Cheers to the inaugural winners of the Koch Institute’s Angelika Amon Young Scientist Award, Alejandro Aguilera and Melanie de Almeida. The new award recognizes graduate students in the life sciences or biomedical research from institutions outside the U.S. who embody Dr. Amon’s infectious enthusiasm for discovery science.
Aguilera, a student at the Weizmann Institute of Science in Israel, has developed a platform for studying mammalian embryogenesis. De Almeida, who recently completed her doctoral work at the Research Institute of Molecular Pathology in Austria, develops CRISPR screens to explore cancer vulnerabilities and gene regulatory networks.
Aguilera and de Almeida will visit the Koch Institute in November to deliver scientific presentations to the MIT community and Amon Lab alumni.
Awards support high-risk, high-impact research from early-career investigators.
Phie Jacobs | School of Science
October 4, 2022
The National Institutes of Health (NIH) has awarded grants to four MIT faculty members as part of its High-Risk, High-Reward Research program.
The program supports unconventional approaches to challenges in biomedical, behavioral, and social sciences. Each year, NIH Director’s Awards are granted to program applicants who propose high-risk, high-impact research in areas relevant to the NIH’s mission. In doing so, the NIH encourages innovative proposals that, due to their inherent risk, might struggle in the traditional peer-review process.
This year, Lindsay Case, Siniša Hrvatin, Deblina Sarkar, and Caroline Uhler have been chosen to receive the New Innovator Award, which funds exceptionally creative research from early-career investigators. The award, which was established in 2007, supports researchers who are within 10 years of their final degree or clinical residency and have not yet received a research project grant or equivalent NIH grant.
Lindsay Case, the Irwin and Helen Sizer Department of Biology Career Development Professor and an extramural member of the Koch Institute for Integrative Cancer Research, uses biochemistry and cell biology to study the spatial organization of signal transduction. Her work focuses on understanding how signaling molecules assemble into compartments with unique biochemical and biophysical properties to enable cells to sense and respond to information in their environment. Earlier this year, Case was one of two MIT assistant professors named as Searle Scholars.
Siniša Hrvatin, who joined the School of Science faculty this past winter, is an assistant professor in the Department of Biology and a core member at the Whitehead Institute for Biomedical Research. He studies how animals and cells enter, regulate, and survive states of dormancy such as torpor and hibernation, aiming to harness the potential of these states therapeutically.
Deblina Sarkar is an assistant professor and AT&T Career Development Chair Professor at the MIT Media Lab. Her research combines the interdisciplinary fields of nanoelectronics, applied physics, and biology to invent disruptive technologies for energy-efficient nanoelectronics and merge such next-generation technologies with living matter to create a new paradigm for life-machine symbiosis. Her high-risk, high-reward proposal received the rare perfect impact score of 10, which is the highest score awarded by NIH.
Caroline Uhler is a professor in the Department of Electrical Engineering and Computer Science and the Institute for Data, Systems, and Society. In addition, she is a core institute member at the Broad Institute of MIT and Harvard, where she co-directs the Eric and Wendy Schmidt Center. By combining machine learning, statistics, and genomics, she develops representation learning and causal inference methods to elucidate gene regulation in health and disease.
The High-Risk, High-Reward Research program is supported by the NIH Common Fund, which oversees programs that pursue major opportunities and gaps in biomedical research that require collaboration across NIH Institutes and Centers. In addition to the New Innovator Award, the NIH also issues three other awards each year: the Pioneer Award, which supports bold and innovative research projects with unusually broad scientific impact; the Transformative Research Award, which supports risky and untested projects with transformative potential; and the Early Independence Award, which allows especially impressive junior scientists to skip the traditional postdoctoral training program to launch independent research careers.
This year, the High-Risk, High-Reward Research program is awarding 103 awards, including eight Pioneer Awards, 72 New Innovator Awards, nine Transformative Research Awards, and 14 Early Independence Awards. These 103 awards total approximately $285 million in support from the institutes, centers, and offices across NIH over five years. “The science advanced by these researchers is poised to blaze new paths of discovery in human health,” says Lawrence A. Tabak DDS, PhD, who is performing the duties of the director of NIH. “This unique cohort of scientists will transform what is known in the biological and behavioral world. We are privileged to support this innovative science.”
Hynes and two other scientists will share the prize for their discoveries of proteins critical for cellular adhesion.
Anne Trafton | MIT News Office
September 28, 2022
MIT Professor Richard Hynes, a pioneer in studying cellular adhesion, has been named a recipient of the 2022 Albert Lasker Basic Medical Research Award.
Hynes, the Daniel K. Ludwig Professor for Cancer Research and a member of MIT’s Koch Institute for Integrative Cancer Research, was honored for the discovery of integrins, proteins that are key to cell-cell and cell-matrix interactions in the body. He will share the prize with Erkki Ruoslahti of Sanford Burnham Prebys and Timothy Springer of Harvard University.
“I’m delighted, and it’s a pleasure to be sharing it with them,” Hynes says. “It’s great for the field, and for the trainees who did much of the work.”
Hynes’ research focuses on proteins that allow cells to adhere to each other and to the extracellular matrix — a mesh-like network that provides structural support for cells. These proteins include integrins, a type of cell surface receptor, and fibronectins, a family of extracellular adhesive proteins. Integrins are the major adhesion receptors connecting the extracellular matrix to the intracellular cytoskeleton.
During embryonic development, cell adhesion is critical for cells to move to the correct locations in the embryo. Hynes’ work has also revealed that dysregulation of cell-to-matrix contact plays an important role in cancer cells’ ability to detach from a tumor and spread to other parts of the body, in a process known as metastasis.
“Professor Hynes’ contributions to the field of cancer biology, and more broadly, cellular biology, are numerous,” says Nergis Mavalvala, the Curtis and Kathleen Marble Professor of Astrophysics and the dean of the School of Science. “His investigations of fundamental biological questions — How do cells interact? How do they stick together? — changed how scientists approach cancer research and opened up avenues in developing potential therapeutics to disrupt metastatic disease.”
Born in Kenya, Hynes grew up in Liverpool, in the United Kingdom. Both of his parents were scientists: His father was a freshwater ecologist, and his mother a physics teacher. Hynes and all three of his siblings followed their parents into scientific fields.
“We talked science at home, and if we asked questions, we got questions back, not answers. So that conditioned me into being a scientist, for sure,” Hynes says.
After earning his bachelor’s and master’s degrees in biochemistry at Cambridge University, Hynes decided to head to the United States to continue graduate school. Colleagues at Cambridge suggested MIT, so he came to the Institute and earned his PhD in 1971. After doing a postdoc at the Imperial Cancer Research Fund Laboratories in London, he returned to MIT in 1975 as a faculty member in the Department of Biology and a founding member of MIT’s Center for Cancer Research (the predecessor of today’s Koch Institute).
Hynes began his career as a developmental biologist, studying how cells move to the correct locations during embryonic development. As a postdoc, he began studying the differences in the surface landscapes of healthy cells and tumor cells. This led to the discovery of a protein called fibronectin, which is often lost when cells become cancerous.
He and others found that fibronectin is part of the extracellular matrix, the network of proteins and other molecules that support cells and tissues in the body. When fibronectin is lost, cancer cells can more easily free themselves from their original location and metastasize to other sites in the body. Cells bind to the matrix through cell surface receptors known as integrins. In humans, 24 integrin proteins have been identified. These proteins help give tissues their structure, enable blood to clot, and are essential for embryonic development.
“These cell-matrix adhesion proteins hold us all together,” Hynes says. “If we didn’t have them, we’d be a pool of cells on the floor. And they’re contributors to lots of diseases: fibrosis, cancer, thrombosis, immune and autoimmune diseases. So, cell adhesion has become a huge field at both the basic science level and the therapeutic level.”
Since joining the MIT faculty, Hynes has also served as head and associate head of the Department of Biology, and as director of the Center for Cancer Research. He has also served as scientific governor of the Wellcome Trust in the United Kingdom, and as co-chair of National Academy committees establishing guidelines for stem cell and genome editing research.
His many awards include the Gairdner Foundation International Award, the Distinguished Investigator Award from the International Society for Matrix Biology, the Robert and Claire Pasarow Medical Research Award, the E.B. Wilson Medal from the American Society for Cell Biology and the Paget-Ewing Award, Metastasis Research Society. Hynes is also a member of the National Academy of Sciences, the National Academy of Medicine, the Royal Society of London, the American Association for the Advancement of Science, and the American Academy of Arts and Sciences.
The Lasker Award comes with a $250,000 prize, which will be shared between the three recipients.
As an MSRP-Bio student in the Vander Heiden lab, Alejandra Rosario helped to reveal how cancer cells maintain access to materials they need to grow.
Grace van Deelen | Department of Biology
September 22, 2022
Alejandra Rosario’s enthusiasm for research is infectious. When she talks about studying cancer cells, or the possibility of getting a PhD, her face lights up. “It’s something I’m really passionate about,” she says.
As a Bernard S. and Sophie G. Gould MIT Summer Research Program in Biology (BSG-MSRP-Bio) student this past summer in the lab of Matt Vander Heiden, MIT’s Lester Wolfe (1919) Professor of Molecular Biology, Rosario worked to understand cancer metabolism. MSRP-Bio is a 10-week, research-intensive summer program intended to introduce non-MIT undergraduates to a research career. Rosario, who is a senior at the University of Puerto Rico at Cayey this fall, was one of two MSRP-Bio students this year who were the first from their campus to attend the program. “It’s a really great opportunity for us,” she says.
Rosario had always been interested in research and understanding natural systems. As a child growing up in San Lorenzo, Puerto Rico, she was surrounded by nature, and got involved at a young age in environmental activism. She also has a special passion for the beach, which contributed to her eventual interest in science and, more specifically, in biology.
Medical connections
When her mother developed thyroid cancer, she focused on cancer research. To support her mother, Rosario tried to learn as much as possible about the type of cancer she was fighting, as well as the treatments available. She noticed the impact of basic cancer research on the therapies her mother was receiving.
As a result of her experience watching her mother battle cancer, too, Rosario has a special interest in translational medicine: working to determine how fundamental discoveries can have specific relevance to human disease treatment. “In cancer research,” she says, “small strides can be huge strides.”
Delving into a career in cancer research became a focus for Rosario, who sought out opportunities to advance her connections to the field. During a virtual conference held by the Society for the Advancement of Chicanos/Hispanics and Native Americans in Science, Rosario met MIT Department of Biology lecturer and science outreach director Mandana Sassanfar, who invited Rosario to visit MIT for a January workshop on computational skills. During the workshop, she met MIT professors, explored possible research ideas, and decided to apply to the MSRP-Bio program.
Rosario, who would like eventually to pursue a PhD or MD/PhD, was especially drawn to the Vander Heiden lab because of its focus on connecting research to medical applications. “I’m really fascinated about that connection, and how that works,” she says.
She especially liked the diversity of research happening in the lab, where projects range from cancer metabolism to genetics to stem cell research. “They’re all exploring different questions,” she says. “But at the end of the day, they all have conversations with each other and help each other out in a collaborative way.”
New insights into brain cancer
This summer, Rosario contributed to that diversity of research by continuing some of the core experiments of the Vander Heiden lab with a new cell line: glioblastoma, a type of brain cancer with a poor prognosis. The lab had never worked with this type of cancer before, so Rosario worked to understand its metabolism and process of cell division.
The main characteristic of cancer cells is that they divide very quickly. In order to do so, they need a lot of new material, like proteins, lipids, and nucleotides. A cancer cell has two options to obtain this new material: it can take it from the environment, or it can produce that new material itself. Glioblastoma occurs in the brain, a microenvironment that provides very little access to the materials necessary for cell division. In order to divide, then, glioblastoma cells must reprogram themselves in order to produce the materials necessary for growth.
Rosario’s research this summer sought to determine how glioblastoma cells survive in the environment of the brain by limiting the cells’ access to certain substances, like certain proteins or amino acids, and then measuring how the cells react. Understanding the cell’s reactions to such changes in the microenvironment could eventually inform cancer therapies.
“Our goal is to understand metabolically how these brain cancer cells are surviving everything we throw at them in order to possibly find a more specific target for treatment,” she says. Rosario presented her research in August in the MSRP-Bio poster session.
Shaped by mentorship
Overall, Rosario really enjoyed her experience as a summer researcher. The collaborative and open atmosphere in the lab, says Rosario, has helped her grow. For example, the lab holds occasional meetings called “Idea Club,” where researchers in the lab bring a question they’re struggling with or an idea they’re excited about, and other lab members give their input. “There’s a lot of scientific independence and curiosity,” says Rosario.
Rosario has especially enjoyed getting to know the graduate students in the lab, like Ryan Elbashir, a rising third-year doctoral student. Elbashir was also an MSRP-Bio student in 2018 and was one of the reasons Rosario chose the Vander Heiden lab. After a discussion with Elbashir about the importance of diversity in research, they formed a connection. “Alejandra is very inquisitive and comfortable around other people in the lab,” says Elbashir.
Rosario’s formal mentor, fourth-year MD/PhD student Sarah Chang, has also supported Rosario’s research goals by helping Rosario design research protocols and understand lab jargon. “Sarah’s been nothing but amazing,” says Rosario. “She’s teaching me how to think like a scientist.”
Rosario plans to build on the research she completed this summer in an MD/PhD program. She’d love to return to MIT or the Vander Heiden lab to carry out her future research and would like to continue to find ways to contribute to the development of cancer therapies. She’s very committed to studying cancer biology and wants to continue exploring the different sub-fields of cancer research during her senior year.
She plans to be a mentor to other young scientists, as well, and “pay it forward” to a new generation of underrepresented researchers. Mentoring, she says, creates a “chain reaction” of scientists supporting other scientists, which leads to better advances in research.
“By doing research and pursuing a question to the best of my abilities, I can impact as many people as possible,” she says.
Family trees of lung cancer cells reveal how cancer evolves from its earliest stages to an aggressive form capable of spreading throughout the body.
Greta Friar | Whitehead Institute
May 5, 2022
Over time, cancer cells can evolve to become resistant to treatment, more aggressive, and metastatic — capable of spreading to additional sites in the body and forming new tumors. The more of these traits that a cancer evolves, the more deadly it becomes. Researchers want to understand how cancers evolve these traits in order to prevent and treat deadly cancers, but by the time cancer is discovered in a patient, it has typically existed for years or even decades. The key evolutionary moments have come and gone unobserved.
MIT Professor Jonathan Weissman and collaborators have developed an approach to track cancer cells through the generations, allowing researchers to follow their evolutionary history. This lineage-tracing approach uses CRISPR technology to embed each cell with an inheritable and evolvable DNA barcode. Each time a cell divides, its barcode gets slightly modified. When the researchers eventually harvest the descendants of the original cells, they can compare the cells’ barcodes to reconstruct a family tree of every individual cell, just like an evolutionary tree of related species. Then researchers can use the cells’ relationships to reconstruct how and when the cells evolved important traits. Researchers have used similar approaches to follow the evolution of the virus that causes Covid-19, in order to track the origins of variants of concern.
Weissman and collaborators have used their lineage-tracing approach before to study how metastatic cancer spreads throughout the body. In their latest work, Weissman; Tyler Jacks, the Daniel K. Ludwig Scholar and David H. Koch Professor of Biology at MIT; and computer scientist Nir Yosef, associate professor at the University of California at Berkeley and the Weizmann Institute of Science, record their most comprehensive cancer cell history to date. The research, published today in Cell, tracks lung cancer cells from the very first activation of cancer-causing mutations. This detailed tumor history reveals new insights into how lung cancer progresses and metastasizes, demonstrating the wealth of understanding that lineage tracing can provide.
“This is a new way of looking at cancer evolution with much higher resolution,” says Weissman, who is a professor of biology at MIT, a member of the Whitehead Institute for Biomedical Research, and an investigator with Howard Hughes Medical Institute. “Previously, the critical events that cause a tumor to become life-threatening have been opaque because they are lost in a tumor’s distant past, but this gives us a window into that history.”
In order to track cancer from its very beginning, the researchers developed an approach to simultaneously trigger cancer-causing mutations in cells and start recording the cells’ history. They engineered mice such that when their lung cells were exposed to a tailor-made virus, that exposure activated a cancer-causing mutation in the Kras gene and deactivated tumor suppressing gene Trp53 in the cells, as well as activating the lineage tracing technology. The mouse model, developed in Jacks’ lab, was also engineered so that lung cancer would develop in it very similarly to how it would in humans.
“In this model, cancer cells develop from normal cells and tumor progression occurs over an extended time in its native environment. This closely replicates what occurs in patients,” Jacks says. Indeed, the researchers’ findings closely align with data about disease progression in lung cancer patients.
The researchers let the cancer cells evolve for several months before harvesting them. They then used a computational approach developed in their previous work to reconstruct the cells’ family trees from their modified DNA barcodes. They also measured gene expression in the cells using RNA sequencing to characterize each individual cell’s state. With this information, they began to piece together how this type of lung cancer becomes aggressive and metastatic.
“Revealing the relationships between cells in a tumor is key to making sense of their gene expression profiles and gaining insight into the emergence of aggressive states,” says Yosef, who is a co-corresponding author on both the current work and the previous lineage tracing paper.
The results showed significant diversity between subpopulations of cells within the same tumor. In this model, cancer cells evolved primarily through inheritable changes to their gene expression, rather than through genetic mutations. Certain subpopulations had evolved to become more fit — better at growth and survival — and more aggressive, and over time they dominated the tumor. Genes that the researchers identified as commonly expressed in the fittest cells could be good candidates for possible therapeutic targets in future research. The researchers also discovered that metastases originated only from these groups of dominant cells, and only late in their evolution. This is different from what has been proposed for some other cancers, in which cells may gain the ability to metastasize early in their evolution. This insight could be important for cancer treatment; metastasis is often when cancers become deadly, and if researchers know which types of cancer develop the ability to metastasize in this stepwise manner, they can design interventions to stop the progression.
“In order to develop better therapies, it’s important to understand the fundamental principles that tumors adopt to develop,” says co-first author Dian Yang, a Damon Runyon Postdoctoral Fellow in Weissman’s lab. “In the future, we want to be able to look at the state of the cancer cells when a patient comes in, and be able to predict how that cancer’s going to evolve, what the risks are, and what is the best treatment to stop that evolution.”
The researchers also figured out important details of the evolutionary paths that cancer subpopulations take to become fit and aggressive. Cells evolve through different states, defined by key characteristics that the cell has at that point in time. In this cancer model the researchers found that early on, cells in a tumor quickly diversified, switching between many different states. However, once a subpopulation landed in a particularly fit and aggressive state, it stayed there, dominating the tumor from that stable state. Furthermore, the ultimately dominant cells seemed to follow one of two distinct paths through different cell states. Either of those paths could then lead to further progression that enabled cancers to enter aggressive “mesenchymal” cell states, which are linked to metastasis.
After the researchers thoroughly mapped the cancer cells’ evolutionary paths, they wondered how those paths would be affected if the cells experienced additional cancer-linked mutations, so they deactivated one of two additional tumor suppressors. One of these affected which state cells stabilized in, while the other led cells to follow a completely new evolutionary pathway to fitness.
The researchers hope that others will use their approach to study all kinds of questions about cancer evolution, and they already have a number of questions in mind for themselves. One goal is to study the evolution of therapeutic resistance, by seeing how cancers evolve in response to different treatments. Another is to study how cancer cells’ local environments shape their evolution.
“The strength of this approach is that it lets us study the evolution of cancers with fine-grained detail,” says co-first author Matthew Jones, a graduate student in the Weissman and Yosef labs. “Every time there is a shift from bulk to single-cell analysis in a technology or approach, it dramatically widens the scope of the biological insights we can attain, and I think we are seeing something like that here.”
Greta Friar | Whitehead Institute
April 11, 2022
Cancer is at its most deadly when it spreads and forms tumors in new tissues. This process, called metastasis, is responsible for the vast majority of cancer deaths, and yet there is still a lot that researchers do not know about how and when it happens. Whitehead Institute Founding Member Robert Weinberg, also the Daniel K. Ludwig Professor for Cancer Research at the Massachusetts Institute of Technology, studies the mechanisms behind metastasis. One such mechanism is a process called the epithelial-mesenchymal transition (EMT), which causes epithelial cells, which normally stick tightly together, to lose their cohesion, enabling them to move around and even invade nearby tissue. This EMT program also operates during embryonic development. Cancer cells can co-opt this process and use it travel from their original tumor site to distant tissues throughout the body. Some of the cancer cells that spread are able, on rare occasions, to form new tumors in these tissues—metastases—while the great majority of these cells remain dormant after entering the distant tissues.
New research from Weinberg and postdoc Yun Zhang shows that cells change in diverse ways through the actions of the EMT, which can influence whether cells are able to form new tumors after they spread. The work, published in Nature Cell Biology on April 11, 2022, also identifies two regulators of the EMT and shows that loss of each regulator leads to a different metastatic risk profile.
“Using triple negative breast cancer as a model, we are trying to go a bit deeper into understanding the molecular mechanisms that regulate the EMT, how cells enter into different EMT intermediate states, and which of these states contribute to metastasis,” Zhang says.
The EMT was originally imagined as a sort of binary switch, in which cells start out epithelial and become mesenchymal, much like a light switch being flicked from off to on. However, researchers are learning that the EMT works more like a dimmer switch that can be shifted along a spectrum of brightness. Cells that undergo the EMT usually end up in hybrid states between the epithelial and mesenchymal extremes. These cells in the middle of the spectrum, which have some characteristics of each extreme, are called “quasi-mesenchymal” cells, and it turns out that they–rather than cells that become fully mesenchymal–are the most capable of metastasizing and forming new tumors throughout the body.
Protected versus plastic cells
Weinberg and Zhang set out to better understand the EMT spectrum and what controls cells’ movement along it. First, they compared epithelial cells to each other and found that some were more plastic or prone to transitioning along the EMT spectrum than others. They also used the CRISPR gene editing tool to screen for genes that might be regulating the cells’ plasticity. If researchers can learn what makes a cell become quasi-mesenchymal—posing a high risk for metastasis—they might be able use this information, at some time in the future, to develop strategies to prevent cells from entering this high-risk state.
The CRISPR gene screen turned up a number of molecules that seemed to influence cells’ epithelial-mesenchymal plasticity. Two groups of these molecules had especially strong effects: PRC2, a complex that operates in chromosomes to silence or inactivate genes, and KMT2D-COMPASS, a complex that helps activate genes. Both complexes help to keep cells in a stable epithelial state. Loss of either complex makes cells more prone to moving along the EMT spectrum.
The researchers then determined how the loss of either complex enables the EMT. PRC2 normally silences several key EMT-related genes. When PRC2 is lost, those genes activate, which in turn sensitizes the cell to a signal that can trigger the EMT. The loss of KMT2D-COMPASS affects how well PRC2 can bind its targets, leading to the same signal sensitivity. In spite of the similar mechanisms at play, the loss of PRC2 versus KMT2D-COMPASS leads cells to transition to end up in different EMT states, an exciting finding for the researchers. Cells without KMT2D-COMPASS became fully mesenchymal, while cells without PRC2 became hybrid or quasi-mesenchymal. Consequently, cells without PRC2 were much more capable of metastasis than cells without KMT2D-COMPASS (or cells in which both complexes were active) in mouse models. When the researchers looked at historical data from breast cancer patients, they observed the same pattern: people with faulty PRC2 component genes had worse outcomes. These findings provide further evidence that cells in the middle of the EMT spectrum are most likely to metastasize.
This work supports the understanding of the EMT as a spectrum rather than a simple switch, and shows that different EMT regulators can program cells to transition to different parts of the EMT spectrum. Additionally, the finding that loss of PRC2 is linked to metastasis has implications for cancer drugs currently in development that work by inactivating PRC2. Benefits of the drugs may outweigh risks for patients with certain types of cancer for which PRC2 is an effective target. However, Weinberg and Zhang caution that researchers leading clinical trials of PRC2-targeting drugs should be careful about selecting patients and monitoring outcomes. In the types of cancer cells that the researchers looked at, even temporary PRC2 inactivation, such as from a therapy trial, was sufficient to trigger cells to become EMT hybrids with increased metastatic capacity.
Weinberg and Zhang intend to continue exploring the genes identified in their CRISPR screen to see if they can identify other hybrid states along the EMT spectrum, in which cells have different combinations of epithelial and mesenchymal features. They hope that by deepening their understanding of the gene expression profiles of cancer cells associated with different EMT trajectories, they can contribute to the development of therapies for people with potentially metastatic cancers.
“Understanding when and how cancer cells become able to form life-threatening metastases is crucial in order to help the many patients for whom this is a risk,” Weinberg says. “This work provides new insights into the mechanisms that enable cells to metastasize and the roles that different EMT programs can play.”
MIT senior Daniel Zhang aims to provide hope for young patients and support to young students.
Celina Zhao | Department of Biology
February 24, 2022
During the virtual spring 2020 semester, Daniel Zhang, a senior majoring in biology, put his time at home to good use. In the garage of his home in San Diego, California, Zhang helped his 13-year-old brother build a lab to study dry eye disease.
This combination of mentorship and medicine feels like second nature to Zhang. When his parents opened a family-run optometry clinic, Zhang was their first patient and then their receptionist. And after a close family member passed away from leukemia, he remembers thinking, “Humans are susceptible to so many diseases — why don’t we have better cures?”
That question propelled him to spend his high school summers studying biomarkers for the early detection of leukemia at the University of California at San Diego. He was invited to present his research at the London International Youth Science Forum, where he spoke to scientists from almost 70 countries. Afterward, he was hooked on the idea of scientific research as a career.
“Research is like standing on the shoulders of giants,” he says. “My experience at the forum was when I knew I loved science and wanted to continue using it to find common ground with others from completely different cultures and backgrounds.”
Exploring the forefront of cancer research
As soon as he arrived at MIT as a first-year undergraduate, Zhang began working under the guidance of postdoc Peter Westcott in professor Tyler Jacks’ lab. The lab focuses on developing better mouse and organoid models to study cancer progression — in Zhang’s case, metastatic colorectal cancer.
One of the ways to model colorectal cancer is by injecting an engineered virus directly into the colons of mice. The viruses, called lentiviral agents, “knock out” tumor suppressor genes and activate the so-called oncogenes that drive cancer forward. However, the imprecise nature of this injection also unintentionally transforms many “off-target” cells into cancer cells, producing a cancer that’s far too widespread and aggressive. Additionally, rare tumors called sarcomas are often initiated rather than adenocarcinomas, the type of tumor found in 95 percent of human cases. As a result, these mouse models are limited in their ability to accurately model colorectal cancer.
To address this problem, Zhang and Westcott designed a method using CRISPR/Cas9 to target a special stem cell called LGR5+, which researchers believe are the types of cells that, when mutated, grow into colorectal cancer. His technique modifies only the LGR5+ cells, which would allow researchers to control the rate at which adenocarcinomas grow. Therefore, it generates a model that is not only much more similar to human colorectal cancer than other models, but also allows researchers to quickly test for other potential cancer driver genes with CRISPR/Cas9. Designing an accurate model is crucial for developing and testing effective new therapies for patients, Zhang says.
During MIT’s virtual spring and fall semesters of 2020, Zhang shifted his focus from benchwork in the lab to computational biology. Using patient data from the Cancer Genome Atlas, Zhang analyzed mutation rates and discovered three genes potentially involved in colorectal cancer tumor suppression. He plans to test their function in his new mouse model to further validate how the dysfunction of these genes drives colorectal cancer progression.
For his work on organoid modeling of colorectal cancer, a third project he’s worked on during his time at the Jacks lab, he also won recognition from the American Association for Cancer Research (AACR). As one of 10 winners of the Undergraduate Scholar Award, he had the opportunity to present his research at the virtual AACR conference in 2021 and again at the next AACR Conference in New Orleans in April 2022.
He credits MIT’s “mens et manus” philosophy, encouraging the hands-on application of knowledge, as a large part of his early success in research.
“I’ve found that, at MIT, a lot of people are pursuing projects and asking questions that have never been thought of before,” Zhang says. “No one has ever been able to develop a late-stage model for colorectal cancer that’s amenable to gene editing. As far as I know, other than us, no one in the world is even working on this.”
Inspiring future generations to pursue STEM
Outside of the lab, Zhang devotes a substantial amount of time to sharing the science he’s so passionate about. Not only has he been awarded the Gene Brown Prize for undergraduate teaching for his time as a teaching assistant for the lab class 7.002 (Fundamentals of Experimental Molecular Biology), but he’s also taken on leadership roles in science outreach activities.
During the 2020-21 academic year, he served as co-director of DynaMIT, an outreach program that organizes a two-week STEM program over the summer for underserved sixth to ninth graders in the greater Boston area. Although the program is traditionally held in-person, in summer 2021 it was held virtually. But Zhang and the rest of the board didn’t let the virtual format deter them from maximizing the fun and interactive nature of the program. They packed and shipped nearly 120 science kits focused on five major topics — astronomy, biology, chemistry, mechanical engineering, and math — allowing the students to explore everything from paper rockets to catapults and trebuchets to homemade ice cream.
“At first, we were worried that most of the students wouldn’t turn on their cameras, since we saw that trend all over MIT classes during the semester,” Zhang says. “But almost everyone had their cameras on the entire time. It was really gratifying to see students come in on Monday really shy, but by Friday be actively participating, making jokes with the mentors, and being really excited about STEM.”
To investigate the long-term impacts of the program, he also helped kick-start a project that followed up with DynaMIT alumni, some of whom have already graduated from college. Zhang says: “We were happy to see that 80-90 percent of DynaMIT alumni enjoyed the program, rating it four or five out of five, and close to 70 percent of them said that DynaMIT had a really positive impact on their trajectory toward a career in STEM.”
Zhang has also served as president of the MIT Pre-medical Society, with the goals of fostering an encouraging environment for premed undergraduates, and providing guidance and resources to first- and second-year students still undecided about the premed path. To achieve these objectives, he pioneered an MIT-hosted mixer with the premedical societies of other Boston colleges, including Wellesley College, Boston University, Tufts University, and Harvard University. At the mixer, students were able to network with each other and listen to guest speakers from the different universities talk about their experiences in medicine. He also started a “big/little” initiative that paired third- and fourth-year mentors with first- and second-year students.
Providing new opportunity and hope
The wealth of activities Zhang has participated in at MIT has inspired his choices for the future. After graduation, he plans to take a gap year and work as a research technician in pediatric oncology before applying to MD/PhD programs.
On the mentorship side, he’s currently working to establish a nonprofit organization called Future African Scientist with his former Ugandan roommate, Martin Lubowa, whom he met at a study abroad program during MIT’s Independent Activities Period in 2020. The organization will teach high schoolers in Africa professional skills and expose them to different STEM topics — a project Zhang plans to work on post-MIT and into the long term.
Ultimately, he hopes to lead his own lab at the intersection of CRISPR-Cas9 technology and cancer biology, and to serve as a mentor to future generations of researchers and physicians.
As he puts it: “All of the experiences I’ve had so far have solidified my goal of conducting research that impacts patients, especially young ones. Being able to provide new opportunity and hope to patients suffering from late-stage metastatic diseases with no current cures is what inspires me every day.”
Postdoc Dig Bijay Mahat became a cancer researcher to improve healthcare in Nepal, but the COVID-19 pandemic exposed additional resource disparities.
Raleigh McElvery
February 17, 2022
When Dig Bijay Mahat arrived at MIT in 2017 to begin his postdoctoral studies, he had one very clear goal: to become an expert in cancer research and diagnostics so he could improve healthcare in Nepal, where he was born. In 2020, when the COVID-19 pandemic laid bare additional discrepancies in resource equity around the world, his goal did not waiver. But it did expand to fill a more immediate need — help Nepal find the best way to navigate widespread COVID testing requirements and vaccine rollouts.
Mahat was born in the western region of Nepal, where his family has owned a large swath of land for generations. Before Mahat was born, his grandfather passed away unexpectedly. And, as the eldest son, Mahat’s father assumed responsibility for his five of siblings at the age of 21. As a result, Mahat’s father missed his chance to pursue the education he’d envisioned. Perhaps because of this, he made it his mission to give Mahat the education he never received. However, no school was quite good enough, and he shuffled Mahat between nine different institutions before the age of 18.
While his father wished him all the success and prestige that would come with pursing a medical career, Mahat had other plans. Toward the end of high school, he became captivated by song writing, and even secretly used his school tuition money one semester to record an album. “It was a disastrous flop,” he now recalls with a smile.
Although his foray into the music industry provides comic relief today, at the time Mahat was dismayed to be back on the medical track. However, he did convince his father to let him go to the US for college. He ended up at Towson University in Maryland, living with his aunt and uncle and delivering pizzas to support his nuclear family back in Nepal. Some weeks, he clocked in over 100 hours of deliveries.
As a molecular biology, biochemistry, and bioinformatics major, he took every research opportunity he could get, and became enthralled by breast cancer research. Shortly thereafter, his mother was diagnosed with the same disease, which further strengthened his conviction to learn as much as he could in the US, and return to Nepal to help as many patients as he could.
“The state of cancer diagnostics is very poor in Nepal,” he explains. Patient biopsies must be sent to other countries such as India — a costly practice at the mercy of politics and travel restrictions. “The least we can do is become self-sufficient and provide these vital molecular diagnostics tools to our own people,” Mahat says.
He went on to earn his PhD in molecular biology and genetics from Cornell University, and by the fall of 2017 he had secured his dream job: a postdoctoral position in the lab of MIT Professor of Biology Susan Lindquist. Mahat had spent much of his time at Cornell studying a protein known as heat shock factor 1, and Lindquist had conducted seminal work showing that this same protein enables healthy cells to suddenly turn into cancer cells. Just as he had finalized his new apartment lease and was preparing to start his new job, Lindquist wrote from the hospital to tell him she had late-stage ovarian cancer, and suggested he complete his postdoctoral studies elsewhere.
Gutted, he scrambled to find another position, and built up the courage to contact MIT professor, Koch Institute member, and Nobel laureate Phil Sharp. Mahat put together a formal research proposal and presented it to Sharp. A few days later, he became the lab’s newest member.
“From the beginning, the things that struck me about Phil were his humility, his attention to experimental detail, and his inexplicable reservoir of insight,” Mahat says. “If I could carry even just some of that same humility with me for the rest of my life, I would be a good human being.”
In 2018, Mahat and Sharp filed a patent with the potential to revolutionize disease diagnostics. Widely-available single-cell sequencing technologies reveal the subset of RNAs inside a cell that build proteins. But Mahat and his colleagues found a way to take a snapshot of all the RNA inside a single cell that is being transcribed from DNA — including RNAs that will never become proteins. Because many ailments arise from mutations in the “non-coding” DNA that gives rise to this “non-coding” RNA, the researchers hope their new method will help expose the function of non-coding variants in diseases like diabetes, autoimmune disorders, neurological diseases, and cancer.
Mahat was still immersed in this research in early 2020 when the COVID-19 pandemic began to escalate. As case numbers soared around the world, it became clear to him that the wealth of COVID testing resources available on MIT’s campus — and throughout the US in general — dwarfed the means available to his family back in Nepal. Polymerase chain reaction (PCR) testing remains the most popular and accurate means to detect the virus in patient samples. While PCR machines are quite common in molecular biology labs across the US, the entire country of Nepal owned just a few at the start of the pandemic, according to Mahat.
“Digbijay was focused intensely on developing our novel single-cell technology when he became aware of Nepal’s challenges to control the COVID-19 pandemic,” Sharp recalls. “While continuing his research in the lab, he spent several months contacting leaders in pharmaceutical companies in the US and leaders in public health in Nepal to help arrange access to vaccines and rapid tests.”
Mahat was already in contact with the Nepali Ministry of Health and Population regarding the state of the country’s cancer diagnostics, and so the government called on him to advise their COVID testing efforts. Given the high cost and limited availability of PCR machines and reagents, Mahat began discussions with MIT spinoff Sherlock Biosciences, in order to bring an alternative testing technology to Nepal. These COVID tests, which were developed at the Broad Institute of MIT and Harvard, use the CRISPR/Cas9 system — rather than PCR — to detect the SARS-CoV2 virus that causes COVID-19, making them cheaper and more readily available. Sherlock Biosciences ultimately donated $100,000-worth of testing kits, supplemented by an additional $100,000 grant from the Open Philanthropy Project to help purchase the equipment necessary to implement the tests. In December of 2020, Mahat and his wife Rupa Shah flew to Nepal to set up a testing center using these new resources.
Although this required Mahat to briefly pause his MIT research, Sharp was supportive of these extracurricular pursuits. “We are very proud of Jay’s effective work benefiting the people of Nepal,” Sharp says.
Around the same time, Mahat reached out to Institute professor and Moderna co-founder Robert Langer to help initiate vaccine talks with the Nepali government. Through Sharp’s contacts, Mahat was also able to connect the government with Johnson & Johnson. In addition, Mahat, Sharp, and Emeritus Professor Uttam RajBhandary wrote a letter to MIT president Rafael Reif, who joined other university leadership in urging the Biden administration to donate vaccines to low-income countries.
Nepal ultimately received its COVID-19 vaccines through the COVAX program, co-led by the Coalition for Epidemic Preparedness Innovations, GAVI Alliance, and the World Health Organization. Today, the country has begun administering boosters. There were also some funds left over from the Open Philanthropy Project grant, which went toward sending Nepal several thousand PCR kits designed to distinguish between the delta and omicron variants. Professor Tyler Jacks, the Koch Institute director at that time, also connected Mahat with the company Thermo Fisher Scientific to secure additional PCR reagents.
Roshan Pokhrel, the Secretary of Nepal’s Ministry of Health and Population, met Mahat prior to the pandemic, and relied on his expertise to begin establishing Nepal’s National Cancer Institute (NCI) in 2020. “It was his cooperation and coordination that helped us set up NCI,” Pokhrel says. “Mr. Mahat’s continuous support during the first two waves of our COVID-19 vaccine distribution was also highly appreciated. During the recent omicron outbreak, his support in our public laboratory helped us to monitor the variant.”
Bhagawan Koirala, chairman of the Nepal Medical Council, participated in the vaccine talks that Mahat organized between Nepal’s Ministry of Health and Johnson & Johnson. Koirala says he was impressed by Mahat’s exceptional credentials and his modesty, as well as his desire to promote cancer research and diagnostics. As the chairman of the Kathmandu Institute of Child Health, Koirala hopes to engage Mahat’s expertise in the future to help advance pediatric cancer research in Nepal.
“We have spoken extensively about the policies regarding cancer diagnostics in Nepal,” Koirala says. “Dr. Mahat and I are eager to work with the government to introduce policies that will help develop local diagnostic capacity and discourage sending patient samples out of the country. This will save costs, ensure patient privacy, and improve quality of care and research.”
These days, Mahat is nothing short of a local celebrity in Nepal. Despite his current drive for ensuring vaccine equity, his ultimate goal is still to work with individuals like Koirala and Pokhrel to bring cancer treatment resources to the country. He not only envisions setting up his own research center there, but also inspiring young people to pursue careers in research. “Before me, no one in my entire village had pursued a scientific career, so if I could motivate even a few young kids to follow that path, it would be a win for me.”
But, he adds, he’s not ready to leave MIT just yet; he still has more to learn. “I feel privileged and honored to be part of this compassionate community,” he says. “I’m also proud — proud that we’ve been able to come together in this time of need.”
MIT biologists show that helper immune cells disguised as cancer cells can help rejuvenate T cells that attack tumors.
Anne Trafton | MIT News Office
November 18, 2021
Under the right circumstances, the body’s T cells can detect and destroy cancer cells. However, in most cancer patients, T cells become disarmed once they enter the environment surrounding a tumor.
Scientists are now trying to find ways to help treat patients by jumpstarting those lackluster T cells. Much of the research in this field, known as cancer immunotherapy, has focused on finding ways to stimulate those T cells directly. MIT researchers have now uncovered a possible new way to indirectly activate those T cells, by recruiting a population of helper immune cells called dendritic cells.
In a new study, the researchers identified a specific subset of dendritic cells that have a unique way of activating T cells. These dendritic cells can cloak themselves in tumor proteins, allowing them to impersonate cancer cells and trigger a strong T cell response.
“We knew that dendritic cells are incredibly important for the antitumor immune response, but we didn’t know what really constitutes the optimal dendritic cell response to a tumor,” says Stefani Spranger, the Howard S. and Linda B. Stern Career Development Professor at MIT and a member of MIT’s Koch Institute for Integrative Cancer Research.
The results suggest that finding ways to stimulate that specific population of dendritic cells could help to enhance the effectiveness of cancer immunotherapy, she says. In a study of mice, the researchers showed that stimulating these dendritic cells slowed the growth of melanoma and colon tumors.
Spranger is the senior author of the study, which appears today in the journal Immunity. The lead author of the paper is MIT graduate student Ellen Duong.
Spontaneous regression
When tumors begin to form, they produce cancerous proteins that T cells recognize as foreign. This sometimes allows T cells to eliminate tumors before they get very large. In other cases, tumors are able to secrete chemical signals that deactivate T cells, allowing the tumors to continue growing unchecked.
Dendritic cells are known to help activate tumor-fighting T cells, but there are many different subtypes of dendritic cells, and their individual roles in T cell activation are not fully characterized. In this study, the MIT team wanted to investigate which types of dendritic cells are involved in T cell responses that successfully eliminate tumors.
To do that, they found a tumor cell line, from a type of muscle tumor, that has been shown to spontaneously regress in mice. Such cell lines are difficult to find because researchers usually don’t keep them around if they can’t form tumors, Spranger says.
Studying mice, they compared tumors produced by that regressive cell line with a type of colon carcinoma, which forms tumors that grow larger after being implanted in the body. The researchers found that in the progressing tumors, the T cell response quickly became exhausted, while in the regressing tumors, T cells remained functional.
The researchers then analyzed the dendritic cell populations that were present in each of these tumors. One of the main functions of dendritic cells is to take up debris from dying cells, such as cancer cells or cells infected with a pathogen, and then present the protein fragments to T cells, alerting them to the infection or tumor.
The best-known type of dendritic cells required for antitumor immunity are DC1 cells, which interact with T cells that are able to eliminate cancer cells. However, the researchers found that DC1 cells were not needed for tumor regression. Instead, using single-cell RNA sequencing technology, they identified a previously unknown activation state of DC2 cells, a different type of dendritic cell, that was driving T cell activation in the regressing tumors.
The MIT team found that instead of ingesting cellular debris, these dendritic cells swipe proteins called MHC complexes from tumor cells and display them on their own surfaces. When T cells encounter these dendritic cells masquerading as tumor cells, the T cells become strongly activated and begin killing the tumor cells.
This specialized population of dendritic cells appears to be activated by type one interferon, a signaling molecule that cells usually produce in response to viral infection. The researchers found a small population of these dendritic cells in colon and melanoma tumors that progress, but they were not properly activated. However, if they treated those tumors with interferon, the dendritic cells began stimulating T cells to attack tumor cells.
Targeted therapy
Some types of interferon have been used to help treat cancer, but it can have widespread side effects when given systemically. The findings from this study suggest that it could be beneficial to deliver interferon in a very targeted way to tumor cells, or to use a drug that would provoke tumor cells to produce type I interferon, Spranger says.
The researchers now plan to investigate just how much type I interferon is needed to generate a strong T cell response. Most tumor cells produce a small amount of type I interferon but not enough to activate the dendritic cell population that invigorates T cells. On the other hand, too much interferon can be toxic to cells.
“Our immune system is hardwired to respond to nuanced differences in type I interferon very dramatically, and that is something that is intriguing from an immunological perspective,” Spranger says.
The research was funded by the Koch Institute Support (core) Grant from the National Cancer Institute, a National Institutes of Health Pre-Doctoral Training Grant, a David H. Koch Graduate Fellowship, and the Pew-Steward Fellowship.
