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Research collaboration puts climate-resilient crops in sight

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Any houseplant owner knows that changes in the amount of water or sunlight a plant receives can put it under immense stress. A dying plant brings certain disappointment to anyone with a green thumb. 

But for farmers who make their living by successfully growing plants, and whose crops may nourish hundreds or thousands of people, the devastation of failing flora is that much greater. As climate change is poised to cause increasingly unpredictable weather patterns globally, crops may be subject to more extreme environmental conditions like droughts, fluctuating temperatures, floods, and wildfire. 

Climate scientists and food systems researchers worry about the stress climate change may put on crops, and on global food security. In an ambitious interdisciplinary project funded by the Abdul Latif Jameel Water and Food Systems Lab (J-WAFS), David Des Marais, the Gale Assistant Professor in the Department of Civil and Environmental Engineering at MIT, and Caroline Uhler, an associate professor in the MIT Department of Electrical Engineering and Computer Science and the Institute for Data, Systems, and Society, are investigating how plant genes communicate with one another under stress. Their research results can be used to breed plants more resilient to climate change.

Crops in trouble

Governing plants’ responses to environmental stress are gene regulatory networks, or GRNs, which guide the development and behaviors of living things. A GRN may be comprised of thousands of genes and proteins that all communicate with one another. GRNs help a particular cell, tissue, or organism respond to environmental changes by signaling certain genes to turn their expression on or off.

Even seemingly minor or short-term changes in weather patterns can have large effects on crop yield and food security. An environmental trigger, like a lack of water during a crucial phase of plant development, can turn a gene on or off, and is likely to affect many others in the GRN. For example, without water, a gene enabling photosynthesis may switch off. This can create a domino effect, where the genes that rely on those regulating photosynthesis are silenced, and the cycle continues. As a result, when photosynthesis is halted, the plant may experience other detrimental side effects, like no longer being able to reproduce or defend against pathogens. The chain reaction could even kill a plant before it has the chance to be revived by a big rain.

Des Marais says he wishes there was a way to stop those genes from completely shutting off in such a situation. To do that, scientists would need to better understand how exactly gene networks respond to different environmental triggers. Bringing light to this molecular process is exactly what he aims to do in this collaborative research effort.

Solving complex problems across disciplines

Despite their crucial importance, GRNs are difficult to study because of how complex and interconnected they are. Usually, to understand how a particular gene is affecting others, biologists must silence one gene and see how the others in the network respond. 

For years, scientists have aspired to an algorithm that could synthesize the massive amount of information contained in GRNs to “identify correct regulatory relationships among genes,” according to a 2019 article in the Encyclopedia of Bioinformatics and Computational Biology

“A GRN can be seen as a large causal network, and understanding the effects that silencing one gene has on all other genes requires understanding the causal relationships among the genes,” says Uhler. “These are exactly the kinds of algorithms my group develops.”

Des Marais and Uhler’s project aims to unravel these complex communication networks and discover how to breed crops that are more resilient to the increased droughts, flooding, and erratic weather patterns that climate change is already causing globally.

In addition to climate change, by 2050, the world will demand 70 percent more food to feed a booming population. “Food systems challenges cannot be addressed individually in disciplinary or topic area silos,” says Greg Sixt, J-WAFS’ research manager for climate and food systems. “They must be addressed in a systems context that reflects the interconnected nature of the food system.”

Des Marais’ background is in biology, and Uhler’s in statistics. “Dave’s project with Caroline was essentially experimental,” says Renee J. Robins, J-WAFS’ executive director. “This kind of exploratory research is exactly what the J-WAFS seed grant program is for.”

Getting inside gene regulatory networks

Des Marais and Uhler’s work begins in a windowless basement on MIT’s campus, where 300 genetically identical Brachypodium distachyon plants grow in large, temperature-controlled chambers. The plant, which contains more than 30,000 genes, is a good model for studying important cereal crops like wheat, barley, maize, and millet. For three weeks, all plants receive the same temperature, humidity, light, and water. Then, half are slowly tapered off water, simulating drought-like conditions.

Six days into the forced drought, the plants are clearly suffering. Des Marais’ PhD student Jie Yun takes tissues from 50 hydrated and 50 dry plants, freezes them in liquid nitrogen to immediately halt metabolic activity, grinds them up into a fine powder, and chemically separates the genetic material. The genes from all 100 samples are then sequenced at a lab across the street.

The team is left with a spreadsheet listing the 30,000 genes found in each of the 100 plants at the moment they were frozen, and how many copies there were. Uhler’s PhD student Anastasiya Belyaeva inputs the massive spreadsheet into the computer program she developed and runs her novel algorithm. Within a few hours, the group can see which genes were most active in one condition over another, how the genes were communicating, and which were causing changes in others. 

The methodology captures important subtleties that could allow researchers to eventually alter gene pathways and breed more resilient crops. “When you expose a plant to drought stress, it’s not like there’s some canonical response,” Des Marais says. “There’s lots of things going on. It’s turning this physiologic process up, this one down, this one didn’t exist before, and now suddenly is turned on.” 

In addition to Des Marais and Uhler’s research, J-WAFS has funded projects in food and water from researchers in 29 departments across all five MIT schools as well as the MIT Schwarzman College of Computing. J-WAFS seed grants typically fund seven to eight new projects every year.

“The grants are really aimed at catalyzing new ideas, providing the sort of support [for MIT researchers] to be pushing boundaries, and also bringing in faculty who may have some interesting ideas that they haven’t yet applied to water or food concerns,” Robins says. “It’s an avenue for researchers all over the Institute to apply their ideas to water and food.”

Alison Gold is a student in MIT’s Graduate Program in Science Writing.

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Source: https://news.mit.edu/2021/interdisciplinary-research-climate-resilient-crops-0917

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Biotechnology

Chemical engineering meets cancer immunotherapy

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Sachin Bhagchandani, a graduate student in the Department of Chemical Engineering currently working at the Koch Institute for Integrative Cancer Research, has won the National Cancer Institute Predoctoral to Postdoctoral Fellow Transition (F99/K00) Award. Bhagchandani is the first student at MIT to receive the award.

The fellowship is given to outstanding graduate students with high potential and interest in becoming independent cancer researchers. Bhagchandani is one of 24 candidates selected for the fellowship this year. Nominations were limited to one student per institution. The award provides six years of funding, which will support Bhagchandani as he completes his PhD in chemical engineering and help him transition into a mentored, cancer-focused postdoctoral research position — one draws on his wide-ranging interests and newfound experiences in synthetic chemistry and immunology.

Making change

Bhagchandani’s research has evolved since his undergraduate days studying chemical engineering at the Indian Institute of Technology, Roorkee. He describes the experience as rigorous, but constraining. While at MIT, he has found more opportunities to explore, leading to highly interdisciplinary projects that allow him to put his training in chemical engineering in service of human health.

Before Bhagchandani arrived at his doctoral project, many pieces had to fall into place. While completing his Master’s thesis, Bhagchandani discovered his interest in the biomedical space while working on a project advised by MIT Institute Professor Robert Langer and Harvard Medical School Professor Jeffrey Karp developing different biomaterials for the sustained delivery of drugs for treating arthritis. As a PhD candidate, he joined the laboratory of chemistry Professor Jeremiah Johnson to learn macromolecular synthesis with a focus on nanomaterials designed for drug delivery. The final piece would fall into place with Bhagchandani’s early forays into immunology — with Darrell Irvine, the Underwood-Prescott Professor of Biological Engineering and Materials Science and Engineering at MIT and Stefani Spranger, the Howard S. (1953) and Linda B. Stern Career Development Professor and assistant professor of biology at MIT.

“When I was exposed to immunology, I learned how relevant the immune system is to our daily life. I found that the biomedical challenges I was working on could be encapsulated by immunology,” Bhagchandani explains. “Drug delivery was my way in, but immunology is my path forward, where I think I will be able to make a contribution to improving human health.”

As a result, his interests have shifted toward cancer immunotherapy — aiming to make these treatments more viable for more patients by making them less toxic. Supported, in part, by the Koch Institute Frontier Research Program, which provides seed funding for high-risk, high-reward/innovative early-stage research, Bhagchandani is focusing on imidazoquinolines, a promising class of drugs that activates the immune system to fight cancer, but can also trigger significant side effects when administered intravenously. In the clinic, topical administration has been shown to minimize these side effects in certain localized cancers, but additional challenges remain for metastatic cancers that have spread throughout the body.

In order to administer imidazoquinolines systemically with minimal toxicity to treat both primary and metastatic tumors, Bhagchandani is adapting a bottlebrush-shaped molecule developed in the Johnson lab to inactivate imidazoquinolines and carry them safely to tumors. Bhagchandani is fine-tuning linking molecules that release as little of the drug as possible while circulating in the blood, and then slowly release the drug once inside the tumor. He is also optimizing the size and architecture of the bottlebrush molecule so that it accumulates in the desired immune cells present in the tumor tissue.

“A lot of students work on interdisciplinary projects as part of a larger team, but Sachin is a one-man crew, able to synthesize new polymers using cutting edge chemistry, characterize these materials, and then test them in animal models of cancer and evaluate their effects on the immune system,” said Irvine. “His knowledge spans polymer chemistry to cancer modeling to immunology.”

Significant figures

Prior to enrolling at MIT, Bhagchandani already had a personal connection to cancer, both through his grandfather, who passed away from prostate cancer, and through working at a children’s hospital in his hometown of Mumbai, spending time with children with cancer. Once on campus, he discovered that working in the biomedical space would allow him to put his skills as a chemical engineer in service of addressing unmet medical needs. In addition, he found that the interdisciplinary nature of the work offered a variety of perspectives on which to build his career.

His doctoral project sits at the nexus of polymer chemistry, drug delivery, and immunology, and requires the collaboration of several laboratories, all members of the Koch Institute for Integrative Cancer Research at MIT. In addition to the Johnson lab, Bhagchandani is working with the Irvine lab for its expertise in immune engineering and the Langer lab for its expertise in drug delivery, and collaborating with the Spranger lab for its expertise in cancer immunology.

“For me, working at the Koch Institute has been one of the most formative experiences of my life, because I’ve gone from traditional chemical engineering training to being exposed to experts in all these different fields with many different perspectives,” said Bhagchandani. When working from the perspective of chemical engineering alone, Bhagchandani said he could not always find solutions to problems that arose.

“I was making the materials and testing them in mouse models, however I couldn’t understand why my experiments weren’t working,” he says. “But by having scientists and engineers who understand immunology, immune engineering, and drug delivery together in the same room, looking at the problem from different angles, that’s when you get that ‘a-ha’ moment, when a project actually works.”

“It is wonderful having brilliant, interdisciplinary scientists like Sachin in my group,” said Johnson. “He was the first student from the Chemical Engineering department to join my group in the Department of Chemistry for their PhD studies, and his ability to bring new perspectives to our work has been highly impactful. Now, led by Sachin, and through our collaborations with Darrell Irvine, Bob Langer, Stefani Spranger, and many others in the Koch Institute, we are able to translate our chemistry in ways we couldn’t have imagined before.”

In his postdoctoral training, Bhagchandani plans to dive deeper into the regulation of the immune system, particularly how different dosing regimens change the body’s response to immunotherapies. Ultimately, he hopes to continue his work as a faculty member leading his own immunology lab — one that focuses on understanding and harnessing early immune responses in cancer therapies.

“I would love to get to a point where I can recreate a lab environment for chemists, engineers, and immunologists to come together and interact and work on interdisciplinary problems. For cancer especially, you need to attack the problem on all different fronts.”

As well as advancing his work in the biomedical space, Bhagchandani hopes to serve as a mentor for future students figuring out their own paths.

“I feel like a lot of people at MIT, myself included, face challenges throughout their PhD where they start to lose belief: ‘Am I the right person, am I good enough for this?’ Having overcome a lot of challenging times when the project wasn’t working as we hoped it would, I think it is important to share these experiences with young trainees to empower them to pursue careers in research. Winning this award helps me look back at those challenges, and persevere, and know, yes, I’m still on the right path. Because I genuinely felt that this is what I want to do with my life and I’ve always felt really passionate coming in to work, that this is where I belong.”

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Source: https://news.mit.edu/2021/chemical-engineering-meets-cancer-immunotherapy-sachin-bhagchandani-0916

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Biotechnology

Chemical engineering meets cancer immunotherapy

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Sachin Bhagchandani, a graduate student in the Department of Chemical Engineering currently working at the Koch Institute for Integrative Cancer Research, has won the National Cancer Institute Predoctoral to Postdoctoral Fellow Transition (F99/K00) Award. Bhagchandani is the first student at MIT to receive the award.

The fellowship is given to outstanding graduate students with high potential and interest in becoming independent cancer researchers. Bhagchandani is one of 24 candidates selected for the fellowship this year. Nominations were limited to one student per institution. The award provides six years of funding, which will support Bhagchandani as he completes his PhD in chemical engineering and help him transition into a mentored, cancer-focused postdoctoral research position — one draws on his wide-ranging interests and newfound experiences in synthetic chemistry and immunology.

Making change

Bhagchandani’s research has evolved since his undergraduate days studying chemical engineering at the Indian Institute of Technology, Roorkee. He describes the experience as rigorous, but constraining. While at MIT, he has found more opportunities to explore, leading to highly interdisciplinary projects that allow him to put his training in chemical engineering in service of human health.

Before Bhagchandani arrived at his doctoral project, many pieces had to fall into place. While completing his Master’s thesis, Bhagchandani discovered his interest in the biomedical space while working on a project advised by MIT Institute Professor Robert Langer and Harvard Medical School Professor Jeffrey Karp developing different biomaterials for the sustained delivery of drugs for treating arthritis. As a PhD candidate, he joined the laboratory of chemistry Professor Jeremiah Johnson to learn macromolecular synthesis with a focus on nanomaterials designed for drug delivery. The final piece would fall into place with Bhagchandani’s early forays into immunology — with Darrell Irvine, the Underwood-Prescott Professor of Biological Engineering and Materials Science and Engineering at MIT and Stefani Spranger, the Howard S. (1953) and Linda B. Stern Career Development Professor and assistant professor of biology at MIT.

“When I was exposed to immunology, I learned how relevant the immune system is to our daily life. I found that the biomedical challenges I was working on could be encapsulated by immunology,” Bhagchandani explains. “Drug delivery was my way in, but immunology is my path forward, where I think I will be able to make a contribution to improving human health.”

As a result, his interests have shifted toward cancer immunotherapy — aiming to make these treatments more viable for more patients by making them less toxic. Supported, in part, by the Koch Institute Frontier Research Program, which provides seed funding for high-risk, high-reward/innovative early-stage research, Bhagchandani is focusing on imidazoquinolines, a promising class of drugs that activates the immune system to fight cancer, but can also trigger significant side effects when administered intravenously. In the clinic, topical administration has been shown to minimize these side effects in certain localized cancers, but additional challenges remain for metastatic cancers that have spread throughout the body.

In order to administer imidazoquinolines systemically with minimal toxicity to treat both primary and metastatic tumors, Bhagchandani is adapting a bottlebrush-shaped molecule developed in the Johnson lab to inactivate imidazoquinolines and carry them safely to tumors. Bhagchandani is fine-tuning linking molecules that release as little of the drug as possible while circulating in the blood, and then slowly release the drug once inside the tumor. He is also optimizing the size and architecture of the bottlebrush molecule so that it accumulates in the desired immune cells present in the tumor tissue.

“A lot of students work on interdisciplinary projects as part of a larger team, but Sachin is a one-man crew, able to synthesize new polymers using cutting edge chemistry, characterize these materials, and then test them in animal models of cancer and evaluate their effects on the immune system,” said Irvine. “His knowledge spans polymer chemistry to cancer modeling to immunology.”

Significant figures

Prior to enrolling at MIT, Bhagchandani already had a personal connection to cancer, both through his grandfather, who passed away from prostate cancer, and through working at a children’s hospital in his hometown of Mumbai, spending time with children with cancer. Once on campus, he discovered that working in the biomedical space would allow him to put his skills as a chemical engineer in service of addressing unmet medical needs. In addition, he found that the interdisciplinary nature of the work offered a variety of perspectives on which to build his career.

His doctoral project sits at the nexus of polymer chemistry, drug delivery, and immunology, and requires the collaboration of several laboratories, all members of the Koch Institute for Integrative Cancer Research at MIT. In addition to the Johnson lab, Bhagchandani is working with the Irvine lab for its expertise in immune engineering and the Langer lab for its expertise in drug delivery, and collaborating with the Spranger lab for its expertise in cancer immunology.

“For me, working at the Koch Institute has been one of the most formative experiences of my life, because I’ve gone from traditional chemical engineering training to being exposed to experts in all these different fields with many different perspectives,” said Bhagchandani. When working from the perspective of chemical engineering alone, Bhagchandani said he could not always find solutions to problems that arose.

“I was making the materials and testing them in mouse models, however I couldn’t understand why my experiments weren’t working,” he says. “But by having scientists and engineers who understand immunology, immune engineering, and drug delivery together in the same room, looking at the problem from different angles, that’s when you get that ‘a-ha’ moment, when a project actually works.”

“It is wonderful having brilliant, interdisciplinary scientists like Sachin in my group,” said Johnson. “He was the first student from the Chemical Engineering department to join my group in the Department of Chemistry for their PhD studies, and his ability to bring new perspectives to our work has been highly impactful. Now, led by Sachin, and through our collaborations with Darrell Irvine, Bob Langer, Stefani Spranger, and many others in the Koch Institute, we are able to translate our chemistry in ways we couldn’t have imagined before.”

In his postdoctoral training, Bhagchandani plans to dive deeper into the regulation of the immune system, particularly how different dosing regimens change the body’s response to immunotherapies. Ultimately, he hopes to continue his work as a faculty member leading his own immunology lab — one that focuses on understanding and harnessing early immune responses in cancer therapies.

“I would love to get to a point where I can recreate a lab environment for chemists, engineers, and immunologists to come together and interact and work on interdisciplinary problems. For cancer especially, you need to attack the problem on all different fronts.”

As well as advancing his work in the biomedical space, Bhagchandani hopes to serve as a mentor for future students figuring out their own paths.

“I feel like a lot of people at MIT, myself included, face challenges throughout their PhD where they start to lose belief: ‘Am I the right person, am I good enough for this?’ Having overcome a lot of challenging times when the project wasn’t working as we hoped it would, I think it is important to share these experiences with young trainees to empower them to pursue careers in research. Winning this award helps me look back at those challenges, and persevere, and know, yes, I’m still on the right path. Because I genuinely felt that this is what I want to do with my life and I’ve always felt really passionate coming in to work, that this is where I belong.”

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Click here to access.

Source: https://news.mit.edu/2021/chemical-engineering-meets-cancer-immunotherapy-sachin-bhagchandani-0916

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Biotechnology

Biologists identify new targets for cancer vaccines

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Over the past decade, scientists have been exploring vaccination as a way to help fight cancer. These experimental cancer vaccines are designed to stimulate the body’s own immune system to destroy a tumor, by injecting fragments of cancer proteins found on the tumor.

So far, none of these vaccines have been approved by the FDA, but some have shown promise in clinical trials to treat melanoma and some types of lung cancer. In a new finding that may help researchers decide what proteins to include in cancer vaccines, MIT researchers have found that vaccinating against certain cancer proteins can boost the overall T cell response and help to shrink tumors in mice.

The research team found that vaccinating against the types of proteins they identified can help to reawaken dormant T cell populations that target those proteins, strengthening the overall immune response.

“This study highlights the importance of exploring the details of immune responses against cancer deeply. We can now see that not all anticancer immune responses are created equal, and that vaccination can unleash a potent response against a target that was otherwise effectively ignored,” says Tyler Jacks, the David H. Koch Professor of Biology, a member of the Koch Institute for Integrative Cancer Research, and the senior author of the study.

MIT postdoc Megan Burger is the lead author of the new study, which appears today in Cell.

T cell competition

When cells begin to turn cancerous, they start producing mutated proteins not seen in healthy cells. These cancerous proteins, also called neoantigens, can alert the body’s immune system that something has gone wrong, and T cells that recognize those neoantigens start destroying the cancerous cells.

Eventually, these T cells experience a phenomenon known as “T cell exhaustion,” which occurs when the tumor creates an immunosuppressive environment that disables the T cells, allowing the tumor to grow unchecked.

Scientists hope that cancer vaccines could help to rejuvenate those T cells and help them to attack tumors. In recent years, they have worked to develop methods for identifying neoantigens in patient tumors to incorporate into personalized cancer vaccines. Some of these vaccines have shown promise in clinical trials to treat melanoma and non-small cell lung cancer.

“These therapies work amazingly in a subset of patients, but the vast majority still don’t respond very well,” Burger says. “A lot of the research in our lab is aimed at trying to understand why that is and what we can do therapeutically to get more of those patients responding.”

Previous studies have shown that of the hundreds of neoantigens found in most tumors, only a small number generate a T cell response.

The new MIT study helps to shed light on why that is. In studies of mice with lung tumors, the researchers found that as tumor-targeting T cells arise, subsets of T cells that target different cancerous proteins compete with each other, eventually leading to the emergence of one dominant population of T cells. After these T cells become exhausted, they still remain in the environment and suppress any competing T cell populations that target different proteins found on the tumor.

However, Burger found that if she vaccinated these mice with one of the neoantigens targeted by the suppressed T cells, she could rejuvenate those T cell populations.

“If you vaccinate against antigens that have suppressed responses, you can unleash those T cell responses,” she says. “Trying to identify these suppressed responses and specifically targeting them might improve patient responses to vaccine therapies.”

Shrinking tumors

In this study, the researchers found that they had the most success when vaccinating with neoantigens that bind weakly to immune cells that are responsible for presenting the antigen to T cells. When they used one of those neoantigens to vaccinate mice with lung tumors, they found the tumors shrank by an average of 27 percent.

“The T cells proliferate more, they target the tumors better, and we see an overall decrease in lung tumor burden in our mouse model as a result of the therapy,” Burger says.

After vaccination, the T cell population included a type of cells that have the potential to continuously refuel the response, which could allow for long-term control of a tumor.

In future work, the researchers hope to test therapeutic approaches that would combine this vaccination strategy with cancer drugs called checkpoint inhibitors, which can take the brakes off exhausted T cells, stimulating them to attack tumors. Supporting that approach, the results published today also indicate that vaccination boosts the number of a specific type of T cells that have been shown to respond well to checkpoint therapies.

The research was funded by the Howard Hughes Medical Institute, the Ludwig Center at Harvard University, the National Institutes of Health, the Koch Institute Support (core) Grant from the National Cancer Institute, the Bridge Project of the Koch Institute and Dana-Farber/Harvard Cancer Center, and fellowship awards from the Jane Coffin Childs Memorial Fund for Medical Research and the Ludwig Center for Molecular Oncology at MIT.

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Source: https://news.mit.edu/2021/tumor-vaccine-t-cells-0916

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