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    An abundant phytoplankton feeds a global network of marine microbes

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    One of the hardest-working organisms in the ocean is the tiny, emerald-tinged Prochlorococcus marinus. These single-celled “picoplankton,” which are smaller than a human red blood cell, can be found in staggering numbers throughout the ocean’s surface waters, making Prochlorococcus the most abundant photosynthesizing organism on the planet. (Collectively, Prochlorococcus fix as much carbon as all the crops on land.) Scientists continue to find new ways that the little green microbe is involved in the ocean’s cycling and storage of carbon.Now, MIT scientists have discovered a new ocean-regulating ability in the small but mighty microbes: cross-feeding of DNA building blocks. In a study appearing today in Science Advances, the team reports that Prochlorococcus shed these extra compounds into their surroundings, where they are then “cross-fed,” or taken up by other ocean organisms, either as nutrients, energy, or for regulating metabolism. Prochlorococcus’ rejects, then, are other microbes’ resources.What’s more, this cross-feeding occurs on a regular cycle: Prochlorococcus tend to shed their molecular baggage at night, when enterprising microbes quickly consume the cast-offs. For a microbe called SAR11, the most abundant bacteria in the ocean, the researchers found that the nighttime snack acts as a relaxant of sorts, forcing the bacteria to slow down their metabolism and effectively recharge for the next day.Through this cross-feeding interaction, Prochlorococcus could be helping many microbial communities to grow sustainably, simply by giving away what it doesn’t need. And they’re doing so in a way that could set the daily rhythms of microbes around the world.“The relationship between the two most abundant groups of microbes in ocean ecosystems has intrigued oceanographers for years,” says co-author and MIT Institute Professor Sallie “Penny” Chisholm, who played a role in the discovery of Prochlorococcus in 1986. “Now we have a glimpse of the finely tuned choreography that contributes to their growth and stability across vast regions of the oceans.”Given that Prochlorococcus and SAR11 suffuse the surface oceans, the team suspects that the exchange of molecules from one to the other could amount to one of the major cross-feeding relationships in the ocean, making it an important regulator of the ocean carbon cycle.“By looking at the details and diversity of cross-feeding processes, we can start to unearth important forces that are shaping the carbon cycle,” says the study’s lead author, Rogier Braakman, a research scientist in MIT’s Department of Earth, Atmospheric and Planetary Sciences (EAPS).Other MIT co-authors include Brandon Satinsky, Tyler O’Keefe, Shane Hogle, Jamie Becker, Robert Li, Keven Dooley, and Aldo Arellano, along with Krista Longnecker, Melissa Soule, and Elizabeth Kujawinski of Woods Hole Oceanographic Institution (WHOI).Spotting castawaysCross-feeding occurs throughout the microbial world, though the process has mainly been studied in close-knit communities. In the human gut, for instance, microbes are in close proximity and can easily exchange and benefit from shared resources.By comparison, Prochlorococcus are free-floating microbes that are regularly tossed and mixed through the ocean’s surface layers. While scientists assume that the plankton are involved in some amount of cross-feeding, exactly how this occurs, and who would benefit, have historically been challenging to probe; any stuff that Prochlorococcus cast away would have vanishingly low concentrations,and be exceedingly difficult to measure.But in work published in 2023, Braakman teamed up with scientists at WHOI, who pioneered ways to measure small organic compounds in seawater. In the lab, they grew various strains of Prochlorococcus under different conditions and characterized what the microbes released. They found that among the major “exudants,” or released molecules, were purines and pyridines, which are molecular building blocks of DNA. The molecules also happen to be nitrogen-rich — a fact that puzzled the team. Prochlorococcus are mainly found in ocean regions that are low in nitrogen, so it was assumed they’d want to retain any and all nitrogen-containing compounds they can. Why, then, were they instead throwing such compounds away?Global symphonyIn their new study, the researchers took a deep dive into the details of Prochlorococcus’ cross-feeding and how it influences various types of ocean microbes.They set out to study how Prochlorococcus use purine and pyridine in the first place, before expelling the compounds into their surroundings. They compared published genomes of the microbes, looking for genes that encode purine and pyridine metabolism. Tracing the genes forward through the genomes, the team found that once the compounds are produced, they are used to make DNA and replicate the microbes’ genome. Any leftover purine and pyridine is recycled and used again, though a fraction of the stuff is ultimately released into the environment. Prochlorococcus appear to make the most of the compounds, then cast off what they can’t.The team also looked to gene expression data and found that genes involved in recycling purine and pyrimidine peak several hours after the recognized peak in genome replication that occurs at dusk. The question then was: What could be benefiting from this nightly shedding?For this, the team looked at the genomes of more than 300 heterotrophic microbes — organisms that consume organic carbon rather than making it themselves through photosynthesis. They suspected that such carbon-feeders could be likely consumers of Prochlorococcus’ organic rejects. They found most of the heterotrophs contained genes that take up either purine or pyridine, or in some cases, both, suggesting microbes have evolved along different paths in terms of how they cross-feed.The group zeroed in on one purine-preferring microbe, SAR11, as it is the most abundant heterotrophic microbe in the ocean. When they then compared the genes across different strains of SAR11, they found that various types use purines for different purposes, from simply taking them up and using them intact to breaking them down for their energy, carbon, or nitrogen. What could explain the diversity in how the microbes were using Prochlorococcus’ cast-offs?It turns out the local environment plays a big role. Braakman and his collaborators performed a metagenome analysis in which they compared the collectively sequenced genomes of all microbes in over 600 seawater samples from around the world, focusing on SAR11 bacteria. Metagenome sequences were collected alongside measurements of various environmental conditions and geographic locations in which they are found. This analysis showed that the bacteria gobble up purine for its nitrogen when the nitrogen in seawater is low, and for its carbon or energy when nitrogen is in surplus — revealing the selective pressures shaping these communities in different ocean regimes.“The work here suggests that microbes in the ocean have developed relationships that advance their growth potential in ways we don’t expect,” says co-author Kujawinski.Finally, the team carried out a simple experiment in the lab, to see if they could directly observe a mechanism by which purine acts on SAR11. They grew the bacteria in cultures, exposed them to various concentrations of purine, and unexpectedly found it causes them to slow down their normal metabolic activities and even growth. However, when the researchers put these same cells under environmentally stressful conditions, they continued growing strong and healthy cells, as if the metabolic pausing by purines helped prime them for growth, thereby avoiding the effects of the stress.“When you think about the ocean, where you see this daily pulse of purines being released by Prochlorococcus, this provides a daily inhibition signal that could be causing a pause in SAR11 metabolism, so that the next day when the sun comes out, they are primed and ready,” Braakman says. “So we think Prochlorococcus is acting as a conductor in the daily symphony of ocean metabolism, and cross-feeding is creating a global synchronization among all these microbial cells.”This work was supported, in part, by the Simons Foundation and the National Science Foundation. More

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      in Environment

      Translating MIT research into real-world results

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      Inventive solutions to some of the world’s most critical problems are being discovered in labs, classrooms, and centers across MIT every day. Many of these solutions move from the lab to the commercial world with the help of over 85 Institute resources that comprise MIT’s robust innovation and entrepreneurship (I&E) ecosystem. The Abdul Latif Jameel Water and Food Systems Lab (J-WAFS) draws on MIT’s wealth of I&E knowledge and experience to help researchers commercialize their breakthrough technologies through the J-WAFS Solutions grant program. By collaborating with I&E programs on campus, J-WAFS prepares MIT researchers for the commercial world, where their novel innovations aim to improve productivity, accessibility, and sustainability of water and food systems, creating economic, environmental, and societal benefits along the way.The J-WAFS Solutions program launched in 2015 with support from Community Jameel, an international organization that advances science and learning for communities to thrive. Since 2015, J-WAFS Solutions has supported 19 projects with one-year grants of up to $150,000, with some projects receiving renewal grants for a second year of support. Solutions projects all address challenges related to water or food. Modeled after the esteemed grant program of MIT’s Deshpande Center for Technological Innovation, and initially administered by Deshpande Center staff, the J-WAFS Solutions program follows a similar approach by supporting projects that have already completed the basic research and proof-of-concept phases. With technologies that are one to three years away from commercialization, grantees work on identifying their potential markets and learn to focus on how their technology can meet the needs of future customers.“Ingenuity thrives at MIT, driving inventions that can be translated into real-world applications for widespread adoption, implantation, and use,” says J-WAFS Director Professor John H. Lienhard V. “But successful commercialization of MIT technology requires engineers to focus on many challenges beyond making the technology work. MIT’s I&E network offers a variety of programs that help researchers develop technology readiness, investigate markets, conduct customer discovery, and initiate product design and development,” Lienhard adds. “With this strong I&E framework, many J-WAFS Solutions teams have established startup companies by the completion of the grant. J-WAFS-supported technologies have had powerful, positive effects on human welfare. Together, the J-WAFS Solutions program and MIT’s I&E ecosystem demonstrate how academic research can evolve into business innovations that make a better world,” Lienhard says.Creating I&E collaborationsIn addition to support for furthering research, J-WAFS Solutions grants allow faculty, students, postdocs, and research staff to learn the fundamentals of how to transform their work into commercial products and companies. As part of the grant requirements, researchers must interact with mentors through MIT Venture Mentoring Service (VMS). VMS connects MIT entrepreneurs with teams of carefully selected professionals who provide free and confidential mentorship, guidance, and other services to help advance ideas into for-profit, for-benefit, or nonprofit ventures. Since 2000, VMS has mentored over 4,600 MIT entrepreneurs across all industries, through a dynamic and accomplished group of nearly 200 mentors who volunteer their time so that others may succeed. The mentors provide impartial and unbiased advice to members of the MIT community, including MIT alumni in the Boston area. J-WAFS Solutions teams have been guided by 21 mentors from numerous companies and nonprofits. Mentors often attend project events and progress meetings throughout the grant period.“Working with VMS has provided me and my organization with a valuable sounding board for a range of topics, big and small,” says Eric Verploegen PhD ’08, former research engineer in MIT’s D-Lab and founder of J-WAFS spinout CoolVeg. Along with professors Leon Glicksman and Daniel Frey, Verploegen received a J-WAFS Solutions grant in 2021 to commercialize cold-storage chambers that use evaporative cooling to help farmers preserve fruits and vegetables in rural off-grid communities. Verploegen started CoolVeg in 2022 to increase access and adoption of open-source, evaporative cooling technologies through collaborations with businesses, research institutions, nongovernmental organizations, and government agencies. “Working as a solo founder at my nonprofit venture, it is always great to have avenues to get feedback on communications approaches, overall strategy, and operational issues that my mentors have experience with,” Verploegen says. Three years after the initial Solutions grant, one of the VMS mentors assigned to the evaporative cooling team still acts as a mentor to Verploegen today.Another Solutions grant requirement is for teams to participate in the Spark program — a free, three-week course that provides an entry point for researchers to explore the potential value of their innovation. Spark is part of the National Science Foundation’s (NSF) Innovation Corps (I-Corps), which is an “immersive, entrepreneurial training program that facilitates the transformation of invention to impact.” In 2018, MIT received an award from the NSF, establishing the New England Regional Innovation Corps Node (NE I-Corps) to deliver I-Corps training to participants across New England. Trainings are open to researchers, engineers, scientists, and others who want to engage in a customer discovery process for their technology. Offered regularly throughout the year, the Spark course helps participants identify markets and explore customer needs in order to understand how their technologies can be positioned competitively in their target markets. They learn to assess barriers to adoption, as well as potential regulatory issues or other challenges to commercialization. NE-I-Corps reports that since its start, over 1,200 researchers from MIT have completed the program and have gone on to launch 175 ventures, raising over $3.3 billion in funding from grants and investors, and creating over 1,800 jobs.Constantinos Katsimpouras, a research scientist in the Department of Chemical Engineering, went through the NE I-Corps Spark program to better understand the customer base for a technology he developed with professors Gregory Stephanopoulos and Anthony Sinskey. The group received a J-WAFS Solutions grant in 2021 for their microbial platform that converts food waste from the dairy industry into valuable products. “As a scientist with no prior experience in entrepreneurship, the program introduced me to important concepts and tools for conducting customer interviews and adopting a new mindset,” notes Katsimpouras. “Most importantly, it encouraged me to get out of the building and engage in interviews with potential customers and stakeholders, providing me with invaluable insights and a deeper understanding of my industry,” he adds. These interviews also helped connect the team with companies willing to provide resources to test and improve their technology — a critical step to the scale-up of any lab invention.In the case of Professor Cem Tasan’s research group in the Department of Materials Science and Engineering, the I-Corps program led them to the J-WAFS Solutions grant, instead of the other way around. Tasan is currently working with postdoc Onur Guvenc on a J-WAFS Solutions project to manufacture formable sheet metal by consolidating steel scrap without melting, thereby reducing water use compared to traditional steel processing. Before applying for the Solutions grant, Guvenc took part in NE I-Corps. Like Katsimpouras, Guvenc benefited from the interaction with industry. “This program required me to step out of the lab and engage with potential customers, allowing me to learn about their immediate challenges and test my initial assumptions about the market,” Guvenc recalls. “My interviews with industry professionals also made me aware of the connection between water consumption and steelmaking processes, which ultimately led to the J-WAFS 2023 Solutions Grant,” says Guvenc.After completing the Spark program, participants may be eligible to apply for the Fusion program, which provides microgrants of up to $1,500 to conduct further customer discovery. The Fusion program is self-paced, requiring teams to conduct 12 additional customer interviews and craft a final presentation summarizing their key learnings. Professor Patrick Doyle’s J-WAFS Solutions team completed the Spark and Fusion programs at MIT. Most recently, their team was accepted to join the NSF I-Corps National program with a $50,000 award. The intensive program requires teams to complete an additional 100 customer discovery interviews over seven weeks. Located in the Department of Chemical Engineering, the Doyle lab is working on a sustainable microparticle hydrogel system to rapidly remove micropollutants from water. The team’s focus has expanded to higher value purifications in amino acid and biopharmaceutical manufacturing applications. Devashish Gokhale PhD ’24 worked with Doyle on much of the underlying science.“Our platform technology could potentially be used for selective separations in very diverse market segments, ranging from individual consumers to large industries and government bodies with varied use-cases,” Gokhale explains. He goes on to say, “The I-Corps Spark program added significant value by providing me with an effective framework to approach this problem … I was assigned a mentor who provided critical feedback, teaching me how to formulate effective questions and identify promising opportunities.” Gokhale says that by the end of Spark, the team was able to identify the best target markets for their products. He also says that the program provided valuable seminars on topics like intellectual property, which was helpful in subsequent discussions the team had with MIT’s Technology Licensing Office.Another member of Doyle’s team, Arjav Shah, a recent PhD from MIT’s Department of Chemical Engineering and a current MBA candidate at the MIT Sloan School of Management, is spearheading the team’s commercialization plans. Shah attended Fusion last fall and hopes to lead efforts to incorporate a startup company called hydroGel.  “I admire the hypothesis-driven approach of the I-Corps program,” says Shah. “It has enabled us to identify our customers’ biggest pain points, which will hopefully lead us to finding a product-market fit.” He adds “based on our learnings from the program, we have been able to pivot to impact-driven, higher-value applications in the food processing and biopharmaceutical industries.” Postdoc Luca Mazzaferro will lead the technical team at hydroGel alongside Shah.In a different project, Qinmin Zheng, a postdoc in the Department of Civil and Environmental Engineering, is working with Professor Andrew Whittle and Lecturer Fábio Duarte. Zheng plans to take the Fusion course this fall to advance their J-WAFS Solutions project that aims to commercialize a novel sensor to quantify the relative abundance of major algal species and provide early detection of harmful algal blooms. After completing Spark, Zheng says he’s “excited to participate in the Fusion program, and potentially the National I-Corps program, to further explore market opportunities and minimize risks in our future product development.”Economic and societal benefitsCommercializing technologies developed at MIT is one of the ways J-WAFS helps ensure that MIT research advances will have real-world impacts in water and food systems. Since its inception, the J-WAFS Solutions program has awarded 28 grants (including renewals), which have supported 19 projects that address a wide range of global water and food challenges. The program has distributed over $4 million to 24 professors, 11 research staff, 15 postdocs, and 30 students across MIT. Nearly half of all J-WAFS Solutions projects have resulted in spinout companies or commercialized products, including eight companies to date plus two open-source technologies.Nona Technologies is an example of a J-WAFS spinout that is helping the world by developing new approaches to produce freshwater for drinking. Desalination — the process of removing salts from seawater — typically requires a large-scale technology called reverse osmosis. But Nona created a desalination device that can work in remote off-grid locations. By separating salt and bacteria from water using electric current through a process called ion concentration polarization (ICP), their technology also reduces overall energy consumption. The novel method was developed by Jongyoon Han, professor of electrical engineering and biological engineering, and research scientist Junghyo Yoon. Along with Bruce Crawford, a Sloan MBA alum, Han and Yoon created Nona Technologies to bring their lightweight, energy-efficient desalination technology to the market.“My feeling early on was that once you have technology, commercialization will take care of itself,” admits Crawford. The team completed both the Spark and Fusion programs and quickly realized that much more work would be required. “Even in our first 24 interviews, we learned that the two first markets we envisioned would not be viable in the near term, and we also got our first hints at the beachhead we ultimately selected,” says Crawford. Nona Technologies has since won MIT’s $100K Entrepreneurship Competition, received media attention from outlets like Newsweek and Fortune, and hired a team that continues to further the technology for deployment in resource-limited areas where clean drinking water may be scarce. Food-borne diseases sicken millions of people worldwide each year, but J-WAFS researchers are addressing this issue by integrating molecular engineering, nanotechnology, and artificial intelligence to revolutionize food pathogen testing. Professors Tim Swager and Alexander Klibanov, of the Department of Chemistry, were awarded one of the first J-WAFS Solutions grants for their sensor that targets food safety pathogens. The sensor uses specialized droplets that behave like a dynamic lens, changing in the presence of target bacteria in order to detect dangerous bacterial contamination in food. In 2018, Swager launched Xibus Systems Inc. to bring the sensor to market and advance food safety for greater public health, sustainability, and economic security.“Our involvement with the J-WAFS Solutions Program has been vital,” says Swager. “It has provided us with a bridge between the academic world and the business world and allowed us to perform more detailed work to create a usable application,” he adds. In 2022, Xibus developed a product called XiSafe, which enables the detection of contaminants like salmonella and listeria faster and with higher sensitivity than other food testing products. The innovation could save food processors billions of dollars worldwide and prevent thousands of food-borne fatalities annually.J-WAFS Solutions companies have raised nearly $66 million in venture capital and other funding. Just this past June, J-WAFS spinout SiTration announced that it raised an $11.8 million seed round. Jeffrey Grossman, a professor in MIT’s Department of Materials Science and Engineering, was another early J-WAFS Solutions grantee for his work on low-cost energy-efficient filters for desalination. The project enabled the development of nanoporous membranes and resulted in two spinout companies, Via Separations and SiTration. SiTration was co-founded by Brendan Smith PhD ’18, who was a part of the original J-WAFS team. Smith is CEO of the company and has overseen the advancement of the membrane technology, which has gone on to reduce cost and resource consumption in industrial wastewater treatment, advanced manufacturing, and resource extraction of materials such as lithium, cobalt, and nickel from recycled electric vehicle batteries. The company also recently announced that it is working with the mining company Rio Tinto to handle harmful wastewater generated at mines.But it’s not just J-WAFS spinout companies that are producing real-world results. Products like the ECC Vial — a portable, low-cost method for E. coli detection in water — have been brought to the market and helped thousands of people. The test kit was developed by MIT D-Lab Lecturer Susan Murcott and Professor Jeffrey Ravel of the MIT History Section. The duo received a J-WAFS Solutions grant in 2018 to promote safely managed drinking water and improved public health in Nepal, where it is difficult to identify which wells are contaminated by E. coli. By the end of their grant period, the team had manufactured approximately 3,200 units, of which 2,350 were distributed — enough to help 12,000 people in Nepal. The researchers also trained local Nepalese on best manufacturing practices.“It’s very important, in my life experience, to follow your dream and to serve others,” says Murcott. Economic success is important to the health of any venture, whether it’s a company or a product, but equally important is the social impact — a philosophy that J-WAFS research strives to uphold. “Do something because it’s worth doing and because it changes people’s lives and saves lives,” Murcott adds.As J-WAFS prepares to celebrate its 10th anniversary this year, we look forward to continued collaboration with MIT’s many I&E programs to advance knowledge and develop solutions that will have tangible effects on the world’s water and food systems.Learn more about the J-WAFS Solutions program and about innovation and entrepreneurship at MIT. More

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      in Security

      Study reveals the benefits and downside of fasting

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      Low-calorie diets and intermittent fasting have been shown to have numerous health benefits: They can delay the onset of some age-related diseases and lengthen lifespan, not only in humans but many other organisms.Many complex mechanisms underlie this phenomenon. Previous work from MIT has shown that one way fasting exerts its beneficial effects is by boosting the regenerative abilities of intestinal stem cells, which helps the intestine recover from injuries or inflammation.In a study of mice, MIT researchers have now identified the pathway that enables this enhanced regeneration, which is activated once the mice begin “refeeding” after the fast. They also found a downside to this regeneration: When cancerous mutations occurred during the regenerative period, the mice were more likely to develop early-stage intestinal tumors.“Having more stem cell activity is good for regeneration, but too much of a good thing over time can have less favorable consequences,” says Omer Yilmaz, an MIT associate professor of biology, a member of MIT’s Koch Institute for Integrative Cancer Research, and the senior author of the new study.Yilmaz adds that further studies are needed before forming any conclusion as to whether fasting has a similar effect in humans.“We still have a lot to learn, but it is interesting that being in either the state of fasting or refeeding when exposure to mutagen occurs can have a profound impact on the likelihood of developing a cancer in these well-defined mouse models,” he says.MIT postdocs Shinya Imada and Saleh Khawaled are the lead authors of the paper, which appears today in Nature.Driving regenerationFor several years, Yilmaz’s lab has been investigating how fasting and low-calorie diets affect intestinal health. In a 2018 study, his team reported that during a fast, intestinal stem cells begin to use lipids as an energy source, instead of carbohydrates. They also showed that fasting led to a significant boost in stem cells’ regenerative ability.However, unanswered questions remained: How does fasting trigger this boost in regenerative ability, and when does the regeneration begin?“Since that paper, we’ve really been focused on understanding what is it about fasting that drives regeneration,” Yilmaz says. “Is it fasting itself that’s driving regeneration, or eating after the fast?”In their new study, the researchers found that stem cell regeneration is suppressed during fasting but then surges during the refeeding period. The researchers followed three groups of mice — one that fasted for 24 hours, another one that fasted for 24 hours and then was allowed to eat whatever they wanted during a 24-hour refeeding period, and a control group that ate whatever they wanted throughout the experiment.The researchers analyzed intestinal stem cells’ ability to proliferate at different time points and found that the stem cells showed the highest levels of proliferation at the end of the 24-hour refeeding period. These cells were also more proliferative than intestinal stem cells from mice that had not fasted at all.“We think that fasting and refeeding represent two distinct states,” Imada says. “In the fasted state, the ability of cells to use lipids and fatty acids as an energy source enables them to survive when nutrients are low. And then it’s the postfast refeeding state that really drives the regeneration. When nutrients become available, these stem cells and progenitor cells activate programs that enable them to build cellular mass and repopulate the intestinal lining.”Further studies revealed that these cells activate a cellular signaling pathway known as mTOR, which is involved in cell growth and metabolism. One of mTOR’s roles is to regulate the translation of messenger RNA into protein, so when it’s activated, cells produce more protein. This protein synthesis is essential for stem cells to proliferate.The researchers showed that mTOR activation in these stem cells also led to production of large quantities of polyamines — small molecules that help cells to grow and divide.“In the refed state, you’ve got more proliferation, and you need to build cellular mass. That requires more protein, to build new cells, and those stem cells go on to build more differentiated cells or specialized intestinal cell types that line the intestine,” Khawaled says.Too much of a good thingThe researchers also found that when stem cells are in this highly regenerative state, they are more prone to become cancerous. Intestinal stem cells are among the most actively dividing cells in the body, as they help the lining of the intestine completely turn over every five to 10 days. Because they divide so frequently, these stem cells are the most common source of precancerous cells in the intestine.In this study, the researchers discovered that if they turned on a cancer-causing gene in the mice during the refeeding stage, they were much more likely to develop precancerous polyps than if the gene was turned on during the fasting state. Cancer-linked mutations that occurred during the refeeding state were also much more likely to produce polyps than mutations that occurred in mice that did not undergo the cycle of fasting and refeeding.“I want to emphasize that this was all done in mice, using very well-defined cancer mutations. In humans it’s going to be a much more complex state,” Yilmaz says. “But it does lead us to the following notion: Fasting is very healthy, but if you’re unlucky and you’re refeeding after a fasting, and you get exposed to a mutagen, like a charred steak or something, you might actually be increasing your chances of developing a lesion that can go on to give rise to cancer.”Yilmaz also noted that the regenerative benefits of fasting could be significant for people who undergo radiation treatment, which can damage the intestinal lining, or other types of intestinal injury. His lab is now studying whether polyamine supplements could help to stimulate this kind of regeneration, without the need to fast.“This fascinating study provides insights into the complex interplay between food consumption, stem cell biology, and cancer risk,” says Ophir Klein, a professor of medicine at the University of California at San Francisco and Cedars-Sinai Medical Center, who was not involved in the study. “Their work lays a foundation for testing polyamines as compounds that may augment intestinal repair after injuries, and it suggests that careful consideration is needed when planning diet-based strategies for regeneration to avoid increasing cancer risk.”The research was funded, in part, by a Pew-Stewart Trust Scholar award, the Marble Center for Cancer Nanomedicine, the Koch Institute-Dana Farber/Harvard Cancer Center Bridge Project, and the MIT Stem Cell Initiative. More

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      in Security

      Food for thought

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      MIT graduate student Juana De La O describes herself as a food-motivated organism, so it’s no surprise that she reaches for food and baking analogies when she’s discussing her thesis work in the lab of undergraduate officer and professor of biology Adam Martin. 

      Consider the formative stages of a croissant, she offers, occasionally providing homemade croissants to accompany the presentation: When one is forming the puff pastry, the dough is folded over the butter again and again. Tissues in a developing mouse embryo must similarly fold and bend, creating layers and structures that become the spine, head, and organs — but these tissues have no hands to induce those formative movements. 

      De La O is studying neural tube closure, the formation of the structure that becomes the spinal cord and the brain. Disorders like anencephaly and craniorachischisis occur when the head region fails to close in a developing fetus. It’s a heartbreaking defect, De La O says, because it’s 100 percent lethal — but the fetus fully develops otherwise. 

      “Your entire central nervous system hinges on this one event happening successfully,” she says. “On the fundamental level, we have a very limited understanding of the mechanisms required for neural closure to happen at all, much less an understanding of what goes wrong that leads to those defects.” 

      Hypothetically speaking

      De La O hails from Chicago, where she received an undergraduate degree from the University of Chicago and worked in the lab of Ilaria Rebay. De La O’s sister was the first person in her family to go to and graduate from college — De La O, in turn, is the first person in her family to pursue a PhD. 

      From her first time visiting campus, De La O could see MIT would provide a thrilling environment in which to study.

      “MIT was one of the few places where the students weren’t constantly complaining about how hard their life was,” she says. “At lunch with prospective students, they’d be talking to each other and then just organically slip into conversations about science.”

      The department emails acceptance letters and sends a physical copy via snail mail. De La O’s letter included a handwritten note from department head Amy Keating, then a graduate officer, who had interviewed De La O during her campus visit. 

      “That’s what really sold it for me,” she recalls. “I went to my PI [principal investigator]’s office and said, ‘I have new data’” and I showed her the letter, and there was lots of unintelligible crying.” 

      To prepare her for graduate school, her parents, both immigrants from Mexico, spent the summer teaching De La O to make all her favorite dishes because “comfort food feels like home.”   

      When she reached MIT, however, the Covid-19 pandemic ground the world to a halt and severely limited what students could experience during rotations. Far from home and living alone, De La O taught herself to bake, creating the confections she craved but couldn’t leave her apartment to purchase. De La O didn’t get to work as extensively as she would have liked during her rotation in the Martin lab. 

      Martin had recently returned from a sabbatical that was spent learning a new research model; historically a fly lab, Martin was planning to delve into mouse research. 

      “My final presentation was, ‘Here’s a hypothetical project I would hypothetically do if I were hypothetically going to work with mice in a fly lab,’” De La O says. 

      Martin recalls being impressed. De La O is skilled at talking about science in an earnest and engaging way, and she dug deep into the literature and identified points Martin hadn’t considered. 

      “This is a level of independence that I look for in a student because it is important to the science to have someone who is contributing their ideas and independent reading and research to a project,” Martin says. 

      After agreeing to join the lab — news she shared with Martin via a meme — she got to work. 

      Charting mouse development

      The neural tube forms from a flat sheet whose sides rise and meet to create a hollow cylinder. De La O has observed patterns of actin and myosin changing in space and time as the embryo develops. Actin and myosin are fibrous proteins that provide structure in eukaryotic cells. They are responsible for some cell movement, like muscle contraction or cell division. Fibers of actin and myosin can also connect across cells, forming vast networks that coordinate the movements of whole tissues. By looking at the structure of these networks, researchers can make predictions about how force is affecting those tissues.

      De La O has found indications of a difference in the tension across the tissue during the critical stages of neural tube closure, which contributes to the tissue’s ability to fold and form a tube. They are not the first research group to propose this, she notes, but they’re suggesting that the patterns of tension are not uniform during a single stage of development.

      “My project, on a really fundamental level, is an atlas for a really early stage of mouse development for actin and myosin,” De La O says. “This dataset doesn’t exist in the field yet.” 

      However, De La O has been performing analyses exclusively in fixed samples, so she may be quantifying phenomena that are not actually how tissues behave. To determine whether that’s the case, De La O plans to analyze live samples.

      The idea is that if one could carefully cut tissue and observe how quickly it recoils, like slicing through a taught rubber band, those measurements could be used to approximate force across the tissue. However, the techniques required are still being developed, and the greater Boston area currently lacks the equipment and expertise needed to attempt those experiments. 

      A big part of her work in the lab has been figuring out how to collect and analyze relevant data. This research has already taken her far and wide, both literally and virtually. 

      “We’ve found that people have been very generous with their time and expertise,” De La O says. “One of the benefits we, as fly people, brought into this field is we don’t know anything — so we’re going to question everything.”

      De La O traveled to the University of Virginia to learn live imaging techniques from associate professor of cell biology Ann Sutherland, and she’s also been in contact with Gabriel Galea at University College London, where Martin and De La O are considering a visit for further training. 

      “There are a lot of reasons why these experiments could go wrong, and one of them is that I’m not trained yet,” she says. “Once you know how to do things on an optimal setup, you can figure out how to make it work on a less-optimal setup.”

      Collaboration and community

      De La O has now expanded her cooking repertoire far beyond her family’s recipes and shares her new creations when she visits home. At MIT, she hosts dinner parties, including one where everything from the savory appetizers to the sweet desserts contained honey, thanks to an Independent Activities Period course about the producers of the sticky substance, and she made and tried apple pie for the first time with her fellow graduate students after an afternoon of apple picking. 

      De La O says she’s still learning how to say no to taking on additional work outside of her regular obligations as a PhD student; she’s found there’s a lot of pressure for underrepresented students to be at the forefront of diversity efforts, and although she finds that work extremely fulfilling, she can, and has, stretched herself too thin in the past. 

      “Every time I see an application that asks ‘How will you work to increase diversity,’ my strongest instinct is just to write ‘I’m brown and around — you’re welcome,’” she jokes. “The greatest amount of diversity work I will do is to get where I’m going. Me achieving my goals increases diversity inherently, but I also want to do well because I know if I do, I will make everything better for people coming after me.”

      De La O is confident her path will be in academia, and troubleshooting, building up protocols, and setting up standards for her work in the Martin Lab has been “an excellent part of my training program.” 

      De La O and Martin embarked on a new project in a new model for the lab for De La O’s thesis, so much of her graduate studies will be spent laying the groundwork for future research. 

      “I hope her travels open Juana’s eyes to science being a larger community and to teach her about how to lead a collaboration,” Martin says. “Overall, I think this project is excellent for a student with aspirations to be a PI. I benefited from extremely open-ended projects as a student and see, in retrospect, how they prepared me for my work today.” More

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      in Energy

      Celebrating five years of MIT.nano

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      There is vast opportunity for nanoscale innovation to transform the world in positive ways — expressed MIT.nano Director Vladimir Bulović as he posed two questions to attendees at the start of the inaugural Nano Summit: “Where are we heading? And what is the next big thing we can develop?”

      “The answer to that puts into perspective our main purpose — and that is to change the world,” Bulović, the Fariborz Maseeh Professor of Emerging Technologies, told an audience of more than 325 in-person and 150 virtual participants gathered for an exploration of nano-related research at MIT and a celebration of MIT.nano’s fifth anniversary.

      Over a decade ago, MIT embarked on a massive project for the ultra-small — building an advanced facility to support research at the nanoscale. Construction of MIT.nano in the heart of MIT’s campus, a process compared to assembling a ship in a bottle, began in 2015, and the facility launched in October 2018.

      Fast forward five years: MIT.nano now contains nearly 170 tools and instruments serving more than 1,200 trained researchers. These individuals come from over 300 principal investigator labs, representing more than 50 MIT departments, labs, and centers. The facility also serves external users from industry, other academic institutions, and over 130 startup and multinational companies.

      A cross section of these faculty and researchers joined industry partners and MIT community members to kick off the first Nano Summit, which is expected to become an annual flagship event for MIT.nano and its industry consortium. Held on Oct. 24, the inaugural conference was co-hosted by the MIT Industrial Liaison Program.

      Six topical sessions highlighted recent developments in quantum science and engineering, materials, advanced electronics, energy, biology, and immersive data technology. The Nano Summit also featured startup ventures and an art exhibition.

      Watch the videos here.

      Seeing and manipulating at the nanoscale — and beyond

      “We need to develop new ways of building the next generation of materials,” said Frances Ross, the TDK Professor in Materials Science and Engineering (DMSE). “We need to use electron microscopy to help us understand not only what the structure is after it’s built, but how it came to be. I think the next few years in this piece of the nano realm are going to be really amazing.”

      Speakers in the session “The Next Materials Revolution,” chaired by MIT.nano co-director for Characterization.nano and associate professor in DMSE James LeBeau, highlighted areas in which cutting-edge microscopy provides insights into the behavior of functional materials at the nanoscale, from anti-ferroelectrics to thin-film photovoltaics and 2D materials. They shared images and videos collected using the instruments in MIT.nano’s characterization suites, which were specifically designed and constructed to minimize mechanical-vibrational and electro-magnetic interference.

      Later, in the “Biology and Human Health” session chaired by Boris Magasanik Professor of Biology Thomas Schwartz, biologists echoed the materials scientists, stressing the importance of the ultra-quiet, low-vibration environment in Characterization.nano to obtain high-resolution images of biological structures.

      “Why is MIT.nano important for us?” asked Schwartz. “An important element of biology is to understand the structure of biology macromolecules. We want to get to an atomic resolution of these structures. CryoEM (cryo-electron microscopy) is an excellent method for this. In order to enable the resolution revolution, we had to get these instruments to MIT. For that, MIT.nano was fantastic.”

      Seychelle Vos, the Robert A. Swanson (1969) Career Development Professor of Life Sciences, shared CryoEM images from her lab’s work, followed by biology Associate Professor Joey Davis who spoke about image processing. When asked about the next stage for CryoEM, Davis said he’s most excited about in-situ tomography, noting that there are new instruments being designed that will improve the current labor-intensive process.

      To chart the future of energy, chemistry associate professor Yogi Surendranath is also using MIT.nano to see what is happening at the nanoscale in his research to use renewable electricity to change carbon dioxide into fuel.

      “MIT.nano has played an immense role, not only in facilitating our ability to make nanostructures, but also to understand nanostructures through advanced imaging capabilities,” said Surendranath. “I see a lot of the future of MIT.nano around the question of how nanostructures evolve and change under the conditions that are relevant to their function. The tools at MIT.nano can help us sort that out.”

      Tech transfer and quantum computing

      The “Advanced Electronics” session chaired by Jesús del Alamo, the Donner Professor of Science in the Department of Electrical Engineering and Computer Science (EECS), brought together industry partners and MIT faculty for a panel discussion on the future of semiconductors and microelectronics. “Excellence in innovation is not enough, we also need to be excellent in transferring these to the marketplace,” said del Alamo. On this point, panelists spoke about strengthening the industry-university connection, as well as the importance of collaborative research environments and of access to advanced facilities, such as MIT.nano, for these environments to thrive.

      The session came on the heels of a startup exhibit in which eleven START.nano companies presented their technologies in health, energy, climate, and virtual reality, among other topics. START.nano, MIT.nano’s hard-tech accelerator, provides participants use of MIT.nano’s facilities at a discounted rate and access to MIT’s startup ecosystem. The program aims to ease hard-tech startups’ transition from the lab to the marketplace, surviving common “valleys of death” as they move from idea to prototype to scaling up.

      When asked about the state of quantum computing in the “Quantum Science and Engineering” session, physics professor Aram Harrow related his response to these startup challenges. “There are quite a few valleys to cross — there are the technical valleys, and then also the commercial valleys.” He spoke about scaling superconducting qubits and qubits made of suspended trapped ions, and the need for more scalable architectures, which we have the ingredients for, he said, but putting everything together is quite challenging.

      Throughout the session, William Oliver, professor of physics and the Henry Ellis Warren (1894) Professor of Electrical Engineering and Computer Science, asked the panelists how MIT.nano can address challenges in assembly and scalability in quantum science.

      “To harness the power of students to innovate, you really need to allow them to get their hands dirty, try new things, try all their crazy ideas, before this goes into a foundry-level process,” responded Kevin O’Brien, associate professor in EECS. “That’s what my group has been working on at MIT.nano, building these superconducting quantum processors using the state-of-the art fabrication techniques in MIT.nano.”

      Connecting the digital to the physical

      In his reflections on the semiconductor industry, Douglas Carlson, senior vice president for technology at MACOM, stressed connecting the digital world to real-world application. Later, in the “Immersive Data Technology” session, MIT.nano associate director Brian Anthony explained how, at the MIT.nano Immersion Lab, researchers are doing just that.

      “We think about and facilitate work that has the human immersed between hardware, data, and experience,” said Anthony, principal research scientist in mechanical engineering. He spoke about using the capabilities of the Immersion Lab to apply immersive technologies to different areas — health, sports, performance, manufacturing, and education, among others. Speakers in this session gave specific examples in hardware, pediatric health, and opera.

      Anthony connected this third pillar of MIT.nano to the fab and characterization facilities, highlighting how the Immersion Lab supports work conducted in other parts of the building. The Immersion Lab’s strength, he said, is taking novel work being developed inside MIT.nano and bringing it up to the human scale to think about applications and uses.

      Artworks that are scientifically inspired

      The Nano Summit closed with a reception at MIT.nano where guests could explore the facility and gaze through the cleanroom windows, where users were actively conducting research. Attendees were encouraged to visit an exhibition on MIT.nano’s first- and second-floor galleries featuring work by students from the MIT Program in Art, Culture, and Technology (ACT) who were invited to utilize MIT.nano’s tool sets and environments as inspiration for art.

      In his closing remarks, Bulović reflected on the community of people who keep MIT.nano running and who are using the tools to advance their research. “Today we are celebrating the facility and all the work that has been done over the last five years to bring it to where it is today. It is there to function not just as a space, but as an essential part of MIT’s mission in research, innovation, and education. I hope that all of us here today take away a deep appreciation and admiration for those who are leading the journey into the nano age.” More

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      in Environment

      Andrea Lo ’21 draws on ecological lessons for life, work, and education

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      Growing up in Los Angeles about 10 minutes away from the Ballona Wetlands, Andrea Lo ’21 has long been interested in ecology. She witnessed, in real-time, the effects of urbanization and the impacts that development had on the wetlands. 

      “In hindsight, it really helped shape my need for a career — and a life — where I can help improve my community and the environment,” she says.

      Lo, who majored in biology at MIT, says a recurring theme in her life has been the pursuit of balance, valuing both extracurricular and curricular activities. She always felt an equal pull toward STEM and the humanities, toward wet lab work and field work, and toward doing research and helping her community. 

      “One of the most important things I learned in 7.30[J] (Fundamentals of Ecology) was that there are always going to be trade-offs. That’s just the way of life,” she says. “The biology major at MIT is really flexible. I got a lot of room to explore what I was interested in and get a good balance overall, with humanities classes along with technical classes.” 

      Lo was drawn to MIT because of the focus on hands-on work — but many of the activities Lo was hoping to do, both extracurricular and curricular, were cut short because of the pandemic, including her lab-based Undergraduate Research Opportunities Program (UROP) project. 

      Instead, she pursued a UROP with MIT Sea Grant, working on a project in partnership with Northeastern University and the Charles River Conservancy with funding support from the MIT Community Service fund as part of STEAM Saturday.  

      She was involved in creating Floating Wetland kits, an educational activity directed at students in grades 4 to 6 to help students understand ecological concepts,the challenges the Charles River faces due to urbanization, and how floating wetlands improve the ecosystem. 

      “Our hope was to educate future generations of local students in Cambridge in order for them to understand the ecology surrounding where they live,” she says. 

      In recent years, many bodies of water in Massachusetts have become unusable during the warmer months due to the process of eutrophication: stormwater runoff picks up everything — from fertilizer and silt to animal excrement — and deposits it at the lowest point, which is often a body of water. This leads to an excess of nutrients in the body of water and, when combined with warm temperatures, can lead to harmful algal blooms, making the water sludgy, bright green, and dangerously toxic. 

      The wetland kits Lo worked with were mini ecosystems, replicating a full-sized floating wetland. One such floating wetland can be seen from the Longfellow Bridge at one end of MIT’s campus — the Charles River floating wetland is a patch of grass attached to a buoy like a boat, which is often visited by birds and inhabited by much smaller critters that cannot be seen from the shore.  

      The Charles River floating wetland has a variety of flora, but the kits Lo helped present use only wheat grass because it is easy to grow and has long, dangling roots that could penetrate the watery medium below. A water tray beneath the grass — the Charles river of the mini ecosystem — contains spirulina powder for replicating algae growth and daphnia, which are small, planktonic crustaceans that help keep freshwater clean and usable. 

      “This work was really fulfilling, but it’s also really important, because environmental sustainability relies on future generations to carry on the work that past generations have been doing,” she says. “MIT’s motto is ‘mens et manus’ — education for practical application, and applying theoretical knowledge to what we do in our daily lives. I think this project really helped reinforce that.” 

      Since 2021, Lo has been working in Denmark in a position she learned about through the MIT-Denmark program. 

      She chose Denmark because of its reputation for environmental and sustainability issues and because she didn’t know much about it except for it being one of the happiest countries in the world, often thought of synonymously with the word “hygge,” which has no direct translation but encapsulates coziness and comfort from the small joys in life. 

      “At MIT, we have a very strong work-hard, play-hard culture. I think we can learn a lot from the work-life balance that Denmark has a reputation for,” she says. “I really wanted to take the opportunity in between graduation and whatever came after to explore beyond my bubble. For me, it was important to step back, out of my comfort zone, step into a different environment — and just live.”

      Currently, her personal project is comparing the conditions of two lagoons on the island of Fyn in Denmark. Both are naturally occurring, but in different states of environmental health. 

      She’s been doing a mix of field work and lab work. She collects sediment and fauna samples using a steel corer, or “butter stick” in her lab’s slang. In the same way that one can use a metal tube-shaped tool to remove the core of an apple, she punches the steel corer into the ground, removing a plug of sample. She then sifts the sample through 1 millimeter mesh, preserves the filtered sample in formalin, and takes everything back to the lab. 

      Once there, she looks through the sample to find macrofauna — mollusks, barnacles, and polychaetes, a bristly-looking segmented worm, for example. Collected over time, sediment characteristics like organic matter content, sediment grain size, and the size and abundance of macrofauna, can reveal trends that can help determine the health of the ecosystem. 

      Lo doesn’t have any concrete results yet, but her data could help researchers project the recovery of a lagoon that was rehabilitated using a technique called managed realignment, where water is allowed to reclaim areas where it was once found. She says she’s glad she gets a mix of field work and lab work, even on Denmark’s stormiest days. 

      “Sometimes there are really cold days where it’s windy and I wish I was in the lab, but, at the same time, it’s nice to have a balance where I can be outside and really be hands-on with my work,” she says.  

      Reflecting her dual interests in the technical and the innovative, she will be back in the Greater Boston area in the fall, pursuing a master of science in innovation and management and an MS in civil and environmental engineering at the Tufts Gordon Institute.

      “So much has happened and changed due to the pandemic that it’s easy to dwell on what could’ve been, but I tell myself to be optimistic and take the positive aspects that have come out of the circumstances,” Lo says. “My opportunities with the Sea Grant, MISTI, and Tufts definitely wouldn’t have happened if the pandemic hadn’t happened.” More

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      in Security

      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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      in Environment

      Inaugural J-WAFS Grand Challenge aims to develop enhanced crop variants and move them from lab to land

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      According to MIT’s charter, established in 1861, part of the Institute’s mission is to advance the “development and practical application of science in connection with arts, agriculture, manufactures, and commerce.” Today, the Abdul Latif Jameel Water and Food Systems Lab (J-WAFS) is one of the driving forces behind water and food-related research on campus, much of which relates to agriculture. In 2022, J-WAFS established the Water and Food Grand Challenge Grant to inspire MIT researchers to work toward a water-secure and food-secure future for our changing planet. Not unlike MIT’s Climate Grand Challenges, the J-WAFS Grand Challenge seeks to leverage multiple areas of expertise, programs, and Institute resources. The initial call for statements of interests returned 23 letters from MIT researchers spanning 18 departments, labs, and centers. J-WAFS hosted workshops for the proposers to present and discuss their initial ideas. These were winnowed down to a smaller set of invited concept papers, followed by the final proposal stage. 

      Today, J-WAFS is delighted to report that the inaugural J-WAFS Grand Challenge Grant has been awarded to a team of researchers led by Professor Matt Shoulders and research scientist Robert Wilson of the Department of Chemistry. A panel of expert, external reviewers highly endorsed their proposal, which tackles a longstanding problem in crop biology — how to make photosynthesis more efficient. The team will receive $1.5 million over three years to facilitate a multistage research project that combines cutting-edge innovations in synthetic and computational biology. If successful, this project could create major benefits for agriculture and food systems worldwide.

      “Food systems are a major source of global greenhouse gas emissions, and they are also increasingly vulnerable to the impacts of climate change. That’s why when we talk about climate change, we have to talk about food systems, and vice versa,” says Maria T. Zuber, MIT’s vice president for research. “J-WAFS is central to MIT’s efforts to address the interlocking challenges of climate, water, and food. This new grant program aims to catalyze innovative projects that will have real and meaningful impacts on water and food. I congratulate Professor Shoulders and the rest of the research team on being the inaugural recipients of this grant.”

      Shoulders will work with Bryan Bryson, associate professor of biological engineering, as well as Bin Zhang, associate professor of chemistry, and Mary Gehring, a professor in the Department of Biology and the Whitehead Institute for Biomedical Research. Robert Wilson from the Shoulders lab will be coordinating the research effort. The team at MIT will work with outside collaborators Spencer Whitney, a professor from the Australian National University, and Ahmed Badran, an assistant professor at the Scripps Research Institute. A milestone-based collaboration will also take place with Stephen Long, a professor from the University of Illinois at Urbana-Champaign. The group consists of experts in continuous directed evolution, machine learning, molecular dynamics simulations, translational plant biochemistry, and field trials.

      “This project seeks to fundamentally improve the RuBisCO enzyme that plants use to convert carbon dioxide into the energy-rich molecules that constitute our food,” says J-WAFS Director John H. Lienhard V. “This difficult problem is a true grand challenge, calling for extensive resources. With J-WAFS’ support, this long-sought goal may finally be achieved through MIT’s leading-edge research,” he adds.

      RuBisCO: No, it’s not a new breakfast cereal; it just might be the key to an agricultural revolution

      A growing global population, the effects of climate change, and social and political conflicts like the war in Ukraine are all threatening food supplies, particularly grain crops. Current projections estimate that crop production must increase by at least 50 percent over the next 30 years to meet food demands. One key barrier to increased crop yields is a photosynthetic enzyme called Ribulose-1,5-Bisphosphate Carboxylase/Oxygenase (RuBisCO). During photosynthesis, crops use energy gathered from light to draw carbon dioxide (CO2) from the atmosphere and transform it into sugars and cellulose for growth, a process known as carbon fixation. RuBisCO is essential for capturing the CO2 from the air to initiate conversion of CO2 into energy-rich molecules like glucose. This reaction occurs during the second stage of photosynthesis, also known as the Calvin cycle. Without RuBisCO, the chemical reactions that account for virtually all carbon acquisition in life could not occur.

      Unfortunately, RuBisCO has biochemical shortcomings. Notably, the enzyme acts slowly. Many other enzymes can process a thousand molecules per second, but RuBisCO in chloroplasts fixes less than six carbon dioxide molecules per second, often limiting the rate of plant photosynthesis. Another problem is that oxygen (O2) molecules and carbon dioxide molecules are relatively similar in shape and chemical properties, and RuBisCO is unable to fully discriminate between the two. The inadvertent fixation of oxygen by RuBisCO leads to energy and carbon loss. What’s more, at higher temperatures RuBisCO reacts even more frequently with oxygen, which will contribute to decreased photosynthetic efficiency in many staple crops as our climate warms.

      The scientific consensus is that genetic engineering and synthetic biology approaches could revolutionize photosynthesis and offer protection against crop losses. To date, crop RuBisCO engineering has been impaired by technological obstacles that have limited any success in significantly enhancing crop production. Excitingly, genetic engineering and synthetic biology tools are now at a point where they can be applied and tested with the aim of creating crops with new or improved biological pathways for producing more food for the growing population.

      An epic plan for fighting food insecurity

      The 2023 J-WAFS Grand Challenge project will use state-of-the-art, transformative protein engineering techniques drawn from biomedicine to improve the biochemistry of photosynthesis, specifically focusing on RuBisCO. Shoulders and his team are planning to build what they call the Enhanced Photosynthesis in Crops (EPiC) platform. The project will evolve and design better crop RuBisCO in the laboratory, followed by validation of the improved enzymes in plants, ultimately resulting in the deployment of enhanced RuBisCO in field trials to evaluate the impact on crop yield. 

      Several recent developments make high-throughput engineering of crop RuBisCO possible. RuBisCO requires a complex chaperone network for proper assembly and function in plants. Chaperones are like helpers that guide proteins during their maturation process, shielding them from aggregation while coordinating their correct assembly. Wilson and his collaborators previously unlocked the ability to recombinantly produce plant RuBisCO outside of plant chloroplasts by reconstructing this chaperone network in Escherichia coli (E. coli). Whitney has now established that the RuBisCO enzymes from a range of agriculturally relevant crops, including potato, carrot, strawberry, and tobacco, can also be expressed using this technology. Whitney and Wilson have further developed a range of RuBisCO-dependent E. coli screens that can identify improved RuBisCO from complex gene libraries. Moreover, Shoulders and his lab have developed sophisticated in vivo mutagenesis technologies that enable efficient continuous directed evolution campaigns. Continuous directed evolution refers to a protein engineering process that can accelerate the steps of natural evolution simultaneously in an uninterrupted cycle in the lab, allowing for rapid testing of protein sequences. While Shoulders and Badran both have prior experience with cutting-edge directed evolution platforms, this will be the first time directed evolution is applied to RuBisCO from plants.

      Artificial intelligence is changing the way enzyme engineering is undertaken by researchers. Principal investigators Zhang and Bryson will leverage modern computational methods to simulate the dynamics of RuBisCO structure and explore its evolutionary landscape. Specifically, Zhang will use molecular dynamics simulations to simulate and monitor the conformational dynamics of the atoms in a protein and its programmed environment over time. This approach will help the team evaluate the effect of mutations and new chemical functionalities on the properties of RuBisCO. Bryson will employ artificial intelligence and machine learning to search the RuBisCO activity landscape for optimal sequences. The computational and biological arms of the EPiC platform will work together to both validate and inform each other’s approaches to accelerate the overall engineering effort.

      Shoulders and the group will deploy their designed enzymes in tobacco plants to evaluate their effects on growth and yield relative to natural RuBisCO. Gehring, a plant biologist, will assist with screening improved RuBisCO variants using the tobacco variety Nicotiana benthamianaI, where transient expression can be deployed. Transient expression is a speedy approach to test whether novel engineered RuBisCO variants can be correctly synthesized in leaf chloroplasts. Variants that pass this quality-control checkpoint at MIT will be passed to the Whitney Lab at the Australian National University for stable transformation into Nicotiana tabacum (tobacco), enabling robust measurements of photosynthetic improvement. In a final step, Professor Long at the University of Illinois at Urbana-Champaign will perform field trials of the most promising variants.

      Even small improvements could have a big impact

      A common criticism of efforts to improve RuBisCO is that natural evolution has not already identified a better enzyme, possibly implying that none will be found. Traditional views have speculated a catalytic trade-off between RuBisCO’s specificity factor for CO2 / O2 versus its CO2 fixation efficiency, leading to the belief that specificity factor improvements might be offset by even slower carbon fixation or vice versa. This trade-off has been suggested to explain why natural evolution has been slow to achieve a better RuBisCO. But Shoulders and the team are convinced that the EPiC platform can unlock significant overall improvements to plant RuBisCO. This view is supported by the fact that Wilson and Whitney have previously used directed evolution to improve CO2 fixation efficiency by 50 percent in RuBisCO from cyanobacteria (the ancient progenitors of plant chloroplasts) while simultaneously increasing the specificity factor. 

      The EPiC researchers anticipate that their initial variants could yield 20 percent increases in RuBisCO’s specificity factor without impairing other aspects of catalysis. More sophisticated variants could lift RuBisCO out of its evolutionary trap and display attributes not currently observed in nature. “If we achieve anywhere close to such an improvement and it translates to crops, the results could help transform agriculture,” Shoulders says. “If our accomplishments are more modest, it will still recruit massive new investments to this essential field.”

      Successful engineering of RuBisCO would be a scientific feat of its own and ignite renewed enthusiasm for improving plant CO2 fixation. Combined with other advances in photosynthetic engineering, such as improved light usage, a new green revolution in agriculture could be achieved. Long-term impacts of the technology’s success will be measured in improvements to crop yield and grain availability, as well as resilience against yield losses under higher field temperatures. Moreover, improved land productivity together with policy initiatives would assist in reducing the environmental footprint of agriculture. With more “crop per drop,” reductions in water consumption from agriculture would be a major boost to sustainable farming practices.

      “Our collaborative team of biochemists and synthetic biologists, computational biologists, and chemists is deeply integrated with plant biologists and field trial experts, yielding a robust feedback loop for enzyme engineering,” Shoulders adds. “Together, this team will be able to make a concerted effort using the most modern, state-of-the-art techniques to engineer crop RuBisCO with an eye to helping make meaningful gains in securing a stable crop supply, hopefully with accompanying improvements in both food and water security.” More

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      Recycling plastics from research labs

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      In 2019, MIT’s Environment, Health, and Safety (EHS) Office collaborated with several research labs in the Department of Biology to determine the feasibility of recycling clean lab plastics. Based on early successes with waste isolation and plastics collection, EHS collaborated with GreenLabs Recycling, a local startup, to remove and recycle lab plastics from campus. It was a huge success.

      Today, EHS spearheads the campus Lab Plastics Recycling Program, and its EHS technicians regularly gather clean lab plastics from 212 MIT labs, transferring them to GreenLabs for recycling. Since its pilot stage, the number of labs participating in the program has grown, increasing the total amount of plastic gathered and recycled. In 2020, EHS collected 170 pounds of plastic waste per week from participating labs. That increased to 250 pounds per week in 2021. In 2022, EHS collected a total of 19,000 pounds, or 280 pounds of plastic per week.

      Joanna Buchthal, a research assistant with the MIT Media Lab, indicates that, prior to joining the EHS Lab Plastics Recycling Program, “our laboratory was continuously troubled by the substantial volume of plastic waste we produced and disheartened by our inability to recycle it. We frequently addressed this issue during our group meetings and explored various ways to repurpose our waste, yet we never arrived at a viable solution.”

      The EHS program now provides a solution to labs facing similar challenges with plastics use. After pickup and removal, the plastics are shredded and sold as free stock for injection mold product manufacturing. Buchthal says, “My entire lab is delighted to recycle our used tip boxes and transform them into useful items for other labs!”

      Recently, GreenLabs presented EHS with a three-gallon bucket that local manufacturers produced from 100 percent recycled plastic gathered from MIT labs. No fillers or additives were used in its production.

      Keeping it clean

      The now-growing EHS service and operation started as a pilot. In June 2019, MIT restricted which lab-generated items could be placed in single-stream recycling. MIT’s waste vendors were no longer accepting possibly contaminated waste, such as gloves, pipette tip boxes, bottles, and other plastic waste typically generated in biological research labs. The waste vendors would audit MIT’s single-stream recycling and reject items if they observed any contamination.

      Facing these challenges, the EHS coordinator for biology, John Fucillo, and several EHS representatives from the department met with EHS staff to brainstorm potential recycling solutions. Ensuring the decontamination of the plastic and coordinating its removal in an efficient way were the primary challenges for the labs, says Fucillo, who shared his and lab members’ concerns about the amount of plastic being thrown away with Mitch Galanek, EHS associate director for the Radiation Protection Program. Galanek says, “I immediately recognized the frustration expressed by John and other lab contacts as an opportunity to collaborate.”

      In July 2019, Galanek and a team of EHS technicians began segregating and collecting clean plastic waste from several labs within the biology department. EHS provided the labs with collection containers, and its technicians managed the waste removal over a four-month period, which produced a snapshot of the volume and type of waste generated. An audit of the waste determined that approximately 80 percent of the clean plastic waste generated was empty pipette tip boxes and conical tube racks.

      Based on these data, EHS launched a lab plastics recycling pilot program in November 2019. Labs from the Department of Biology and the Koch Institute for Integrative Cancer Research were invited to participate by recycling their clean, uncontaminated pipette tip boxes and conical tube racks. In addition to providing these labs with collection boxes and plastic liners, EHS also developed an online waste collection request tool to submit plastic pickup requests. EHS also collected the waste containers once they were full.

      Assistant professor of biology Seychelle Vos joined the pilot program as soon as she started her lab in fall 2019. Vos shares that “we already use pipette tips boxes that produce minimal waste, and this program allows us to basically recycle any part of the box except for tips. Pipette boxes are a significant source of plastic waste. This program helps us to be more environmentally and climate friendly.” 

      Given the increased participation in the program, EHS technician Dave Pavone says that plastic pickup is now a “regular component of our work schedules.”

      Together, the EHS technicians, commonly known as “techs,” manage the pickup of nearly 300 plastic collection containers across campus. Normand Desrochers, one of the EHS techs, shares that each morning he plans his pickup route “to get the job done efficiently.” While weekly pickups are a growing part of their schedules, Desrochers notes that everyone has been “super appreciative in what we do for their labs. And what we do makes their job that much easier, being able to focus on their research.”

      Barbara Karampalas, a lab operations manager within the Department of Biological Engineering, is one of many to express appreciation for the program: “We have a fairly large lab with 35 researchers, so we generate a lot of plastic waste … [and] knowing how many tip boxes we were using concerned me. I really appreciate the effort EHS has made to implement this program to help us reduce our impact on the environment.” The program also “makes people in the lab more aware of the issue of plastic waste and MIT’s commitment to reduce its impact on the environment,” says Karampalas.

      Looking ahead

      MIT labs continue to enthusiastically embrace the EHS Lab Plastics Recycling Program: 112 faculty across 212 labs are currently participating in the program. While only empty pipette tip boxes and conical tube racks are currently collected, EHS is exploring which lab plastics could be manufactured into products for use in the labs and repeatedly recycled. Specifically, the EHS Office is considering whether recycled plastic could be used to produce secondary containers for collecting hazardous waste and benchtop transfer containers used for collecting medical waste. As Seychelle notes, “Most plastics cannot be recycled in the current schemes due to their use in laboratory science.”

      Says Fucillo, “Our hope is that this program can be expanded to include other products which could be recycled from the wet labs.” John MacFarlane, research engineer and EHS coordinator for civil and environmental engineering, echoes this sentiment: “With plastic recycling facing economic constraints, this effort by the Institute deserves to be promoted and, hopefully, expanded.”

      “Having more opportunities to recycle ’biologically clean’ plastics would help us have a smaller carbon footprint,” agrees Vos. “We love this program and hope it expands further!”

      MIT labs interested in participating in the EHS Lab Plastics Recycling Program can contact pipetip@mit.edu to learn more. More