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    To design better water filters, MIT engineers look to manta rays

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    Filter feeders are everywhere in the animal world, from tiny crustaceans and certain types of coral and krill, to various molluscs, barnacles, and even massive basking sharks and baleen whales. Now, MIT engineers have found that one filter feeder has evolved to sift food in ways that could improve the design of industrial water filters.In a paper appearing this week in the Proceedings of the National Academy of Sciences, the team characterizes the filter-feeding mechanism of the mobula ray — a family of aquatic rays that includes two manta species and seven devil rays. Mobula rays feed by swimming open-mouthed through plankton-rich regions of the ocean and filtering plankton particles into their gullet as water streams into their mouths and out through their gills.The floor of the mobula ray’s mouth is lined on either side with parallel, comb-like structures, called plates, that siphon water into the ray’s gills. The MIT team has shown that the dimensions of these plates may allow for incoming plankton to bounce all the way across the plates and further into the ray’s cavity, rather than out through the gills. What’s more, the ray’s gills absorb oxygen from the outflowing water, helping the ray to simultaneously breathe while feeding.“We show that the mobula ray has evolved the geometry of these plates to be the perfect size to balance feeding and breathing,” says study author Anette “Peko” Hosoi, the Pappalardo Professor of Mechanical Engineering at MIT.The engineers fabricated a simple water filter modeled after the mobula ray’s plankton-filtering features. They studied how water flowed through the filter when it was fitted with 3D-printed plate-like structures. The team took the results of these experiments and drew up a blueprint, which they say designers can use to optimize industrial cross-flow filters, which are broadly similar in configuration to that of the mobula ray.“We want to expand the design space of traditional cross-flow filtration with new knowledge from the manta ray,” says lead author and MIT postdoc Xinyu Mao PhD ’24. “People can choose a parameter regime of the mobula ray so they could potentially improve overall filter performance.”Hosoi and Mao co-authored the new study with Irmgard Bischofberger, associate professor of mechanical engineering at MIT.A better trade-offThe new study grew out of the group’s focus on filtration during the height of the Covid pandemic, when the researchers were designing face masks to filter out the virus. Since then, Mao has shifted focus to study filtration in animals and how certain filter-feeding mechanisms might improve filters used in industry, such as in water treatment plants.Mao observed that any industrial filter must strike a balance between permeability (how easily fluid can flow through a filter), and selectivity (how successful a filter is at keeping out particles of a target size). For instance, a membrane that is studded with large holes might be highly permeable, meaning a lot of water can be pumped through using very little energy. However, the membrane’s large holes would let many particles through, making it very low in selectivity. Likewise, a membrane with much smaller pores would be more selective yet also require more energy to pump the water through the smaller openings.“We asked ourselves, how do we do better with this tradeoff between permeability and selectivity?” Hosoi says.As Mao looked into filter-feeding animals, he found that the mobula ray has struck an ideal balance between permeability and selectivity: The ray is highly permeable, in that it can let water into its mouth and out through its gills quickly enough to capture oxygen to breathe. At the same time, it is highly selective, filtering and feeding on plankton rather than letting the particles stream out through the gills.The researchers realized that the ray’s filtering features are broadly similar to that of industrial cross-flow filters. These filters are designed such that fluid flows across a permeable membrane that lets through most of the fluid, while any polluting particles continue flowing across the membrane and eventually out into a reservoir of waste.The team wondered whether the mobula ray might inspire design improvements to industrial cross-flow filters. For that, they took a deeper dive into the dynamics of mobula ray filtration.A vortex keyAs part of their new study, the team fabricated a simple filter inspired by the mobula ray. The filter’s design is what engineers refer to as a “leaky channel” — effectively, a pipe with holes along its sides. In this case, the team’s “channel” consists of two flat, transparent acrylic plates that are glued together at the edges, with a slight opening between the plates through which fluid can be pumped. At one end of the channel, the researchers inserted 3D-printed structures resembling the grooved plates that run along the floor of the mobula ray’s mouth.The team then pumped water through the channel at various rates, along with colored dye to visualize the flow. They took images across the channel and observed an interesting transition: At slow pumping rates, the flow was “very peaceful,” and fluid easily slipped through the grooves in the printed plates and out into a reservoir. When the researchers increased the pumping rate, the faster-flowing fluid did not slip through, but appeared to swirl at the mouth of each groove, creating a vortex, similar to a small knot of hair between the tips of a comb’s teeth.“This vortex is not blocking water, but it is blocking particles,” Hosoi explains. “Whereas in a slower flow, particles go through the filter with the water, at higher flow rates, particles try to get through the filter but are blocked by this vortex and are shot down the channel instead. The vortex is helpful because it prevents particles from flowing out.”The team surmised that vortices are the key to mobula rays’ filter-feeding ability. The ray is able to swim at just the right speed that water, streaming into its mouth, can form vortices between the grooved plates. These vortices effectively block any plankton particles — even those that are smaller than the space between plates. The particles then bounce across the plates and head further into the ray’s cavity, while the rest of the water can still flow between the plates and out through the gills.The researchers used the results of their experiments, along with dimensions of the filtering features of mobula rays, to develop a blueprint for cross-flow filtration.“We have provided practical guidance on how to actually filter as the mobula ray does,” Mao offers.“You want to design a filter such that you’re in the regime where you generate vortices,” Hosoi says. “Our guidelines tell you: If you want your plant to pump at a certain rate, then your filter has to have a particular pore diameter and spacing to generate vortices that will filter out particles of this size. The mobula ray is giving us a really nice rule of thumb for rational design.”This work was supported, in part, by the U.S. National Institutes of Health, and the Harvey P. Greenspan Fellowship Fund.  More

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      Engineers develop a vibrating, ingestible capsule that might help treat obesity

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      When you eat a large meal, your stomach sends signals to your brain that create a feeling of fullness, which helps you realize it’s time to stop eating. A stomach full of liquid can also send these messages, which is why dieters are often advised to drink a glass of water before eating.

      MIT engineers have now come up with a new way to take advantage of that phenomenon, using an ingestible capsule that vibrates within the stomach. These vibrations activate the same stretch receptors that sense when the stomach is distended, creating an illusory sense of fullness.

      In animals who were given this pill 20 minutes before eating, the researchers found that this treatment not only stimulated the release of hormones that signal satiety, but also reduced the animals’ food intake by about 40 percent. Scientists have much more to learn about the mechanisms that influence human body weight, but if further research suggests this technology could be safely used in humans, such a pill might offer a minimally invasive way to treat obesity, the researchers say.

      “For somebody who wants to lose weight or control their appetite, it could be taken before each meal,” says Shriya Srinivasan PhD ’20, a former MIT graduate student and postdoc who is now an assistant professor of bioengineering at Harvard University. “This could be really interesting in that it would provide an option that could minimize the side effects that we see with the other pharmacological treatments out there.”

      Srinivasan is the lead author of the new study, which appears today in Science Advances. Giovanni Traverso, an associate professor of mechanical engineering at MIT and a gastroenterologist at Brigham and Women’s Hospital, is the senior author of the paper.

      A sense of fullness

      When the stomach becomes distended, specialized cells called mechanoreceptors sense that stretching and send signals to the brain via the vagus nerve. As a result, the brain stimulates production of insulin, as well as hormones such as C-peptide, Pyy, and GLP-1. All of these hormones work together to help people digest their food, feel full, and stop eating. At the same time, levels of ghrelin, a hunger-promoting hormone, go down.

      While a graduate student at MIT, Srinivasan became interested in the idea of controlling this process by artificially stretching the mechanoreceptors that line the stomach, through vibration. Previous research had shown that vibration applied to a muscle can induce a sense that the muscle has stretched farther than it actually has.

      “I wondered if we could activate stretch receptors in the stomach by vibrating them and having them perceive that the entire stomach has been expanded, to create an illusory sense of distension that could modulate hormones and eating patterns,” Srinivasan says.

      As a postdoc in MIT’s Koch Institute for Integrative Cancer Research, Srinivasan worked closely with Traverso’s lab, which has developed many novel approaches to oral delivery of drugs and electronic devices. For this study, Srinivasan, Traverso, and a team of researchers designed a capsule about the size of a multivitamin, that includes a vibrating element. When the pill, which is powered by a small silver oxide battery, reaches the stomach, acidic gastric fluids dissolve a gelatinous membrane that covers the capsule, completing the electronic circuit that activates the vibrating motor.

      In a study in animals, the researchers showed that once the pill begins vibrating, it activates mechanoreceptors, which send signals to the brain through stimulation of the vagus nerve. The researchers tracked hormone levels during the periods when the device was vibrating and found that they mirrored the hormone release patterns seen following a meal, even when the animals had fasted.

      The researchers then tested the effects of this stimulation on the animals’ appetite. They found that when the pill was activated for about 20 minutes, before the animals were offered food, they consumed 40 percent less, on average, than they did when the pill was not activated. The animals also gained weight more slowly during periods when they were treated with the vibrating pill.

      “The behavioral change is profound, and that’s using the endogenous system rather than any exogenous therapeutic. We have the potential to overcome some of the challenges and costs associated with delivery of biologic drugs by modulating the enteric nervous system,” Traverso says.

      The current version of the pill is designed to vibrate for about 30 minutes after arriving in the stomach, but the researchers plan to explore the possibility of adapting it to remain in the stomach for longer periods of time, where it could be turned on and off wirelessly as needed. In the animal studies, the pills passed through the digestive tract within four or five days.

      The study also found that the animals did not show any signs of obstruction, perforation, or other negative impacts while the pill was in their digestive tract.

      An alternative approach

      This type of pill could offer an alternative to the current approaches to treating obesity, the researchers say. Nonmedical interventions such as diet exercise don’t always work, and many of the existing medical interventions are fairly invasive. These include gastric bypass surgery, as well as gastric balloons, which are no longer used widely in the United States due to safety concerns.

      Drugs such as GLP-1 agonists can also aid weight loss, but most of them have to be injected, and they are unaffordable for many people. According to Srinivasan, the MIT capsules could be manufactured at a cost that would make them available to people who don’t have access to more expensive treatment options.

      “For a lot of populations, some of the more effective therapies for obesity are very costly. At scale, our device could be manufactured at a pretty cost-effective price point,” she says. “I’d love to see how this would transform care and therapy for people in global health settings who may not have access to some of the more sophisticated or expensive options that are available today.”

      The researchers now plan to explore ways to scale up the manufacturing of the capsules, which could enable clinical trials in humans. Such studies would be important to learn more about the devices’ safety, as well as determine the best time to swallow the capsule before to a meal and how often it would need to be administered.

      Other authors of the paper include Amro Alshareef, Alexandria Hwang, Ceara Byrne, Johannes Kuosmann, Keiko Ishida, Joshua Jenkins, Sabrina Liu, Wiam Abdalla Mohammed Madani, Alison Hayward, and Niora Fabian.

      The research was funded by the National Institutes of Health, Novo Nordisk, the Department of Mechanical Engineering at MIT, a Schmidt Science Fellowship, and the National Science Foundation. More

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      in Environment

      Keeping indoor humidity levels at a “sweet spot” may reduce spread of Covid-19

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      We know proper indoor ventilation is key to reducing the spread of Covid-19. Now, a study by MIT researchers finds that indoor relative humidity may also influence transmission of the virus.

      Relative humidity is the amount of moisture in the air compared to the total moisture the air can hold at a given temperature before saturating and forming condensation.

      In a study appearing today in the Journal of the Royal Society Interface, the MIT team reports that maintaining an indoor relative humidity between 40 and 60 percent is associated with relatively lower rates of Covid-19 infections and deaths, while indoor conditions outside this range are associated with worse Covid-19 outcomes. To put this into perspective, most people are comfortable between 30 and 50 percent relative humidity, and an airplane cabin is at around 20 percent relative humidity.

      The findings are based on the team’s analysis of Covid-19 data combined with meteorological measurements from 121 countries, from January 2020 through August 2020. Their study suggests a strong connection between regional outbreaks and indoor relative humidity.

      In general, the researchers found that whenever a region experienced a rise in Covid-19 cases and deaths prevaccination, the estimated indoor relative humidity in that region, on average, was either lower than 40 percent or higher than 60 percent regardless of season. Nearly all regions in the study experienced fewer Covid-19 cases and deaths during periods when estimated indoor relative humidity was within a “sweet spot” between 40 and 60 percent.

      “There’s potentially a protective effect of this intermediate indoor relative humidity,” suggests lead author Connor Verheyen, a PhD student in medical engineering and medical physics in the Harvard-MIT Program in Health Sciences and Technology.

      “Indoor ventilation is still critical,” says co-author Lydia Bourouiba, director of the MIT Fluid Dynamics of Disease Transmission Laboratory and associate professor in the departments of Civil and Environmental Engineering and Mechanical Engineering, and at the Institute for Medical Engineering and Science at MIT. “However, we find that maintaining an indoor relative humidity in that sweet spot — of 40 to 60 percent — is associated with reduced Covid-19 cases and deaths.”

      Seasonal swing?

      Since the start of the Covid-19 pandemic, scientists have considered the possibility that the virus’ virulence swings with the seasons. Infections and associated deaths appear to rise in winter and ebb in summer. But studies looking to link the virus’ patterns to seasonal outdoor conditions have yielded mixed results.

      Verheyen and Bourouiba examined whether Covid-19 is influenced instead by indoor — rather than outdoor — conditions, and, specifically, relative humidity. After all, they note that most societies spend more than 90 percent of their time indoors, where the majority of viral transmission has been shown to occur. What’s more, indoor conditions can be quite different from outdoor conditions as a result of climate control systems, such as heaters that significantly dry out indoor air.

      Could indoor relative humidity have affected the spread and severity of Covid-19 around the world? And could it help explain the differences in health outcomes from region to region?

      Tracking humidity

      For answers, the team focused on the early period of the pandemic when vaccines were not yet available, reasoning that vaccinated populations would obscure the influence of any other factor such as indoor humidity. They gathered global Covid-19 data, including case counts and reported deaths, from January 2020 to August 2020,  and identified countries with at least 50 deaths, indicating at least one outbreak had occurred in those countries.

      In all, they focused on 121 countries where Covid-19 outbreaks occurred. For each country, they also tracked the local Covid-19 related policies, such as isolation, quarantine, and testing measures, and their statistical association with Covid-19 outcomes.

      For each day that Covid-19 data was available, they used meteorological data to calculate a country’s outdoor relative humidity. They then estimated the average indoor relative humidity, based on outdoor relative humidity and guidelines on temperature ranges for human comfort. For instance, guidelines report that humans are comfortable between 66 to 77 degrees Fahrenheit indoors. They also assumed that on average, most populations have the means to heat indoor spaces to comfortable temperatures. Finally, they also collected experimental data, which they used to validate their estimation approach.

      For every instance when outdoor temperatures were below the typical human comfort range, they assumed indoor spaces were heated to reach that comfort range. Based on the added heating, they calculated the associated drop in indoor relative humidity.

      In warmer times, both outdoor and indoor relative humidity for each country was about the same, but they quickly diverged in colder times. While outdoor humidity remained around 50 percent throughout the year, indoor relative humidity for countries in the Northern and Southern Hemispheres dropped below 40 percent in their respective colder periods, when Covid-19 cases and deaths also spiked in these regions.

      For countries in the tropics, relative humidity was about the same indoors and outdoors throughout the year, with a gradual rise indoors during the region’s summer season, when high outdoor humidity likely raised the indoor relative humidity over 60 percent. They found this rise mirrored the gradual increase in Covid-19 deaths in the tropics.

      “We saw more reported Covid-19 deaths on the low and high end of indoor relative humidity, and less in this sweet spot of 40 to 60 percent,” Verheyen says. “This intermediate relative humidity window is associated with a better outcome, meaning fewer deaths and a deceleration of the pandemic.”

      “We were very skeptical initially, especially as the Covid-19 data can be noisy and inconsistent,” Bourouiba says. “We thus were very thorough trying to poke holes in our own analysis, using a range of approaches to test the limits and robustness of the findings, including taking into account factors such as government intervention. Despite all our best efforts, we found that even when considering countries with very strong versus very weak Covid-19 mitigation policies, or wildly different outdoor conditions, indoor — rather than outdoor — relative humidity maintains an underlying strong and robust link with Covid-19 outcomes.”

      It’s still unclear how indoor relative humidity affects Covid-19 outcomes. The team’s follow-up studies suggest that pathogens may survive longer in respiratory droplets in both very dry and very humid conditions.

      “Our ongoing work shows that there are emerging hints of mechanistic links between these factors,” Bourouiba says. “For now however, we can say that indoor relative humidity emerges in a robust manner as another mitigation lever that organizations and individuals can monitor, adjust, and maintain in the optimal 40 to 60 percent range, in addition to proper ventillation.”

      This research was made possible, in part, by an MIT Alumni Class fund, the Richard and Susan Smith Family Foundation, the National Institutes of Health, and the National Science Foundation. More

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      Scientists chart how exercise affects the body

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      Exercise is well-known to help people lose weight and avoid gaining it. However, identifying the cellular mechanisms that underlie this process has proven difficult because so many cells and tissues are involved.

      In a new study in mice that expands researchers’ understanding of how exercise and diet affect the body, MIT and Harvard Medical School researchers have mapped out many of the cells, genes, and cellular pathways that are modified by exercise or high-fat diet. The findings could offer potential targets for drugs that could help to enhance or mimic the benefits of exercise, the researchers say.

      “It is extremely important to understand the molecular mechanisms that are drivers of the beneficial effects of exercise and the detrimental effects of a high-fat diet, so that we can understand how we can intervene, and develop drugs that mimic the impact of exercise across multiple tissues,” says Manolis Kellis, a professor of computer science in MIT’s Computer Science and Artificial Intelligence Laboratory (CSAIL) and a member of the Broad Institute of MIT and Harvard.

      The researchers studied mice with high-fat or normal diets, who were either sedentary or given the opportunity to exercise whenever they wanted. Using single-cell RNA sequencing, the researchers cataloged the responses of 53 types of cells found in skeletal muscle and two types of fatty tissue.

      “One of the general points that we found in our study, which is overwhelmingly clear, is how high-fat diets push all of these cells and systems in one way, and exercise seems to be pushing them nearly all in the opposite way,” Kellis says. “It says that exercise can really have a major effect throughout the body.”

      Kellis and Laurie Goodyear, a professor of medicine at Harvard Medical School and senior investigator at the Joslin Diabetes Center, are the senior authors of the study, which appears today in the journal Cell Metabolism. Jiekun Yang, a research scientist in MIT CSAIL; Maria Vamvini, an instructor of medicine at the Joslin Diabetes Center; and Pasquale Nigro, an instructor of medicine at the Joslin Diabetes Center, are the lead authors of the paper.

      The risks of obesity

      Obesity is a growing health problem around the world. In the United States, more than 40 percent of the population is considered obese, and nearly 75 percent is overweight. Being overweight is a risk factor for many diseases, including heart disease, cancer, Alzheimer’s disease, and even infectious diseases such as Covid-19.

      “Obesity, along with aging, is a global factor that contributes to every aspect of human health,” Kellis says.

      Several years ago, his lab performed a study on the FTO gene region, which has been strongly linked to obesity risk. In that 2015 study, the research team found that genes in this region control a pathway that prompts immature fat cells called progenitor adipocytes to either become fat-burning cells or fat-storing cells.

      That finding, which demonstrated a clear genetic component to obesity, motivated Kellis to begin looking at how exercise, a well-known behavioral intervention that can prevent obesity, might act on progenitor adipocytes at the cellular level.

      To explore that question, Kellis and his colleagues decided to perform single-cell RNA sequencing of three types of tissue — skeletal muscle, visceral white adipose tissue (found packed around internal organs, where it stores fat), and subcutaneous white adipose tissue (which is found under the skin and primarily burns fat).

      These tissues came from mice from four different experimental groups. For three weeks, two groups of mice were fed either a normal diet or a high-fat diet. For the next three weeks, each of those two groups were further divided into a sedentary group and an exercise group, which had continuous access to a treadmill.

      By analyzing tissues from those mice, the researchers were able to comprehensively catalog the genes that were activated or suppressed by exercise in 53 different cell types.

      The researchers found that in all three tissue types, mesenchymal stem cells (MSCs) appeared to control many of the diet and exercise-induced effects that they observed. MSCs are stem cells that can differentiate into other cell types, including fat cells and fibroblasts. In adipose tissue, the researchers found that a high-fat diet modulated MSCs’ capacity to differentiate into fat-storing cells, while exercise reversed this effect.

      In addition to promoting fat storage, the researchers found that a high-fat diet also stimulated MSCs to secrete factors that remodel the extracellular matrix (ECM) — a network of proteins and other molecules that surround and support cells and tissues in the body. This ECM remodeling helps provide structure for enlarged fat-storing cells and also creates a more inflammatory environment.

      “As the adipocytes become overloaded with lipids, there’s an extreme amount of stress, and that causes low-grade inflammation, which is systemic and preserved for a long time,” Kellis says. “That is one of the factors that is contributing to many of the adverse effects of obesity.”

      Circadian effects

      The researchers also found that high-fat diets and exercise had opposing effects on cellular pathways that control circadian rhythms — the 24-hour cycles that govern many functions, from sleep to body temperature, hormone release, and digestion. The study revealed that exercise boosts the expression of genes that regulate these rhythms, while a high-fat diet suppresses them.

      “There have been a lot of studies showing that when you eat during the day is extremely important in how you absorb the calories,” Kellis says. “The circadian rhythm connection is a very important one, and shows how obesity and exercise are in fact directly impacting that circadian rhythm in peripheral organs, which could act systemically on distal clocks and regulate stem cell functions and immunity.”

      The researchers then compared their results to a database of human genes that have been linked with metabolic traits. They found that two of the circadian rhythm genes they identified in this study, known as DBP and CDKN1A, have genetic variants that have been associated with a higher risk of obesity in humans.

      “These results help us see the translational values of these targets, and how we could potentially target specific biological processes in specific cell types,” Yang says.

      The researchers are now analyzing samples of small intestine, liver, and brain tissue from the mice in this study, to explore the effects of exercise and high-fat diets on those tissues. They are also conducting work with human volunteers to sample blood and biopsies and study similarities and differences between human and mouse physiology. They hope that their findings will help guide drug developers in designing drugs that might mimic some of the beneficial effects of exercise.

      “The message for everyone should be, eat a healthy diet and exercise if possible,” Kellis says. “For those for whom this is not possible, due to low access to healthy foods, or due to disabilities or other factors that prevent exercise, or simply lack of time to have a healthy diet or a healthy lifestyle, what this study says is that we now have a better handle on the pathways, the specific genes, and the specific molecular and cellular processes that we should be manipulating therapeutically.”

      The research was funded by the National Institutes of Health and the Novo Nordisk Research Center in Seattle. More

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      in Security

      These neurons have food on the brain

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      A gooey slice of pizza. A pile of crispy French fries. Ice cream dripping down a cone on a hot summer day. When you look at any of these foods, a specialized part of your visual cortex lights up, according to a new study from MIT neuroscientists.

      This newly discovered population of food-responsive neurons is located in the ventral visual stream, alongside populations that respond specifically to faces, bodies, places, and words. The unexpected finding may reflect the special significance of food in human culture, the researchers say. 

      “Food is central to human social interactions and cultural practices. It’s not just sustenance,” says Nancy Kanwisher, the Walter A. Rosenblith Professor of Cognitive Neuroscience and a member of MIT’s McGovern Institute for Brain Research and Center for Brains, Minds, and Machines. “Food is core to so many elements of our cultural identity, religious practice, and social interactions, and many other things that humans do.”

      The findings, based on an analysis of a large public database of human brain responses to a set of 10,000 images, raise many additional questions about how and why this neural population develops. In future studies, the researchers hope to explore how people’s responses to certain foods might differ depending on their likes and dislikes, or their familiarity with certain types of food.

      MIT postdoc Meenakshi Khosla is the lead author of the paper, along with MIT research scientist N. Apurva Ratan Murty. The study appears today in the journal Current Biology.

      Visual categories

      More than 20 years ago, while studying the ventral visual stream, the part of the brain that recognizes objects, Kanwisher discovered cortical regions that respond selectively to faces. Later, she and other scientists discovered other regions that respond selectively to places, bodies, or words. Most of those areas were discovered when researchers specifically set out to look for them. However, that hypothesis-driven approach can limit what you end up finding, Kanwisher says.

      “There could be other things that we might not think to look for,” she says. “And even when we find something, how do we know that that’s actually part of the basic dominant structure of that pathway, and not something we found just because we were looking for it?”

      To try to uncover the fundamental structure of the ventral visual stream, Kanwisher and Khosla decided to analyze a large, publicly available dataset of full-brain functional magnetic resonance imaging (fMRI) responses from eight human subjects as they viewed thousands of images.

      “We wanted to see when we apply a data-driven, hypothesis-free strategy, what kinds of selectivities pop up, and whether those are consistent with what had been discovered before. A second goal was to see if we could discover novel selectivities that either haven’t been hypothesized before, or that have remained hidden due to the lower spatial resolution of fMRI data,” Khosla says.

      To do that, the researchers applied a mathematical method that allows them to discover neural populations that can’t be identified from traditional fMRI data. An fMRI image is made up of many voxels — three-dimensional units that represent a cube of brain tissue. Each voxel contains hundreds of thousands of neurons, and if some of those neurons belong to smaller populations that respond to one type of visual input, their responses may be drowned out by other populations within the same voxel.

      The new analytical method, which Kanwisher’s lab has previously used on fMRI data from the auditory cortex, can tease out responses of neural populations within each voxel of fMRI data.

      Using this approach, the researchers found four populations that corresponded to previously identified clusters that respond to faces, places, bodies, and words. “That tells us that this method works, and it tells us that the things that we found before are not just obscure properties of that pathway, but major, dominant properties,” Kanwisher says.

      Intriguingly, a fifth population also emerged, and this one appeared to be selective for images of food.

      “We were first quite puzzled by this because food is not a visually homogenous category,” Khosla says. “Things like apples and corn and pasta all look so unlike each other, yet we found a single population that responds similarly to all these diverse food items.”

      The food-specific population, which the researchers call the ventral food component (VFC), appears to be spread across two clusters of neurons, located on either side of the FFA. The fact that the food-specific populations are spread out between other category-specific populations may help explain why they have not been seen before, the researchers say.

      “We think that food selectivity had been harder to characterize before because the populations that are selective for food are intermingled with other nearby populations that have distinct responses to other stimulus attributes. The low spatial resolution of fMRI prevents us from seeing this selectivity because the responses of different neural population get mixed in a voxel,” Khosla says.

      “The technique which the researchers used to identify category-sensitive cells or areas is impressive, and it recovered known category-sensitive systems, making the food category findings most impressive,” says Paul Rozin, a professor of psychology at the University of Pennsylvania, who was not involved in the study. “I can’t imagine a way for the brain to reliably identify the diversity of foods based on sensory features. That makes this all the more fascinating, and likely to clue us in about something really new.”

      Food vs non-food

      The researchers also used the data to train a computational model of the VFC, based on previous models Murty had developed for the brain’s face and place recognition areas. This allowed the researchers to run additional experiments and predict the responses of the VFC. In one experiment, they fed the model matched images of food and non-food items that looked very similar — for example, a banana and a yellow crescent moon.

      “Those matched stimuli have very similar visual properties, but the main attribute in which they differ is edible versus inedible,” Khosla says. “We could feed those arbitrary stimuli through the predictive model and see whether it would still respond more to food than non-food, without having to collect the fMRI data.”

      They could also use the computational model to analyze much larger datasets, consisting of millions of images. Those simulations helped to confirm that the VFC is highly selective for images of food.

      From their analysis of the human fMRI data, the researchers found that in some subjects, the VFC responded slightly more to processed foods such as pizza than unprocessed foods like apples. In the future they hope to explore how factors such as familiarity and like or dislike of a particular food might affect individuals’ responses to that food.

      They also hope to study when and how this region becomes specialized during early childhood, and what other parts of the brain it communicates with. Another question is whether this food-selective population will be seen in other animals such as monkeys, who do not attach the cultural significance to food that humans do.

      The research was funded by the National Institutes of Health, the National Eye Institute, and the National Science Foundation through the MIT Center for Brains, Minds, and Machines. More

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      in Security

      Structures considered key to gene expression are surprisingly fleeting

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      In human chromosomes, DNA is coated by proteins to form an exceedingly long beaded string. This “string” is folded into numerous loops, which are believed to help cells control gene expression and facilitate DNA repair, among other functions. A new study from MIT suggests that these loops are very dynamic and shorter-lived than previously thought.

      In the new study, the researchers were able to monitor the movement of one stretch of the genome in a living cell for about two hours. They saw that this stretch was fully looped for only 3 to 6 percent of the time, with the loop lasting for only about 10 to 30 minutes. The findings suggest that scientists’ current understanding of how loops influence gene expression may need to be revised, the researchers say.

      “Many models in the field have been these pictures of static loops regulating these processes. What our new paper shows is that this picture is not really correct,” says Anders Sejr Hansen, the Underwood-Prescott Career Development Assistant Professor of Biological Engineering at MIT. “We suggest that the functional state of these domains is much more dynamic.”

      Hansen is one of the senior authors of the new study, along with Leonid Mirny, a professor in MIT’s Institute for Medical Engineering and Science and the Department of Physics, and Christoph Zechner, a group leader at the Max Planck Institute of Molecular Cell Biology and Genetics in Dresden, Germany, and the Center for Systems Biology Dresden. MIT postdoc Michele Gabriele, recent Harvard University PhD recipient Hugo Brandão, and MIT graduate student Simon Grosse-Holz are the lead authors of the paper, which appears today in Science.

      Out of the loop

      Using computer simulations and experimental data, scientists including Mirny’s group at MIT have shown that loops in the genome are formed by a process called extrusion, in which a molecular motor promotes the growth of progressively larger loops. The motor stops each time it encounters a “stop sign” on DNA. The motor that extrudes such loops is a protein complex called cohesin, while the DNA-bound protein CTCF serves as the stop sign. These cohesin-mediated loops between CTCF sites were seen in previous experiments.

      However, those experiments only offered a snapshot of a moment in time, with no information on how the loops change over time. In their new study, the researchers developed techniques that allowed them to fluorescently label CTCF DNA sites so they could image the DNA loops over several hours. They also created a new computational method that can infer the looping events from the imaging data.

      “This method was crucial for us to distinguish signal from noise in our experimental data and quantify looping,” Zechner says. “We believe that such approaches will become increasingly important for biology as we continue to push the limits of detection with experiments.”

      The researchers used their method to image a stretch of the genome in mouse embryonic stem cells. “If we put our data in the context of one cell division cycle, which lasts about 12 hours, the fully formed loop only actually exists for about 20 to 45 minutes, or about 3 to 6 percent of the time,” Grosse-Holz says.

      “If the loop is only present for such a tiny period of the cell cycle and very short-lived, we shouldn’t think of this fully looped state as being the primary regulator of gene expression,” Hansen says. “We think we need new models for how the 3D structure of the genome regulates gene expression, DNA repair, and other functional downstream processes.”

      While fully formed loops were rare, the researchers found that partially extruded loops were present about 92 percent of the time. These smaller loops have been difficult to observe with the previous methods of detecting loops in the genome.

      “In this study, by integrating our experimental data with polymer simulations, we have now been able to quantify the relative extents of the unlooped, partially extruded, and fully looped states,” Brandão says.

      “Since these interactions are very short, but very frequent, the previous methodologies were not able to fully capture their dynamics,” Gabriele adds. “With our new technique, we can start to resolve transitions between fully looped and unlooped states.”

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      The researchers hypothesize that these partial loops may play more important roles in gene regulation than fully formed loops. Strands of DNA run along each other as loops begin to form and then fall apart, and these interactions may help regulatory elements such as enhancers and gene promoters find each other.

      “More than 90 percent of the time, there are some transient loops, and presumably what’s important is having those loops that are being perpetually extruded,” Mirny says. “The process of extrusion itself may be more important than the fully looped state that only occurs for a short period of time.”

      More loops to study

      Since most of the other loops in the genome are weaker than the one the researchers studied in this paper, they suspect that many other loops will also prove to be highly transient. They now plan to use their new technique study some of those other loops, in a variety of cell types.

      “There are about 10,000 of these loops, and we’ve looked at one,” Hansen says. “We have a lot of indirect evidence to suggest that the results would be generalizable, but we haven’t demonstrated that. Using the technology platform we’ve set up, which combines new experimental and computational methods, we can begin to approach other loops in the genome.”

      The researchers also plan to investigate the role of specific loops in disease. Many diseases, including a neurodevelopmental disorder called FOXG1 syndrome, could be linked to faulty loop dynamics. The researchers are now studying how both the normal and mutated form of the FOXG1 gene, as well as the cancer-causing gene MYC, are affected by genome loop formation.

      The research was funded by the National Institutes of Health, the National Science Foundation, the Mathers Foundation, a Pew-Stewart Cancer Research Scholar grant, the Chaires d’excellence Internationale Blaise Pascal, an American-Italian Cancer Foundation research scholarship, and the Max Planck Institute for Molecular Cell Biology and Genetics. More

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      in Security

      How diet affects tumors

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      In recent years, there has been some evidence that dietary interventions can help to slow the growth of tumors. A new study from MIT, which analyzed two different diets in mice, reveals how those diets affect cancer cells, and offers an explanation for why restricting calories may slow tumor growth.

      The study examined the effects of a calorically restricted diet and a ketogenic diet in mice with pancreatic tumors. While both of these diets reduce the amount of sugar available to tumors, the researchers found that only the calorically restricted diet reduced the availability of fatty acids, and this was linked to a slowdown in tumor growth.

      The findings do not suggest that cancer patients should try to follow either of these diets, the researchers say. Instead, they believe the findings warrant further study to determine how dietary interventions might be combined with existing or emerging drugs to help patients with cancer.

      “There’s a lot of evidence that diet can affect how fast your cancer progresses, but this is not a cure,” says Matthew Vander Heiden, director of MIT’s Koch Institute for Integrative Cancer Research and the senior author of the study. “While the findings are provocative, further study is needed, and individual patients should talk to their doctor about the right dietary interventions for their cancer.”

      MIT postdoc Evan Lien is the lead author of the paper, which appears today in Nature.

      Metabolic mechanism

      Vander Heiden, who is also a medical oncologist at Dana-Farber Cancer Institute, says his patients often ask him about the potential benefits of various diets, but there is not enough scientific evidence available to offer any definitive advice. Many of the dietary questions that patients have focus on either a calorie-restricted diet, which reduces calorie consumption by 25 to 50 percent, or a ketogenic diet, which is low in carbohydrates and high in fat and protein.

      Previous studies have suggested that a calorically restricted diet might slow tumor growth in some contexts, and such a diet has been shown to extend lifespan in mice and many other animal species. A smaller number of studies exploring the effects of a ketogenic diet on cancer have produced inconclusive results.

      “A lot of the advice or cultural fads that are out there aren’t necessarily always based on very good science,” Lien says. “It seemed like there was an opportunity, especially with our understanding of cancer metabolism having evolved so much over the past 10 years or so, that we could take some of the biochemical principles that we’ve learned and apply those concepts to understanding this complex question.”

      Cancer cells consume a great deal of glucose, so some scientists had hypothesized that either the ketogenic diet or calorie restriction might slow tumor growth by reducing the amount of glucose available. However, the MIT team’s initial experiments in mice with pancreatic tumors showed that calorie restriction has a much greater effect on tumor growth than the ketogenic diet, so the researchers suspected that glucose levels were not playing a major role in the slowdown.

      To dig deeper into the mechanism, the researchers analyzed tumor growth and nutrient concentration in mice with pancreatic tumors, which were fed either a normal, ketogenic, or calorie-restricted diet. In both the ketogenic and calorie-restricted mice, glucose levels went down. In the calorie-restricted mice, lipid levels also went down, but in mice on the ketogenic diet, they went up.

      Lipid shortages impair tumor growth because cancer cells need lipids to construct their cell membranes. Normally, when lipids aren’t available in a tissue, cells can make their own. As part of this process, they need to maintain the right balance of saturated and unsaturated fatty acids, which requires an enzyme called stearoyl-CoA desaturase (SCD). This enzyme is responsible for converting saturated fatty acids into unsaturated fatty acids.

      Both calorie-restricted and ketogenic diets reduce SCD activity, but mice on the ketogenic diet had lipids available to them from their diet, so they didn’t need to use SCD. Mice on the calorie-restricted diet, however, couldn’t get fatty acids from their diet or produce their own. In these mice, tumor growth slowed significantly, compared to mice on the ketogenic diet.

      “Not only does caloric restriction starve tumors of lipids, it also impairs the process that allows them to adapt to it. That combination is really contributing to the inhibition of tumor growth,” Lien says.

      Dietary effects

      In addition to their mouse research, the researchers also looked at some human data. Working with Brian Wolpin, an oncologist at Dana-Farber Cancer Institute and an author of the paper, the team obtained data from a large cohort study that allowed them to analyze the relationship between dietary patterns and survival times in pancreatic cancer patients. From that study, the researchers found that the type of fat consumed appears to influence how patients on a low-sugar diet fare after a pancreatic cancer diagnosis, although the data are not complete enough to draw any conclusions about the effect of diet, the researchers say.

      Although this study showed that calorie restriction has beneficial effects in mice, the researchers say they do not recommend that cancer patients follow a calorie-restricted diet, which is difficult to maintain and can have harmful side effects. However, they believe that cancer cells’ dependence on the availability of unsaturated fatty acids could be exploited to develop drugs that might help slow tumor growth.

      One possible therapeutic strategy could be inhibition of the SCD enzyme, which would cut off tumor cells’ ability to produce unsaturated fatty acids.

      “The purpose of these studies isn’t necessarily to recommend a diet, but it’s to really understand the underlying biology,” Lien says. “They provide some sense of the mechanisms of how these diets work, and that can lead to rational ideas on how we might mimic those situations for cancer therapy.”

      The researchers now plan to study how diets with a variety of fat sources — including plant or animal-based fats with defined differences in saturated, monounsaturated, and polyunsaturated fatty acid content — alter tumor fatty acid metabolism and the ratio of unsaturated to saturated fatty acids.

      The research was funded by the Damon Runyon Cancer Research Foundation, the National Institutes of Health, the Lustgarten Foundation, the Dana-Farber Cancer Institute Hale Family Center for Pancreatic Cancer Research, Stand Up to Cancer, the Pancreatic Cancer Action Network, the Noble Effort Fund, the Wexler Family Fund, Promises for Purple, the Bob Parsons Fund, the Emerald Foundation, the Howard Hughes Medical Institute, the MIT Center for Precision Cancer Medicine, and the Ludwig Center at MIT. More

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      in Environment

      Study: Global cancer risk from burning organic matter comes from unregulated chemicals

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      Whenever organic matter is burned, such as in a wildfire, a power plant, a car’s exhaust, or in daily cooking, the combustion releases polycyclic aromatic hydrocarbons (PAHs) — a class of pollutants that is known to cause lung cancer.

      There are more than 100 known types of PAH compounds emitted daily into the atmosphere. Regulators, however, have historically relied on measurements of a single compound, benzo(a)pyrene, to gauge a community’s risk of developing cancer from PAH exposure. Now MIT scientists have found that benzo(a)pyrene may be a poor indicator of this type of cancer risk.

      In a modeling study appearing today in the journal GeoHealth, the team reports that benzo(a)pyrene plays a small part — about 11 percent — in the global risk of developing PAH-associated cancer. Instead, 89 percent of that cancer risk comes from other PAH compounds, many of which are not directly regulated.

      Interestingly, about 17 percent of PAH-associated cancer risk comes from “degradation products” — chemicals that are formed when emitted PAHs react in the atmosphere. Many of these degradation products can in fact be more toxic than the emitted PAH from which they formed.

      The team hopes the results will encourage scientists and regulators to look beyond benzo(a)pyrene, to consider a broader class of PAHs when assessing a community’s cancer risk.

      “Most of the regulatory science and standards for PAHs are based on benzo(a)pyrene levels. But that is a big blind spot that could lead you down a very wrong path in terms of assessing whether cancer risk is improving or not, and whether it’s relatively worse in one place than another,” says study author Noelle Selin, a professor in MIT’s Institute for Data, Systems and Society, and the Department of Earth, Atmospheric and Planetary Sciences.

      Selin’s MIT co-authors include Jesse Kroll, Amy Hrdina, Ishwar Kohale, Forest White, and Bevin Engelward, and Jamie Kelly (who is now at University College London). Peter Ivatt and Mathew Evans at the University of York are also co-authors.

      Chemical pixels

      Benzo(a)pyrene has historically been the poster chemical for PAH exposure. The compound’s indicator status is largely based on early toxicology studies. But recent research suggests the chemical may not be the PAH representative that regulators have long relied upon.   

      “There has been a bit of evidence suggesting benzo(a)pyrene may not be very important, but this was from just a few field studies,” says Kelly, a former postdoc in Selin’s group and the study’s lead author.

      Kelly and his colleagues instead took a systematic approach to evaluate benzo(a)pyrene’s suitability as a PAH indicator. The team began by using GEOS-Chem, a global, three-dimensional chemical transport model that breaks the world into individual grid boxes and simulates within each box the reactions and concentrations of chemicals in the atmosphere.

      They extended this model to include chemical descriptions of how various PAH compounds, including benzo(a)pyrene, would react in the atmosphere. The team then plugged in recent data from emissions inventories and meteorological observations, and ran the model forward to simulate the concentrations of various PAH chemicals around the world over time.

      Risky reactions

      In their simulations, the researchers started with 16 relatively well-studied PAH chemicals, including benzo(a)pyrene, and traced the concentrations of these chemicals, plus the concentration of their degradation products over two generations, or chemical transformations. In total, the team evaluated 48 PAH species.

      They then compared these concentrations with actual concentrations of the same chemicals, recorded by monitoring stations around the world. This comparison was close enough to show that the model’s concentration predictions were realistic.

      Then within each model’s grid box, the researchers related the concentration of each PAH chemical to its associated cancer risk; to do this, they had to develop a new method based on previous studies in the literature to avoid double-counting risk from the different chemicals. Finally, they overlaid population density maps to predict the number of cancer cases globally, based on the concentration and toxicity of a specific PAH chemical in each location.

      Dividing the cancer cases by population produced the cancer risk associated with that chemical. In this way, the team calculated the cancer risk for each of the 48 compounds, then determined each chemical’s individual contribution to the total risk.

      This analysis revealed that benzo(a)pyrene had a surprisingly small contribution, of about 11 percent, to the overall risk of developing cancer from PAH exposure globally. Eighty-nine percent of cancer risk came from other chemicals. And 17 percent of this risk arose from degradation products.

      “We see places where you can find concentrations of benzo(a)pyrene are lower, but the risk is higher because of these degradation products,” Selin says. “These products can be orders of magnitude more toxic, so the fact that they’re at tiny concentrations doesn’t mean you can write them off.”

      When the researchers compared calculated PAH-associated cancer risks around the world, they found significant differences depending on whether that risk calculation was based solely on concentrations of benzo(a)pyrene or on a region’s broader mix of PAH compounds.

      “If you use the old method, you would find the lifetime cancer risk is 3.5 times higher in Hong Kong versus southern India, but taking into account the differences in PAH mixtures, you get a difference of 12 times,” Kelly says. “So, there’s a big difference in the relative cancer risk between the two places. And we think it’s important to expand the group of compounds that regulators are thinking about, beyond just a single chemical.”

      The team’s study “provides an excellent contribution to better understanding these ubiquitous pollutants,” says Elisabeth Galarneau, an air quality expert and PhD research scientist in Canada’s Department of the Environment. “It will be interesting to see how these results compare to work being done elsewhere … to pin down which (compounds) need to be tracked and considered for the protection of human and environmental health.”

      This research was conducted in MIT’s Superfund Research Center and is supported in part by the National Institute of Environmental Health Sciences Superfund Basic Research Program, and the National Institutes of Health. More