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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. 

      Play video

      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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      Scientists uncover the amazing way sandgrouse hold water in their feathers

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      Many birds’ feathers are remarkably efficient at shedding water — so much so that “like water off a duck’s back” is a common expression. Much more unusual are the belly feathers of the sandgrouse, especially Namaqua sandgrouse, which absorb and retain water so efficiently the male birds can fly more than 20 kilometers from a distant watering hole back to the nest and still retain enough water in their feathers for the chicks to drink and sustain themselves in the searing deserts of Namibia, Botswana, and South Africa.

      How do those feathers work? While scientists had inferred a rough picture, it took the latest tools of microscopy, and patient work with a collection of sandgrouse feathers, to unlock the unique structural details that enable the feathers to hold water. The findings appear today in the Journal of the Royal Society Interface, in a paper by Lorna Gibson, the Matoula S. Salapatas Professor of Materials Science and Engineering and a professor of mechanical engineering at MIT, and Professor Jochen Mueller of Johns Hopkins University.

      The unique water-carrying ability of sandgrouse feathers was first reported back in 1896, Gibson says, by E.G.B. Meade-Waldo, who was breeding the birds in captivity. “He saw them behaving like this, and nobody believed him! I mean, it just sounded so outlandish,” Gibson says.

      In 1967, Tom Cade and Gordon MacLean reported detailed observations of the birds at watering holes, in a study that proved the unique behavior was indeed real. The scientists found that male sandgrouse feathers could hold about 25 milliliters of water, or about a tenth of a cup, after the bird had spent about five minutes dipping in the water and fluffing its feathers.

      About half of that amount can evaporate during the male bird’s half-hour-long flight back to the nest, where the chicks, which cannot fly for about their first month, drink the remainder straight from the feathers.

      Cade and MacLean “had part of the story,” Gibson says, but the tools didn’t exist at the time to carry out the detailed imaging of the feather structures that the new study was able to do.

      Gibson and Mueller carried out their study using scanning electron microscopy, micro-computed tomography, and video imaging. They borrowed Namaqua sandgrouse belly feathers from Harvard University’s Museum of Comparative Zoology, which has a collection of specimens of about 80 percent of the world’s birds.

      Bird feathers in general have a central shaft, from which smaller barbs extend, and then smaller barbules extend out from those. Sandgrouse feathers are structured differently, however. In the inner zone of the feather, the barbules have a helically coiled structure close to their base and then a straight extension. In the outer zone of the feather, the barbules lack the helical coil and are simply straight. Both parts lack the grooves and hooks that hold the vane of contour feathers together in most other birds.
      Video of water spreading through the specialized sandgrouse feathers, under magnification, shows the uncoiling and spreading of the feather’s barbules as they become wet. Initially, most barbules in the outer zone of the feather form tubular features.Credit: Specimen #142928, Museum of Comparative Zoology, Harvard University © President and Fellows of Harvard College.

      When wetted, the coiled portions of the barbules unwind and rotate to be perpendicular to the vane, producing a dense forest of fibers that can hold water through capillary action. At the same time, the barbules in the outer zone curl inward, helping to hold the water in.

      The microscopy techniques used in the new study allowed the dimensions of the different parts of the feather to be measured. In the inner zone, the barb shafts are large and stiff enough to provide a rigid base about which the other parts of the feather deform, and the barbules are small and flexible enough that surface tension is sufficient to bend the straight extensions into tear-like structures that hold water. And in the outer zone, the barb shafts and barbules are smaller still, allowing them to curl around the inner zone, further retaining water.

      While previous work had suggested that surface tension produced the water retention characteristics, “what we did was make measurements of the dimensions and do some calculations to show that that’s what is actually happening,” Gibson says. Her group’s work demonstrated that the varying stiffnesses of the different feather parts plays a key role in their ability to hold water.

      The study was mostly driven by intellectual curiosity about this unique behavioral phenomenon, Gibson says. “We just wanted to see how it works. The whole story just seemed so interesting.” But she says it might lead to some useful applications. For example, in desert regions where water is scarce but fog and dew regularly occur, such as in Chile’s Atacama Desert, some adaptation of this feather structure might be incorporated into the systems of huge nets that are used to collect water. “You could imagine this could be a way to improve those systems,” she says. “A material with this kind of structure might be more effective at fog harvesting and holding the water.”

      “This fascinating and in-depth study reveals how the different parts of the sandgrouse’s belly feathers — including the microscopic barb shafts and barbules — work together to hold water,” says Mary Caswell Stoddard, an evolutionary biologist at Princeton University, who was not associated with this study. “By using a suite of advanced imaging techniques to describe the belly feathers and estimate their bending stiffnesses, Mueller and Gibson add rich new details to our understanding of the sandgrouse’s water-carrying feathers. … This study may inspire others to take a closer look at diverse feather microstructures across bird species — and to wonder whether these structures, as in sandgrouse, help support unusual or surprising functions.”

      The work was partly supported by the National Science Foundation and the Matoula S. Salapatas Professorship in Materials Science and Engineering at MIT. More

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      Tackling counterfeit seeds with “unclonable” labels

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      Average crop yields in Africa are consistently far below those expected, and one significant reason is the prevalence of counterfeit seeds whose germination rates are far lower than those of the genuine ones. The World Bank estimates that as much as half of all seeds sold in some African countries are fake, which could help to account for crop production that is far below potential.

      There have been many attempts to prevent this counterfeiting through tracking labels, but none have proved effective; among other issues, such labels have been vulnerable to hacking because of the deterministic nature of their encoding systems. But now, a team of MIT researchers has come up with a kind of tiny, biodegradable tag that can be applied directly to the seeds themselves, and that provides a unique randomly created code that cannot be duplicated.

      The new system, which uses minuscule dots of silk-based material, each containing a unique combination of different chemical signatures, is described today in the journal Science Advances in a paper by MIT’s dean of engineering Anantha Chandrakasan, professor of civil and environmental engineering Benedetto Marelli, postdoc Hui Sun, and graduate student Saurav Maji.

      The problem of counterfeiting is an enormous one globally, the researchers point out, affecting everything from drugs to luxury goods, and many different systems have been developed to try to combat this. But there has been less attention to the problem in the area of agriculture, even though the consequences can be severe. In sub-Saharan Africa, for example, the World Bank estimates that counterfeit seeds are a significant factor in crop yields that average less than one-fifth of the potential for maize, and less than one-third for rice.

      Marelli explains that a key to the new system is creating a randomly-produced physical object whose exact composition is virtually impossible to duplicate. The labels they create “leverage randomness and uncertainty in the process of application, to generate unique signature features that can be read, and that cannot be replicated,” he says.

      What they’re dealing with, Sun adds, “is the very old job of trying, basically, not to get your stuff stolen. And you can try as much as you can, but eventually somebody is always smart enough to figure out how to do it, so nothing is really unbreakable. But the idea is, it’s almost impossible, if not impossible, to replicate it, or it takes so much effort that it’s not worth it anymore.”

      The idea of an “unclonable” code was originally developed as a way of protecting the authenticity of computer chips, explains Chandrakasan, who is the Vannevar Bush Professor of Electrical Engineering and Computer Science. “In integrated circuits, individual transistors have slightly different properties coined device variations,” he explains, “and you could then use that variability and combine that variability with higher-level circuits to create a unique ID for the device. And once you have that, then you can use that unique ID as a part of a security protocol. Something like transistor variability is hard to replicate from device to device, so that’s what gives it its uniqueness, versus storing a particular fixed ID.” The concept is based on what are known as physically unclonable functions, or PUFs.

      The team decided to try to apply that PUF principle to the problem of fake seeds, and the use of silk proteins was a natural choice because the material is not only harmless to the environment but also classified by the Food and Drug Administration in the “generally recognized as safe” category, so it requires no special approval for use on food products.

      “You could coat it on top of seeds,” Maji says, “and if you synthesize silk in a certain way, it will also have natural random variations. So that’s the idea, that every seed or every bag could have a unique signature.”

      Developing effective secure system solutions has long been one of Chandrakasan’s specialties, while Marelli has spent many years developing systems for applying silk coatings to a variety of fruits, vegetables, and seeds, so their collaboration was a natural for developing such a silk-based coding system toward enhanced security.

      “The challenge was what type of form factor to give to silk,” Sun says, “so that it can be fabricated very easily.” They developed a simple drop-casting approach that produces tags that are less than one-tenth of an inch in diameter. The second challenge was to develop “a way where we can read the uniqueness, in also a very high throughput and easy way.”

      For the unique silk-based codes, Marelli says, “eventually we found a way to add a color to these microparticles so that they assemble in random structures.” The resulting unique patterns can be read out not only by a spectrograph or a portable microscope, but even by an ordinary cellphone camera with a macro lens. This image can be processed locally to generate the PUF code and then sent to the cloud and compared with a secure database to ensure the authenticity of the product. “It’s random so that people cannot easily replicate it,” says Sun. “People cannot predict it without measuring it.”

      And the number of possible permutations that could result from the way they mix four basic types of colored silk nanoparticles is astronomical. “We were able to show that with a minimal amount of silk, we were able to generate 128 random bits of security,” Maji says. “So this gives rise to 2 to the power 128 possible combinations, which is extremely difficult to crack given the computational capabilities of the state-of-the-art computing systems.”

      Marelli says that “for us, it’s a good test bed in order to think out-of-the-box, and how we can have a path that somehow is more democratic.” In this case, that means “something that you can literally read with your phone, and you can fabricate by simply drop casting a solution, without using any advanced manufacturing technique, without going in a clean room.”

      Some additional work will be needed to make this a practical commercial product, Chandrakasan says. “There will have to be a development for at-scale reading” via smartphones. “So, that’s clearly a future opportunity.” But the principle now shows a clear path to the day when “a farmer could at least, maybe not every seed, but could maybe take some random seeds in a particular batch and verify them,” he says.

      The research was partially supported by the U.S. Office of Naval research and the National Science Foundation, Analog Devices Inc., an EECS Mathworks fellowship, and a Paul M. Cook Career Development Professorship. More

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      Titanic robots make farming more sustainable

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      There’s a lot riding on farmers’ ability to fight weeds, which can strangle crops and destroy yields. To protect crops, farmers have two options: They can spray herbicides that pollute the environment and harm human health, or they can hire more workers.

      Unfortunately, both choices are becoming less tenable. Herbicide resistance is a growing problem in crops around the world, while widespread labor shortages have hit the agricultural sector particularly hard.

      Now the startup FarmWise, co-founded by Sebastien Boyer SM ’16, is giving farmers a third option. The company has developed autonomous weeding robots that use artificial intelligence to cut out weeds while leaving crops untouched.

      The company’s first robot, fittingly called the Titan — picture a large tractor that makes use of a trailer in lieu of a driver’s seat — uses machine vision to distinguish weeds from crops including leafy greens, cauliflower, artichokes, and tomatoes while snipping weeds with sub-inch precision.

      About 15 Titans have been roaming the fields of 30 large farms in California and Arizona for the last few years, providing weeding as a service while being directed by an iPad. Last month, the company unveiled its newest robot, Vulcan, which is more lightweight and pulled by a tractor.

      “We have growing population, and we can’t expand the land or water we have, so we need to drastically increase the efficiency of the farming industry,” Boyer says. “I think AI and data are going to be major players in that journey.”

      Finding a road to impact

      Boyer came to MIT in 2014 and earned masters’ degrees in technology and policy as well as electrical engineering and computer science over the next two years.

      “What stood out is the passion that my classmates had for what they did — the drive and passion people had to change the world,” Boyer says.

      As part of his graduate work, Boyer researched machine learning and machine vision techniques, and he soon began exploring ways to apply those technologies to environmental problems. He received a small amount of funding from MIT Sandbox to further develop the idea.

      “That helped me make the decision to not take a real job,” Boyer recalls.

      Following graduation, he and FarmWise co-founder Thomas Palomares, a graduate of Stanford University whom Boyer met in his home country of France, began going to farmers’ markets, introducing themselves to small farmers and asking for tours of their farms. About one in three farmers were happy to show them around. From there they’d ask for referrals to larger farmers and service providers in the industry.

      “We realized agriculture is a large contributor of both emissions and, more broadly, to the negative impact of human activities on the environment,” Boyer says. “It also hasn’t been as disrupted by software, cloud computing, AI, and robotics as other industries. That combination really excites us.”

      Through their conversations, the founders learned herbicides are becoming less effective as weeds develop genetic resistance. The only alternative is to hire more workers, which itself was becoming more difficult for farmers.

      “Labor is extremely tight,” says Boyer, adding that bending over and weeding for 10 hours a day is one of the hardest jobs out there. “The labor supply is shrinking if not collapsing in the U.S., and it’s a worldwide trend. That has real environmental implications because of the tradeoff [between labor and herbicides].”

      The problem is especially acute for farmers of specialty crops, including many fruits, vegetables, and nuts, which grow on smaller farms than corn and soybean and each require slightly different growing practices, limiting the effectiveness of many technical and chemical solutions.

      “We don’t harvest corn by hand today, but we still harvest lettuces and nuts and apples by hand,” Boyer says.

      The Titan was built to complement field workers’ efforts to grow and maintain crops. An operator directs it using an iPad, walking alongside the machine and inspecting progress. Both the Titan and Vulcan are powered by an AI that directs hundreds of tiny blades to snip out weeds around each crop. The Vulcan is controlled directly from the tractor cab, where the operator has a touchscreen interface Boyer compares to those found in a Tesla.

      With more than 15,000 commercial hours under its belt, FarmWise hopes the data it collects can be used for more than just weeding in the near future.

      “It’s all about precision,” Boyer says. “We’re going to better understand what the plant needs and make smarter decisions for each one. That will bring us to a point where we can use the same amount of land, much less water, almost no chemicals, much less fertilizer, and still produce more food than we’re producing today. That’s the mission. That’s what excites me.”

      Weeding out farming challenges

      A customer recently told Boyer that without the Titan, he would have to switch all of his organic crops back to conventional because he couldn’t find enough workers.

      “That’s happening with a lot of customers,” Boyer says. “They have no choice but to rely on herbicides. Acres are staying organic because of our product, and conventional farms are reducing their use of herbicides.”

      Now FarmWise is expanding its database to support weeding for six to 12 new crops each year, and Boyer says adding new crops is getting easier and easier for its system.

      As early partners have sought to expand their deployments, Boyer says the only thing limiting the company’s growth is how fast it can build new robots. FarmWise’s new machines will begin being deployed later this year.

      Although the hulking Titan robots are the face of the company today, the founders hope to leverage the data they’ve collected to further improve farming operations.

      “The mission of the company is to turn AI into a tool that is as reliable and dependable as GPS is now in the farming industry,” Boyer says. “Twenty-five years ago, GPS was a very complicated technology. You had to connect to satellites and do some crazy computation to define your position. But a few companies brought GPS to a new level of reliability and simplicity. Today, every farmer in the world uses GPS. We think AI can have an even deeper impact than GPS has had on the farming industry, and we want to be the company that makes it available and easy to use for every farmer in the world.” More

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      Professor Emeritus Richard Wurtman, influential figure in translational research, dies at 86

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      Richard Wurtman, the Cecil H. Green Distinguished Professor Emeritus and a member of the MIT faculty for 44 years, died on Dec. 13. He was 86.

      Wurtman received an MD from Harvard Medical School in 1960 and trained at Massachusetts General Hospital before joining the laboratory of Nobel laureate Julius Axelrod at the National Institutes of Health in 1962. In 1967, MIT invited him to start a neurochemistry and neuropharmacology program in the Department of Nutrition and Food Science. In the early 1980s he joined the newly formed Department of Brain and Cognitive Sciences. Wurtman was also deeply involved in the National Institutes of Health-established Clinical Research Center at MIT, which he also directed for 25 years.

      His initial placement in Nutrition and Food Science was fortuitous, recalled Wurtman in a 2011 profile, because it “sensitized me to the fact that nutrients are chemicals the way drugs are chemicals. A compound like folic acid is a vitamin in foods, but when given alone in higher doses it becomes a drug that safeguards the developing nervous system.”

      Wurtman’s search for new biological properties and therapeutic uses of known molecules — hormones, nutrients, or existing pharmaceuticals — was highly fruitful. His research on the pineal gland, which started when he was a medical student, led to the discovery that melatonin, the hormone made by the gland, regulates sleep. 

      “Dick Wurtman was a pioneer in studying the role of neurotransmitters in the brain, and neuroendocrine regulation of normal and abnormal brain function,” says Newton Professor of Neuroscience Mriganka Sur, who served as head of the Department of Brain and Cognitive Sciences from 1997 to 2012. “His work on the impact of nutrition on neurotransmitters such as acetylcholine and on neuronal membrane synthesis laid the groundwork for later translational work on brain diseases such as Alzheimer’s disease.”

      Wurtman’s lab discovered that consuming carbohydrates increases tryptophan levels in the brain and consequently the production of the neurotransmitter serotonin. This led to a long collaboration with his wife Judith Wurtman, an MIT research affiliate, in which they found that carbohydrates were often consumed by individuals as a form of self-medication when they experienced changes in mood, such as late in the afternoon or when suffering from premenstrual syndrome (PMS). The Wurtmans’ research led to the development of Sarafem, the first drug for severe PMS, and a drink, PMS Escape, used for milder forms of this syndrome.

      To commercialize some of his findings, Wurtman founded Interneuron Pharmaceuticals in 1988; the company was renamed Indevus in 2002 and acquired by Endo Pharmaceuticals in 2009.

      Wurtman’s research advanced the idea that substrate availability, and not simply enzyme activity, can control metabolic processes in the brain. He discovered that the dietary availability of neurotransmitter precursors (e.g., acetylcholine, dopamine, and GABA) can increase their levels in the brain and modulate their metabolism. Moreover, he applied this concept to synaptic structural components such as brain phosphatides and found that dietary intake of three rate-limiting precursors — uridine, choline, and the omega-3 fatty acid DHA — led to increased brain phosphatide levels, increased dendritic spine density, and improved memory performance. These findings led to the development of Souvenaid, a specifically formulated multi-nutrient drink based on the three essential phosphatide precursors of Wurtman’s later research. It has been the subject of numerous clinical trials for Alzheimer’s disease, and, most recently, for age-related cognitive decline.

      “Dick Wurtman was a pioneer on studying how nutrients influence brain function,” says Li-Huei Tsai, Picower Professor of Neuroscience and director of The Picower Institute for Learning and Memory. “His nutrient clinical trial work and establishment of the MIT Clinical Research Center have been tremendously helpful for my own work on understanding how high doses of supplement choline could potentially help reduce certain Alzheimer’s risk, and our team’s development of clinical studies at MIT to test Alzheimer’s therapies.”

      “Dick’s legacy resides within the careers of hundreds of trainees and collaborators he launched or enhanced, the 1,000-plus published research articles, his numerous patent awards, and people who benefited from his therapeutic approaches,” says former postdoc Bertha Madras, now a professor of psychobiology at McLean Hospital and Harvard Medical School. “Yet, these quantitative metrics, legacies of research and mentoring, do not illustrate the charitable qualities of this remarkable man. I witnessed his deep intellect, boundless energy, enthusiasm, optimism, and generosity toward trainees, qualities that helped to sustain me during crests and troughs encountered in the adventures of a scientific career. Dr. Richard Wurtman was a creative, brilliant scientist, a mentor, a devoted husband to his beloved wife.”

      “Dick was an inspiration, a motivation, and a guide to all his students and colleagues in shaping thoughts to be precise and purposeful,” says Tony Nader PhD ’89, who did his doctoral research with Wurtman. “His rigorous scientific approach and the application of his findings have contributed to make life better. His legacy is huge.”

      Richard and Judith Wurtman have also made a lasting philanthropic impact at MIT. They endowed a professorship in the Department of Brain and Cognitive Sciences in honor of the late Institute Professor and provost Walter Rosenblith; the chair was held first by Ann Graybiel, who is now an Institute Professor; Nancy Kanwisher is the current Walter A. Rosenblith Professor of Cognitive Neuroscience. The Wurtmans have also been longtime supporters of MIT Hillel.

      Elazer R. Edelman, the Edward J. Poitras Professor in Medical Engineering and Science at MIT, professor of medicine at Harvard Medical School, and director of the MIT Institute for Medical Engineering and Science, recalls that Wurtman was also supportive of the Harvard-MIT Program in Health Sciences and Technology: “He changed our school and our world — he and Judith coupled immense charity with exceptional intellect and they made us all better for it.”

      Richard Wurtman is survived by his wife, Judith; daughter Rachael; son David and daughter-in-law Jean Chang; and grandchildren Dvora Toren, Yael Toren and Jacob Vider.  More

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      Food for thought, thought for food

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      According to the Food and Agriculture Organization of the United Nations, approximately 3.1 billion people worldwide were unable to afford a healthy diet in 2020. Meanwhile, in 2021 close to 2.3 billion people were moderately or severely food insecure. Given the strong link between malnutrition and income disparity, the numbers paint a grim picture representing one of the grand challenges of our time.

      “I’m probably an idealist,” says MIT Research Scientist Christopher Mejía Argueta, “but I really believe that if we change our diets and think about ways to help others, we can make a difference — that’s my motivation.”

      Mejía Argueta is the founder and director of the MIT Food and Retail Operations Lab (FaROL). He has more than a decade of experience in supply chain management, optimization, and effective data-driven decision-making on pressing issues like the evolution of end consumers for retail and e-tail supply chains, food waste, and equitable access to nutrition.  

      Supply chain network designs typically focus on minimizing costs without considering the implications (e.g., cost) of changes in consumer behavior. Mejía Argueta and his colleagues at the FaROL, however, are working to understand and design optimal supply chains to create high-performance operations based on consumer choice. “Understanding the significant factors of consumer choice and analyzing their evolution over time becomes critical to designing forward-looking retail operations with data-driven and customer-centric supply chains, inventory management, and distribution systems,” explains Mejía Argueta. 

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      One of his recent projects examined the challenges of small retailers worldwide. These mom-and-pop outlets, or nanostores, account for 50 percent of the global market share and are the primary source of consumer packaged goods for people in urban areas. Worldwide there are nearly 50 million nanostores, each serving between 100-200 households in a community. In India alone, there are 14 million nanostores known as kiranas. And while these retailers are more prevalent in emerging markets, they play an important role in developed markets, particularly in under-resourced communities, and are frequently located in “food deserts,” where they are the only source of essential goods for the community.  

      These small retailers thrive thanks, partly, to their ability to offer the right combination of affordability and convenience while fostering trust with local customers, who often lack access to a supermarket or a grocery store. They often exist in fragmented, densely populated areas where infrastructure and public transportation services are poor and consumers have limited purchasing power. But nanostore shopkeepers and owners are intimately familiar with their customers and their consumption patterns, which means they can connect those consumption patterns or information to the larger supply chain. According to Mejía Argueta, when it comes to the future of retail, nanostores will be the cornerstones of growth in emerging economies. 

      But it’s a complicated scenario. Mom-and-pop shops don’t have the capacity to offer a broad range of products to their customers, and often, they lack access to nutritious food options. Logistically speaking, it is expensive to supply them, and the cost-to-serve (i.e., the logistics cost) is between 10 to 30 percent more expensive than other retailers. According to Mejía Argueta, this has a significant ripple effect, impacting education, productivity, and, eventually, the economic performance of an entire nation.  

      “The high fragmentation of nanostores causes substantial distribution inefficiencies, especially in congested megacities,” he says. “At my lab, we study how to make nanostores more efficient and effective by considering various commercial and logistics strategies while considering inherent technical challenges. We need to serve these small retailers better to help them survive and thrive, to provide a greater impact for underserved communities and the entire economic ecosystem.”

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      Mejía Argueta and his team recently collaborated with Tufts University and the City of Somerville, Massachusetts, to conduct research on food access models in underserved communities. The Somerville Project explored various interventions to supply fresh produce in food desert neighborhoods.

      “A lack of nutrition does not simply mean a lack of food,” Mejía Argueta says. “It can also be caused by an overabundance of unhealthy foods in a given market, which is particularly troublesome for U.S. cities where people in underserved communities don’t have access to healthy food options. We believe that one way to combat the problem of food deserts is to supply these areas with healthy food options affordably and create awareness programs.”  

      The collaborative project saw Mejía Argueta and his colleagues assessing the impact of several intervention schemes designed to empower the end consumer. For example, they implemented a low-cost grocery delivery model similar to Instacart as well as a ride sharing system to transport people from their homes to grocery stores and back. They also collaborated with a nonprofit organization, Partnership for a Healthier America, and began working with retailers to deliver “veggie boxes” in underserved communities. Models like these provide low-income people access to food while providing dignity of choice, Mejía Argueta explains.  

      When it comes to supply chain management research, sustainability and societal impact often fall by the wayside, but Mejía Argueta’s bottom-up approach shirks tradition. “We’re trying to build a community, employing a socially driven perspective because if you work with the community, you gain their trust. If you want to make something sustainable in the long term, people need to trust in these solutions and engage with the ecosystem as a whole.”  

      And to achieve real-world impact, collaboration is key. Mejía Argueta says that government has an important role to play, developing policy to connect the models he and his colleagues develop in academia to societal challenges. Meanwhile, he believes startups and entrepreneurs can function as bridge-builders to link the flows of information, the flows of goods and cash, and even knowledge and security in an ecosystem that suffers from fragmentation and siloed thinking among stakeholders.

      Finally, Mejía Argueta reflects on the role of corporations and his belief that the MIT Industrial Liaison Program is essential to getting his research to the frontline of business challenges. “The Industrial Liaison Program does a fantastic job of connecting our research to real-world scenarios,” he says. “It creates opportunities for us to have meaningful interactions with corporates for real-world impact. I believe strongly in the MIT motto ‘mens et manus,’ and ILP helps drive our research into practice.” More

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      Microparticles could help prevent vitamin A deficiency

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      Vitamin A deficiency is the world’s leading cause of childhood blindness, and in severe cases, it can be fatal. About one-third of the global population of preschool-aged children suffer from this vitamin deficiency, which is most prevalent in sub-Saharan Africa and South Asia.

      MIT researchers have now developed a new way to fortify foods with vitamin A, which they hope could help to improve the health of millions of people around the world. In a new study, they showed that encapsulating vitamin A in a protective polymer prevents the nutrient from being broken down during cooking or storage.

      “Vitamin A is a very important micronutrient, but it’s an unstable molecule,” says Ana Jaklenec, a research scientist at MIT’s Koch Institute for Integrative Cancer Research. “We wanted to see if our encapsulated vitamin A could fortify a food vehicle like bouillon cubes or flour, throughout storage and cooking, and whether the vitamin A could remain biologically active and be absorbed.”

      In a small clinical trial, the researchers showed that when people ate bread fortified with encapsulated vitamin A, the bioavailability of the nutrient was similar to when they consumed vitamin A on its own. The technology has been licensed to two companies that hope to develop it for use in food products.

      “This is a study that our team is really excited about because it shows that everything we did in test tubes and animals works safely and effectively in humans,” says Robert Langer, the David H. Koch Institute Professor at MIT and a member of the Koch Institute. “We hope this opens the door for someday helping millions, if not billions, of people in the developing world.”

      Jaklenec and Langer are the senior authors of the new study, which appears this week in the Proceedings of the National Academy of Sciences. The paper’s lead author is former MIT postdoc Wen Tang, who is now an associate professor at South China University of Technology.

      Nutrient stability

      Vitamin A is critical not only for vision but also the functioning of the immune system and organs such as the heart and lungs. Efforts to add vitamin A to bread or other foods such as bouillon cubes, which are commonly consumed in West African countries, have been largely unsuccessful because the vitamin breaks down during storage or cooking.

      In a 2019 study, the MIT team showed that they could use a polymer called BMC to encapsulate nutrients, including iron, vitamin A, and several others. They showed that this protective coating improved the shelf life of the nutrients, and that people who consumed bread fortified with encapsulated iron were able to absorb the iron.

      BMC is classified by the FDA as “generally regarded as safe,” and is already used in coatings for drugs and dietary supplements. In the new study, the researchers focused on using this polymer to encapsulate vitamin A, a nutrient that is very sensitive to temperature and ultraviolet light.

      Using an industrial process known as a spinning disc process, the researchers mixed vitamin A with the polymer to form particles 100 to 200 microns in diameter. They also coated the particles with starch, which prevents them from sticking to each other.

      The researchers found that vitamin A encapsulated in the polymer particles were more resistant to degradation by intense light, high temperatures, or boiling water. Under those conditions, much more vitamin A remained active than when the vitamin A was free or when it was delivered in a form called VitA 250, which is currently the most stable form of vitamin A used for food fortification.

      The researchers also showed that the encapsulated particles could be easily incorporated into flour or bouillon cubes. To test how well they would survive long-term storage, the researchers exposed the cubes to harsh conditions, as recommended by the World Health Organization: 40 degrees Celsius (104 degrees Fahrenheit) and 75 percent humidity. Under those conditions, the encapsulated vitamin A was much more stable than other forms of vitamin A. 

      “The enhanced stability of vitamin A with our technology can ensure that the vitamin A-fortified food does provide the recommended daily uptake of vitamin A, even after long-term storage in a hot humidified environment, and cooking processes such as boiling or baking,” Tang says. “People who are suffering from vitamin A deficiency and want to get vitamin A through fortified food will benefit, without changing their daily routines, and without wondering how much vitamin A is still in the food.”

      Vitamin absorption

      When the researchers cooked their encapsulated particles and then fed them to animals, they found that 30 percent of the vitamin A was absorbed, the same as free uncooked vitamin A, compared to about 3 percent of free vitamin A that had been cooked.

      Working with Biofortis, a company that does dietary clinical testing, the researchers then evaluated how well vitamin A was absorbed in people who ate foods fortified with the particles. For this study, the researchers incorporated the particles into bread, then measured vitamin A levels in the blood over a 24-hour period after the bread was consumed. They found that when vitamin A was encapsulated in the BMC polymer, it was absorbed from the food at levels comparable to free vitamin A, indicating that it is readily released in bioactive form.

      Two companies have licensed the technology and are focusing on developing products fortified with vitamin A and other nutrients. A benefit corporation called Particles for Humanity, funded by the Bill and Melinda Gates Foundation, is working with partners in Africa to incorporate this technology into existing fortification efforts. Another company called VitaKey, founded by Jaklenec, Langer, and others, is working on using this approach to add nutrients to a variety of foods and beverages.

      The research was funded by the Bill and Melinda Gates Foundation. Other authors of the paper include Jia Zhuang, Aaron Anselmo, Xian Xu, Aranda Duan, Ruojie Zhang, James Sugarman, Yingying Zeng, Evan Rosenberg, Tyler Graf, Kevin McHugh, Stephany Tzeng, Adam Behrens, Lisa Freed, Lihong Jing, Surangi Jayawardena, Shelley Weinstock, Xiao Le, Christopher Sears, James Oxley, John Daristotle, and Joe Collins. More