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Brain cell types are affected differently by Rett Syndrome mutation

New research from Jaenisch Lab postdoc Danielle Tomasello focuses on an understudied question: how Rett Syndrome affects cell types in the human brain other than neurons.

Greta Friar | Whitehead Institute
September 6, 2024

Rett Syndrome is a X-chromosome-linked neurodevelopmental disorder; it can lead to loss of coordination, mobility, ability to speak, and use of the hands, among other symptoms. The syndrome is typically caused by mutations within the gene MECP2. Researchers in Whitehead Institute Founding Member Rudolf Jaenisch’s lab have studied Rett Syndrome for many years in order to understand the biological mechanisms that cause disease symptoms, and to identify possible avenues for treatments or a cure. Jaenisch and colleagues have gained many insights into the biology of Rett syndrome and developed tools that can rescue neurons from Rett syndrome symptoms in lab models.

However, much about the biology of Rett Syndrome remains unknown. New research from Jaenisch and postdoc in his lab Danielle Tomasello focuses on an understudied question: how Rett Syndrome affects cell types in the human brain other than neurons. Specifically, Tomasello investigated the effects of Rett Syndrome on astrocytes, a type of brain cell that supports and provides energy for neurons. The work, shared in the journal Scientific Reports on September 6, details changes that occur in Rett syndrome astrocytes, in particular in relation to their mitochondria, and shows how these changes directly impact neurons. The findings provide a new framework for thinking about Rett Syndrome and possible new avenues for therapies.

“By considering Rett Syndrome from a different perspective, this project expands our understanding of a multifaceted and thus far incurable disease,” says Jaenisch, who is also a professor of biology at the Massachusetts Institute of Technology.

Energy metabolism in Rett Syndrome

Mitochondria are organelles that generate energy, which cells use to carry out their functions, and mitochondrial dysfunction was known to occur in Rett Syndrome. Jaenisch and Tomasello found that mitochondria in astrocytes are particularly affected, even more so than mitochondria in neurons. Tomasello grew human stem-cell-derived astrocytes in 2D cultures and also grew 3D organoids: mini brain-like tissues that contain multiple cell types growing in a structure that resembles actual brain anatomy. This approach allowed Tomasello to use human cells, rather than an animal model, and to study how cells behave within a brain-like environment.

When the researchers observed Rett astrocytes grown in these conditions, they found that the mitochondria were misshapen: short, small circles instead of large, long ovals. Additional studies showed evidence of the mitochondria experiencing stress and not being able to generate enough energy through their usual processes. The mitochondria did not have enough of the typical proteins they use to make energy, and so began to break down the cell’s supply of the building blocks of proteins, amino acids, for parts to make up for the missing material. Additionally, the researchers observed an increase in reactive oxygen species, byproducts of mitochondrial metabolism that are toxic to the cell.

Further experiments suggested that the cells try to compensate for this mitochondrial stress by increasing transcription of mitochondrial genes. For example, Tomasello found that regions of DNA called promoters that can increase expression of key mitochondrial genes were more open for the cell to use in Rett astrocytes. Altogether, these findings paint a picture of severe mitochondrial dysfunction in Rett astrocytes.

Although mitochondria in Rett neurons did not have such severe defects, astrocytes and neurons have a close relationship. Not only do neurons rely on astrocytes to supply them with energy, they even accept mitochondria from astrocytes to use for themselves. Jaenisch and Tomasello found that neurons take up dysfunctional mitochondria from Rett astrocytes at a higher rate than they take up mitochondria from unaffected astrocytes. This means that the effects of Rett syndrome on astrocytes have a direct effect on neurons: the dysfunctional mitochondria from the astrocytes end up in the neurons, where they cause damage. Tomasello took mitochondria from Rett astrocytes and placed them on both healthy and Rett neurons. In either case, the neurons took up the dysfunctional mitochondria in large numbers and then experienced significant problems. The neurons entered a hyperexcitable state that is ultimately toxic to the brain. The neurons also contained higher levels of reactive oxygen species, the toxic byproducts of mitochondrial metabolism, which can cause widespread damage. These effects occurred even in otherwise healthy neurons that did not themselves contain a Rett-causing MECP2 mutation.

“This shows that in order to understand Rett Syndrome, we need to look beyond what’s happening in neurons to other cell types,” Tomasello says.

Learning about the role that astrocytes play in Rett Syndrome could provide new avenues for therapies. The researchers found that supplying affected astrocytes with healthy mitochondria helped them to recover normal mitochondrial function. This suggests to Tomasello that one possibility for future Rett Syndrome therapies could be something that either targets mitochondria, or supplies additional mitochondria through the bloodstream.

Together, these insights and their possible medical implications demonstrate the importance of taking a broader look at the foundational biology underlying a disease.

No detail too small

For Sarah Sterling, the new director of the Cryo-Electron Microscopy facility at MIT.nano, better planning and more communication leads to better science.

Nikole L. Fendler | Department of Biology
September 6, 2024

Sarah Sterling, director of the Cryo-Electron Microscopy, or Cryo-EM, core facility, often compares her job to running a small business. Each day brings a unique set of jobs ranging from administrative duties and managing facility users to balancing budgets and maintaining equipment.

Although one could easily be overwhelmed by the seemingly never-ending to-do list, Sterling finds a great deal of joy in wearing so many different hats. One of her most essential tasks involves clear communication with users when the delicate instruments in the facility are unusable because of routine maintenance and repairs.

“Better planning allows for better science,” Sterling says. “Luckily, I’m very comfortable with building and fixing things. Let’s troubleshoot. Let’s take it apart. Let’s put it back together.”

Out of all her duties as a core facility director, she most looks forward to the opportunities to teach, especially helping students develop research projects.

“Undergraduate or early-stage graduate students ask the best questions,” she says. “They’re so curious about the tiny details, and they’re always ready to hit the ground running on their projects.”

A non-linear scientific journey

When Sterling enrolled in Russell Sage College, a women’s college in New York, she was planning to pursue a career as a physical therapist. However, she quickly realized she loved her chemistry classes more than her other subjects. She graduated with a bachelor of science degree in chemistry and immediately enrolled in a master’s degree program in chemical engineering at the University of Maine.

Sterling was convinced to continue her studies at the University of Maine with a dual PhD in chemical engineering and biomedical sciences. That decision required the daunting process of taking two sets of core courses and completing a qualifying exam in each field.

“I wouldn’t recommend doing that,” she says with a laugh. “To celebrate after finishing that intense experience, I took a year off to figure out what came next.”

Sterling chose to do a postdoc in the lab of Eva Nogales, a structural biology professor at the University of California at Berkeley. Nogales was looking for a scientist with experience working with lipids, a class of molecules that Sterling had studied extensively in graduate school.

At the time Sterling joined, the Nogales Lab was at the forefront of implementing an exciting structural biology approach: cryo-EM.

“When I was interviewing, I’d never even seen the type of microscope required for cryo-EM, let alone performed any experiments,” Sterling says. “But I remember thinking ‘I’m sure I can figure this out.’”

Cryo-EM is a technique that allows researchers to determine the three-dimensional shape, or structure, of the macromolecules that make up cells. A researcher can take a sample of their macromolecule of choice, suspend it in a liquid solution, and rapidly freeze it onto a grid to capture the macromolecules in random positions — the “cryo” part of the name. Powerful electron microscopes then collect images of the macromolecule — the EM part of cryo-EM.

The two-dimensional images of the macromolecules from different angles can be combined to produce a three-dimensional structure. Structural information like this can reveal the macromolecule’s function inside cells or inform how it differs in a disease state. The rapidly expanding use of cryo-EM has unlocked so many mechanistic insights that the researchers who developed the technology were awarded the 2017 Nobel Prize in Chemistry.

The MIT.nano facility opened its doors in 2018. The open-access, state-of-the-art facility now has more than 160 tools and more than 1,500 users representing nearly every department at MIT. The Cryo-EM facility lives in the basement of the MIT.nano building and houses multiple electron microscopes and laboratory space for cryo-specimen preparation.

Thanks to her work at UC Berkeley, Sterling’s career trajectory has long been intertwined with the expanding use of cryo-EM in research. Sterling anticipated the need for experienced scientists to run core facilities in order to maintain the electron microscopes needed for cryo-EM, which range in cost from a staggering $1 million to $10 million each.

After completing her postdoc, Sterling worked at the Harvard University cryo-EM core facility for five years. When the director position for the MIT.nano Cryo-EM facility opened, she decided to apply.

“I like that the core facility at MIT was smaller and more frequently used by students,” Sterling says. “There’s a lot more teaching, which is a challenge sometimes, but it’s rewarding to impact someone’s career at such an early stage.”

A focus on users

When Sterling arrived at MIT, her first initiative was to meet directly with all the students in research labs that use the core facility to learn what would make using the facility a better experience. She also implemented clear and standard operating procedures for cryo-EM beginners.

“I think being consistent and available has really improved users’ experiences,” Sterling says.

The users themselves report that her initiatives have proven highly successful — and have helped them grow as scientists.

“Sterling cultivates an environment where I can freely ask questions about anything to support my learning,” says Bonnie Su, a frequent Cryo-EM facility user and graduate student from the Vos lab.

But Sterling does not want to stop there. Looking ahead, she hopes to expand the facility by acquiring an additional electron microscope to allow more users to utilize this powerful technology in their research. She also plans to build a more collaborative community of cryo-EM scientists at MIT with additional symposia and casual interactions such as coffee hours.

Under her management, cryo-EM research has flourished. In the last year, the Cryo-EM core facility has supported research resulting in 12 new publications across five different departments at MIT. The facility has also provided access to 16 industry and non-MIT academic entities. These studies have revealed important insights into various biological processes, from visualizing how large protein machinery reads our DNA to the protein aggregates found in neurodegenerative disorders.

If anyone wants to conduct cryo-EM experiments or learn more about the technique, Sterling encourages anyone in the MIT community to reach out.

“Come visit us!” she says. “We give lots of tours, and you can stop by to say hi anytime.”

RNA processing and gene expression governing

Renee Barbosa, a Schimmel scholar and a graduate student in the Soto-Feliciano Lab, uses a multidisciplinary approach to understand the epigenetic factors in gene expression.

Bendta Schroeder | Koch Institute
July 29, 2024

Professor Emeritus of Biology Paul Schimmel PhD ’67 and his wife Cleo Schimmel are among the biggest champions and supporters of graduate students conducting life science research in the Department of Biology at MIT, as well as in departments such as the Department of Brain and Cognitive Sciences, the Department of Biological Engineering, and the Department of Chemistry, and in cross-disciplinary degree programs including the Computational and Systems Biology Program, the Molecular and Cellular Neuroscience Program, and the Microbiology Graduate Program. In addition to the Cleo and Paul Schimmel (1967) Scholars Fund to support graduate women students in the Department of Biology, in 2021, the Schimmels established the MIT Schimmel Family Program for Life Sciences.

Their generous pledge of $50 million in matching funds called for other donors to join them in supporting the training of graduate students who will tackle some of the world’s most urgent challenges. Driven by their unwavering belief that graduate students are the driving force behind much life science research and witnessing a decline in federal funding for graduate education, the Schimmel family established their one-to-one match program. They reached the ambitious goal of $100 million in endowed support in just two years.

The discovery that mutations in genes can drive cancer revolutionized cancer research. In the decades following the identification of the first “oncogene” in a chicken retrovirus in 1970 and the first human oncogene in 1982 by Robert Weinberg at MIT’s Center for Cancer Research, scientists uncovered hundreds more oncogenes, transformed our understanding of how cancer begins and progresses, and developed sophisticated gene-targeted cancer therapies.

A majority of oncogenes were identified in factors controlling cell signaling, proliferation, and differentiation. However, a growing understanding of epigenetics has shown that many cancers, such as some leukemias and sarcomas, are not driven by mutations to these factors themselves, but by disruptions to the molecular pathways that regulate their expression. About 10 percent of all leukemias are driven by abnormal versions of the protein MLL1, one cog in the epigenetic machinery controlling these factors.

Renee Barbosa, a graduate student in the laboratory of Howard S. (1953) and Linda B. Stern Career Development Professor Yadira Soto-Feliciano in the Department of Biology, is joining this next wave of research, using leukemia as a model. A member of MIT’s Koch Institute for Integrative Cancer Research, Soto-Feliciano and her lab study chromatin, the densely coiled structures of DNA and scaffolding proteins that make up our genomes and help ensure genes are expressed at the right times and in the right amounts.

Barbosa focuses on the role of RNA processing and the precisely choreographed alterations to chromatin that govern gene expression. RNA molecules serve as messengers between DNA and its final product, protein, and are subject to extensive processing and regulation. However, not much is known about the interplay between RNA processing and epigenetic machinery, particularly in cancer.

“I hope that my work will uncover additional layers of complexity in the dynamic landscape of gene regulation,” says Barbosa. “It might also identify new mechanisms that can be targeted to help treat leukemia and other cancers.”

Before Barbosa arrived at the Soto-Feliciano Lab, she was already steeped in the molecular intricacies of cancer.

While at the University of Pennsylvania, she earned a BA in biochemistry and biophysics concurrently with a master’s degree in chemistry. Early on, she joined the lab of Ronen Marmorstein, which used molecular approaches to characterize MEK and ERK, two cancer-relevant members of a class of signaling proteins. Upon starting graduate school, she was excited to branch out into other disciplines.

Barbosa has always taken every opportunity she can to learn. Beginning in grade school, science and math were her favorite subjects, but she also explored music, dance, and foreign languages. At the University of Pennsylvania, she even squeezed in a minor in neuroscience.

With its interdisciplinary approach, the Soto-Feliciano Lab provides Barbosa ample opportunities to learn. Because epigenetic factors can elude traditional approaches, the Soto-Feliciano Lab uses a multidisciplinary strategy, ranging from molecular, to large-scale omics analyses, to disease modeling.

“When I was a grad student, we saw the arrival of powerful new massive sequencing and gene editing technologies — and were enabled to ask big new questions,” says Soto- Feliciano. “I am excited that Renee will have even more resources and opportunities, as we enter the next stage of cancer genetics and epigenetics.”

With the support of a Schimmel Fellowship, Barbosa will be ready to take advantage of new developments in her field.

“Support for research early on in graduate school is an incredible opportunity,” says Barbosa. “It means time to delve deep into the literature of the field and identify challenging open questions that I can pursue in my project. Though exploring these unknown areas requires taking bigger risks, I hope that we will get invaluable insight from an understanding of these nuanced and complex mechanisms.”

Back to the basics of gene regulation

Graduate student and Schimmel Scholar Annette Jun Diao uses a minimal system to parse the mechanisms underlying gene expression

Lillian Eden | Department of Biology
July 29, 2024

Professor Emeritus of Biology Paul Schimmel PhD ’67 and his wife Cleo Schimmel are among the biggest champions and supporters of graduate students conducting life science research in the Department of Biology at MIT, as well as in departments such as the Department of Brain and Cognitive Sciences, the Department of Biological Engineering, and the Department of Chemistry, and in cross-disciplinary degree programs including the Computational and Systems Biology Program, the Molecular and Cellular Neuroscience Program, and the Microbiology Graduate Program. In addition to the Cleo and Paul Schimmel (1967) Scholars Fund to support graduate women students in the Department of Biology, in 2021, the Schimmels established the MIT Schimmel Family Program for Life Sciences.

Their generous pledge of $50 million in matching funds called for other donors to join them in supporting the training of graduate students who will tackle some of the world’s most urgent challenges. Driven by their unwavering belief that graduate students are the driving force behind much life science research and witnessing a decline in federal funding for graduate education, the Schimmel family established their one-to-one match program. They reached the ambitious goal of $100 million in endowed support in just two years.

Annette Jun Diao’s mother loves to tell the story of Diao’s childhood aversion to the study of life — the gross and the squishy. Unlike some future biologists, Diao wasn’t the type to stomp through creeks or investigate the life of frogs. Instead, she was interested in astronomy and only ended up in a high school biology class because of a bureaucratic snafu. The physics course she’d been hoping to take was canceled due to low enrollment, and she was informed molecular biology was being offered instead.

She attended the University of Toronto and joined the molecular genetics department because of the numerous opportunities for hands-on research. She’s now a third-year graduate student in the Department of Biology at MIT.

“I’m fascinated by the mechanisms that underlie the regulation of gene expression,” Diao says. “All of our genetic information is in DNA, and that DNA is an actual molecule with chemical properties that allow it to be passed from one generation to the next.”

Every cell in our bodies contains a genome of approximately 20,000 genes, but the cells in our retinas are vastly different than the cells in our hearts — not all genes are in action simultaneously, and cell fates vary depending on how which genes are active.

“What is really awesome about the department — and what was attractive to me when I was applying to graduate school — is that I wasn’t sure exactly what methods I wanted to use to answer the questions I was interested in,” Diao says. “A huge advantage of the program was that I had a lot to choose from.”

Diao chose to pursue her thesis work with Seychelle Vos, the Robert A. Swanson (1969) Career Development Professor of Life Sciences and HHMI Freeman Hrabowski Scholar. Diao has been recognized with a Natural Sciences and Engineering Research Council of Canada Fellowship, which is similar to a National Science Foundation graduate fellowship in the United States.

Vos’s lab is generally interested in understanding how transcription is regulated, the interplay of genome organization and gene expression, and the molecular machinery involved. Diao has been working with an enzyme called RNA polymerase II (RNAP II), the molecular machine that reads DNA and creates an RNA copy called mRNA. That mRNA goes on to be read by ribosomes to create proteins.

Many questions remain about RNAP II, including what signals instruct it to begin transcription and, once engaged, whether it will transcribe and how quickly it moves.

RNAP II doesn’t work alone. Diao is working to understand how a transcription factor called negative elongation factor associates with RNAP II and whether the DNA sequence affects that interaction.

Within the broader context of the genome, DNA is packaged extremely tightly; if it were allowed to unfold, its total length could stretch from Cambridge to Connecticut. What RNAP II has access to at any given time is therefore quite restricted, which Diao is also exploring.

She has been exploring this topic in what she refers to as a “reductionist approach.” By creating a minimal system — a strand of DNA and the precise addition of certain other isolated components — she can potentially parse out what ingredients and what sequence of events are essential “in order to really get to the nitty-gritty of how genes are regulated.”

Outside of her work in the lab, Diao is part of BioREFS, a peer support group for graduate students, and gwiBio. Both organizations bring members of the department together for scientific talks and socializing activities outside of the lab, and gwiBio also participates in community outreach.

Diao is also a Schimmel Scholar, supported by Professor Emeritus of Biology Paul Schimmel PhD ’67 and his wife Cleo Schimmel.

“It was really great to learn that I was being supported by a scientist who has done a lot of awesome work that’s relevant to my world,” Diao says.

“It is awesome that they are so committed to supporting the graduate program at MIT, especially when federal resources have become more limited,” Vos says. “With their support, our lab can train basic scientists who can then use their knowledge to transform our study of disease. I hope others follow Paul and Cleo’s example.”

Whitehead Institute researchers uncover a new clue toward understanding the molecular basis of Parkinson’s disease

In Parkinson's disease, a mutation that causes protein misfolding can also turn the brain’s immune cells from friends to foes, possibly accelerating the progression of the disease. New Research from the Jaenisch Lab aims to uncover mechanisms that go awry in the brain, which may inform the development of new therapies that can halt or even reverse the progression of neurological conditions such as Parkinson's.

Shafaq Zia | Whitehead Institute
August 29, 2024

Dopamine is more than the “rush molecule”. This chemical messenger, produced by neurons in the midbrain, acts as a traffic controller that regulates the flow of electrical signals between neurons, assisting with brain functions like cognition, attention, movement, and behavior. But, in instances of Parkinson’s disease (PD), a progressive brain disorder, dopamine-producing neurons begin to die at an unprecedented rate, leading to dwindling levels of this vital chemical and impaired neural communication.

The lab of Whitehead Institute’s Founding Member Rudolf Jaenisch studies genetic and epigenetic factors — changes in gene expression that control which genes are turned on and off, and to what extent, without altering the DNA sequence itself — underlying neurological disorders like PD, Alzheimer’s disease, and Rett Syndrome. Their work aims to uncover the mechanisms that go awry in the brain, which may inform the development of new therapies that can halt or even reverse the progression of these conditions.

In their latest work, Jaenisch and former postdoctoral associate Marine Krzisch examine how a mutation in the gene that encodes for alpha-synuclein, a protein regulating the release of dopamine, affects the resident immune cells of the brain called microglia. The researchers’ detailed findings, published in the journal Biological Psychiatry on August 29, reveal that the mutation renders microglia extremely sensitive, worsening the problem of inflammation in the brain and potentially exacerbating damage to neurons in Parkinson’s disease.

“In fact, even when these mutant microglia are transplanted into a healthy, young brain, they have heightened activation upon stimulation, and low levels of the protective antioxidant catalase,” Krzisch says. “This tells us that in Familial Parkinson’s disease, which is due to genetic mutations, these microglia may be playing an important role in neuron degeneration.”

When nature’s origami falters

The human body is home to tens of thousands of unique proteins, each essential for processes sustaining life. These proteins are composed of linear chains of smaller building blocks called amino acids that are linked together in a specific sequence. For the proteins to perform their functions, the amino acid chains must crumple, rotate, and twist into stable three-dimensional structures. The stakes are high — just as precise folds and creases are crucial to the art of origami, even minor errors in the protein folding process can result in dysfunctional proteins that contribute to disease.

To date, scientists have identified over 20 causative genes in which mutations can result in Familial Parkinson’s disease, a rare, genetically inherited form of PD affecting individuals under or around the age of 50. Among them is SNCA, which encodes for alpha-synuclein, a small protein abundant in dopamine-producing neurons.

The A53T mutation in SNCA promotes the formation of dysfunctional alpha-synuclein proteins that clump together — almost like a ball of yarn — within dopamine-producing neurons. The accumulation of these protein clumps, also known as Lewy bodies, triggers inflammatory signaling in the brain, eventually killing the affected neurons. However, prior research has also shown that the A53T mutation accelerates the progression of PD, or the rate at which neurons die, although the full molecular mechanisms underlying this process are not yet fully understood.

To uncover pathways involved in this progression, researchers in the Jaenisch Lab turned their attention to star-shaped patrollers called microglia that protect the brain from foreign invaders and respond to injuries, including protein aggregates within neurons. This immune response includes activated microglia trying to clear out Lewy bodies by digesting them, recruiting additional immune cells to the site of neurons with protein aggregates, and even killing off diseased neurons to limit damage to the brain.

But these friends can quickly turn to foes. Over-activated microglia can also degrade healthy neurons in the brain, prompting Jaenisch, Krzisch, and colleagues to investigate if excessive microglia activation is one pathway that contributes to progression in PD.

Microglia go rogue

To explore how the A53T mutation in the SNCA gene affects microglia function in PD, scientists at the Jaenisch Lab began by growing human myeloid precursors — the cells that eventually develop into microglia — in lab culture and transplanting them into the brains of immune-deprived mice.

Given the complexity of the brain, it’s common for researchers to study brain cells in the Petri dish. “But in cell cultures, microglia do not have the same morphology [form] as in the brain, show signs of chronic activation, and they don’t survive for a very long time,” says Krzisch. “When we transplant them in mice, the precursors differentiate into microglia that look and function like those in the human brain, and survive for the mouse’s lifespan.”

Using this method, the researchers compared the gene expression profiles of A53T-mutant microglia with those that did not carry the mutation, revealing differences in pathways linked to inflammation, microglia activation, and DNA repair. Additionally, when A53T-mutant microglia were exposed to an immune activator called lipopolysaccharide, they exhibited a heightened inflammatory response compared to non-mutant microglia.

In fact, even in non-inflammatory conditions, A53T-mutant microglia had decreased expression of catalase, an enzyme that helps break down harmful reactive oxygen species produced in response to protein aggregates in PD.

Understanding the molecular basis of progression in PD is challenging, which explains why there are currently no drugs to alter the disease’s course. With these findings in hand, researchers at the Jaenisch Lab are now eager to explore how factors like aging also influence microglia function and contribute to an increased rate of progression in PD.

“Overactivation of microglia isn’t the only cause of neuron death in Parkinson’s,” says Jaenisch. “But if we can decrease their activation, it will help us get to the point where we can slow down or actually stop the disease.”

 

Pursuing the secrets of a stealthy parasite

By unraveling the genetic pathways that help Toxoplasma gondii persist in human cells, Sebastian Lourido hopes to find new ways to treat toxoplasmosis.

Anne Trafton | MIT News
August 25, 2024

Toxoplasma gondii, the parasite that causes toxoplasmosis, is believed to infect as much as one-third of the world’s population. Many of those people have no symptoms, but the parasite can remain dormant for years and later reawaken to cause disease in anyone who becomes immunocompromised.

Why this single-celled parasite is so widespread, and what triggers it to reemerge, are questions that intrigue Sebastian Lourido, an associate professor of biology at MIT and member of the Whitehead Institute for Biomedical Research. In his lab, research is unraveling the genetic pathways that help to keep the parasite in a dormant state, and the factors that lead it to burst free from that state.

“One of the missions of my lab to improve our ability to manipulate the parasite genome, and to do that at a scale that allows us to ask questions about the functions of many genes, or even the entire genome, in a variety of contexts,” Lourido says.

There are drugs that can treat the acute symptoms of Toxoplasma infection, which include headache, fever, and inflammation of the heart and lungs. However, once the parasite enters the dormant stage, those drugs don’t affect it. Lourido hopes that his lab’s work will lead to potential new treatments for this stage, as well as drugs that could combat similar parasites such as a tickborne parasite known as Babesia, which is becoming more common in New England.

“There are a lot of people who are affected by these parasites, and parasitology often doesn’t get the attention that it deserves at the highest levels of research. It’s really important to bring the latest scientific advances, the latest tools, and the latest concepts to the field of parasitology,” Lourido says.

A fascination with microbiology

As a child in Cali, Colombia, Lourido was enthralled by what he could see through the microscopes at his mother’s medical genetics lab at the University of Valle del Cauca. His father ran the family’s farm and also worked in government, at one point serving as interim governor of the state.

“From my mom, I was exposed to the ideas of gene expression and the influence of genetics on biology, and I think that really sparked an early interest in understanding biology at a fundamental level,” Lourido says. “On the other hand, my dad was in agriculture, and so there were other influences there around how the environment shapes biology.”

Lourido decided to go to college in the United States, in part because at the time, in the early 2000s, Colombia was experiencing a surge in violence. He was also drawn to the idea of attending a liberal arts college, where he could study both science and art. He ended up going to Tulane University, where he double-majored in fine arts and cell and molecular biology.

As an artist, Lourido focused on printmaking and painting. One area he especially enjoyed was stone lithography, which involves etching images on large blocks of limestone with oil-based inks, treating the images with chemicals, and then transferring the images onto paper using a large press.

“I ended up doing a lot of printmaking, which I think attracted me because it felt like a mode of expression that leveraged different techniques and technical elements,” he says.

At the same time, he worked in a biology lab that studied Daphnia, tiny crustaceans found in fresh water that have helped scientists learn about how organisms can develop new traits in response to changes to their environment. As an undergraduate, he helped develop ways to use viruses to introduce new genes into Daphnia. By the time he graduated from Tulane, Lourido had decided to go into science rather than art.

“I had really fallen in love with lab science as an undergrad. I loved the freedom and the creativity that came from it, the ability to work in teams and to build on ideas, to not have to completely reinvent the entire system, but really be able to develop it over a longer period of time,” he says.

After graduating from college, Lourido spent two years in Germany, working at the Max Planck Institute for Infection Biology. In Arturo Zychlinksy’s lab, Lourido studied two bacteria known as Shigella and Salmonella, which can cause severe illnesses, including diarrhea. His studies there helped to reveal how these bacteria get into cells and how they modify the host cells’ own pathways to help them replicate inside cells.

As a graduate student at Washington University in St. Louis, Lourido worked in several labs focusing on different aspects of microbiology, including virology and bacteriology, but eventually ended up working with David Sibley, a prominent researcher specializing in Toxoplasma.

“I had not thought much about Toxoplasma before going to graduate school,” Lourido recalls. “I was pretty unaware of parasitology in general, despite some undergrad courses, which honestly very superficially treated the subject. What I liked about it was here was a system where we knew so little — organisms that are so different from the textbook models of eukaryotic cells.”

Toxoplasma gondii belongs to a group of parasites known as apicomplexans — a type of protozoans that can cause a variety of diseases. After infecting a human host, Toxoplasma gondii can hide from the immune system for decades, usually in cysts found in the brain or muscles. Lourido found the organism especially intriguing because as a 17-year-old, he had been diagnosed with toxoplasmosis. His only symptom was swollen glands, but doctors found that his blood contained antibodies against Toxoplasma.

“It is really fascinating that in all of these people, about a quarter to a third of the world’s population, the parasite persists. Chances are I still have live parasites somewhere in my body, and if I became immunocompromised, it would become a big problem. They would start replicating in an uncontrolled fashion,” he says.

A transformative approach

One of the challenges in studying Toxoplasma is that the organism’s genetics are very different from those of either bacteria or other eukaryotes such as yeast and mammals. That makes it harder to study parasitic gene functions by mutating or knocking out the genes.

Because of that difficulty, it took Lourido his entire graduate career to study the functions of just a couple of Toxoplasma genes. After finishing his PhD, he started his own lab as a fellow at the Whitehead Institute and began working on ways to study the Toxoplasma genome at a larger scale, using the CRISPR genome-editing technique.

With CRISPR, scientists can systematically knock out every gene in the genome and then study how each missing gene affects parasite function and survival.

“Through the adaptation of CRISPR to Toxoplasma, we’ve been able to survey the entire parasite genome. That has been transformative,” says Lourido, who became a Whitehead member and MIT faculty member in 2017. “Since its original application in 2016, we’ve been able to uncover mechanisms of drug resistance and susceptibility, trace metabolic pathways, and explore many other aspects of parasite biology.”

Using CRISPR-based screens, Lourido’s lab has identified a regulatory gene called BFD1 that appears to drive the expression of genes that the parasite needs for long-term survival within a host. His lab has also revealed many of the molecular steps required for the parasite to shift between active and dormant states.

“We’re actively working to understand how environmental inputs end up guiding the parasite in one direction or another,” Lourido says. “They seem to preferentially go into those chronic stages in certain cells like neurons or muscle cells, and they proliferate more exuberantly in the acute phase when nutrient conditions are appropriate or when there are low levels of immunity in the host.”

Uphill battles: Across the country in 75 days

Amulya Aluru ’23, MEng ’24 and the MIT Spokes have spent the summer spreading science, over 3,000 miles on two wheels.

Lillian Eden | Department of Biology
August 22, 2024

Amulya Aluru ’23, MEng ’24, will head to the University of California at Berkeley for a PhD in molecular and cell biology PhD this fall. Aluru knows her undergraduate 6-7 major and MEng program, where she worked on a computational project in a biology lab, have prepared her for the next step of her academic journey.

“I’m a lot more comfortable with the unknown in terms of research — and also life,” she says. “While I’ve enjoyed what I’ve done so far, I think it’s equally valuable to try and explore new topics. I feel like there’s still a lot more for me to learn in biology.”

Unlike many of her peers, however, Aluru won’t reach the San Francisco Bay Area by car, plane, or train. She will arrive by bike — a journey she began in Washington just a few days after receiving her master’s degree.

Showing that science is accessible

Spokes is an MIT-based nonprofit that each year sends students on a transcontinental bike ride. Aluru worked for months with seven fellow MIT students on logistics and planning. Since setting out, the team has bonded over their love of memes and cycling-themed nicknames: Hank “Handlebar Hank” Stennes, Clelia “Climbing Cleo” Lacarriere, Varsha “Vroom Vroom Varsha” Sandadi, Rebecca “Railtrail Rebecca” Lizarde, JD “JDerailleur Hanger” Hagood, Sophia “Speedy Sophia” Wang, Amulya “Aero Amulya” Aluru, and Jessica “Joyride Jess” Xu. The support minivan, carrying food, luggage, and occasionally injured or sick cyclists, even earned its own nickname: “Chrissy”, short for Chrysler Pacifica.

“I really wanted to do something to challenge myself, but not in a strictly academic sense,” Aluru says of her decision to join the team and bike more than 3,000 miles this summer.

The Spokes team is not biking across the country solely to accomplish such a feat. Throughout their journey, they’ll be offering a variety of science demonstrations, including making concrete with Rice Krispies, demonstrating the physics of sound, using 3D printers, and, in Aluru’s case, extracting DNA from strawberries.

“We’re going to be in a lot of really different learning environments,” she says. “I hope to demonstrate that science can be accessible, even if you don’t have a lab at your disposal.”

These demonstrations have been held in venues such as a D.C. jail, a space camp, and libraries and youth centers across the country; their learning festivals were even featured on a local news channel in Kentucky.

Some derailments

The team was beset with challenges from the first day they started their journey. Aluru’s first day on the road involved driving to every bike shop and REI store in the D.C. metro area to purchase bike computers for navigation because the ones the team had already purchased would only display maps of Europe.

Four days in and four Chrysler Pacificas later — the first was unsafe due to bald tires, the second made a weird sound as they pulled out of the rental lot, and the third’s gas pedal stopped working over 50 miles away from the nearest rental agency — the team was back together again in Waynesboro, Virginia, for the first time since they’d set out.

Since then, they’ve had run-ins with local fauna — including mean dogs and a meaner turtle — attempted to repair a tubeless bike that was not, in fact, tubeless, and slept in Chrissy the minivan after their tents got soaked and blew away.

Although it hasn’t all been smooth riding, the team has made time for fun. They’ve perfected the art of eating a Clif bar while on two wheels, played around on monkey bars in Colorado, met up with Stanford Spokes, enjoyed pounds of ice cream, and downed gallons of lattes.

The team prioritized routes on bike trails, rather than highways, as much as possible. Their teaching activities are scheduled between visits to National Parks like Tahoe, Zion, Bryce Canyon, Arches, and touring and hiking places like Breaks Interstate Park, Mammoth Cave, and the Collegiate Peaks.

Aluru says she’s excited to see parts of the country she’s never visited before, and experience the terrain under her own power — except for breaks when it’s her turn to drive Chrissy.

Rolling with the ups and downs

Aluru was only a few weeks into her first Undergraduate Research Opportunities Program project in the late professor Angelika Amon’s lab when the Covid-19 pandemic hit, quickly transforming her wet lab project into a computational one. David Waterman, her postdoc mentor in the Amon Lab, was trained as a biologist, not a computational scientist. Luckily, Aluru had just taken two computer science classes.

“I was able to have a big hand in formulating my project and bouncing ideas off of him,” she recalls. “That helped me think about scientific questions, which I was able to apply when I came back to campus and started doing wet lab research again.”

When Aluru returned to campus, she began work in the Page Lab at the Whitehead Institute for Biomedical Research. She continued working there for the rest of her time at MIT, first as an undergraduate student and then as an MEng student.

The Page Lab’s work primarily concerns sex differences and how those differences play out in genetics, development, and disease — and the Department of Electronic Engineering and Computer Science, which oversees the MEng program, allows students to pursue computational projects across disciplines, no matter the department.

For her MEng work, Aluru looked at sex differences in human height, a continuation of a paper that the Page Lab published in 2019. Height is an easily observable human trait and, from previous research, is known to be sex-biased across at least five species. Genes that have sex-biased expression patterns, or expression patterns that are higher or lower in males compared to females, may play a role in establishing or maintaining these sex differences. Through statistical genetics, Aluru replicated the findings of the earlier paper and expanded them using newly published datasets.

“Amulya has had an amazing journey in our department,” says David Page, professor of biology and core member of the Whitehead Institute. “There is simply no stopping her insatiable curiosity and zest for life.”

Working with the lab as a graduate student came with more day-to-day responsibility and independence than when she was an undergrad.

“It was a shift I quite appreciated,” Aluru says. “At times it was challenging, but I think it was a good challenge: learning how to structure my research on my own, while still getting a lot of support from lab members and my PI [principal investigator].”

Gearing up for the future

Since departing MIT, Aluru and the rest of the Spokes team have spent their nights camping, sleeping in churches, and staying with hosts. They enjoyed the longest day of the year in a surprisingly “Brooklyn chic” house, spent a lazy afternoon on a river, and pinky-promised to be in each other’s weddings. The team has also been hosted by, met up with, and run into MIT alums as they’ve crossed the country.

As Aluru looks to the future, she admits she’s not exactly sure what she’ll study — but when she reaches the West Coast, she knows she’s not leaving what she’s built through MIT far behind.

“There’s going to be a small MIT community even there — a lot of my friends are in San Francisco, and a few people I know are also going to be at Berkeley,” she says. “I have formed a community at MIT that I know will support me in all my future endeavors.”

Study reveals the benefits and downside of fasting

Fasting helps intestinal stem cells regenerate and heal injuries but also leads to a higher risk of cancer in mice, MIT researchers report.

Anne Trafton | MIT News
August 21, 2024

Low-calorie diets and intermittent fasting have been shown to have numerous health benefits: They can delay the onset of some age-related diseases and lengthen lifespan, not only in humans but many other organisms.

Many complex mechanisms underlie this phenomenon. Previous work from MIT has shown that one way fasting exerts its beneficial effects is by boosting the regenerative abilities of intestinal stem cells, which helps the intestine recover from injuries or inflammation.

In a study of mice, MIT researchers have now identified the pathway that enables this enhanced regeneration, which is activated once the mice begin “refeeding” after the fast. They also found a downside to this regeneration: When cancerous mutations occurred during the regenerative period, the mice were more likely to develop early-stage intestinal tumors.

“Having more stem cell activity is good for regeneration, but too much of a good thing over time can have less favorable consequences,” says Omer Yilmaz, an MIT associate professor of biology, a member of MIT’s Koch Institute for Integrative Cancer Research, and the senior author of the new study.

Yilmaz adds that further studies are needed before forming any conclusion as to whether fasting has a similar effect in humans.

“We still have a lot to learn, but it is interesting that being in either the state of fasting or refeeding when exposure to mutagen occurs can have a profound impact on the likelihood of developing a cancer in these well-defined mouse models,” he says.

MIT postdocs Shinya Imada and Saleh Khawaled are the lead authors of the paper, which appears today in Nature.

Driving regeneration

For several years, Yilmaz’s lab has been investigating how fasting and low-calorie diets affect intestinal health. In a 2018 study, his team reported that during a fast, intestinal stem cells begin to use lipids as an energy source, instead of carbohydrates. They also showed that fasting led to a significant boost in stem cells’ regenerative ability.

However, unanswered questions remained: How does fasting trigger this boost in regenerative ability, and when does the regeneration begin?

“Since that paper, we’ve really been focused on understanding what is it about fasting that drives regeneration,” Yilmaz says. “Is it fasting itself that’s driving regeneration, or eating after the fast?”

In their new study, the researchers found that stem cell regeneration is suppressed during fasting but then surges during the refeeding period. The researchers followed three groups of mice — one that fasted for 24 hours, another one that fasted for 24 hours and then was allowed to eat whatever they wanted during a 24-hour refeeding period, and a control group that ate whatever they wanted throughout the experiment.

The researchers analyzed intestinal stem cells’ ability to proliferate at different time points and found that the stem cells showed the highest levels of proliferation at the end of the 24-hour refeeding period. These cells were also more proliferative than intestinal stem cells from mice that had not fasted at all.

“We think that fasting and refeeding represent two distinct states,” Imada says. “In the fasted state, the ability of cells to use lipids and fatty acids as an energy source enables them to survive when nutrients are low. And then it’s the postfast refeeding state that really drives the regeneration. When nutrients become available, these stem cells and progenitor cells activate programs that enable them to build cellular mass and repopulate the intestinal lining.”

Further studies revealed that these cells activate a cellular signaling pathway known as mTOR, which is involved in cell growth and metabolism. One of mTOR’s roles is to regulate the translation of messenger RNA into protein, so when it’s activated, cells produce more protein. This protein synthesis is essential for stem cells to proliferate.

The researchers showed that mTOR activation in these stem cells also led to production of large quantities of polyamines — small molecules that help cells to grow and divide.

“In the refed state, you’ve got more proliferation, and you need to build cellular mass. That requires more protein, to build new cells, and those stem cells go on to build more differentiated cells or specialized intestinal cell types that line the intestine,” Khawaled says.

Too much of a good thing

The researchers also found that when stem cells are in this highly regenerative state, they are more prone to become cancerous. Intestinal stem cells are among the most actively dividing cells in the body, as they help the lining of the intestine completely turn over every five to 10 days. Because they divide so frequently, these stem cells are the most common source of precancerous cells in the intestine.

In this study, the researchers discovered that if they turned on a cancer-causing gene in the mice during the refeeding stage, they were much more likely to develop precancerous polyps than if the gene was turned on during the fasting state. Cancer-linked mutations that occurred during the refeeding state were also much more likely to produce polyps than mutations that occurred in mice that did not undergo the cycle of fasting and refeeding.

“I want to emphasize that this was all done in mice, using very well-defined cancer mutations. In humans it’s going to be a much more complex state,” Yilmaz says. “But it does lead us to the following notion: Fasting is very healthy, but if you’re unlucky and you’re refeeding after a fasting, and you get exposed to a mutagen, like a charred steak or something, you might actually be increasing your chances of developing a lesion that can go on to give rise to cancer.”

Yilmaz also noted that the regenerative benefits of fasting could be significant for people who undergo radiation treatment, which can damage the intestinal lining, or other types of intestinal injury. His lab is now studying whether polyamine supplements could help to stimulate this kind of regeneration, without the need to fast.

“This fascinating study provides insights into the complex interplay between food consumption, stem cell biology, and cancer risk,” says Ophir Klein, a professor of medicine at the University of California at San Francisco and Cedars-Sinai Medical Center, who was not involved in the study. “Their work lays a foundation for testing polyamines as compounds that may augment intestinal repair after injuries, and it suggests that careful consideration is needed when planning diet-based strategies for regeneration to avoid increasing cancer risk.”

The research was funded, in part, by a Pew-Stewart Trust Scholar award, the Marble Center for Cancer Nanomedicine, the Koch Institute-Dana Farber/Harvard Cancer Center Bridge Project, and the MIT Stem Cell Initiative.

New approach enables a closer look at brain cell organelle

Microglia are involved in brain development, as well as neurodegeneration and brain cancer. A new approach from the Jaenisch Lab allows researchers to isolate and analyze microglia phagosomes.

Greta Friar | Whitehead Institute
August 14, 2024

Microglia are the immune system’s front-line enforcers in the brain. They are cells that patrol the brain and destroy anything harmful that they encounter, from invading bacteria to cellular debris. They also remove plaques and prune dysfunctional synapses between neurons. Microglia eliminate their targets by eating them: they envelope material and seal it in bubble-like organelles called phagosomes. A phagosome can then fuse with other organelles that break down its contents.

Microglial phagosomes play important roles in brain development, brain function and a plethora of brain diseases, including neurodegeneration and brain cancer. Therefore, understanding microglial phagosome biology could help to develop new therapies for currently untreatable brain diseases. However, microglia and their organelles have been difficult to study because existing stem cell and animal models insufficiently resemble microglia in the human brain, and because microglia, as vigilant immune patrollers, react to even subtle stimuli and so experimental conditions can trigger changes in the cells that confound analyses.

To overcome those issues, Whitehead Institute Founding Member Rudolf Jaenisch, also a professor of biology at the Massachusetts Institute of Technology; University of Freiburg Professor of Neuropathology Marco Prinz; and University of Freiburg neuropathologist Emile Wogram, who began this project as a postdoctoral researcher in Jaenisch’s lab, have developed a method to isolate and analyze microglia phagosomes in a rapid, gentle, and unbiased fashion.

In research shared in the journal Immunity on August 15, the researchers describe how they can isolate and profile phagosomes from stem cell-derived microglia and fresh human brain tissue. They also share new insights into phagosome biology in the human brain, regarding synaptic pruning and generation of NAD+, a broadly used molecule in the brain, by microglia.

The method that the researchers developed to isolate phagosomes from cells uses immunoprecipitation, in which antibodies latch on to a specific target protein on an organelle’s surface. When the antibodies are collected, they pull the organelles with them. This technique avoids many chemical perturbations that might alter the microglial profile. Sometimes researchers genetically engineer a target for the antibodies, but in order to isolate phagosomes from human brain tissue, Wogram had to find a naturally expressed target. Eventually, he and colleagues found one: the protein CD68.

The researchers first isolated phagosomes from stem cell-derived microglia. They co-cultured the microglia with other brain cell types to create a more brain-like environment, which led to a better match between brain and stem cell-derived microglia gene expression. They triggered some of the microglia to enter an inflammatory or disease-like state to see how that affected the phagosomes. Additionally, Wogram collaborated with the neurosurgery department at the University of Freiburg to get access to brain tissues immediately after their removal during surgery. He isolated phagosomes from brain tissue within a half hour of its removal, allowing him to profile the organelles before their contents could change much.

The profiles that the researchers built included what proteins and metabolites the phagosomes contained, and the whole-cell gene expression profile. The profiles differed significantly between sets of phagosomes, but the researchers identified a core of consistent proteins, including many known and also some unknown phagosome proteins. The results showed that phagosomes contain sensitive signaling molecules that allow them to react quickly to even subtle environmental stimuli.

Additionally, the protein contents of the co-cultured microglia provided strong evidence that when microglia prune synapses, they predominantly prune the side that sends a signal and not the side that receives one. This insight could be useful for understanding how microglia interact with synapses in health and disease.

The researchers also gained insights into a key metabolic pathway that occurs inside of microglia. In excess, the molecule quinolinic acid can be toxic to neurons; it is implicated as involved in many neurodegenerative diseases. However, cells can use quinolinic acid to make NAD+, a molecule broadly used to carry out essential cellular functions. Microglia are the only brain cells that generate NAD+. Wogram and colleagues found that key steps in this process occur in phagosomes. Phagosomes are therefore necessary both for removing excess quinolinic acid to prevent toxicity and for helping to generate NAD+ in the brain.

Finally, Wogram used brain tissues to compare phagosomes from within a tumor to those in the surrounding healthy tissue. The phagosomes in the tumor contained excess quinolinic acid. Although follow-up studies would be needed to confirm the results, these findings are consistent with research that suggests cancer cells use quinolinic acid to fuel their growth.

Collectively, these findings illuminate aspects of phagosome biology and the roles that phagosomes may play in normal brain development and maintenance, as well as in cancer and neurodegeneration. The researchers also anticipate that their method could prove useful for profiling other organelles, especially when the organelles need to be rapidly isolated from human tissue.

Talented high schoolers excel while they explore the brain

Over six years of operation, pre-college outreach programs administered by Mandana Sassanfar, Senior Lecturer and Director of Diversity and Outreach, have placed seven exceptional pre-college students, often from underserved or underrepresented backgrounds, with research groups in The Picower Institute.

David Orenstein | The Picower Institute for Learning and Memory
August 14, 2024

During the pandemic, when many classes delivered online could barely hold students’ attention, Presley Simelus became captivated by the subject of biology thanks to their boundless curiosity and their uncommonly engaging teacher at Prospect Hill Academy Charter School in Cambridge. Meanwhile for Eli Hanechak, the science bug must have bit her very early. She’s wanted to be a doctor for as long as she can remember and in fifth grade built a model of a space station the size of a car out of duct tape, cardboard and broomsticks.

Not every teenager is expected to want to spend their summer breaks exploring science at a bench in an MIT lab, but each year students like Simelus and Hanechak, who have a distinct passion for research, can bring that to The Picower Institute and other research entities around MIT. Over six years of operation, pre-college outreach programs administered by Mandana Sassanfar, Director of Diversity and Outreach, have placed seven exceptional pre-college students, often from underserved or underrepresented backgrounds, with research groups in The Picower Institute. Despite their relative lack of experience compared to the technicians, graduate students, postdocs and professors around them, the students typically thrive.

“Eli has been a wonderful addition to our lab for the summer,” said Kendyll Burnell, the graduate student in the lab of Professor Elly Nedivi who has been working closely with Hanechak. “She is a hard worker, has caught on to techniques quickly, and is constantly asking excellent questions about science and doing research.”

Simelus, too, has been not only learning but also contributing, said their summer host, Yire Jeong, a postdoc in the lab of Associate Professor Gloria Choi.

“Presley has been amazing in our lab, and I was impressed by Presley’s eagerness to learn so much about neuroscience,” Jeong said. “Even when facing technical difficulties, Presley diligently worked to overcome them and achieved meaningful results.”

‘Dive into it’

Simelus, who hails from Everett, Mass., and will be enrolling in Swarthmore College this fall to study biochemistry, first came to MIT through the Leah Knox Scholars Program. Friends who’d been in the program before encouraged them to apply and they got in. During five weeks last summer Simelus and their cohort of fellow Leah Knox high-schoolers had the geeky pleasure of extracting bacteria out of the Charles River and performing a battery of tests to genetically characterize the novel organisms they found. Sassanfar noted that Simelus did the lab work exceptionally well, which is something she looks for when determining whom she might invite back the next summer to do research in an MIT Brain and Cognitive Sciences or Biology lab.

This spring when it came time for Simelus to decide where they might like to take that opportunity, they chose the Choi lab, which studies how the central nervous systems and immune systems interact, sometimes with consequences relevant to disorders including autism. Those keywords intrigued Simelus but really they made the choice because of the potential to learn something entirely new.

“It was all this stuff I just simply wasn’t familiar with and I wanted to learn more about it,” Simelus said. “With Gloria’s lab I was truly mystified and I wanted to dive into it. That’s the reason I chose it.”

This summer Simelus has been working with Jeong on a study of how brain cell activity differs when mice are sick vs. when they are well. The project has involved imaging neurons in the brain to detect telltale signs of recent activation, expression of a protein called c-fos. Learning about neuroscience and gaining skills like preparing, staining and imaging tissue have been a very fulfilling outcome of the internship, Simelus said.

“I truly have learned so much about neuroscience,” they said. “I feel like the field, anything related to the brain or neuroscience, is always under this sort of veil and nobody really knows what’s going on. But I feel like my time at the Choi lab has really allowed me to see what neuroscience is about. It’s taught be more about the brain itself and also more about different biology techniques and skills I might need.”

Now the only problem, Simelus said, is that there are even more things to be deeply curious about. Simelus feels committed to harnessing the life sciences in some way in the future to sustain human life and experience. And as someone who not only plays the viola but also composes, they’ve begun thinking more about how the brain responds to music.

There will no doubt be many chances to continue exploring these interests at Swarthmore, but during the summer at MIT, Simelus said they’ve expanded their horizons while still hanging out with friends, some of whom have been working in other nearby labs.

“I don’t think I would have changed my summer,” Simelus said.

‘The perfect opportunity’

Hanechak lives in the tiny Western Massachusetts town of Russell (population: 1,643) and commutes 45 minutes to Pope Francis Preparatory School in Springfield, where she is a rising senior.

In her freshman year at a different school, she yearned for an extra challenge so she got involved in science fair. Interested in medicine, but eager for a project in which she could make a difference without having clinical credentials, she chose to work on reducing pollution by developing a microbe-derived enzyme that could biodegrade plastics. She had read about such enzymes in the research literature and learned that they don’t work as well as engineers have hoped. In successive years she has scrounged lab space and general supervision in labs at Westfield State University and UMass Amherst to create and screen beneficial mutations in the enzyme and to synthesize structures that might help the enzyme work better. The enzyme she presented at the International Science and Engineering Fair last year can degrade plastics in 24 hours.

Sasssanfar, who also directs the Massachusetts Junior Academy of Science (MassJAS), learned of Hanechak’s award-winning science fair presentation and invited her to present at the MassJAS symposium, held at MIT last October. Hanechak did so well, Sassanfar said, she earned a spot present at the American Junior Academy of Science meeting (adjacent to the American Association for the Advancement of Science Annual Meeting) in Denver in February. She also earned Sassanfar’s invitation to join a lab this summer at MIT.

Hanechak has long had an MIT pennant on her wall at home and has admired MIT as a place where regardless of one’s background, if one has a passion for science and technology, that’s what matters.

“No one in my family has gone to college and no one has been involved in a science-related career of any kind,” she said. “One of the reasons MIT has always stood out to me is that there are especially great minds here, but they didn’t all come from established families or super prestigious backgrounds or anything like that. They kind of just were able to make their own way.”

Moreover, the chance to come to MIT to learn about the brain in the Nedivi lab seemed like a great step to take toward that longer-term goal of medicine.

“It seemed like the perfect opportunity to start transitioning into what I want my career to look like and to get some experience doing neuroscience research,” Hanechak said. “I’m very glad I’m able to have this summer experience, like learning the techniques. When I go into my college major of neuroscience, I will have a good background of what I’m doing, besides just my environmental research.”

With Burnell, Hanechak is working on finding a DNA promoter specific for a rare but interesting kind of neuron in the visual cortex, where the brain processes what the eyes see. Finding this genetic signature would allow the lab to label these cells and image them under the microscope, so that they could see how the cells contribute to visual processing.

Hanechak acknowledged she was anxious at first about joining a bigger lab with scientists who have much more experience.

“But my entire summer has been incredibly gratifying and exciting—just being able to work in Cambridge, and live in this area, and experience city life, and then also be in a lab environment where it’s so collaborative and everyone’s very friendly,” she said.

For many teens, summer provides a chance to do what they want to do. Simelus and Hanechak chose the opportunity to explore the brain at The Picower Institute and have made the most of it.