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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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      Supporting sustainability, digital health, and the future of work

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      The MIT and Accenture Convergence Initiative for Industry and Technology has selected three new research projects that will receive support from the initiative. The research projects aim to accelerate progress in meeting complex societal needs through new business convergence insights in technology and innovation.

      Established in MIT’s School of Engineering and now in its third year, the MIT and Accenture Convergence Initiative is furthering its mission to bring together technological experts from across business and academia to share insights and learn from one another. Recently, Thomas W. Malone, the Patrick J. McGovern (1959) Professor of Management, joined the initiative as its first-ever faculty lead. The research projects relate to three of the initiative’s key focus areas: sustainability, digital health, and the future of work.

      “The solutions these research teams are developing have the potential to have tremendous impact,” says Anantha Chandrakasan, dean of the School of Engineering and the Vannevar Bush Professor of Electrical Engineering and Computer Science. “They embody the initiative’s focus on advancing data-driven research that addresses technology and industry convergence.”

      “The convergence of science and technology driven by advancements in generative AI, digital twins, quantum computing, and other technologies makes this an especially exciting time for Accenture and MIT to be undertaking this joint research,” says Kenneth Munie, senior managing director at Accenture Strategy, Life Sciences. “Our three new research projects focusing on sustainability, digital health, and the future of work have the potential to help guide and shape future innovations that will benefit the way we work and live.”

      The MIT and Accenture Convergence Initiative charter project researchers are described below.

      Accelerating the journey to net zero with industrial clusters

      Jessika Trancik is a professor at the Institute for Data, Systems, and Society (IDSS). Trancik’s research examines the dynamic costs, performance, and environmental impacts of energy systems to inform climate policy and accelerate beneficial and equitable technology innovation. Trancik’s project aims to identify how industrial clusters can enable companies to derive greater value from decarbonization, potentially making companies more willing to invest in the clean energy transition.

      To meet the ambitious climate goals that have been set by countries around the world, rising greenhouse gas emissions trends must be rapidly reversed. Industrial clusters — geographically co-located or otherwise-aligned groups of companies representing one or more industries — account for a significant portion of greenhouse gas emissions globally. With major energy consumers “clustered” in proximity, industrial clusters provide a potential platform to scale low-carbon solutions by enabling the aggregation of demand and the coordinated investment in physical energy supply infrastructure.

      In addition to Trancik, the research team working on this project will include Aliza Khurram, a postdoc in IDSS; Micah Ziegler, an IDSS research scientist; Melissa Stark, global energy transition services lead at Accenture; Laura Sanderfer, strategy consulting manager at Accenture; and Maria De Miguel, strategy senior analyst at Accenture.

      Eliminating childhood obesity

      Anette “Peko” Hosoi is the Neil and Jane Pappalardo Professor of Mechanical Engineering. A common theme in her work is the fundamental study of shape, kinematic, and rheological optimization of biological systems with applications to the emergent field of soft robotics. Her project will use both data from existing studies and synthetic data to create a return-on-investment (ROI) calculator for childhood obesity interventions so that companies can identify earlier returns on their investment beyond reduced health-care costs.

      Childhood obesity is too prevalent to be solved by a single company, industry, drug, application, or program. In addition to the physical and emotional impact on children, society bears a cost through excess health care spending, lost workforce productivity, poor school performance, and increased family trauma. Meaningful solutions require multiple organizations, representing different parts of society, working together with a common understanding of the problem, the economic benefits, and the return on investment. ROI is particularly difficult to defend for any single organization because investment and return can be separated by many years and involve asymmetric investments, returns, and allocation of risk. Hosoi’s project will consider the incentives for a particular entity to invest in programs in order to reduce childhood obesity.

      Hosoi will be joined by graduate students Pragya Neupane and Rachael Kha, both of IDSS, as well a team from Accenture that includes Kenneth Munie, senior managing director at Accenture Strategy, Life Sciences; Kaveh Safavi, senior managing director in Accenture Health Industry; and Elizabeth Naik, global health and public service research lead.

      Generating innovative organizational configurations and algorithms for dealing with the problem of post-pandemic employment

      Thomas Malone is the Patrick J. McGovern (1959) Professor of Management at the MIT Sloan School of Management and the founding director of the MIT Center for Collective Intelligence. His research focuses on how new organizations can be designed to take advantage of the possibilities provided by information technology. Malone will be joined in this project by John Horton, the Richard S. Leghorn (1939) Career Development Professor at the MIT Sloan School of Management, whose research focuses on the intersection of labor economics, market design, and information systems. Malone and Horton’s project will look to reshape the future of work with the help of lessons learned in the wake of the pandemic.

      The Covid-19 pandemic has been a major disrupter of work and employment, and it is not at all obvious how governments, businesses, and other organizations should manage the transition to a desirable state of employment as the pandemic recedes. Using natural language processing algorithms such as GPT-4, this project will look to identify new ways that companies can use AI to better match applicants to necessary jobs, create new types of jobs, assess skill training needed, and identify interventions to help include women and other groups whose employment was disproportionately affected by the pandemic.

      In addition to Malone and Horton, the research team will include Rob Laubacher, associate director and research scientist at the MIT Center for Collective Intelligence, and Kathleen Kennedy, executive director at the MIT Center for Collective Intelligence and senior director at MIT Horizon. The team will also include Nitu Nivedita, managing director of artificial intelligence at Accenture, and Thomas Hancock, data science senior manager at Accenture. More

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      Exploring the links between diet and cancer

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      Every three to five days, all of the cells lining the human intestine are replaced. That constant replenishment of cells helps the intestinal lining withstand the damage caused by food passing through the digestive tract.

      This rapid turnover of cells relies on intestinal stem cells, which give rise to all of the other types of cells found in the intestine. Recent research has shown that those stem cells are heavily influenced by diet, which can help keep them healthy or stimulate them to become cancerous.

      “Low-calorie diets such as fasting and caloric restriction can have antiaging effects and antitumor effects, and we want to understand why that is. On the other hand, diets that lead to obesity can promote diseases of aging, such as cancer,” says Omer Yilmaz, the Eisen and Chang Career Development Associate Professor of Biology at MIT.

      For the past decade, Yilmaz has been studying how different diets and environmental conditions affect intestinal stem cells, and how those factors can increase the risk of cancer and other diseases. This work could help researchers develop new ways to improve gastrointestinal health, either through dietary interventions or drugs that mimic the beneficial effects of certain diets, he says. 

      “Our findings have raised the possibility that fasting interventions, or small molecules that mimic the effects of fasting, might have a role in improving intestinal regeneration,” says Yilmaz, who is also a member of MIT’s Koch Institute for Integrative Cancer Research.

      A clinical approach

      Yilmaz’s interest in disease and medicine arose at an early age. His father practiced internal medicine, and Yilmaz spent a great deal of time at his father’s office after school, or tagging along at the hospital where his father saw patients.

      “I was very interested in medicines and how medicines were used to treat diseases,” Yilmaz recalls. “He’d ask me questions, and many times I wouldn’t know the answer, but he would encourage me to figure out the answers to his questions. That really stimulated my interest in biology and in wanting to become a doctor.”

      Knowing that he wanted to go into medicine, Yilmaz applied and was accepted to an eight-year, combined bachelor’s and MD program at the University of Michigan. As an undergraduate, this gave him the freedom to explore areas of interest without worrying about applying to medical school. While majoring in biochemistry and physics, he did undergraduate research in the field of protein folding.

      During his first year of medical school, Yilmaz realized that he missed doing research, so he decided to apply to the MD/PhD program at the University of Michigan. For his PhD research, he studied blood-forming stem cells and identified new markers that allowed such cells to be more easily isolated from the bone marrow.

      “This was important because there’s a lot of interest in understanding what makes a stem cell a stem cell, and how much of it is an internal program versus signals from the microenvironment,” Yilmaz says.

      After finishing his PhD and MD, he thought about going straight into research and skipping a medical residency, but ended up doing a residency in pathology at Massachusetts General Hospital. During that time, he decided to switch his research focus from blood-forming stem cells to stem cells found in the gastrointestinal tract.

      “The GI tract seemed very interesting because in contrast to the bone marrow, we knew very little about the identity of GI stem cells,” Yilmaz says. “I knew that once GI stem cells were identified, there’d be a lot of interesting questions about how they respond to diet and how they respond to other environmental stimuli.”

      Dietary questions

      To delve into those questions, Yilmaz did postdoctoral research at the Whitehead Institute, where he began investigating the connections between stem cells, metabolism, diet, and cancer.

      Because intestinal stem cells are so long-lived, they are more likely to accumulate genetic mutations that make them susceptible to becoming cancerous. At the Whitehead Institute, Yilmaz began studying how different diets might influence this vulnerability to cancer, a topic that he carried into his lab at MIT when he joined the faculty in 2014.

      One question his lab has been exploring is why low-calorie diets often have protective effects, including a boost in longevity — a phenomenon that has been seen in many studies in animals and humans.

      In a 2018 study, his lab found that a 24-hour fast dramatically improves stem cells’ ability to regenerate. This effect was seen in both young and aged mice, suggesting that even in old age, fasting or drugs that mimic the effects of fasting could have a beneficial effect.

      On the flip side, Yilmaz is also interested in why a high-fat diet appears to promote the development of cancer, especially colorectal cancer. In a 2016 study, he found that when mice consume a high-fat diet, it triggers a significant increase in the number of intestinal stem cells. Also, some non-stem-cell populations begin to resemble stem cells in their behavior. “The upshot of these changes is that both stem cells and non-stem-cells can give rise to tumors in a high-fat diet state,” Yilmaz says.

      To help with these studies, Yilmaz’s lab has developed a way to use mouse or human intestinal stem cells to generate miniature intestines or colons in cell culture. These “organoids” can then be exposed to different nutrients in a very controlled setting, allowing researchers to analyze how different diets affect the system.

      Recently, his lab adapted the system to allow them to expand their studies to include the role of immune cells, fibroblasts, and other supportive cells found in the microenvironment of stem cells. “It would be remiss of us to focus on just one cell type,” Yilmaz says. “We’re looking at how these different dietary interventions impact the entire stem cell neighborhood.”

      While Yilmaz spends most of his time running his lab at MIT, he also devotes six to eight weeks per year to his work at MGH, where he is an associate pathologist focusing on gastrointestinal pathology.

      “I enjoy my clinical work, and it always reminds me about the importance of the research we do,” he says. “Seeing colon cancer and other GI cancers under the microscope, and seeing their complexity, reminds me of the importance of our mission to figure out how we can prevent these cancers from forming.” More

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      Ingestible “electroceutical” capsule stimulates hunger-regulating hormone

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      Hormones released by the stomach, such as ghrelin, play a key role in stimulating appetite. These hormones are produced by endocrine cells that are part of the enteric nervous system, which controls hunger, nausea, and feelings of fullness.

      MIT engineers have now shown that they can stimulate these endocrine cells to produce ghrelin, using an ingestible capsule that delivers an electrical current to the cells. This approach could prove useful for treating diseases that involve nausea or loss of appetite, such as cachexia (loss of body mass that can occur in patients with cancer or other chronic diseases).

      In tests in animals, the researchers showed that this “electroceutical” capsule could significantly boost ghrelin production in the stomach. They believe this approach could also be adapted to deliver electrical stimulation to other parts of the GI tract.

      “This study helps establish electrical stimulation by ingestible electroceuticals as a mode of triggering hormone release via the GI tract,” says Giovanni Traverso, an associate professor of mechanical engineering at MIT, a gastroenterologist at Brigham and Women’s Hospital, and the senior author of the study. “We show one example of how we’re able to engage with the stomach mucosa and release hormones, and we anticipate that this could be used in other sites in the GI tract that we haven’t explored here.”

      Khalil Ramadi SM ’16, PhD ’19, a graduate of the Department of Mechanical Engineering and the Harvard-MIT Program in Health Sciences and Technology who is now an assistant professor of bioengineering at the New York University (NYU) Tandon School of Engineering and the director of the Laboratory for Advanced Neuroengineering and Translational Medicine at NYU Abu Dhabi, and James McRae, an MIT graduate student, are the lead authors of the paper, which appears today in Science Robotics.

      Electrical stimulation

      The enteric nervous system controls all aspects of digestion, including the movement of food through the GI tract. Some patients with gastroparesis, a disorder of the stomach nerves that leads to very slow movement of food, have shown symptomatic improvement after electrical stimulation generated by a pacemaker-like device that can be surgically implanted in the stomach.

      Doctors had theorized that the electrical stimulation would provoke the stomach into contracting, which would help push food along. However, it was later found that while the treatment does help patients feel better, it affected motility to a lesser degree. The MIT team hypothesized that the electrical stimulation of the stomach might be leading to the release of ghrelin, which is known to promote hunger and reduce feelings of nausea.

      To test that hypothesis, the researchers used an electrical probe to deliver electrical stimulation in the stomachs of animals. They found that after 20 minutes of stimulation, ghrelin levels in the bloodstream were considerably elevated. They also found that electrical stimulation did not lead to any significant inflammation or other adverse effects.

      Once they established that electrical stimulation was provoking ghrelin release, the researchers set out to see if they could achieve the same thing using a device that could be swallowed and temporarily reside in the stomach. One of the main challenges in designing such a device is ensuring that the electrodes on the capsule can contact the stomach tissue, which are coated with fluid. 

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      To create a drier surface that electrodes can interact with, the researchers gave their capsule a grooved surface that wicks fluid away from the electrodes. The surface they designed is inspired by the skin of the Australian thorny devil lizard, which uses ridged scales to collect water. When the lizard touches water with any part of its skin, water is transported by capillary action along the channels to the lizard’s mouth.

      “We were inspired by that to incorporate surface textures and patterns onto the outside of this capsule,” McRae says. “That surface can manage the fluid that could potentially prevent the electrodes from touching the tissue in the stomach, so it can reliably deliver electrical stimulation.”

      The capsule surface consists of grooves with a hydrophilic coating. These grooves function as channels that draw fluid away from the stomach tissue. Inside the device are battery-powered electronics that produce an electric current that flows across electrodes on the surface of the capsule. In the prototype used in this study, the current runs constantly, but future versions could be designed so that the current can be wirelessly turned on and off, according to the researchers.

      Hormone boost

      The researchers tested their capsule by administering it into the stomachs of large animals, and they found that the capsule produced a substantial spike in ghrelin levels in the bloodstream.

      “As far as we know, this is the first example of using electrical stimuli through an ingestible device to increase endogenous levels of hormones in the body, like ghrelin. And so, it has this effect of utilizing the body’s own systems rather than introducing external agents,” Ramadi says.

      The researchers found that in order for this stimulation to work, the vagus nerve, which controls digestion, must be intact. They theorize that the electrical pulses transmit to the brain via the vagus nerve, which then stimulates endocrine cells in the stomach to produce ghrelin.

      Traverso’s lab now plans to explore using this approach in other parts of the GI tract, and the researchers hope to test the device in human patients within the next three years. If developed for use in human patients, this type of treatment could potentially replace or complement some of the existing drugs used to prevent nausea and stimulate appetite in people with cachexia or anorexia, the researchers say.

      “It’s a relatively simple device, so we believe it’s something that we can get into humans on a relatively quick time scale,” Traverso says.

      The research was funded by the Koch Institute Support (core) Grant from the National Cancer Institute, the National Institute for Diabetes and Digestive and Kidney Diseases, the Division of Engineering at New York University Abu Dhabi, a National Science Foundation graduate research fellowship, Novo Nordisk, and the Department of Mechanical Engineering at MIT. More

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      Two first-year students named Rise Global Winners for 2022

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      In 2019, former Google CEO Eric Schmidt and his wife, Wendy, launched a $1 billion philanthropic commitment to identify global talent. Part of that effort is the Rise initiative, which selects 100 young scholars, ages 15-17, from around the world who show unusual promise and a drive to serve others. This year’s cohort of 100 Rise Global Winners includes two MIT first-year students, Jacqueline Prawira and Safiya Sankari.

      Rise intentionally targets younger-aged students and focuses on identifying what the program terms “hidden brilliance” in any form, anywhere in the world, whether it be in a high school or a refugee camp. Another defining aspect of the program is that Rise winners receive sustained support — not just in secondary school, but throughout their lives.

      “We believe that the answers to the world’s toughest problems lie in the imagination of the world’s brightest minds,” says Eric Braverman, CEO of Schmidt Futures, which manages Rise along with the Rhodes Trust. “Rise is an integral part of our mission to create the best, largest, and most enduring pipeline of exceptional talent globally and match it to opportunities to serve others for life.”

      The Rise program creates this enduring pipeline by providing a lifetime of benefits, including funding, programming, and mentoring opportunities. These resources can be tailored to each person as they evolve throughout their career. In addition to a four-year college scholarship, winners receive mentoring and career services; networking opportunities with other Rise recipients and partner organizations; technical equipment such as laptops or tablets; courses on topics like leadership and human-centered design; and opportunities to apply for graduate scholarships and for funding throughout their careers to support their innovative ideas, such as grants or seed money to start a social enterprise.

      Prawira and Sankari’s winning service projects focus on global sustainability and global medical access, respectively. Prawira invented a way to use upcycled fish-scale waste to absorb heavy metals in wastewater. She first started experimenting with fish-scale waste in middle school to try to find a bio-based alternative to plastic. More recently, she discovered that the calcium salts and collagen in fish scales can absorb up to 82 percent of heavy metals from water, and 91 percent if an electric current is passed through the water. Her work has global implications for treating contaminated water at wastewater plants and in developing countries.

      Prawiri published her research in 2021 and has won awards from the U.S. Environmental Protection Agency and several other organizations. She’s planning to major in Course 3 (materials science and engineering), perhaps with an environmentally related minor. “I believe that sustainability and solving environmental problems requires a multifaced approach,” she says. “Creating greener materials for use in our daily lives will have a major impact in solving current environmental issues.”

      For Sankari’s service project, she developed an algorithm to analyze data from electronic nano-sensor devices, or e-noses, which can detect certain diseases from a patient’s breath. The devices are calibrated to detect volatile organic compound biosignatures that are indicative of diseases like diabetes and cancer. “E-nose disease detection is much faster and cheaper than traditional methods of diagnosis, making medical care more accessible to many,” she explains. The Python-based algorithm she created can translate raw data from e-noses into a result that the user can read.

      Sankari is a lifetime member of the American Junior Academy of Science and has been a finalist in several prestigious science competitions. She is considering a major in Course 6-7 (computer science and molecular biology) at MIT and hopes to continue to explore the intersection between nanotechnology and medicine.

      While the 2022 Rise recipients share a desire to tackle some of the world’s most intractable problems, their ideas and interests, as reflected by their service projects, are broad, innovative, and diverse. A winner from Belarus used bioinformatics to predict the molecular effect of a potential Alzheimer’s drug. A Romanian student created a magazine that aims to promote acceptance of transgender bodies. A Vietnamese teen created a prototype of a toothbrush that uses a nano chip to detect cancerous cells in saliva. And a recipient from the United States designed modular, tiny homes for the unhoused that are affordable and sustainable, as an alternative to homeless shelters.

      This year’s winners were selected from over 13,000 applicants from 47 countries, from Azerbaijan and Burkina Faso to Lebanon and Paraguay. The selection process includes group interviews, peer and expert review of each applicant’s service project, and formal talent assessments. 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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      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