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Chemical engineering meets cancer immunotherapy



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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Documentary short, “The Uprising,” showcases women in science who pressed for equal rights at MIT in the 1990s



The MIT Press today announced the digital release of “The Uprising,” a documentary short about the unprecedented behind-the-scenes effort that amassed irrefutable evidence of differential treatment of men and women on the MIT faculty in the 1990s. Directed by Ian Cheney and Sharon Shattuck, the film premiered on the MIT Press’ YouTube channel, and is now openly distributed. 

A 13-minute film, “The Uprising” introduces the story behind the 1999 Study on the Status of Women Faculty in Science at MIT and its impact both at the Institute and around the globe. Featuring Nancy Hopkins, professor emerita of biology at MIT, the film chronicles the experiences of marginalization and discouragement that accompanied Hopkins’ research leading up to the study and further highlights the steps a group of 16 female faculty members took to make science more diverse and equitable.

The MIT report is today widely credited with advancing gender equity in universities both nationally and internationally. This ripple effect is highlighted in the film by Hopkins, who says, “Look at the talent of these women. This is what you lose when you do not solve this problem. It’s true not just of women, it’s true of minorities, it’s true of all groups that get excluded. It’s all of that talent that you lose. For me, the success of these women is the reward for the work we did. That’s really what it’s about. It’s about the science.”

“The Uprising” features interviews with leading current and former MIT scientists, including social psychologist Lotte Bailyn, biomedical engineer Sangeeta N. Bhatia, chemist Sylvia Ceyer, ecologist Sallie “Penny” Chisholm, materials engineer Lorna Gibson, biologist Ruth Lehmann, geophysicist and National Academy of Sciences President Marcia McNutt, cognitive scientist Mary Potter, oceanographer Paola Rizzoli, geophysicist Leigh Royden, and biologist Lisa Steiner. “The Uprising” was produced in conjunction with the feature-length documentary film, “Picture a Scientist.

“The Uprising” was funded by a grant from the Alfred P. Sloan Foundation, as well as support from Nancy Blachman and an anonymous donor. The film was produced by Manette Pottle, in collaboration with the MIT Press. Amy Brand, director and publisher at the MIT Press, served as executive producer. 

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Volta Labs: Improving workflows for genetic applications



The cost of DNA sequencing has plummeted at a rate faster than Moore’s Law, opening large markets in the sequencing space. Genomics for cancer care alone is predicted to hit $23 billion by 2025, but sample preparation costs for sequencing have stagnated, causing a significant bottleneck in the space.

Conventional sample preparation, converting DNA from a saliva sample, for example, into something that can be fed to a sequencing machine, relies on a liquid-handling robot. It is essentially a mechanical arm equipped with pipette tips that moves liquid samples to plastic plates and other instruments placed on the deck. These systems involve multiple fluidic transfers that lead to poor utilization of reagents and samples, which means less DNA sequenced. Moreover, they are systems of separate data silos that lack integration and rely on expensive consumables.

Unlike traditional liquid-handling automation, the suite of solutions developed by MIT Media Lab spinoff Volta Labs provides end-to-end integration for a wide variety of workflows. It’s a sleek alternative to costly liquid handling machines and manual pipetting. “Our technology is a small-scale, benchtop device that is low-cost and has minimal consumable usage, enabling rapid and flexible composition of new biological workflows,” says Volta Labs co-founder and Head of Engineering Will Langford SM ’14, PhD ’19.

The Volta platform is based on digital microfluidic technology developed at MIT by Langford’s co-founder, Volta Labs CEO Udayan Umapathi SM ’17. The core principle behind the innovation is called electrowetting. It allows its users to manipulate droplets around a printed circuit board to perform biological reactions, automating from raw sample to prepared library that can be run on a sequencing machine.

Umapathi arrived at the Media Lab with what he describes as “a fascination for building automation from the ground up.” Though trained as an engineer, Umapathi has applied his skills to a variety of fields. In 2015, he founded a startup that created web and physical tools to enable content creation for digital manufacturing. However, it was while working for a synthetic biology company, engineering liquid-handling systems for genome engineering solutions, that he identified the scaling up of automation as a pain point for the field.

Meanwhile, Langford spent his MIT days at the Center for Bits and Atoms, a proudly interdisciplinary program that explores the boundary between computer science and physical science. His research centered on the idea that engineering could learn from biology. Put another way, all of life is assembled from 20 amino acids, so, thought Langford, why not attempt something similar with engineering?

In practice, this meant he built integrated robots from a small set of millimeter-scale parts. “Ultimately, I was trying to make engineering more like biology,” he reflects. “I see Volta as an opportunity to flip that on its head and use automation to treat biology more like engineering. We want to give biologists tools to manipulate liquids and biological reactions at a finer granularity and with more digital flexibility.”

While Volta’s automation platform simplifies sample prep by integrating complicated workflows, it also drives down costs in the space with a new consumable construction. Between the circuit board and the sample board is a consumable layer, which is removed and replaced after each run. Conventional consumables are expensive, conductively coded plastics or large microfluidic structures. Volta, however, uses a simple plastic film to reduce the cost of consumables, which opens the door for the widespread adoption of gene sequencing.

All of this points to a more efficient and inclusionary model in the gene sequencing space. Thanks to Volta, soon, it won’t be just large biotechnology companies with the ability to invest in automation. Academic labs, core facilities, and small-to-medium biotech companies won’t need to worry about whether they can afford an expensive mechanical robot. “The thing that excites me is that we’re providing early-stage and mid-to-low-throughput biotech companies with powerful tools that will allow them to compete with bigger players, which is good for the industry as a whole,” says Umapathi.

And the fact is that traditional automation machines used in the biotechnology space come with their own set of problems. They’re error-prone and you can’t scale them. Consider Illumina’s NovaSeq sequencer. It’s capable of sequencing 48 whole human genomes in under two days — that’s 20 billion unique reads — but there is currently no automation to feed those machines at scale. “To run those machines day in and day out, the cost simply doesn’t make sense, which is why we have to tackle the cost of sequencing and sample prep,” says Umapathi.

Volta’s system is built on solid-state electronics, and the Boston-based startup is looking to leverage the scalability of the semiconductor fabrication industry and the PCB manufacturing industry. “The goal,” explains Langford, “is to enable biologists to create an experiment and modify it quickly, iterate on it, and generate the data necessary to see biology at scale.”

Beyond the sample prep bottleneck, eventually, the work of Umapathi and Langfordwork will impact a variety of applications in the synthetic biology industry and the biopharma industry. Diagnostics will be transformed, according to Umapathi. “We can help the biology industry by cutting down on the use of pipette tips by 20 or 50 times. In specific workflows, we can almost entirely eliminate this bottleneck in the supply chain,” he says.

To accomplish all of this, to truly innovate in a field as complex as biology, Umapathi and Langford insist that a multidisciplinary systems perspective is essential. It’s what informs the Volta approach to genomic sequencing in particular, and biology as a whole. “Volta is a new type of biotechnology company,” says Umapathi. “It’s inevitable that more engineers and systems thinkers and those who want to build tools to engineer biology better will join companies like ours or start their own.”

Turning biology into an engineering principle is no small feat, but according to Umapathi and Langford, it’s a necessity.

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Cellular environments shape molecular architecture



Context matters. It’s true for many facets of life, including the tiny molecular machines that perform vital functions inside our cells.

Scientists often purify cellular components, such as proteins or organelles, in order to examine them individually. However, a new study published today in the journal Nature suggests that this practice can drastically alter the components in question.

The researchers devised a method to study a large, donut-shaped structure called the nuclear pore complex (NPC) directly inside cells. Their results revealed that the pore had larger dimensions than previously thought, emphasizing the importance of analyzing complex molecules in their native environments.

“We’ve shown that the cellular environment has a significant impact on large structures like the NPC, which was something we weren’t expecting when we started,” says Thomas Schwartz, the Boris Magasanik Professor of Biology at MIT and the study’s co-senior author. “Scientists have generally thought that large molecules are stable enough to maintain their fundamental properties both inside and outside a cell, but our findings turn that assumption on its head.”

In eukaryotes like humans and animals, most of a cell’s DNA is stored in a rounded structure called the nucleus. This organelle is shielded by the nuclear envelope, a protective barrier that separates the genetic material in the nucleus from the thick fluid filling the rest of the cell. But molecules still need a way to come in and out of the nucleus in order to facilitate important processes, including gene expression. That’s where the NPC comes in. Hundreds — sometimes thousands — of these pores are embedded in the nuclear envelope, creating gateways that allow certain molecules to pass.

The study’s first author, former MIT postdoc Anthony Schuller, compares NPCs to gates at a sports stadium. “If you want to access the game inside, you have to show your ticket and go through one of these gates,” he explains.

Video thumbnail Play video

A Closer Look at the Nuclear Pore Complex

CR = Cytoplasmic Ring
IR = Inner Ring
NR = Nucleoplasmic Ring

The NPC may be tiny by human standards, but it’s one of the largest structures in the cell. It’s comprised of roughly 500 proteins, which has made its structure challenging to parse. Traditionally, scientists have broken it up into individual components to study it piecemeal using a method called X-ray crystallography. According to Schwartz, the technology required to analyze the NPC in a more natural environment has only recently become available.

Together with researchers from the University of Zurich, Schuller and Schwartz employed two cutting-edge approaches to solve the pore’s structure: cryo-focused ion beam (cryo-FIB) milling and cryo-electron tomography (cryo-ET).

An entire cell is too thick to look at under an electron microscope. But the researchers sliced frozen colon cells into thin layers using the cryo-FIB equipment housed at MIT.nano’s Center for Automated Cryogenic Electron Microscopy and the Koch Institute for Integrative Cancer Research’s Peterson (1957) Nanotechnology Materials Core Facility. In doing so, the team captured cross-sections of the cells that included NPCs, rather than simply looking at the NPCs in isolation.

“The amazing thing about this approach is that we’ve barely manipulated the cell at all,” Schwartz says. “We haven’t perturbed the cell’s internal structure. That’s the revolution.”

What the researchers saw when they looked at their microscopy images was quite different from existing descriptions of the NPC. They were surprised to find that the innermost ring structure, which forms the pore’s central channel, is much wider than previously thought. When it’s left in its natural environment, the pore opens up to 57 nanometers — resulting in a 75 percent increase in volume compared to previous estimates. The team was also able to take a closer look at how the NPC’s various components work together to define the pore’s dimensions and overall architecture.

“We’ve shown that the cellular environment impacts NPC structure, but now we have to figure out how and why,” Schuller says. Not all proteins can be purified, he adds, so the combination of cryo-ET and cryo-FIB will also be useful for examining a variety of other cellular components. “This dual approach unlocks everything.”

“The paper nicely illustrates how technical advances, in this case cryo-electron tomography on cryo-focused ion beam milled human cells, provide a fresh picture of cellular structures,” says Wolfram Antonin, a professor of biochemistry at RWTH Aachen University in Germany who was not involved in the study. The fact that the diameter of the NPC’s central transport channel is larger than previously thought hints that the pore could have impressive structural flexibility. “That may be important for the cell to adapt to increased transport demands,” Antonin explains.

Next, Schuller and Schwartz hope to understand how the size of the pore affects which molecules can pass through. For instance, scientists only recently determined that the pore was big enough to allow intact viruses like HIV into the nucleus. The same principle applies to medical treatments: only appropriately-sized drugs with specific properties will be able to access the cell’s DNA.

Schwartz is especially curious to know whether all NPCs are created equal, or if their structure differs between species or cell types.

“We’ve always manipulated cells and taken the individual components out of their native context,” he says. “Now we know this method may have much bigger consequences than we thought.”

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Seven from MIT receive National Institutes of Health awards for 2021



On Oct. 5, the National Institutes of Health announced the names of 106 scientists who have been awarded grants through the High-Risk, High-Reward Research program to advance highly innovative biomedical and behavioral research. Seven of the recipients are MIT faculty members.

The High-Risk, High-Reward Research program catalyzes scientific discovery by supporting research proposals that, due to their inherent risk, may struggle in the traditional peer-review process despite their transformative potential. Program applicants are encouraged to pursue trailblazing ideas in any area of research relevant to the NIH’s mission to advance knowledge and enhance health.

“The science put forward by this cohort is exceptionally novel and creative and is sure to push at the boundaries of what is known,” says NIH Director Francis S. Collins. “These visionary investigators come from a wide breadth of career stages and show that groundbreaking science can happen at any career level given the right opportunity.”

New innovators

Four MIT researchers received New Innovator Awards, which recognize “unusually innovative research from early career investigators.” They are:

  • Pulin Li is a member at the Whitehead Institute for Biomedical Research and an assistant professor in the Department of Biology. Li combines approaches from synthetic biology, developmental biology, biophysics and systems biology to quantitatively understand the genetic circuits underlying cell-cell communication that creates multicellular behaviors.
  • Seychelle Vos, the Robert A. Swanson (1969) Career Development Professor of Life Sciences in the Department of Biology, studies the interplay of gene expression and genome organization. Her work focuses on understanding how large molecular machineries involved in genome organization and gene transcription regulate each others’ function to ultimately determine cell fate and identity.
  • Xiao Wang, the Thomas D. and Virginia Cabot Assistant Professor of Chemistry and a member of the Broad Institute of MIT and Harvard, aims to develop high-resolution and highly-multiplexed molecular imaging methods across multiple scales toward understanding the physical and chemical basis of brain wiring and function.
  • Alison Wendlandt is a Cecil and Ida Green Career Development Assistant Professor of Chemistry. Wendlandt focuses on the development of selective, catalytic reactions using the tools of organic and organometallic synthesis and physical organic chemistry. Mechanistic study plays a central role in the development of these new transformations.

Transformative researchers

Two MIT researchers have received Transformative Research Awards, which “promote cross-cutting, interdisciplinary approaches that could potentially create or challenge existing paradigms.” The recipients are:

  • Manolis Kellis is a professor of computer science at MIT in the area of computational biology, an associate member of the Broad Institute, and a principal investigator with MIT’s Computer Science and Artificial Intelligence Laboratory. He aims to further our understanding of the human genome by computational integration of large-scale functional and comparative genomics datasets.
  • Myriam Heiman is the Latham Family Career Development Associate Professor of Neuroscience in the Department of Brain and Cognitive Sciences and an investigator in the Picower Institute for Learning and Memory. Heiman studies the selective vulnerability and pathophysiology seen in two neurodegenerative diseases of the basal ganglia, Huntington’s disease, and Parkinson’s disease.

Together, Heiman, Kellis and colleagues will launch a five-year investigation to pinpoint what may be going wrong in specific brain cells and to help identify new treatment approaches for amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with motor neuron disease (FTLD/MND). The project will bring together four labs, including Heiman and Kellis’ labs at MIT, to apply innovative techniques ranging from computational, genomic, and epigenomic analyses of cells from a rich sample of central nervous system tissue, to precision genetic engineering of stem cells and animal models.

Pioneering researchers

  • Polina Anikeeva received a Pioneer Award, which “challenges investigators at all career levels to pursue new research directions and develop groundbreaking, high-impact approaches to a broad area of biomedical, behavioral, or social science.” Anikeeva is an MIT professor of materials science and engineering, a professor of brain and cognitive sciences, and a McGovern Institute for Brain Research associate investigator. She has established a research program that uniquely combines materials synthesis, device fabrication, neurophysiology, and animal models of behavior. Her group carries out projects that understand, invent, and design materials from the level of atoms to functional devices with applications in fundamental neuroscience.

The program is supported by the NIH Common Fund, which oversees programs that pursue major opportunities and gaps throughout the research enterprise that are of great importance to NIH and require collaboration across the agency to succeed. It issues four awards each year: the Pioneer Award, the New Innovator Award, the Transformative Research Award, and the Early Independence Award.

This year, NIH issued 10 Pioneer awards, 64 New Innovator awards, 19 Transformative Research awards (10 general, four ALS-related, and five Covid-19-related), and 13 Early Independence awards for 2021. Funding for the awards comes from the NIH Common Fund, the National Institute of General Medical Sciences, the National Institute of Mental Health, and the National Institute of Neurological Disorders and Stroke.

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