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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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      What words can convey

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      From search engines to voice assistants, computers are getting better at understanding what we mean. That’s thanks to language-processing programs that make sense of a staggering number of words, without ever being told explicitly what those words mean. Such programs infer meaning instead through statistics — and a new study reveals that this computational approach can assign many kinds of information to a single word, just like the human brain.

      The study, published April 14 in the journal Nature Human Behavior, was co-led by Gabriel Grand, a graduate student in electrical engineering and computer science who is affiliated with MIT’s Computer Science and Artificial Intelligence Laboratory, and Idan Blank PhD ’16, an assistant professor at the University of California at Los Angeles. The work was supervised by McGovern Institute for Brain Research investigator Ev Fedorenko, a cognitive neuroscientist who studies how the human brain uses and understands language, and Francisco Pereira at the National Institute of Mental Health. Fedorenko says the rich knowledge her team was able to find within computational language models demonstrates just how much can be learned about the world through language alone.

      The research team began its analysis of statistics-based language processing models in 2015, when the approach was new. Such models derive meaning by analyzing how often pairs of words co-occur in texts and using those relationships to assess the similarities of words’ meanings. For example, such a program might conclude that “bread” and “apple” are more similar to one another than they are to “notebook,” because “bread” and “apple” are often found in proximity to words like “eat” or “snack,” whereas “notebook” is not.

      The models were clearly good at measuring words’ overall similarity to one another. But most words carry many kinds of information, and their similarities depend on which qualities are being evaluated. “Humans can come up with all these different mental scales to help organize their understanding of words,” explains Grand, a former undergraduate researcher in the Fedorenko lab. For example, he says, “dolphins and alligators might be similar in size, but one is much more dangerous than the other.”

      Grand and Blank, who was then a graduate student at the McGovern Institute, wanted to know whether the models captured that same nuance. And if they did, how was the information organized?

      To learn how the information in such a model stacked up to humans’ understanding of words, the team first asked human volunteers to score words along many different scales: Were the concepts those words conveyed big or small, safe or dangerous, wet or dry? Then, having mapped where people position different words along these scales, they looked to see whether language processing models did the same.

      Grand explains that distributional semantic models use co-occurrence statistics to organize words into a huge, multidimensional matrix. The more similar words are to one another, the closer they are within that space. The dimensions of the space are vast, and there is no inherent meaning built into its structure. “In these word embeddings, there are hundreds of dimensions, and we have no idea what any dimension means,” he says. “We’re really trying to peer into this black box and say, ‘is there structure in here?’”

      Specifically, they asked whether the semantic scales they had asked their volunteers use were represented in the model. So they looked to see where words in the space lined up along vectors defined by the extremes of those scales. Where did dolphins and tigers fall on line from “big” to “small,” for example? And were they closer together along that line than they were on a line representing danger (“safe” to “dangerous”)?

      Across more than 50 sets of world categories and semantic scales, they found that the model had organized words very much like the human volunteers. Dolphins and tigers were judged to be similar in terms of size, but far apart on scales measuring danger or wetness. The model had organized the words in a way that represented many kinds of meaning — and it had done so based entirely on the words’ co-occurrences.

      That, Fedorenko says, tells us something about the power of language. “The fact that we can recover so much of this rich semantic information from just these simple word co-occurrence statistics suggests that this is one very powerful source of learning about things that you may not even have direct perceptual experience with.” More

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      in Data Management & Statistics

      New integrative computational neuroscience center established at MIT’s McGovern Institute

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      With the tools of modern neuroscience, researchers can peer into the brain with unprecedented accuracy. Recording devices listen in on the electrical conversations between neurons, picking up the voices of hundreds of cells at a time. Genetic tools allow us to focus on specific types of neurons based on their molecular signatures. Microscopes zoom in to illuminate the brain’s circuitry, capturing thousands of images of elaborately branched dendrites. Functional MRIs detect changes in blood flow to map activity within a person’s brain, generating a complete picture by compiling hundreds of scans.

      This deluge of data provides insights into brain function and dynamics at different levels — molecules, cells, circuits, and behavior — but the insights remain compartmentalized in separate research silos for each level. An innovative new center at MIT’s McGovern Institute for Brain Research aims to leverage them into powerful revelations of the brain’s inner workings.

      The K. Lisa Yang Integrative Computational Neuroscience (ICoN) Center will create advanced mathematical models and computational tools to synthesize the deluge of data across scales and advance our understanding of the brain and mental health.

      The center, funded by a $24 million donation from philanthropist Lisa Yang and led by McGovern Institute Associate Investigator Ila Fiete, will take a collaborative approach to computational neuroscience, integrating cutting-edge modeling techniques and data from MIT labs to explain brain function at every level, from the molecular to the behavioral.

      “Our goal is that sophisticated, truly integrated computational models of the brain will make it possible to identify how ‘control knobs’ such as genes, proteins, chemicals, and environment drive thoughts and behavior, and to make inroads toward urgent unmet needs in understanding and treating brain disorders,” says Fiete, who is also a brain and cognitive sciences professor at MIT.

      “Driven by technologies that generate massive amounts of data, we are entering a new era of translational neuroscience research,” says Yang, whose philanthropic investment in MIT research now exceeds $130 million. “I am confident that the multidisciplinary expertise convened by the ICoN center will revolutionize how we synthesize this data and ultimately understand the brain in health and disease.”

      Connecting the data

      It is impossible to separate the molecules in the brain from their effects on behavior — although those aspects of neuroscience have traditionally been studied independently, by researchers with vastly different expertise. The ICoN Center will eliminate the divides, bringing together neuroscientists and software engineers to deal with all types of data about the brain.

      “The center’s highly collaborative structure, which is essential for unifying multiple levels of understanding, will enable us to recruit talented young scientists eager to revolutionize the field of computational neuroscience,” says Robert Desimone, director of the McGovern Institute. “It is our hope that the ICoN Center’s unique research environment will truly demonstrate a new academic research structure that catalyzes bold, creative research.”

      To foster interdisciplinary collaboration, every postdoc and engineer at the center will work with multiple faculty mentors. In order to attract young scientists and engineers to the field of computational neuroscience, the center will also provide four graduate fellowships to MIT students each year in perpetuity. Interacting closely with three scientific cores, engineers and fellows will develop computational models and technologies for analyzing molecular data, neural circuits, and behavior, such as tools to identify patterns in neural recordings or automate the analysis of human behavior to aid psychiatric diagnoses. These technologies and models will be instrumental in synthesizing data into knowledge and understanding.

      Center priorities

      In its first five years, the ICoN Center will prioritize four areas of investigation: episodic memory and exploration, including functions like navigation and spatial memory; complex or stereotypical behavior, such as the perseverative behaviors associated with autism and obsessive-compulsive disorder; cognition and attention; and sleep. Models of complex behavior will be created in collaboration with clinicians and researchers at Children’s Hospital of Philadelphia.

      The goal, Fiete says, is to model the neuronal interactions that underlie these functions so that researchers can predict what will happen when something changes — when certain neurons become more active or when a genetic mutation is introduced, for example. When paired with experimental data from MIT labs, the center’s models will help explain not just how these circuits work, but also how they are altered by genes, the environment, aging, and disease. These focus areas encompass circuits and behaviors often affected by psychiatric disorders and neurodegeneration, and models will give researchers new opportunities to explore their origins and potential treatment strategies.

      “Lisa Yang is focused on helping the scientific community realize its goals in translational research,” says Nergis Mavalvala, dean of the School of Science and the Curtis and Kathleen Marble Professor of Astrophysics. “With her generous support, we can accelerate the pace of research by connecting the data to the delivery of tangible results.” More