Author: mantulin

Through mentorship, a deeper understanding of brain cancer metabolism grows

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.

Biologists glean insight into repetitive protein sequences

A computational analysis reveals that many repetitive sequences are shared across proteins and are similar in species from bacteria to humans.

Anne Trafton | MIT News Office
September 13, 2022

About 70 percent of all human proteins include at least one sequence consisting of a single amino acid repeated many times, with a few other amino acids sprinkled in. These “low-complexity regions” are also found in most other organisms.

The proteins that contain these sequences have many different functions, but MIT biologists have now come up with a way to identify and study them as a unified group. Their technique allows them to analyze similarities and differences between LCRs from different species, and helps them to determine the functions of these sequences and the proteins in which they are found.

Using their technique, the researchers have analyzed all of the proteins found in eight different species, from bacteria to humans. They found that while LCRs can vary between proteins and species, they often share a similar role — helping the protein in which they’re found to join a larger-scale assembly such as the nucleolus, an organelle found in nearly all human cells.

“Instead of looking at specific LCRs and their functions, which might seem separate because they’re involved in different processes, our broader approach allows us to see similarities between their properties, suggesting that maybe the functions of LCRs aren’t so disparate after all,” says Byron Lee, an MIT graduate student.

The researchers also found some differences between LCRs of different species and showed that these species-specific LCR sequences correspond to species-specific functions, such as forming plant cell walls.

Lee and graduate student Nima Jaberi-Lashkari are the lead authors of the study, which appears today in eLife. Eliezer Calo, an assistant professor of biology at MIT, is the senior author of the paper.

Large-scale study

Previous research has revealed that LCRs are involved in a variety of cellular processes, including cell adhesion and DNA binding. These LCRs are often rich in a single amino acid such as alanine, lysine, or glutamic acid.

Finding these sequences and then studying their functions individually is a time-consuming process, so the MIT team decided to use bioinformatics — an approach that uses computational methods to analyze large sets of biological data — to evaluate them as a larger group.

“What we wanted to do is take a step back and instead of looking at individual LCRs, to try to take a look at all of them and to see if we could observe some patterns on a larger scale that might help us figure out what the ones that have assigned functions are doing, and also help us learn a bit about what the ones that don’t have assigned functions are doing,” Jaberi-Lashkari says.

To do that, the researchers used a technique called dotplot matrix, which is a way to visually represent amino acid sequences, to generate images of each protein under study. They then used computational image processing methods to compare thousands of these matrices at the same time.

Using this technique, the researchers were able to categorize LCRs based on which amino acids were most frequently repeated in the LCR. They also grouped LCR-containing proteins by the number of copies of each LCR type found in the protein. Analyzing these traits helped the researchers to learn more about the functions of these LCRs.

As one demonstration, the researchers picked out a human protein, known as RPA43, that has three lysine-rich LCRs. This protein is one of many subunits that make up an enzyme called RNA polymerase 1, which synthesizes ribosomal RNA. The researchers found that the copy number of lysine-rich LCRs is important for helping the protein integrate into the nucleolus, the organelle responsible for synthesizing ribosomes.

Biological assemblies

In a comparison of the proteins found in eight different species, the researchers found that some LCR types are highly conserved between species, meaning that the sequences have changed very little over evolutionary timescales. These sequences tend to be found in proteins and cell structures that are also highly conserved, such as the nucleolus.

“These sequences seem to be important for the assembly of certain parts of the nucleolus,” Lee says. “Some of the principles that are known to be important for higher order assembly seem to be at play because the copy number, which might control how many interactions a protein can make, is important for the protein to integrate into that compartment.”

The researchers also found differences between LCRs seen in two different types of proteins that are involved in nucleolus assembly. They discovered that a nucleolar protein known as TCOF contains many glutamine-rich LCRs that can help scaffold the formation of assemblies, while nucleolar proteins with only a few of these glutamic acid-rich LCRs could be recruited as clients (proteins that interact with the scaffold).

Another structure that appears to have many conserved LCRs is the nuclear speckle, which is found inside the cell nucleus. The researchers also found many similarities between LCRs that are involved in forming larger-scale assemblies such as the extracellular matrix, a network of molecules that provides structural support to cells in plants and animals.

The research team also found examples of structures with LCRs that seem to have diverged between species. For example, plants have distinctive LCR sequences in the proteins that they use to scaffold their cell walls, and these LCRs are not seen in other types of organisms.

The researchers now plan to expand their LCR analysis to additional species.

“There’s so much to explore, because we can expand this map to essentially any species,” Lee says. “That gives us the opportunity and the framework to identify new biological assemblies.”

The research was funded by the National Institute of General Medical Sciences, National Cancer Institute, the Ludwig Center at MIT, a National Institutes of Health Pre-Doctoral Training Grant, and the Pew Charitable Trusts.

Scientists identify a plant molecule that sops up iron-rich heme

The peptide is used by legumes to control nitrogen-fixing bacteria; it may also offer leads for treating patients with too much heme in their blood.

Anne Trafton | MIT News Office
August 11, 2022

Symbiotic relationships between legumes and the bacteria that grow in their roots are critical for plant survival. Without those bacteria, the plants would have no source of nitrogen, an element that is essential for building proteins and other biomolecules, and they would be dependent on nitrogen fertilizer in the soil.

To establish that symbiosis, some legume plants produce hundreds of peptides that help bacteria live within structures known as nodules within their roots. A new study from MIT reveals that one of these peptides has an unexpected function: It sops up all available heme, an iron-containing molecule. This sends the bacteria into an iron-starvation mode that ramps up their production of ammonia, the form of nitrogen that is usable for plants.

“This is the first of the 700 peptides in this system for which a really detailed molecular mechanism has been worked out,” says Graham Walker, the American Cancer Society Research Professor of Biology at MIT, a Howard Hughes Medical Institute Professor, and the senior author of the study.

This heme-sequestering peptide could have beneficial uses in treating a variety of human diseases, the researchers say. Removing free heme from the blood could help to treat diseases caused by bacteria or parasites that need heme to survive, such as P. gingivalis (periodontal disease) or toxoplasmosis, or diseases such as sickle cell disease or sepsis that release too much heme into the bloodstream.

“This study demonstrates that basic research in plant-microbe interactions also has potential to be translated to therapeutic applications,” says Siva Sankari, an MIT research scientist and the lead author of the study, which appears today in Nature Microbiology.

Other authors of the paper include Vignesh Babu, an MIT research scientist; Kevin Bian and Mary Andorfer, both MIT postdocs; Areej Alhhazmi, a former KACST-MIT Ibn Khaldun Fellowship for Saudi Arabian Women scholar; Kwan Yoon and Dante Avalos, MIT graduate students; Tyler Smith, an MIT instructor in biology; Catherine Drennan, an MIT professor of chemistry and biology and a Howard Hughes Medical Institute investigator; Michael Yaffe, a David H. Koch Professor of Science and a member of MIT’s Koch Institute for Integrative Cancer Research; and Sebastian Lourido, the Latham Family Career Development Professor of Biology at MIT and a member of the Whitehead Institute for Biomedical Research.

Iron control

For nearly 40 years, Walker’s lab has been studying the symbiosis between legumes and rhizobia, a type of nitrogen-fixing bacteria. These bacteria convert nitrogen gas to ammonia, a critical step of the Earth’s nitrogen cycle that makes the element available to plants (and to animals that eat the plants).

Most of Walker’s work has focused on a clover-like plant called Medicago truncatula. Nitrogen-fixing bacteria elicit the formation of nodules on the roots of these plants and eventually end up inside the plant cells, where they convert to their symbiotic form called bacteroids.

Several years ago, plant biologists discovered that Medicago truncatula produces about 700 peptides that contribute to the formation of these bacteroids. These peptides are generated in waves that help the bacteria make the transition from living freely to becoming embedded into plant cells where they act as nitrogen-fixing machines.

Walker and his students picked one of these peptides, known as NCR247, to dig into more deeply. Initial studies revealed that when nitrogen-fixing bacteria were exposed to this peptide, 15 percent of their genes were affected. Many of the genes that became more active were involved in importing iron.

The researchers then found that when they fused NCR247 to a larger protein, the hybrid protein was unexpectedly reddish in color. This serendipitous observation led to the discovery that NCR247 binds heme, an organic ring-shaped iron-containing molecule that is an important component of hemoglobin, the protein that red blood cells use to carry oxygen.

Further studies revealed that when NCR247 is released into bacterial cells, it sequesters most of the heme in the cell, sending the cells into an iron-starvation mode that triggers them to begin importing more iron from the external environment.

“Usually bacteria fine-tune their iron metabolism, and they don’t take up more iron when there is already enough,” Sankari says. “What’s cool about this peptide is that it overrides that mechanism and indirectly regulates the iron content of the bacteria.”

Nitrogenase, the main enzyme that bacteria use to fix nitrogen, requires 24 to 32 atoms of iron per enzyme molecule, so the influx of extra iron likely helps those enzymes to become more active, the researchers say. This influx is timed to coincide with nitrogen fixation, they found.

“These peptides are produced in a wave in the nodules, and the production of this particular peptide is higher when the bacteria are preparing to fix nitrogen. If this peptide was secreted throughout the whole process, then the cell would have too much iron all the time, which is bad for the cell,” Sankari says.

Without the NCR247 peptide, Medicago truncatula and rhizobium cannot form an effective nitrogen-fixing symbiosis, the researchers showed.

“Many possible directions”

The peptide that the researchers studied in this work may have potential therapeutic uses. When heme is incorporated into hemoglobin, it performs a critical function in the body, but when it’s loose in the bloodstream, it can kill cells and promote inflammation. Free heme can accumulate in stored blood, so having a way to filter out the heme before the blood is transfused into a patient could be potentially useful.

A variety of human diseases lead to free heme circulating in the bloodstream, including sickle cell anemia, sepsis, and malaria. Additionally, some infectious parasites and bacteria depend on heme for their survival but cannot produce it, so they scavenge it from their environment. Treating such infections with a protein that takes up all available heme could help prevent the parasitic or bacterial cells from being able to grow and reproduce.

In this study, Lourido and members of his lab showed that treating the parasite Toxoplasma gondii with NCR427 prevented the parasite from forming plaques on human cells.

The researchers are now pursuing collaborations with other labs at MIT to explore some of these potential applications, with funding from a Professor Amar G. Bose Research Grant.

“There are many possible directions, but they’re all at a very early stage,” Walker says. “The number of potential clinical applications is very broad. You can place more than one bet in this game, which is an intriguing thing.”

Currently, the human protein hemopexin, which also binds to heme, is being explored as a possible treatment for sickle cell anemia. The NCR247 peptide could provide an easier to deploy alternative, the researchers say, because it is much smaller and could be easier to manufacture and deliver into the body.

The research was funded in part by the MIT Center for Environmental Health Sciences, the National Science Foundation, and the National Institutes of Health.

New findings reveal how neurons build and maintain their capacity to communicate

Nerve cells regulate and routinely refresh the collection of calcium channels that enable them to send messages across circuit connections.

David Orenstein | Picower Institute for Learning and Memory
July 21, 2022

The nervous system works because neurons communicate across connections called synapses. They “talk” when calcium ions flow through channels into “active zones” that are loaded with vesicles carrying molecular messages. The electrically charged calcium causes vesicles to “fuse” to the outer membrane of presynaptic neurons, releasing their communicative chemical cargo to the postsynaptic cell. In a new study, scientists at The Picower Institute for Learning and Memory at MIT provide several revelations about how neurons set up and sustain this vital infrastructure.

“Calcium channels are the major determinant of calcium influx, which then triggers vesicle fusion, so it is a critical component of the engine on the presynaptic side that converts electrical signals to chemical synaptic transmission,” says Troy Littleton, senior author of the new study in eLife and Menicon Professor of Neuroscience in MIT’s departments of Biology and Brain and Cognitive Sciences. “How they accumulate at active zones was really unclear. Our study reveals clues into how active zones accumulate and regulate the abundance of calcium channels.”

Neuroscientists have wanted these clues. One reason is that understanding this process can help reveal how neurons change how they communicate, an ability called “plasticity” that underlies learning and memory and other important brain functions. Another is that drugs such as gabapentin, which treats conditions as diverse as epilepsy, anxiety, and nerve pain, binds a protein called alpha2delta that is closely associated with calcium channels. By revealing more about alpha2delta’s exact function, the study better explains what those treatments affect.

“Modulation of the function of presynaptic calcium channels is known to have very important clinical effects,” Littleton says. “Understanding the baseline of how these channels are regulated is really important.”

MIT postdoc Karen Cunningham led the study, which was her doctoral thesis work in Littleton’s lab. Using the model system of fruit fly motor neurons, she employed a wide variety of techniques and experiments to show for the first time the step-by-step process that accounts for the distribution and upkeep of calcium channels at active zones.

A cap on Cac

Cunningham’s first question was whether calcium channels are necessary for active zones to develop in larvae. The fly calcium channel gene (called “cacophony,” or Cac) is so important, flies literally can’t live without it. So rather than knocking out Cac across the fly, Cunningham used a technique to knock it out in just one population of neurons. By doing so, she was able to show that even without Cac, active zones grow and mature normally.

Using another technique that artificially prolongs the larval stage of the fly she was also able to see that given extra time the active zone will continue to build up its structure with a protein called BRP, but that Cac accumulation ceases after the normal six days. Cunningham also found that moderate increases or decreases in the supply of available Cac in the neuron did not affect how much Cac ended up at each active zone. Even more curious, she found that while Cac amount did scale with each active zone’s size, it barely budged if she took away a lot of the BRP in the active zone. Indeed, for each active zone, the neuron seemed to enforce a consistent cap on the amount of Cac present.

“It was revealing that the neuron had very different rules for the structural proteins at the active zone like BRP that continued to accumulate over time, versus the calcium channel that was tightly regulated and had its abundance capped” Cunningham says.

Regular refresh

The findings showed there must be factors other than Cac supply or changes in BRP that regulate Cac levels so tightly. Cunningham turned to alpha2delta. When she genetically manipulated how much of that was expressed, she found that alpha2delta levels directly determined how much Cac accumulated at active zones.

In further experiments, Cunningham was also able to show that alpha2delta’s ability to maintain Cac levels depended on the neuron’s overall Cac supply. That finding suggested that rather than controlling Cac amount at active zones by stabilizing it, alpha2delta likely functioned upstream, during Cac trafficking, to supply and resupply Cac to active zones.

Cunningham used two different techniques to watch that resupply happen, producing measurements of its extent and its timing. She chose a moment after a few days of development to image active zones and measure Cac abundance to ascertain the landscape. Then she bleached out that Cac fluorescence to erase it. After 24 hours, she visualized Cac fluorescence anew to highlight only the new Cac that was delivered to active zones over that 24 hours. She saw that over that day there was Cac delivery across virtually all active zones, but that one day’s work was indeed only a fraction compared to what had built up over several days before. Moreover, she could see that the larger active zones accrued more Cac than smaller ones. And in flies with mutated alpha2delta, there was very little new Cac delivery at all.

If Cac channels were indeed constantly being resupplied, then Cunningham wanted to know at what pace Cac channels are removed from active zones. To determine that, she used a staining technology with a photoconvertible protein called Maple tagged to the Cac protein that allowed her to change the color with a flash of light at the time of her choosing. That way she could first see how much Cac accumulated by a certain time (shown in green) and then flash the light to turn that Cac red. When she checked back five days later, about 30 percent of the red Cac had been replaced with new green Cac, suggesting 30 percent turnover. When she reduced Cac delivery levels by mutating alpha2 delta or reducing Cac biosynthesis, Cac turnover stopped. That means a significant amount of Cac is turned over each day at active zones and that the turnover is prompted by new Cac delivery.

Littleton says his lab is eager to build on these results. Now that the rules of calcium channel abundance and replenishment are clear, he wants to know how they differ when neurons undergo plasticity — for instance, when new incoming information requires neurons to adjust their communication to scale up or down synaptic communication. He says he is also eager to track individual calcium channels as they are made in the cell body and then move down the neural axon to the active zones, and he wants to determine what other genes may affect Cac abundance.

In addition to Cunningham and Littleton, the paper’s other authors are Chad Sauvola and Sara Tavana.

The National Institutes of Health and the JPB Foundation provided support for the research.

MIT announces 2022 Bose grants for ambitious ideas

Tenth anniversary of the program rewards three innovative projects.

Aaron Braddock | Office of the Provost
June 13, 2022

MIT Provost Cynthia Barnhart has announced three Professor Amar G. Bose Research Grants to support bold research projects across diverse areas of study including biology, engineering, and the humanities.

The three grants honor the visionary and bold thinking in the winning proposals of the following nine researchers: John J. and Dorothy Wilson Professor of Health Sciences and Technology and Electrical Engineering and Computer Science Sangeeta Bhatia; Carl Richard Soderberg Professor of Power Engineering Gang Chen; professor of biology Jianzhu Chen; associate professor of biology Michael Hemann; professor of anthropology and Margaret MacVicar Faculty Fellow Graham Jones; Latham Family Career Development Professor Sebastian Lourido; assistant professor of computer science Arvind Satayanaryan; Howard Hughes Medical Institute Professor Graham Walker; and David H. Koch Professor in Science Michael Yaffe;

“Innovation is born when a unique vision drives daring researchers to take on risky and adventurous projects, a notion that Amar Bose understood well,” says Barnhart. “With support and recognition from this program, these nine talented and forward-thinking faculty have the freedom to explore and study areas not typically backed by conventional funding sources.”

The program was named for the visionary founder of the Bose Corporation and MIT alumnus, Amar G. Bose ’51, SM ’52, ScD ’56. After gaining admission to MIT, Bose became a top math student and a Fulbright Scholarship recipient. He spent 46 years as a professor at MIT, led innovations in sound design, and founded the Bose Corporation in 1964. MIT launched the program a decade ago.

“The legendary explorations and innovations of Professor Amar Bose inspire the Bose Research Grant program,” says President Emerita and Professor Susan Hockfield. “The grants support projects that reach beyond the horizon and so would not receive funding from standard sources. Since its inception, the program has supported 49 MIT faculty to pursue their most compelling ideas and, in doing so, to join the Bose Fellows community of like-minded adventurers.”

The program, which has honored 35 projects to date, is a tribute to the legacy of Bose, who believed that passion and curiosity drive innovation. With that spirit in mind, the projects typically supported by the program are original, cross-disciplinary, and high-risk. The program has encouraged collaborative projects, as reflected in this year’s winners.

This year’s recipients are:

Gang Chen of the Department of Mechanical Engineering. With his proposal, “Photomolecular Effect and Clouds Thinning,” Chen will advance research into his discovery of a way in which photons can be absorbed by cleaving off water clusters from the water-air surface, significantly impacting technologies related to energy and water and climate models.

Graham Jones of the Anthropology Section and Arvind Satayanaryan of the Department of Electrical Engineering and Computer Science (EECS). Their “Magical Data Visualization” proposal uses performance magic to create new visualizations that are responsive to the users’ intent, potentially impacting how misinformation spreads.

Graham Walker, Michael Hemann, Michael Yaffe, Sebastian Lourido, Jianzhu Chen of the Department of Biology and Sangeeta Bhatia of EECS and the Institute of Medical Engineering and Science. Their proposal, “Addressing Critical Human Health Problems with a Special Heme-binding Peptide,” uses a recently discovered plant peptide that binds and sequesters a molecule critical in hemoglobin oxygen binding in a new way, which has significant implications on many health issues.

“This year, more than a dozen faculty members from departments across all five schools and the college participated in the evaluations,” says Chancellor for Academic Advancement Eric Grimson. “Their diverse perspectives were critical in assessing what was a very strong field of interesting proposals. We are grateful for their generous commitment of time and energy and the thoughtfulness with which they approached the selection process.”

The program explores out-of-the-box ideas that would face difficulty in acquiring funding through traditional means but have the potential for strong impacts on the scientific community. Any member of the faculty in any discipline in MIT’s five schools and college is eligible to submit a proposal for a Bose Research Grant, which provides funding over three years.

New CRISPR-based map ties every human gene to its function

Jonathan Weissman and collaborators used their single-cell sequencing tool Perturb-seq on every expressed gene in the human genome, linking each to its job in the cell.

Eva Frederick | Whitehead Institute
June 9, 2022

The Human Genome Project was an ambitious initiative to sequence every piece of human DNA. The project drew together collaborators from research institutions around the world, including MIT’s Whitehead Institute for Biomedical Research, and was finally completed in 2003. Now, over two decades later, MIT Professor Jonathan Weissman and colleagues have gone beyond the sequence to present the first comprehensive functional map of genes that are expressed in human cells. The data from this project, published online June 9 in Cell, ties each gene to its job in the cell, and is the culmination of years of collaboration on the single-cell sequencing method Perturb-seq.

The data are available for other scientists to use. “It’s a big resource in the way the human genome is a big resource, in that you can go in and do discovery-based research,” says Weissman, who is also a member of the Whitehead Institute and an investigator with the Howard Hughes Medical Institute. “Rather than defining ahead of time what biology you’re going to be looking at, you have this map of the genotype-phenotype relationships and you can go in and screen the database without having to do any experiments.”

The screen allowed the researchers to delve into diverse biological questions. They used it to explore the cellular effects of genes with unknown functions, to investigate the response of mitochondria to stress, and to screen for genes that cause chromosomes to be lost or gained, a phenotype that has proved difficult to study in the past. “I think this dataset is going to enable all sorts of analyses that we haven’t even thought up yet by people who come from other parts of biology, and suddenly they just have this available to draw on,” says former Weissman Lab postdoc Tom Norman, a co-senior author of the paper.

Pioneering Perturb-seq

The project takes advantage of the Perturb-seq approach that makes it possible to follow the impact of turning on or off genes with unprecedented depth. This method was first published in 2016 by a group of researchers including Weissman and fellow MIT professor Aviv Regev, but could only be used on small sets of genes and at great expense.

The massive Perturb-seq map was made possible by foundational work from Joseph Replogle, an MD-PhD student in Weissman’s lab and co-first author of the present paper. Replogle, in collaboration with Norman, who now leads a lab at Memorial Sloan Kettering Cancer Center; Britt Adamson, an assistant professor in the Department of Molecular Biology at Princeton University; and a group at 10x Genomics, set out to create a new version of Perturb-seq that could be scaled up. The researchers published a proof-of-concept paper in Nature Biotechnology in 2020.

The Perturb-seq method uses CRISPR-Cas9 genome editing to introduce genetic changes into cells, and then uses single-cell RNA sequencing to capture information about the RNAs that are expressed resulting from a given genetic change. Because RNAs control all aspects of how cells behave, this method can help decode the many cellular effects of genetic changes.

Since their initial proof-of-concept paper, Weissman, Regev, and others have used this sequencing method on smaller scales. For example, the researchers used Perturb-seq in 2021 to explore how human and viral genes interact over the course of an infection with HCMV, a common herpesvirus.

In the new study, Replogle and collaborators including Reuben Saunders, a graduate student in Weissman’s lab and co-first author of the paper, scaled up the method to the entire genome. Using human blood cancer cell lines as well noncancerous cells derived from the retina, he performed Perturb-seq across more than 2.5 million cells, and used the data to build a comprehensive map tying genotypes to phenotypes.

Delving into the data

Upon completing the screen, the researchers decided to put their new dataset to use and examine a few biological questions. “The advantage of Perturb-seq is it lets you get a big dataset in an unbiased way,” says Tom Norman. “No one knows entirely what the limits are of what you can get out of that kind of dataset. Now, the question is, what do you actually do with it?”

The first, most obvious application was to look into genes with unknown functions. Because the screen also read out phenotypes of many known genes, the researchers could use the data to compare unknown genes to known ones and look for similar transcriptional outcomes, which could suggest the gene products worked together as part of a larger complex.

The mutation of one gene called C7orf26 in particular stood out. Researchers noticed that genes whose removal led to a similar phenotype were part of a protein complex called Integrator that played a role in creating small nuclear RNAs. The Integrator complex is made up of many smaller subunits — previous studies had suggested 14 individual proteins — and the researchers were able to confirm that C7orf26 made up a 15th component of the complex.

They also discovered that the 15 subunits worked together in smaller modules to perform specific functions within the Integrator complex. “Absent this thousand-foot-high view of the situation, it was not so clear that these different modules were so functionally distinct,” says Saunders.

Another perk of Perturb-seq is that because the assay focuses on single cells, the researchers could use the data to look at more complex phenotypes that become muddied when they are studied together with data from other cells. “We often take all the cells where ‘gene X’ is knocked down and average them together to look at how they changed,” Weissman says. “But sometimes when you knock down a gene, different cells that are losing that same gene behave differently, and that behavior may be missed by the average.”

The researchers found that a subset of genes whose removal led to different outcomes from cell to cell were responsible for chromosome segregation. Their removal was causing cells to lose a chromosome or pick up an extra one, a condition known as aneuploidy. “You couldn’t predict what the transcriptional response to losing this gene was because it depended on the secondary effect of what chromosome you gained or lost,” Weissman says. “We realized we could then turn this around and create this composite phenotype looking for signatures of chromosomes being gained and lost. In this way, we’ve done the first genome-wide screen for factors that are required for the correct segregation of DNA.”

“I think the aneuploidy study is the most interesting application of this data so far,” Norman says. “It captures a phenotype that you can only get using a single-cell readout. You can’t go after it any other way.”

The researchers also used their dataset to study how mitochondria responded to stress. Mitochondria, which evolved from free-living bacteria, carry 13 genes in their genomes. Within the nuclear DNA, around 1,000 genes are somehow related to mitochondrial function. “People have been interested for a long time in how nuclear and mitochondrial DNA are coordinated and regulated in different cellular conditions, especially when a cell is stressed,” Replogle says.

The researchers found that when they perturbed different mitochondria-related genes, the nuclear genome responded similarly to many different genetic changes. However, the mitochondrial genome responses were much more variable.

“There’s still an open question of why mitochondria still have their own DNA,” said Replogle. “A big-picture takeaway from our work is that one benefit of having a separate mitochondrial genome might be having localized or very specific genetic regulation in response to different stressors.”

“If you have one mitochondria that’s broken, and another one that is broken in a different way, those mitochondria could be responding differentially,” Weissman says.

In the future, the researchers hope to use Perturb-seq on different types of cells besides the cancer cell line they started in. They also hope to continue to explore their map of gene functions, and hope others will do the same. “This really is the culmination of many years of work by the authors and other collaborators, and I’m really pleased to see it continue to succeed and expand,” says Norman.

MIT Climate and Sustainability Consortium announces recipients of inaugural MCSC Seed Awards

Twenty winning projects will link industry member priorities with research groups across campus to develop scalable climate solutions.

Molly Chase | Climate and Sustainability Consortium
May 23, 2022

The MIT Climate and Sustainability Consortium (MCSC) has awarded 20 projects a total of $5 million over two years in its first-ever 2022 MCSC Seed Awards program. The winning projects are led by principal investigators across all five of MIT’s schools.

The goal of the MCSC Seed Awards is to engage MIT researchers and link the economy-wide work of the consortium to ongoing and emerging climate and sustainability efforts across campus. The program offers further opportunity to build networks among the awarded projects to deepen the impact of each and ensure the total is greater than the sum of its parts.

For example, to drive progress under the awards category Circularity and Materials, the MCSC can facilitate connections between the technologists at MIT who are developing recovery approaches for metals, plastics, and fiber; the urban planners who are uncovering barriers to reuse; and the engineers, who will look for efficiency opportunities in reverse supply chains.

“The MCSC Seed Awards are designed to complement actions previously outlined in Fast Forward: MIT’s Climate Action Plan for the Decade and, more specifically, the Climate Grand Challenges,” says Anantha P. Chandrakasan, dean of the MIT School of Engineering, Vannevar Bush Professor of Electrical Engineering and Computer Science, and chair of the MIT Climate and Sustainability Consortium. “In collaboration with seed award recipients and MCSC industry members, we are eager to engage in interdisciplinary exploration and propel urgent advancements in climate and sustainability.”

By supporting MIT researchers with expertise in economics, infrastructure, community risk assessment, mobility, and alternative fuels, the MCSC will accelerate implementation of cross-disciplinary solutions in the awards category Decarbonized and Resilient Value Chains. Enhancing Natural Carbon Sinks and building connections to local communities will require associations across experts in ecosystem change, biodiversity, improved agricultural practice and engagement with farmers, all of which the consortium can begin to foster through the seed awards.

“Funding opportunities across campus has been a top priority since launching the MCSC,” says Jeremy Gregory, MCSC executive director. “It is our honor to support innovative teams of MIT researchers through the inaugural 2022 MCSC Seed Awards program.”

The winning projects are tightly aligned with the MCSC’s areas of focus, which were derived from a year of highly engaged collaborations with MCSC member companies. The projects apply across the member’s climate and sustainability goals.

The MCSC’s 16 member companies span many industries, and since early 2021, have met with members of the MIT community to define focused problem statements for industry-specific challenges, identify meaningful partnerships and collaborations, and develop clear and scalable priorities. Outcomes from these collaborations laid the foundation for the focus areas, which have shaped the work of the MCSC. Specifically, the MCSC Industry Advisory Board engaged with MIT on key strategic directions, and played a critical role in the MCSC’s series of interactive events. These included virtual workshops hosted last summer, each on a specific topic that allowed companies to work with MIT and each other to align key assumptions, identify blind spots in corporate goal-setting, and leverage synergies between members, across industries. The work continued in follow-up sessions and an annual symposium.

“We are excited to see how the seed award efforts will help our member companies reach or even exceed their ambitious climate targets, find new cross-sector links among each other, seek opportunities to lead, and ripple key lessons within their industry, while also deepening the Institute’s strong foundation in climate and sustainability research,” says Elsa Olivetti, the Esther and Harold E. Edgerton Associate Professor in Materials Science and Engineering and MCSC co-director.

As the seed projects take shape, the MCSC will provide ongoing opportunities for awardees to engage with the Industry Advisory Board and technical teams from the MCSC member companies to learn more about the potential for linking efforts to support and accelerate their climate and sustainability goals. Awardees will also have the chance to engage with other members of the MCSC community, including its interdisciplinary Faculty Steering Committee.

“One of our mantras in the MCSC is to ‘amplify and extend’ existing efforts across campus; we’re always looking for ways to connect the collaborative industry relationships we’re building and the work we’re doing with other efforts on campus,” notes Jeffrey Grossman, the Morton and Claire Goulder and Family Professor in Environmental Systems, head of the Department of Materials Science and Engineering, and MCSC co-director. “We feel the urgency as well as the potential, and we don’t want to miss opportunities to do more and go faster.”

The MCSC Seed Awards complement the Climate Grand Challenges, a new initiative to mobilize the entire MIT research community around developing the bold, interdisciplinary solutions needed to address difficult, unsolved climate problems. The 27 finalist teams addressed four broad research themes, which align with the MCSC’s focus areas. From these finalist teams, five flagship projects were announced in April 2022.

The parallels between MCSC’s focus areas and the Climate Grand Challenges themes underscore an important connection between the shared long-term research interests of industry and academia. The challenges that some of the world’s largest and most influential companies have identified are complementary to MIT’s ongoing research and innovation — highlighting the tremendous opportunity to develop breakthroughs and scalable solutions quickly and effectively. Special Presidential Envoy for Climate John Kerry underscored the importance of developing these scalable solutions, including critical new technology, during a conversation with MIT President L. Rafael Reif at MIT’s first Climate Grand Challenges showcase event last month.

Both the MCSC Seed Awards and the Climate Grand Challenges are part of MIT’s larger commitment and initiative to combat climate change. Underscored in “Fast Forward: MIT’s Climate Action Plan for the Decade,” which the Institute published in May 2021.

The project titles and research leads for each of the 20 awardees listed below are categorized by MCSC focus area.

Decarbonized and resilient value chains

  • “Collaborative community mapping toolkit for resilience planning,” led by Miho Mazereeuw, associate professor of architecture and urbanism in the Department of Architecture and director of the Urban Risk Lab (a research lead on Climate Grand Challenges flagship project) and Nicholas de Monchaux, professor and department head in the Department of Architecture
  • “CP4All: Fast and local climate projections with scientific machine learning — towards accessibility for all of humanity,” led by Chris Hill, principal research scientist in the Department of Earth, Atmospheric and Planetary Sciences and Dava Newman, director of the MIT Media Lab and the Apollo Program Professor in the Department of Aeronautics and Astronautics
  • “Emissions reductions and productivity in U.S. manufacturing,” led by Mert Demirer, assistant professor of applied economics at the MIT Sloan School of Management and Jing Li, assistant professor and William Barton Rogers Career Development Chair of Energy Economics in the MIT Sloan School of Management
  • “Logistics electrification through scalable and inter-operable charging infrastructure: operations, planning, and policy,” led by Alex Jacquillat, the 1942 Career Development Professor and assistant professor of operations research and statistics in the MIT Sloan School of Management
  • “Powertrain and system design for LOHC-powered long-haul trucking,” led by William Green, the Hoyt Hottel Professor in Chemical Engineering in the Department of Chemical Engineering and postdoctoral officer, and Wai K. Cheng, professor in the Department of Mechanical Engineering and director of the Sloan Automotive Laboratory
  • “Sustainable Separation and Purification of Biochemicals and Biofuels using Membranes,” led by John Lienhard, the Abdul Latif Jameel Professor of Water in the Department of Mechanical Engineering, director of the Abdul Latif Jameel Water and Food Systems Lab, and director of the Rohsenow Kendall Heat Transfer Laboratory; and Nicolas Hadjiconstantinou, professor in the Department of Mechanical Engineering, co-director of the Center for Computational Science and Engineering, associate director of the Center for Exascale Simulation of Materials in Extreme Environments, and graduate officer
  • “Toolkit for assessing the vulnerability of industry infrastructure siting to climate change,” led by Michael Howland, assistant professor in the Department of Civil and Environmental Engineering

Circularity and Materials

  • “Colorimetric Sulfidation for Aluminum Recycling,” led by Antoine Allanore, associate professor of metallurgy in the Department of Materials Science and Engineering
  • “Double Loop Circularity in Materials Design Demonstrated on Polyurethanes,” led by Brad Olsen, the Alexander and I. Michael Kasser (1960) Professor and graduate admissions co-chair in the Department of Chemical Engineering, and Kristala Prather, the Arthur Dehon Little Professor and department executive officer in the Department of Chemical Engineering
  • “Engineering of a microbial consortium to degrade and valorize plastic waste,” led by Otto Cordero, associate professor in the Department of Civil and Environmental Engineering, and Desiree Plata, the Gilbert W. Winslow (1937) Career Development Professor in Civil Engineering and associate professor in the Department of Civil and Environmental Engineering
  • “Fruit-peel-inspired, biodegradable packaging platform with multifunctional barrier properties,” led by Kripa Varanasi, professor in the Department of Mechanical Engineering
  • “High Throughput Screening of Sustainable Polyesters for Fibers,” led by Gregory Rutledge, the Lammot du Pont Professor in the Department of Chemical Engineering, and Brad Olsen, Alexander and I. Michael Kasser (1960) Professor and graduate admissions co-chair in the Department of Chemical Engineering
  • “Short-term and long-term efficiency gains in reverse supply chains,” led by Yossi Sheffi, the Elisha Gray II Professor of Engineering Systems, professor in the Department of Civil and Environmental Engineering, and director of the Center for Transportation and Logistics
  • The costs and benefits of circularity in building construction, led by Siqi Zheng, the STL Champion Professor of Urban and Real Estate Sustainability at the MIT Center for Real Estate and Department of Urban Studies and Planning, faculty director of the MIT Center for Real Estate, and faculty director for the MIT Sustainable Urbanization Lab; and Randolph Kirchain, principal research scientist and co-director of MIT Concrete Sustainability Hub

Natural carbon sinks

  • “Carbon sequestration through sustainable practices by smallholder farmers,” led by Joann de Zegher, the Maurice F. Strong Career Development Professor and assistant professor of operations management in the MIT Sloan School of Management, and Karen Zheng the George M. Bunker Professor and associate professor of operations management in the MIT Sloan School of Management
  • “Coatings to protect and enhance diverse microbes for improved soil health and crop yields,” led by Ariel Furst, the Raymond A. (1921) And Helen E. St. Laurent Career Development Professor of Chemical Engineering in the Department of Chemical Engineering, and Mary Gehring, associate professor of biology in the Department of Biology, core member of the Whitehead Institute for Biomedical Research, and graduate officer
  • “ECO-LENS: Mainstreaming biodiversity data through AI,” led by John Fernández, professor of building technology in the Department of Architecture and director of MIT Environmental Solutions Initiative
  • “Growing season length, productivity, and carbon balance of global ecosystems under climate change,” led by Charles Harvey, professor in the Department of Civil and Environmental Engineering, and César Terrer, assistant professor in the Department of Civil and Environmental Engineering

Social dimensions and adaptation

  • “Anthro-engineering decarbonization at the million-person scale,” led by Manduhai Buyandelger, professor in the Anthropology Section, and Michael Short, the Class of ’42 Associate Professor of Nuclear Science and Engineering in the Department of Nuclear Science and Engineering
  • “Sustainable solutions for climate change adaptation: weaving traditional ecological knowledge and STEAM,” led by Janelle Knox-Hayes, the Lister Brothers Associate Professor of Economic Geography and Planning and head of the Environmental Policy and Planning Group in the Department of Urban Studies and Planning, and Miho Mazereeuw, associate professor of architecture and urbanism in the Department of Architecture and director of the Urban Risk Lab (a research lead on a Climate Grand Challenges flagship project)
Lindsay Case and Guangyu Robert Yang named 2022 Searle Scholars

MIT cell biologist and computational neuroscientist recognized for their innovative research contributions.

Raleigh McElvery | Julie Pryor | McGovern Institute for Brain Research | Department of Biology
May 13, 2022

MIT cell biologist Lindsay Case and computational neuroscientist Guangyu Robert Yang have been named 2022 Searle Scholars, an award given annually to 15 outstanding U.S. assistant professors who have high potential for ongoing innovative research contributions in medicine, chemistry, or the biological sciences.

Case is an assistant professor of biology, while Yang is an assistant professor of brain and cognitive sciences and electrical engineering and computer science, and an associate investigator at the McGovern Institute for Brain Research. They will each receive $300,000 in flexible funding to support their high-risk, high-reward work over the next three years.

Lindsay Case

Case arrived at MIT in 2021, after completing a postdoc at the University of Texas Southwestern Medical Center in the lab of Michael Rosen. Prior to that, she earned her PhD from the University of North Carolina at Chapel Hill, working in the lab of Clare Waterman at the National Heart Lung and Blood Institute.

Situated in MIT’s Building 68, Case’s lab studies how molecules within cells organize themselves, and how such organization begets cellular function. Oftentimes, molecules will assemble at the cell’s plasma membrane — a complex signaling platform where hundreds of receptors sense information from outside the cell and initiate cellular changes in response. Through her experiments, Case has found that molecules at the plasma membrane can undergo a process known as phase separation, condensing to form liquid-like droplets.

As a Searle Scholar, Case is investigating the role that phase separation plays in regulating a specific class of signaling molecules called kinases. Her team will take a multidisciplinary approach to probe what happens when kinases phase separate into signaling clusters, and what cellular changes occur as a result. Because phase separation is emerging as a promising new target for small molecule therapies, this work will help identify kinases that are strong candidates for new therapeutic interventions to treat diseases such as cancer.

“I am honored to be recognized by the Searle Scholars Program, and thrilled to join such an incredible community of scientists,” Case says. “This support will enable my group to broaden our research efforts and take our preliminary findings in exciting new directions. I look forward to better understanding how phase separation impacts cellular function.”

Guangyu Robert Yang

Before coming to MIT in 2021, Yang trained in physics at Peking University, obtained a PhD in computational neuroscience at New York University with Xiao-Jing Wang, and further trained as a postdoc at the Center for Theoretical Neuroscience of Columbia University, as an intern at Google Brain, and as a junior fellow at the Simons Society of Fellows.

His research team at MIT, the MetaConscious Group, develops models of mental functions by incorporating multiple interacting modules. They are designing pipelines to process and compare large-scale experimental datasets that span modalities ranging from behavioral data to neural activity data to molecular data. These datasets are then be integrated to train individual computational modules based on the experimental tasks that were evaluated such as vision, memory, or movement.

Ultimately, Yang seeks to combine these modules into a “network of networks” that models higher-level brain functions such as the ability to flexibly and rapidly learn a variety of tasks. Such integrative models are rare because, until recently, it was not possible to acquire data that spans modalities and brain regions in real time as animals perform tasks. The time is finally right for integrative network models. Computational models that incorporate such multisystem, multilevel datasets will allow scientists to make new predictions about the neural basis of cognition and open a window to a mathematical understanding the mind.

“This is a new research direction for me, and I think for the field too. It comes with many exciting opportunities as well as challenges. Having this recognition from the Searle Scholars program really gives me extra courage to take on the uncertainties and challenges,” says Yang.

Since 1981, 647 scientists have been named Searle Scholars. Including this year, the program has awarded more than $147 million. Eighty-five Searle Scholars have been inducted into the National Academy of Sciences. Twenty scholars have been recognized with a MacArthur Fellowship, known as the “genius grant,” and two Searle Scholars have been awarded the Nobel Prize in Chemistry. The Searle Scholars Program is funded through the Searle Funds at The Chicago Community Trust and administered by Kinship Foundation.

Fellowship funds graduate studies at Stanford University.

Julia Mongo | Office of Distinguished Fellowships
May 11, 2022

MIT seniors Desmond Edwards, Michelle Lee, and Syamantak Payra; graduate student Tomás Guarna; and Pranav Lalgudi ’21 have been honored by this year’s Knight-Hennessy Scholars program. They will head to Stanford University this fall to commence their doctoral programs.

Knight-Hennessy Scholars receive full funding for up to three years of graduate studies in any field at Stanford University. Fellows, who hail from countries around the world, also participate in the King Global Leadership Program, which aims to prepare them to become inspiring and visionary leaders who are committed to the greater good.

MIT students seeking more information on the Knight-Hennessy Scholar program can contact Kim Benard, associate dean of distinguished fellowships in Career Advising and Professional Development.

Desmond Edwards

Desmond Edwards, from St. Mary, Jamaica, will graduate this May from MIT with bachelor’s degrees in biological engineering and biology, with a minor in French. As a Knight-Hennessy Scholar, he will embark on a PhD in microbiology and immunology at Stanford School of Medicine. Edwards is interested in infectious diseases — both in understanding their underlying mechanisms and devising novel therapeutics to fulfill unmet patient needs. He further aspires to blend this research with public policy, outreach, and education. He has investigated and engineered host-pathogen interactions in MIT’s Lamason lab and has evaluated AAV gene therapies in Caltech’s Gradinaru lab and at Voyager Therapeutics. Edwards is the first undergraduate to serve as MIT Biotech Group co-president, is president of MIT’s chapter of the Tau Beta Pi Engineering Honour Society, was co-president of MIT’s Biological Engineering Undergraduate Board, and vice-captained MIT’s Quidditch Team. Edwards is a recipient of MIT’s Whitehead Prize in Biology, MIT’s Peter J Eloranta Summer Undergraduate Research Fellowship, a 2022 NSF Graduate Research Fellowship, and a 2021 Amgen Scholars Fellowship.

Tomás Guarna

Tomás Guarna, from Buenos Aires, Argentina, will pursue a PhD in Stanford’s Communication Department. He graduated from Universidad Torcuato Di Tella with a degree in social sciences, and then worked in the Office of the President of Argentina’s digital communications team. He is currently completing his SM in comparative media studies at MIT. Guarna aims to explore the role of technology in our civic life, understanding the relations between governments, technology companies, and civil society. Guarna was a Human Rights and Technology Fellow at the MIT Center for International Studies and a fellow at MIT’s Priscilla King Gray Public Service Center. He will be joining Stanford as a Knight-Hennessy Scholar and as a Stanford EDGE Fellow.

Pranav Lalgudi

Pranav Lalgudi, from San Jose, California, graduated from MIT in 2021 with a bachelor’s degree in biology, a minor in data science, and a concentration in philosophy. He will pursue a PhD in genetics at Stanford School of Medicine. Lalgudi is keen to answer fundamental questions in biology to improve our understanding of human health. At MIT, he uncovered how cells regulate metabolism in response to nutrients, processes which are disrupted in cancer and diabetes. He previously worked at Stanford, creating new tools for studying the genetic diversity of cancers. Lalgudi aspires to make academic research more collaborative, rigorous, and accessible. He is also passionate about addressing inequities in access to education and has worked at schools in Spain and Italy to develop more interactive STEM curricula for students. Lalgudi’s research has been accepted for publication in several peer-reviewed journals, including Nature, and he was awarded the NSF GRFP and NDSEG Fellowships.

Michelle Lee

Michelle Lee, from Seoul, South Korea, is an MIT senior majoring in chemistry. She will continue on at Stanford for a PhD in chemistry as a Knight-Hennessy Scholar and NSF GRFP Fellow. Lee’s goal is to understand and precisely manipulate the cellular machinery with synthetic molecules, which will open a door for novel, efficient, and affordable therapeutic strategies, especially in curing genetic diseases. At MIT, she designed a small molecule “switch” to CRISPR activity, which can precisely manipulate the activity of CRISPR-Cas protein, increasing its efficacy and reducing off-target effects. She also designed an affordable, rapid “mix-and-read” Covid-19 diagnostics tool for use in low- and middle-income countries, the work for which she was a first author of a publication. Lee has pushed to increase the accessibility of education by leading multiple educational enrichment programs.

Syamantak Payra

Syamantak Payra, from Friendswood, Texas, will graduate this spring from MIT with a bachelor’s degree in electrical engineering and computer science, and minors in public policy and in entrepreneurship and innovation. He will pursue a PhD in electrical engineering at Stanford School of Engineering as a Knight-Hennessy Scholar and Paul and Daisy Soros Fellow. Alongside creating new biomedical devices that can help improve daily life for patients worldwide, Payra aspires to shape American educational and scientific ecosystems to better empower upcoming generations. At MIT, he conducted research creating digital sensor fibers that have been woven into health-monitoring garments and next-generation spacesuits. He has organized and led literacy and STEM outreach programs benefiting a thousand underprivileged students nationwide. Payra earned multiple first-place awards at International Science and Engineering Fairs, placed ninth in the 2018 Regeneron Science Talent Search, was inducted into the National Gallery of America’s Young Inventors, and was an Astronaut Scholar, Coca-Cola Scholar, and U.S. Presidential Scholar.

Tracing a cancer’s family tree to its roots reveals how tumors grow

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.”