electronic materials, particularly chalcogenide compound semiconductors. His work has applications in microelectronics, integrated photonics, telecommunications, and photovoltaics. 
      Benedetto Marelli, associate professor of civil and environmental engineering, conducts research on the synthesis, assembly, and nanomanufacturing of structural biopolymers. He and his research team develop biomaterials for applications in agriculture, food security, and food safety. 
      Ellen Roche, Latham Family Career Development Professor, an associate professor of mechanical engineering, and a core faculty of IMES, designs and develops implantable, biomimetic therapeutic devices and soft robotics that mechanically assist and repair tissue, deliver therapies, and enable enhanced preclinical testing. Her devices have a wide range of applications in human health, including cardiovascular and respiratory disease. 
      Serguei Saavedra, associate professor of civil and environmental engineering, uses systems thinking, synthesis, and mathematical modeling to study the persistence of ecological systems under changing environments. His theoretical research is used to develop hypotheses and corroborate predictions of how ecological systems respond to climate change. 
      Justin Solomon, associate professor of electrical engineering and computer science and member of the MIT Computer Science and Artificial Intelligence Laboratory and MIT Center for Computational Science and Engineering, works at the intersection of geometry, large-scale optimization, computer graphics, and machine learning. His research has diverse applications in machine learning, computer graphics, and geometric data processing.  More

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      Making sense of cell fate

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      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

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      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

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      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

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      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

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      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