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Establishing boundaries of the genetic kind

The pseudoautosomal region (PAR) is a critical area on the Y chromosome that swaps genetic information with the X chromosome. Recent research from the Page Lab reaffirms the location of PAR and offers a refined understanding of where crossover events occur.

Shafaq Zia | Whitehead Institute
October 14, 2024

At first, the X and the Y sex chromosomes seemed like an unlikely pair. But then, researchers, including Whitehead Institute Member David Page, began finding clues that suggested otherwise: identical DNA sequences on the X and Y chromosomes.

Soon, it became clear that the tips of the X and Y chromosomes join together in a tight embrace, swapping genetic material during the process of sperm production from immature male germ cells. This limited area of genetic exchange between the two sex chromosomes is called the pseudoautosomal region (PAR).

But science is an iterative process—a continuous cycle of questioning, testing, and revising knowledge. Last fall, what had long been considered well established in genetics was called into question when new research suggested that the boundary of the PAR might be half a million base pairs away from the accepted location. Given that a typical human gene is about tens of thousands of base pairs, this length would potentially span multiple genes on the X and Y chromosomes, raising serious concerns about the accuracy and validity of decades of scientific literature.

Fortunately, new work from Page, research scientist Daniel Winston Bellott, and colleagues—published Oct. 14 in the American Journal of Human Genetics—offers clarity. In this study, the group re-examines the size of the PAR using sequencing data presented by outside researchers in their 2023 work, alongside decades of genomic resources, and single-cell sequencing of human sperm. Their findings confirm that the location of the boundary to the PAR, as identified by scientists in 1989, still holds true.

“If one is interested in understanding sex differences in health and disease, the boundary of the pseudoautosomal region is arguably the most fundamental landmark in the genome,” says Page, who is also a professor of biology at the Massachusetts Institute of Technology and an Investigator with Howard Hughes Medical Institute. “Had this boundary been multiple genes off, the field would have been shaken to its foundations.”

Dance of the chromosomes

The X and Y chromosomes evolved from an ancestral pair of chromosomes with identical structures. Over time, the Y chromosome degenerated drastically, losing hundreds of functional genes. Despite their differences, the X and Y chromosomes come together during a special type of cell division called male meiosis, which produces sperm cells.

This process begins with the tips of the sex chromosomes aligning side by side like two strands of rope. As the X and Y chromosomes embrace each other, enzymes create breaks in the DNA. These breaks are repaired using the opposite chromosome as a template, linking the X and Y together. About half of the time, an entire segment of DNA, which often contains multiple genes, will cross over onto the opposite chromosome.

The genetic exchange, called recombination, concludes with the X and Y chromosomes being pulled apart to opposite ends of the dividing cell, ensuring that each chromosome ends up in a different daughter cell. “This intricate dance of the X and Y chromosomes is essential to a sperm getting either an X or a Y—not both, and not neither,” says Page.

This way when the sperm—carrying either an X or a Y—fuses with the egg—carrying an X—during fertilization, the resulting zygote has the right number of chromosomes and a mix of genetic material from both parents.

But that’s not all. The swapping of DNA during recombination also allows for the chromosomes to have the same genes but with slight variations. These unique combinations of genetic material across sex chromosomes are key to genetic diversity within a species, enabling it to survive, adapt, and reproduce successfully.

Beyond the region of recombination, the Y chromosome contains genes that are important for sex determination, for sperm production, and for general cellular functioning. The primary sex-defining gene, SRY, which triggers the development of an embryo into a male, is located only 10,000 bases from the boundary of the PAR.

Advancing together

To determine whether the location of this critical boundary on the human sex chromosomes—where they stop crossing over during meiosis and become X-specific or Y-specific—had been misidentified for over three decades, researchers began by comparing publicly-available DNA sequences from the X and the Y chromosomes of seven primate species: humans, chimpanzees, gorillas, orangutans, siamangs, rhesus macaques, and colobus monkeys.

Based on the patterns of crossover between the X and the Y chromosomes of these species, the researchers constructed an evolutionary tree. Upon analyzing how DNA sequences close to and distant from the PAR boundary group together across species, the researchers found a substitution mutation—where a letter in a long string of letters is swapped for a different one—in the DNA of the human X and Y chromosomes. This change was also present in the chimpanzee Y chromosome, suggesting that the mutation originally occurred in the last common ancestor of humans and chimpanzees and was then transferred to the human X chromosome.

“These alignments between various primates allowed us to observe where the X and the Y chromosomes have preserved identity over millions of years and where they have diverged,” says Bellott. “That [pseudoautosomal] boundary has remained unchanged for 25 million years.”

Next, the group studied crossover events in living humans using a vast dataset of single-cell sequencing of sperm samples. They found 795 sperm with clear swapping of genetic material somewhere between the originally proposed boundary of the PAR and the newly-proposed 2023 boundary.

Once these analyses confirmed that the original location of the PAR boundary remains valid, Page and his team turned their attention to data from the 2023 study that contested this 1989 finding. The researchers focused on 10 male genomes assembled by the outside group, which contained contiguous sequences from the PAR.

Since substitutions on the Y chromosome typically occur at a steady rate, but in the PAR, changes on the X chromosome can transfer to the Y through recombination, the researchers compared the DNA sequences from the ten genomes to determine whether they followed the expected steady rate of change or if they varied.

The team found that close to the originally proposed PAR boundary, the DNA sequences changed at a steady rate. But further away from the boundary, the rate of change varied, suggesting that crossover events likely occurred in this region. Furthermore, the group identified several shared genetic differences between the X and the Y chromosomes of these genomes, which demonstrates that recombination has occurred even closer to the PAR boundary than scientists observed in 1989.

“Ironically, instead of contradicting the original boundary, the 2023 work has helped us refine the location of crossover to an even narrower area near the boundary,” says Page.

Thanks to the efforts of Page’s group at Whitehead Institute, our understanding of the PAR is clearer than ever, and business can go on as usual for researchers investigating sex differences in health and disease.

Bat cells possess a unique antiviral mechanism, preventing the SARS-CoV-2 virus from taking control

Bats have the amazing ability to coexist with viruses that are deadly to humans. New work from the Jaenisch Lab uncovers an antiviral mechanism that allows viruses to enter bat cells but prevents them from replicating.

Shafaq Zia | Whitehead Institute
October 14, 2024

Viruses are masters of stealth. From the moment a virus enters the host’s body, it begins hijacking its cells. First, the virus binds to a specific protein on the cell’s surface through a lock-and-key mechanism. This protein, known as a receptor, facilitates the entry of the virus’s genetic material into the cell. Once inside, this genetic code takes over the cell’s machinery, directing it to produce copies of the virus and assemble new viral particles, which can go on to infect other cells. Upon detecting the invasion, the host’s immune system responds by attacking infected cells in hopes of curbing the virus’s spread.

But in bats, this process unfolds differently. Despite carrying several viruses — Marburg, Ebola, Nipah, among others — bats rarely get sick from these infections. It seems their immune systems are highly specialized, allowing them to live with viruses that would typically be deadly in humans, without any clinical symptoms.

Since the onset of the COVID-19 pandemic, the lab of Whitehead Institute Founding Member Rudolf Jaenisch has been investigating the molecular basis of bats’ extraordinary resilience to viruses like SARS-CoV-2. In their latest study, published in the journal PNAS on Oct. 14 , Jaenisch lab postdoc Punam Bisht and colleagues have uncovered an antiviral mechanism in bat cells that allows viruses to enter the cells but prevents them from replicating their genome and completing the hijacking process.

“These cells have elevated expressions of antiviral genes that act immediately, neutralizing the virus before it can spread,” says Jaenisch, a professor of biology at the Massachusetts Institute of Technology. “What’s particularly interesting is that many of these antiviral genes have counterparts, or orthologs in humans.”

Striking a delicate balance

The innate immune system is the body’s first line of defense against foreign invaders like the SARS-CoV-2 virus. This built-in security system is always on alert, responding swiftly — within minutes to hours — to perceived threats.

Upon detecting danger, immune cells rush to the site of infection, where they target the virus with little precision in attempts to slow it down and buy time for the more specialized adaptive immune system to take over. During this process, these cells release small signaling proteins called cytokines, which coordinate the immune response by recruiting additional immune cells and directing them to the battleground.

If the innate immune response alone isn’t sufficient to defeat the virus, it signals the adaptive immune system for support. The adaptive immune system tailors its attacks to the exact pathogen it is fighting and can even keep records of past infections to launch a faster, more aggressive attack the next time it encounters the same pathogen.

But in some infections, the innate immune response can quickly spiral out of control before the adaptive immune response is activated. This phenomenon, called a cytokine storm, is a life-threatening condition characterized by the overproduction of cytokines. These proteins continue to signal the innate immune system for backup even when it’s not necessary, leading to a flood of immune cells at the site of infection, where they inadvertently begin damaging organs and healthy tissues.

Bats, on the other hand, are uniquely equipped to manage viral infections without triggering an overwhelming immune response or allowing the virus to take control. To understand how their innate immune system achieves this delicate balance, Bisht and her colleagues turned their attention to bat cells.

In this study, researchers compared how the SARS-CoV-2 virus replicates in human and bat stem cells and fibroblasts — a type of cell involved in the formation of connective tissue. While fibroblasts are not immune cells, they can secrete cytokines and guide immune response, particularly to help with tissue repair.

After exposing these cells to the SARS-CoV-2 virus for 48 hours, the researchers used a Green Fluorescent Protein (GFP) tag to track the virus’s activity. GFP is a fluorescent protein whose genetic code can be added as a tag to a gene of interest. This causes the products of that gene to glow, providing researchers with a visual marker of where and when the gene is expressed.

They observed that over 80% of control cells — derived from the kidneys of African green monkeys and known to be highly susceptible to SARS-CoV-2 — showed evidence of the virus replicating. In contrast, they did not detect any viral activity in human and bat stem cells or fibroblasts.

In fact, even after introducing the human ACE2 receptor — which SARS-CoV-2 uses to bind and enter cells — into bat cells, the infected bat fibroblasts were able to replicate viral RNA and produce viral proteins, but at much lower levels compared to infected human fibroblasts.

These bat fibroblasts, however, could not assemble these viral proteins into fully infectious virus particles, suggesting an abortive infection, where the virus is able to initiate replication but fails to complete the process and produce progeny viruses.

Using electron microscopy to look inside bat and human cells, they began to understand why: in human cells, SARS-CoV-2 had created special structures called double-membrane vesicles (DMV). These vesicles acted like a bubble, shielding the viral genome from detection and providing it safe space to replicate more effectively. However, these “viral replication factories” were absent in bat fibroblasts.

When the researchers examined the gene expression profiles of these bat fibroblasts and compared them those of infected human cells, they found that although both human and bat cells have genes regulating the release of a type of cytokine called interferons, these genes are already turned on in bat fibroblasts — unlike in human cells — even before virus infection occurs.

These findings suggest that bat cells are in a constant state of vigilance. This allows their innate immune system to stop the SARS-CoV-2 virus in its tracks early on in the replication process before it can entirely hijack cellular machinery.

Surprisingly, this antiviral mechanism does not protect bat cells against all viruses. When the researchers infected bat fibroblasts with Zika virus, the virus was able to replicate and produce new viral particles.

“This means there are still many questions unanswered about how bat cells resist infection,” says Bisht. “COVID-19 continues to circulate, and the virus is evolving quickly. Filling in these gaps in our knowledge will help us develop better vaccines and antiviral strategies.”
The researchers are now focused on identifying the specific genes involved in this antiviral mechanism, and exploring how they interact with the virus during infection.

Picower Events: 2024 Kuggie Vallee Distinguished Lectures and Workshops

Mixing joy and resolve, event celebrates women in science and addresses persistent inequalities

David Orenstein | The Picower Institute for Learning and Memory
October 2, 2024

The Kuggie Vallee Distinguished Lectures and Workshops presented inspiring examples of success, even as the event evoked frank discussions of the barriers that still hinder many women scientists. 

For two days at The Picower Institute for Learning and Memory at MIT, participants in the Kuggie Vallee Distinguished Lectures and Workshops celebrated the success of women in science and shared strategies to persist through, or better yet dissipate, the stiff headwinds women still face in the field.

“Everyone is here to celebrate and to inspire and advance the accomplishments of all women in science,” said host Li-Huei Tsai, Picower Professor in Brain and Cognitive Sciences and director of The Picower Institute, as she welcomed an audience that included scores of students, postdocs and other research trainees. “It is a great feeling to have the opportunity to showcase examples of our successes and to help lift up the next generation.”

Tsai earned the honor of hosting the event after she was named a Vallee Visiting Professor in 2022 by the Vallee Foundation. Foundation President Peter Howley, a professor of pathological anatomy at Harvard, said the global series of lectureships and workshops were created to honor Kuggie Vallee, a former Lesley College Professor who worked to advance the careers of women.

During the program Sept. 24-25, speakers and audience members alike made it clear that helping women succeed requires both recognizing their achievements and resolving to change social structures in which they face marginalization.

Inspiring achievements

Lectures on the first day featured two brain scientists who have each led acclaimed discoveries that have been transforming their fields.

Michelle Monje, a pediatric neuro-oncologist at Stanford whose recognitions include a MacArthur Fellowship, described her lab’s studies of brain cancers in children, which emerge at specific times in development as young brains adapt to their world by wiring up new circuits and insulating neurons with a fatty sheathing called myelin. Monje has discovered that when the precursors to myelinating cells called oligodendrocyte precursor cells harbor cancerous mutations, the tumors that arise—called gliomas—can hijack those cellular and molecular mechanisms. To promote their own growth, gliomas tap directly into the electrical activity of neural circuits by forging functional neuron-to-cancer connections, akin to the “synapse” junctions healthy neurons make with each other. Years of her lab’s studies, often led by female trainees, have not only revealed this insidious behavior (and linked aberrant myelination to many other diseases as well), but also revealed specific molecular factors involved. Those findings, Monje said, present completely novel potential avenues for therapeutic intervention.

“This cancer is an electrically active tissue and that is not how we have been approaching understanding it,” she said.

Erin Schuman, who directs the Max Planck Institute for Brain Research in Frankfurt and has won honors including the Brain Prize, described her groundbreaking discoveries related to how neurons form and edit synapses along the very long branches—axons and dendrites—that give the cells their exotic shapes. Synapses form very far from the cell body where scientists had long thought all proteins, including those needed for synapse structure and activity, must be made. In the mid-1990s Schuman showed that the protein-making process can occur at the synapse and that neurons stage the needed infrastructure—mRNA and ribosomes—near those sites. Her lab has continued to develop innovative tools to build on that insight, cataloging the stunning array of thousands of mRNAs involved, including about 800 that are primarily translated at the synapse, studying the diversity of synapses that arise from that collection, and imaging individual ribosomes such that her lab can detect when they are actively making proteins in synaptic neighborhoods.

Persistent headwinds

While the first day’s lectures showcased examples of women’s success, the second day’s workshops turned the spotlight on the social and systemic hindrances that continue to make such achievements an uphill climb. Speakers and audience members engaged in frank dialogues aimed at calling out those barriers, overcoming them, and dismantling them.

Susan Silbey, Leon and Anne Goldberg Professor of Humanities, Sociology and Anthropology at MIT and Professor of Behavioral and Policy Sciences in the Sloan School of Management, told the group that as bad as sexual harassment and assault in the workplace are, the more pervasive, damaging and persistent headwinds for women across a variety of professions are “deeply sedimented cultural habits” that marginalize their expertise and contributions in workplaces, rendering them invisible to male counterparts, even when they are in powerful positions. High-ranking women in Silicon Valley who answered the “Elephant in the Valley” survey, for instance, reported high rates of many demeaning comments and demeanor,  as well as exclusion from social circles. Even Supreme Court justices are not immune, she noted, citing research showing that for decades female justices have been interrupted with disproportionate frequency during oral arguments at the court. Silbey’s research has shown that young women entering the engineering workforce often become discouraged by a system that appears meritocratic but in which they are often excluded from opportunities to demonstrate or be credited for that merit and are paid significantly less.

“Women’s occupational inequality is a consequence of being ignored, having contributions overlooked or appropriated, of being assigned to lower status roles, while men are pushed ahead, honored and celebrated, often on the basis of women’s work,” Silbey said.

Often relatively small in numbers, women in such workplaces become tokens—visible as different but still treated as outsiders, Silbey said. Women tend to internalize this status, becoming very cautious about their work while some men surge ahead in more cavalier fashion. Silbey and speakers who followed illustrated the effect this can have on women’s careers in science. Kara McKinley, an assistant professor of stem cell and regenerative biology at Harvard, noted that while the scientific career “pipeline” is some areas of science is full of female graduate students and postdocs, only about 20 percent of natural sciences faculty positions are held by women. Strikingly, women are already significantly depleted in the applicant pools for assistant professor positions, she said. Those who do apply tend to wait until they are more qualified than the men they are competing against. McKinley and Silbey each noted that women scientists submit fewer papers to prestigious journals, with Silbey explaining that it’s often because women are more likely to worry that their studies need to tie up every loose end. Yet, said Stacie Weninger, a venture capitalist and president of the F-Prime Biomedical Research Initiative and a former editor at Cell Press, women were also less likely than men to rebut rejections from journal editors, thereby accepting the rejection even though rebuttals sometimes work.

Several speakers including Weninger and Silbey said pedagogy must change to help women overcome a social tendency to couch their assertions in caveats when many men speak with confidence and are therefore perceived as more knowledgeable.

At lunch, trainees sat in small groups with the speakers. They shared sometimes harrowing personal stories of gender-related difficulties in their young careers and sought advice on how to persist and remain resilient. Schuman advised the trainees to report mistreatment, even if they aren’t confident that university officials will be able to effect change, at least to make sure patterns of mistreatment get on the record. Reflecting on discouraging comments she experienced early in her career, Monje advised students to build up and maintain an inner voice of confidence and draw upon it when criticism is unfair.

“It feels terrible in the moment, but cream rises,” Monje said. “Believe in yourself. It will be OK in the end.”

Lifting each other up

Speakers at the conference shared many ideas to help overcome inequalities. McKinley described a program she launched in 2020 to ensure that a diversity of well-qualified women and non-binary postdocs are recruited for and apply for life sciences faculty jobs: the Leading Edge Symposium. The program identifies and names fellows—200 so far—and provides career mentoring advice, a supportive community, and a platform to ensure they are visible to recruiters. Since the program began, 99 of the fellows have gone on to accept faculty positions at various institutions.

In a talk tracing the arc of her career, Weninger, who trained as a neuroscientist at Harvard, said she left bench work for a job as an editor because she wanted to enjoy the breadth of science, but also noted that her postdoc salary didn’t even cover the cost of child care. She left Cell Press in 2005 to help lead a task force on women in science that Harvard formed in the wake of comments by then-president Lawrence Summers widely understood as suggesting that women lacked “natural ability” in science and engineering. Working feverishly for months, the task force recommended steps to increase the number of senior women in science, including providing financial support for researchers who were also caregivers at home so they’d have the money to hire a technician. That extra set of hands would afford them the flexibility to keep research running even as they also attended to their families. Notably, Monje said she does this for the postdocs in her lab.

A graduate student asked Silbey at the end of her talk how to change a culture in which traditionally male-oriented norms marginalize women. Silbey said it starts with calling out those norms and recognizing that they are the issue, rather than increasing women’s representation in, or asking them to adapt to, existing systems.

“To make change it requires that you do recognize the differences of the experiences and not try to make women exactly like men or continue the past practices and think, ‘Oh, we just have to add women into it’,” she said.

Silbey also praised the Kuggie Vallee event at MIT for assembling a new community around these issues. Women in science need more social networks where they can exchange information and resources, she said.

“This is where an organ, an event like this, is an example of making just that kind of change: women making new networks for women,” she said.

Research Reflections: Alison Biester (PhD ’24), Drennan Lab

New snapshots of ancient life

Alison Biester | Department of Chemistry
October 3, 2024

The resolution revolution, beating “blobology”, and shedding light on how ancient microbes thrived in a primordial soup.

The earliest life on earth created biological molecules despite the limited materials available in the primordial soup such as CO2, hydrogen gas, and minerals containing iron, nickel, and sulfur.

As ancient microbes evolved, they developed proteins that sped up chemical reactions, called enzymes. Enzymes were evolutionarily advantageous because they created local environments called active sites optimized for reaction performance.

Although we know that carbon is the building block of life on earth–we wouldn’t exist without carbon-based molecules such as proteins and DNA–much remains unclear about how more complex carbon-based molecules were originally generated from CO2. Proteins and DNA are huge molecules with thousands of carbon atoms, so creating life from CO2 would be no small undertaking.

Catherine Drennan, Professor of Biology and Chemistry and HHMI Investigator and Professor, has long studied the enzymes that perform these crucial reactions wherein CO2 is converted into a form of carbon that cells can use, which requires iron, nickel, and sulfur.

In particular, she uses structural biology to study carbon monoxide dehydrogenase (CODH), which reacts with CO2 to produce CO, and acetyl-CoA synthase (ACS), which uses CO with another single unit of carbon to create a carbon-carbon bond. Crystallographic work by Drennan and others has provided structural snapshots of bacterial CODH and ACS, but its structure in other contexts remains elusive. During my PhD, I worked with Drennan on the structural characterization of CODH and ACS, culminating in a publication in PNAS, published October 3, 2024.

Throughout Drennan’s career, the lab has used a method known as X-ray crystallography to determine enzyme structures at atomic resolution. In recent years, however, cryogenic electron microscopy (cryo-EM) has risen in popularity as a structural biology technique.

Cryo-EM offers some key advantages over X-ray crystallography, such as its ability to capture structures of large and dynamic complexes. However, cryo-EM is limited in its ability to elucidate structures of small proteins, an area where X-ray crystallography continues to excel.

To perform a cryo-EM experiment, proteins are rapidly frozen in a thin layer of ice and imaged on an electron microscope. By capturing images of the protein in various orientations, researchers can generate a 3D model of their protein of interest.

Around 2015, cryo-EM reached a tipping point known as the “resolution revolution.” Due to improvements in both the hardware for collecting cryo-EM data and the software used for data processing, the technique could, for the first time, be used to determine protein structures at near-atomic resolution.

Seeing the potential for this new technique, MIT opened its very own cryo-EM facility with two electron microscopes in 2018. Just a year later, I joined the Drennan lab. When I began my thesis work, Cathy asked “Would you like to do crystallography or cryo-EM?”

Eager to try something that was both novel for researchers and new to me, I chose cryo-EM.

Ancient microbes

An ancient type of microbe, archaea, also uses CODH and ACS. Without information on how these protein chains interact, we cannot understand how these proteins work together within this complex–but it’s a difficult question to answer. In total, the complex contains forty protein chains that interact with one another and adopt various conformations to perform their chemistry.

We don’t know for sure which ACS enzyme came first, the bacterial or archaeal one, but we know they are both very ancient.

Archaeal CODH has been visualized via X-ray crystallography, but that CODH was isolated from the enormous megadalton enzyme complex present in the native archaea.

A CO2 molecule, which reacts with CODH, is 44 daltons; the enzyme complex at 2.2 megadaltons is 50,000 times the size of CO2. The complex consists of several copies of CODH, ACS, and a cobalt-containing enzyme that donates the second one-carbon unit used by ACS. Due to the large and dynamic nature of the complex, it was a great candidate for visualizing with cryo-EM.

Before I joined the lab, a collaboration had been initiated between the Drennan Lab and Dr. David Grahame of the Uniformed Services University of the Health Sciences, an expert in archaeal CODH and ACS.

Just before his retirement, Grahame grew hundreds of liters of archaea and isolated approximately one gram of the enzyme complex that he provided to the Drennan Lab for structural characterization. Each cryo-EM experiment can use as little as a microgram of protein. For a structural biologist, having one gram of protein–in theory, enough for one million experiments–to work with is a dream.

Blobology

With an abundance of protein, I embarked on this project with this exciting new technique on a promising target. I prepared my cryo-EM sample and collected data at the new MIT cryo-EM facility. As I was collecting data, I could see in the images large protein complexes that appeared to be my complex of interest. I could also see some smaller proteins that were consistent with the shape of isolated CODH. When I went on to process my data, I focused on the larger protein complexes, since the structure of isolated CODH was already known.

However, when I finished processing my first dataset, I was a bit disappointed. My resolution was very low–instead of atoms, I was seeing amorphous blobs, and I had no idea which blob matched with which protein, or how the proteins fit together. Rather than post-revolution cryo-EM, I felt like I was performing the “blobology” of the past.

Our cryo-EM data contains detailed structural information that becomes evident after significant data processing. On the left is the initial structure of our proteins of interest, carbon monoxide dehydrogenase (CODH) and acetyl-CoA synthase (ACS), and on the right is our final, detailed one. Photo courtesy of Alison Biester.

But the project was young, and a few failed experiments are par for the course of a PhD.

The next step was sample optimization, and luckily I had plenty of sample to work with. I tried preparing the protein in a different way, changed the protein concentration, used different additives, and scaled up my data collection.

Nothing helped. No matter what I tried, I could not move out of blobology territory. So, as one does when a project is failing, I stepped away. I worked on other projects and stopped thinking about the archaeal CODH and ACS.

A few months later, the cryo-EM facility was seeking users to try a new sample preparation instrument called the chameleon. Chameleon automates the sample preparation process and is intended to improve sample quality. With plenty of sample still to spare, I volunteered to try the instrument.

Just prior to my data collection, the facility had also installed a new software that allows data processing as it is being collected. The software uses automated processes to select proteins within your data; previously, I had only selected large protein complexes consistent with my complex of interest after the fact.

The new software is not very discriminating–but I was surprised when I looked at the results of the live processing. The processing showed that I had a protein complex in my sample that I did not expect – a complex of CODH and ACS!

This complex had just one copy of CODH and one copy of ACS, unlike the full complex that has multiple copies of each. My excitement for the project was reinvigorated. With this new target, could I leave blobology behind and finally join the resolution revolution?

After running more experiments and collecting more data and a few months of data processing, I realized that the sample contained three different states: isolated CODH, CODH with one copy of ACS, and CODH with two copies of ACS. I was able to use the Model-based Analysis of Volume Ensembles (MAVEn) tool developed by the Davis Lab at MIT to sort out these three states. When I finished the data processing, I achieved near-atomic resolution of all three states.

Through this work, for the first time, we can see what the archaeal ACS looks like. The archaeal ACS is fundamentally different from the bacterial one: a huge portion of the enzyme is missing, including part of the enzyme that makes up the active site in bacteria, leaving open the question of what the ACS active site looks like in archaea.

In our structure of archaeal ACS in complex with CODH, we were surprised to see that the active site looks almost identical to the bacterial one. This similarity is enabled by the archaeal CODH, which compensates for the missing part of ACS.

Given how similar the ACS active site environment in bacterial and archaea, we are likely getting a look at an active site that has remained conserved over billions of years of evolution.

Although the project didn’t fulfill its original promise of solving the structure of the large, dynamic protein complex, I did find intriguing insights. The tools available in 2015 would not have enabled me to achieve these results; it is clear to me that the resolution revolution is far from over, and the evolution of structural biology has been fascinating to experience. Cryo-EM has and will continue to evolve, as amazing new tools are still being developed.

Since graduating from MIT, I’ve been working at the Protein Data Bank, the data center that houses all available protein structure information. Working here gives me a front-row view of new discoveries in structural biology. I’m so excited to see where this field will go in the future.

Cancer biologists discover a new mechanism for an old drug

Study reveals the drug, 5-fluorouracil, acts differently in different types of cancer — a finding that could help researchers design better drug combinations.

Anne Trafton | MIT News
October 7, 2024

Since the 1950s, a chemotherapy drug known as 5-fluorouracil has been used to treat many types of cancer, including blood cancers and cancers of the digestive tract.

Doctors have long believed that this drug works by damaging the building blocks of DNA. However, a new study from MIT has found that in cancers of the colon and other gastrointestinal cancers, it actually kills cells by interfering with RNA synthesis.

The findings could have a significant effect on how doctors treat many cancer patients. Usually, 5-fluorouracil is given in combination with chemotherapy drugs that damage DNA, but the new study found that for colon cancer, this combination does not achieve the synergistic effects that were hoped for. Instead, combining 5-FU with drugs that affect RNA synthesis could make it more effective in patients with GI cancers, the researchers say.

“Our work is the most definitive study to date showing that RNA incorporation of the drug, leading to an RNA damage response, is responsible for how the drug works in GI cancers,” says Michael Yaffe, a David H. Koch Professor of Science at MIT, the director of the MIT Center for Precision Cancer Medicine, and a member of MIT’s Koch Institute for Integrative Cancer Research. “Textbooks implicate the DNA effects of the drug as the mechanism in all cancer types, but our data shows that RNA damage is what’s really important for the types of tumors, like GI cancers, where the drug is used clinically.”

Yaffe, the senior author of the new study, hopes to plan clinical trials of 5-fluorouracil with drugs that would enhance its RNA-damaging effects and kill cancer cells more effectively.

Jung-Kuei Chen, a Koch Institute research scientist, and Karl Merrick, a former MIT postdoc, are the lead authors of the paper, which appears today in Cell Reports Medicine.

An unexpected mechanism

Clinicians use 5-fluorouracil (5-FU) as a first-line drug for colon, rectal, and pancreatic cancers. It’s usually given in combination with oxaliplatin or irinotecan, which damage DNA in cancer cells. The combination was thought to be effective because 5-FU can disrupt the synthesis of DNA nucleotides. Without those building blocks, cells with damaged DNA wouldn’t be able to efficiently repair the damage and would undergo cell death.

Yaffe’s lab, which studies cell signaling pathways, wanted to further explore the underlying mechanisms of how these drug combinations preferentially kill cancer cells.

The researchers began by testing 5-FU in combination with oxaliplatin or irinotecan in colon cancer cells grown in the lab. To their surprise, they found that not only were the drugs not synergistic, in many cases they were less effective at killing cancer cells than what one would expect by simply adding together the effects of 5-FU or the DNA-damaging drug given alone.

“One would have expected that these combinations to cause synergistic cancer cell death because you are targeting two different aspects of a shared process: breaking DNA, and making nucleotides,” Yaffe says. “Karl looked at a dozen colon cancer cell lines, and not only were the drugs not synergistic, in most cases they were antagonistic. One drug seemed to be undoing what the other drug was doing.”

Yaffe’s lab then teamed up with Adam Palmer, an assistant professor of pharmacology at the University of North Carolina School of Medicine, who specializes in analyzing data from clinical trials. Palmer’s research group examined data from colon cancer patients who had been on one or more of these drugs and showed that the drugs did not show synergistic effects on survival in most patients.

“This confirmed that when you give these combinations to people, it’s not generally true that the drugs are actually working together in a beneficial way within an individual patient,” Yaffe says. “Instead, it appears that one drug in the combination works well for some patients while another drug in the combination works well in other patients. We just cannot yet predict which drug by itself is best for which patient, so everyone gets the combination.”

These results led the researchers to wonder just how 5-FU was working, if not by disrupting DNA repair. Studies in yeast and mammalian cells had shown that the drug also gets incorporated into RNA nucleotides, but there has been dispute over how much this RNA damage contributes to the drug’s toxic effects on cancer cells.

Inside cells, 5-FU is broken down into two different metabolites. One of these gets incorporated into DNA nucleotides, and other into RNA nucleotides. In studies of colon cancer cells, the researchers found that the metabolite that interferes with RNA was much more effective at killing colon cancer cells than the one that disrupts DNA.

That RNA damage appears to primarily affect ribosomal RNA, a molecule that forms part of the ribosome — a cell organelle responsible for assembling new proteins. If cells can’t form new ribosomes, they can’t produce enough proteins to function. Additionally, the lack of undamaged ribosomal RNA causes cells to destroy a large set of proteins that normally bind up the RNA to make new functional ribosomes.

The researchers are now exploring how this ribosomal RNA damage leads cells to under programmed cell death, or apoptosis. They hypothesize that sensing of the damaged RNAs within cell structures called lysosomes somehow triggers an apoptotic signal.

“My lab is very interested in trying to understand the signaling events during disruption of ribosome biogenesis, particularly in GI cancers and even some ovarian cancers, that cause the cells to die. Somehow, they must be monitoring the quality control of new ribosome synthesis, which somehow is connected to the death pathway machinery,” Yaffe says.

New combinations

The findings suggest that drugs that stimulate ribosome production could work together with 5-FU to make a highly synergistic combination. In their study, the researchers showed that a molecule that inhibits KDM2A, a suppressor of ribosome production, helped to boost the rate of cell death in colon cancer cells treated with 5-FU.

The findings also suggest a possible explanation for why combining 5-FU with a DNA-damaging drug often makes both drugs less effective. Some DNA damaging drugs send a signal to the cell to stop making new ribosomes, which would negate 5-FU’s effect on RNA. A better approach may be to give each drug a few days apart, which would give patients the potential benefits of each drug, without having them cancel each other out.

“Importantly, our data doesn’t say that these combination therapies are wrong. We know they’re effective clinically. It just says that if you adjust how you give these drugs, you could potentially make those therapies even better, with relatively minor changes in the timing of when the drugs are given,” Yaffe says.

He is now hoping to work with collaborators at other institutions to run a phase 2 or 3 clinical trial in which patients receive the drugs on an altered schedule.

“A trial is clearly needed to look for efficacy, but it should be straightforward to initiate because these are already clinically accepted drugs that form the standard of care for GI cancers. All we’re doing is changing the timing with which we give them,” he says.

The researchers also hope that their work could lead to the identification of biomarkers that predict which patients’ tumors will be more susceptible to drug combinations that include 5-FU. One such biomarker could be RNA polymerase I, which is active when cells are producing a lot of ribosomal RNA.

The research was funded by the Damon Runyon Cancer Research Fund, a Ludwig Center at MIT Fellowship, the National Institutes of Health, the Ovarian Cancer Research Fund, the Holloway Foundation, and the STARR Cancer Consortium.

Victor Ambros ’75, PhD ’79 and Gary Ruvkun share Nobel Prize in Physiology or Medicine

The scientists, who worked together as postdocs at MIT, are honored for their discovery of microRNA — a class of molecules that are critical for gene regulation.

Anne Trafton | MIT News
October 7, 2024

MIT alumnus Victor Ambros ’75, PhD ’79 and Gary Ruvkun, who did his postdoctoral training at MIT, will share the 2024 Nobel Prize in Physiology or Medicine, the Royal Swedish Academy of Sciences announced this morning in Stockholm.

Ambros, a professor at the University of Massachusetts Chan Medical School, and Ruvkun, a professor at Harvard Medical School and Massachusetts General Hospital, were honored for their discovery of microRNA, a class of tiny RNA molecules that play a critical role in gene control.

“Their groundbreaking discovery revealed a completely new principle of gene regulation that turned out to be essential for multicellular organisms, including humans. It is now known that the human genome codes for over one thousand microRNAs. Their surprising discovery revealed an entirely new dimension to gene regulation. MicroRNAs are proving to be fundamentally important for how organisms develop and function,” the Nobel committee said in its announcement today.

During the late 1980s, Ambros and Ruvkun both worked as postdocs in the laboratory of H. Robert Horvitz, a David H. Koch Professor at MIT, who was awarded the Nobel Prize in 2002.

While in Horvitz’s lab, the pair began studying gene control in the roundworm C. elegans — an effort that laid the groundwork for their Nobel discoveries. They studied two mutant forms of the worm, known as lin-4 and lin-14, that showed defects in the timing of the activation of genetic programs that control development.

In the early 1990s, while Ambros was a faculty member at Harvard University, he made a surprising discovery. The lin-4 gene, instead of encoding a protein, produced a very short RNA molecule that appeared in inhibit the expression of lin-14.

At the same time, Ruvkun was continuing to study these C. elegans genes in his lab at MGH and Harvard. He showed that lin-4 did not inhibit lin-14 by preventing the lin-14 gene from being transcribed into messenger RNA; instead, it appeared to turn off the gene’s expression later on, by preventing production of the protein encoded by lin-14.

The two compared results and realized that the sequence of lin-4 was complementary to some short sequences of lin-14. Lin-4, they showed, was binding to messenger RNA encoding lin-14 and blocking it from being translated into protein — a mechanism for gene control that had never been seen before. Those results were published in two articles in the journal Cell in 1993.

In an interview with the Journal of Cell Biology, Ambros credited the contributions of his collaborators, including his wife, Rosalind “Candy” Lee ’76, and postdoc Rhonda Feinbaum, who both worked in his lab, cloned and characterized the lin-4 microRNA, and were co-authors on one of the 1993 Cell papers.

In 2000, Ruvkun published the discovery of another microRNA molecule, encoded by a gene called let-7, which is found throughout the animal kingdom. Since then, more than 1,000 microRNA genes have been found in humans.

“Ambros and Ruvkun’s seminal discovery in the small worm C. elegans was unexpected, and revealed a new dimension to gene regulation, essential for all complex life forms,” the Nobel citation declared.

Ambros, who was born in New Hampshire and grew up in Vermont, earned his PhD at MIT under the supervision of David Baltimore, then an MIT professor of biology, who received a Nobel Prize in 1973. Ambros was a longtime faculty member at Dartmouth College before joining the faculty at the University of Massachusetts Chan Medical School in 2008.

Ruvkun is a graduate of the University of California at Berkeley and earned his PhD at Harvard University before joining Horvitz’s lab at MIT.

BSG-MSRP-Bio Student Profile: Adriana Camacho-Badillow, Calo Lab

Understanding the Role of PARPs and UBF1 in Building Ribosomes

Noah Daly | Department of Biology
September 25, 2024

While pursuing her passion for research, BSG-MSRP-Bio student Adriana Camacho-Badillo made major contributions to research in the Calo Lab in the Department of Biology at MIT.

Growing up in Puerto Rico, Adriana Camacho-Badillo had no explanation for her recurrent multiple fracture injuries. In her teens, she was finally able to see a geneticist who diagnosed her with a genetic syndrome that affects connective tissue throughout the body. 

This awakened an interest in genetics that led her to immerse herself in her genetic panel results, curious about the role of each gene that was tested. 

“I realized I wanted to find out how mutations affect gene expression that could possibly lead to a distinct phenotype or even a genetic syndrome,” she says. 

Within a few years of setting her sights on becoming a scientist, Camacho-Badillo began her first research experience working in the laboratory of Professors Hector Areizaga-Martínez and Elddie Román-Morales. Her work focused on experiments using enzymes to degrade Dichloro-diphenyl-trichloroethane, or DDT, a once-common pesticide known to be highly toxic to humans and other mammals that remains in the environment long after application to crops. 

As she became familiar with the day-to-day routines of designing and executing research experiments, she realized she was drawn to biochemistry and molecular biology. Camacho-Badillo soon applied to the molecular neuroscience lab of Professor Miguel Méndez at the University of Puerto Rico at Aguadilla and joined their team working on the effects of high glucose in the central nervous system of mice.

Expanding Experiences While Narrowing Focus

When Camacho-Badillo was sixteen, alongside Méndez and other students, she participated in the Quantitative Methods Workshop at MIT. The workshop allows undergraduate students from universities around the United States and the Caribbean to come together for a few days in January to learn how to apply computational tools that can help biological research. 

One of the sessions she attended was a talk about machine learning and studying the brain, presented by graduate student Taylor Baum. 

“I loved Taylor’s workshop,” Camacho-Badillo said, “When Taylor asked if anyone would be interested in volunteering to teach Spanish-speaking students in grade school science, I said yes without hesitation.” 

Baum, a neuroscientist and computer scientist working in the Munther Dahleh Research Group at MIT, is also the founder of Sprouting, Inc. The organization equips high-school students and undergraduates in Puerto Rico with STEM skills to help them pursue careers in science and technology.

After participating in QMW, it wasn’t long before Camacho-Badillo was back at MIT. She participated in the Bernard S. and Sophie G. Gould MIT Summer Research Program in Biology in 2023 and worked in the Yamashita Lab, studying two phenotypes of genetic mutations associated with cancer during cell division. 

The BSG-MSRP-Bio program offers lab experience and extracurricular activities such as journal clubs and dinners with professors. At one of these events, she met Associate Professor of Biology Eliezer Calo.

Camacho-Badillo and her mentor Eliezer Calo, Associate Professor of Biology. Photo Credit: Mandana Sassanfar.

“I loved meeting another scientist from Puerto Rico working on molecular biology, so I decided to look further into his research,” Camacho-Badillo recalls. 

In 2024, she was delighted to have the opportunity to return to the BSG-MSRP-Bio Program for a second time, and now to work in Calo’s Lab. 

The Unsolved Mysteries of UBF1

Although BSG-MSRP-Bio students are often mentored by graduate students or postdocs, Calo spent the summer mentoring Camacho-Badillo directly. As an alumnus of the MSRP-Bio program himself, Calo understands firsthand how much of an impact meaningful research can have for an undergraduate student spending a few months experiencing life in the lab at MIT. 

In the Calo Lab, Camacho-Badillo spent the early days of this summer poring over past research papers on genetic transcription, trying to answer a big question in molecular biology. Camacho-Badillo has been helping Calo understand how a particular protein affects the production of ribosomes in cells.

A ribosome is the molecular machinery that synthesizes proteins, and an average cell can produce around 10 million ribosomes to sustain its essential functions. Creating these protein engines requires the transcription of ribosomal DNA, or rDNA. 

In order to synthesize RNA, specific proteins called polymerases must bind to the DNA. Camacho-Badillo’s work focuses on one of those binding proteins called upstream binding factor, or UBF1. UBF1 is essential for the synthesis of the ribosomal RNA. The UBF1 transcription factor is responsible for recruiting the polymerase, RNA polymerase I, to transcribe the rDNA into rRNA.

Despite knowing the importance of UBF1 in ribosomal production, it’s unclear what its full purpose is in this process. Calo and Camacho-Badillo think that clarifying the role of UBF1 in ribosomal biogenesis will help scientists understand how certain neurological diseases occur. UBF1 is known to be associated with diseases such as acute myeloid leukemia and childhood-onset neurodegeneration with brain atrophy, but the mechanism is not yet understood.

UBF1 is a peculiar transcription factor. Before it can transcribe a gene, UBF1 must first dimerize, forming a bond with another UBF1 protein. After binding to the rDNA, UBF1 can recruit the remaining RNA transcription machinery. The dimer is crucial for transcription to occur, yet this protein can make further connections with other UBF1 monomers, a process called oligomerization. 

Nothing is concretely understood about how oligomers of UBF1 form: they could be critical for transcription, forming clusters that can no longer bind with rDNA or inhibit the recruitment of the remaining RNA transcription machinery. These clusters could also be directly contributing to a variety of neurological diseases.

“The genome contains multiple rDNA copies, but not all are utilized,” Calo explains. “UBF1 must precisely identify the correct copies to activate while avoiding the formation of aggregates that could impair its function.”

The regulation of these dimers is also a mystery. Early in the summer, Camacho-Badillo helped make an important connection: prior research from the Calo Lab showed that enzymes called poly ADP-ribose polymerases, or PARPs, play a role in maintaining chemical properties in the nucleolus, where ribosomes are produced and assembled. The main target of these proteins within the RNA transcriptional machinery before transcription is initiated is UBF1.  

Based on this initial result, Camacho-Badillo’s entire summer project shifted to further characterize PARPs in ribosome biogenesis.

“This observation about the role PARPs plays is a big deal for us,” Calo says. “We do many experiments in my lab, but Adriana’s work this summer has opened a key gateway to understanding the mysteries behind UBF1 regulation, leading to proper ribosome production and allowing the Calo lab to pursue this goal. She’s going to be a superstar.” 

Camacho-Badillo’s work hasn’t ended with the BSG-MSRP-Bio program, however. She’ll spend the fall semester at MIT, continuing to work on understanding how rDNA transcription is regulated as a visiting student in the Calo Lab. Although she still has a year and a half to go in her undergraduate degree, she’s already set her sights on graduate school. 

“This program has meant so much to me and brought so much into my life,” she says. “All I want to do right now is keep this research going.”

Want to know more about our BSG-MSRP-Bio Students? Read more testimonials and stories here.

BSG-MSRP-Bio student profile: Yeongseo Son, Spranger Lab

All It takes to titer: discovering a love of troubleshooting at MIT

Noah Daly | Department of Biology
September 25, 2024

BSG-MSRP-Bio student Yeongseo Son breathed new life into her love of science over the summer in the Spranger Lab studying immune responses in the lung in the Department of Biology at MIT.

When Yeongseo Son was initially invited to join the Spranger Lab as part of the Bernard S. and Sophie G. Gould MIT Research Program in Biology, she thought the email was spam. Having grown up in the South for most of her life, she had never pictured herself at MIT.

Back home at the University of Georgia, Son studies neutrophils, a kind of innate immune cell that serves as the body’s first line of defense against foreign pathogens. After taking a graduate-level course on immunology last semester, Son realized she needed to increase her basic understanding of the broad discipline.

“I knew that coming to work with Professor Spranger would give me a chance to work on cancer immunology and T cell biology, two really cool and important fields I haven’t been exposed to,” Son says.

It took several attempts from the Senior Lecturer and BSG-MSRP-Bio program coordinator Mandana Sassanfar to reach her before Son accepted.  

“Before I arrived, I was worried it would be too intense or that I wouldn’t fit in,” Son says. “I couldn’t have been more wrong: yes, the work is challenging, but everyone is here because they truly love science.”

Vexing Viruses

In the lab of Stefani Spranger, Associate Professor in the Department of Biology and Intramural Faculty of the Koch Institute for Integrative Cancer Research, Son was first tasked with a seemingly simple second project: growing a new strain of influenza to infect mice that had recently recovered from another strain. 

This quest involved multiple steps, such as culturing cells, infecting the cells with the virus, and measuring how lethal it is to host cells, working with a strain that her lab hadn’t used before.   

To test the strength of the virus, the virus is mixed with host cells in order to infect them. Then the host cells are placed on a layer of agar, a gelatinous substance that provides nutrients for the host cells. When a virus-infected cell dies, it creates a hole in the layer of cells called a plaque. The number of plaques is recorded to determine the virus’s titer, or frequency. 

Son excitedly executed her plaque assay after breezing through the first two steps. The next day, to her surprise and disappointment, all her cells — including the negative control — had died. 

“The first time it failed, I was crushed because I had written the protocol over and over,” Son says. 

That initial disappointment, however, turned into excitement to solve the problem. She worked closely with her mentor, Postdoc Taylor Heim, who helped motivate her to keep trying to figure out what had gone wrong.

Son spent weeks designing a process to effectively titer the virus. She laid out a plan of action to assess what could be toxic to the cells and systematically tested each component of the protocol that could affect the growth of her strain of influenza. 

It took Son four attempts before she had a eureka moment: the success of her cell cultures depended on the precise measurement of just one reagent. 

Too much of the reagent meant the cells would all die on arrival, but just a little bit, and they would survive. It took Son three more attempts — seven experiments in total — to fully ensure the success of the assay.

Throughout this process, and despite her many failures, Son realized she finds troubleshooting very enjoyable. Each failure was unique and crucial for her eventual success.  

“I’m making a difference — I’m figuring something out that can really help with future experiments,” Son says. “That moment of success is why I gained such confidence in being a scientist.”

Yeongseo Son and Professor Spranger in the lab at the Koch Institute. Photo credit: Mandana Sassanfar.

Lighting Up the Lungs

In the Spranger Lab, Son’s other summer project focused on the respiratory system. She was examining a type of specialized cell called resident memory CD8+ T cells in the lungs and lymph nodes of mice infected with influenza. These specialized T cells gain a kind of memory of how to fight off a virus and remain in the lungs and lung-draining lymph node tissues long after the tissues have overcome the immune challenge of something like influenza. 

Son’s postdoctoral student mentor Taylor Heim is especially interested in the potential of these cells for cancer immunotherapy.

To better understand how the resident memory T cell populations change over time, Son and Heim conducted a time-point experiment in which mice were studied at different points after being infected with influenza. They do this by injecting antibodies into the mouse’s bloodstream after infection, which mark any immune cells circulating in the blood, allowing the researchers to gauge if the cells are recruited to help fight a virus.

Son’s work this summer goes deeper, examining proteins known as cytokines that enable the immune system to combat germs or other substances that can harm an organism. 

Son used a genetically modified mouse to track the production of interferon-gamma, IFN‐γ. IFN‐γ is a cytokine that plays a key role in regulating immune responses, often helping fight off infection and cancer. Son found evidence that resident memory T cells produce this cytokine in both the lungs and lung-draining lymph nodes. 

The goal of this research is to one day use the information collected on resident memory CD8+ T cell populations and cytokine expression to help systematically target cancerous cells that appear in the body.

“Yeongseo has helped us pioneer a system to track how these cells move within tissues of living mice,” Spranger explains. “By using this approach, we will be able to understand how they are affecting cancer development and how cancer is affecting them, and that’s pretty exciting.”

Learning Outside the Lab

The BSG-MSRP-Bio program also gave Son near-constant access to faculty from across the biology department, both through extracurricular offerings such as dinner seminars and journal clubs as well as departmental retreats. 

She’s also sat down with professors individually and heard more about their stories and research as part of her podcast Let’s Talk Chemistry. Nobel Laureate Phil Sharp, whose office is on the same floor as the Spranger Lab, joined the show after Son dropped by his office to introduce herself. Son learned more about his discoveries in RNA splicing and the behind-the-scenes details of his Nobel Prize ceremonies. 

At MIT, Son has found a welcoming community of enthusiastic scientists working towards common goals, especially in her lab. Every day, members of the Spranger Lab actively seek each other out to have lunch together, and she feels right at home with them.

“I realized that yes, the people in this community are intensely passionate about their work, but they’re also multi-dimensional with a ton of different interests,” Son says. “One of the graduate students in my lab even gave me tennis lessons, and I’m already a better player because of it.”

As she returns to her studies in Georgia and begins the process of applying to graduate schools, Son is excited about her future in science. Armed with new knowledge, confidence, and community, she’s ready for whatever curveball her career in science will throw her next.

Want to know more about our BSG-MSRP-Bio Students? Read more testimonials and stories here.

BSG-MSRP-Bio student profile: Praise Lasekan, Vos Lab

A scientist’s toolkit: practice, patience, and plenty of questions

Noah Daly | Department of Biology
September 24, 2024

A childhood interest in the complex worlds within an organism that the naked eye cannot see ultimately led Praise Lasekan to the BSG-MSRP-Bio program at MIT working in the Vos Lab in the Department of Biology at MIT. 

Praise Lasekan talks about the fast protein liquid chromatography machines he used in the Vos Lab as though they were colleagues. 

“We have two of them,” he explains. “Sam and Frodo.” 

FPLC machines separate and analyze proteins based on their properties, such as size, charge, and binding affinity. When Lasekan first saw the FPLC machines, the tubing and valves, hooked up to a computer, reminded him of a fancy piece of plumbing. Much like an expert plumber, proficiency​​ with these machines required him to understand every valve and tube.

Although Lasekan is a Biology major with a Chemistry Minor at the University of Maryland, Baltimore County, Lasekan had the opportunity to spend his summer living in Boston and working on MIT’s campus as a Bernard S. and Sophie G. Gould MIT Summer Research Program in Biology student.

“I loved every part of this summer: Waking up in the morning, coming to the lab, setting up some stuff — whether it goes well or not,” Lasekan says. “Taking that experience and coming back the next day, you’re ready to keep going and improving.”

Lasekan spent his days in the lab of Seychelle Vos, Robert A. Swanson Career Development Professor of Life Sciences and HHMI Freeman Hrabowski Scholar. The Vos Lab examines how genetic information is stored so compactly yet is still accessible enough for genes to be expressed. All cells in an organism have the same DNA, but the organization of that DNA and how genes are expressed determine why one cell becomes part of the liver and another cell part of the brain. 

Lasekan worked with a highly conserved protein that plays a role in gene transcription called CCCTCF-binding factor, or CTCF. He worked to understand how adding a phosphate group, a process called phosphorylation, affects CTCF’s binding to DNA. Binding to DNA is the first step in the process of transcription, which creates proteins within a cell.

The Vos lab uses various tools and techniques that Vos learned during her training, often using simple systems with limited components to study phenomena such as molecular structures, the dynamics of proteins and nucleic acids, and how structural alterations affect the function of these molecules. The lab has also recently been delving into more systemic work, such as removing genes from cells to observe how that affects gene expression. 

“My lab is a little unconventional in some ways,” Vos says. “We use a lot of biochemistry and structural biology, but we want to use the tools of genetics and cell biology as well to understand how genome organization and genome expression are coupled.” 

BSG-MSRP-Bio Student Praise with Graduate Student and mentor, Bonnie Su, of the Vos Lab.

CTCF can play many roles during transcription, able to act as an activator or as a roadblock for transcription. Lasekan’s mentor, graduate student Bonnie Su, has been trying to figure out how cells control CTCF behavior.

“What if the cell needed something done ASAP, and CTCF was blocking its route to its destination on a DNA sequence?” Vos asks. “How does the cell regulate it?” 

Praise mutated different sites on CTCF that have been reported in previous research as possible points of phosphorylation of the CTCF protein. Several other amino acids can also be phosphorylated. Still, Su was particularly interested in the work other researchers have done on three specific sites along a segment called the zinc finger domain.  A zinc finger domain is a zinc ion that helps proteins stabilize their shape and the domain has a function in various cellular processes such as genetic transcription. The ion is regulated by amino acids to give it a finger-like structure that helps in binding the protein to DNA during transcription.

“Before we went on a wild goose chase,” Lasekan explains, “we needed to identify a specific area of the protein to concentrate on and examine the behavior of CTCF locally there.”

Off of the Drawing Board and Into the Laboratory

Lasekan was introduced to the microscopic world of the body — cells, organelles, molecules, and even atoms — in the pages of his secondary school science textbooks in Ondo, Nigeria. There began his curiosity about atomic structures, cells, and the complex worlds within an organism that the naked eye cannot see. He would spend much of his class time flipping through the pages of diagrams and ultimately decided to pursue science as his core focus during senior secondary school.

“It was there that I could take my first classes in chemistry, biology, and physics,” he says. “I realized I love all of the sciences, so my focus in school was science and technology.”

Initially drawn to engineering, Lasekan ended up dropping out of a technical drawing course.

“I loved the course,” Lasekan smiles, “but the course didn’t like me one bit.” 

Lasekan’s dreams shifted toward medicine and, with it, more science and math courses. 

When he graduated valedictorian from Staff Secondary School at the Federal University of Technology in Akure, his parents — both pharmacists — encouraged him to apply to university to become a medical doctor. However, getting into a good university is challenging in Nigeria. 

Praise opted instead to remain at home after graduating, building a successful business doing portrait photography. He also took chemistry, physics, and biology courses through Cambridge University International.

Despite making good money with photography, Praise was determined to go to university but wasn’t confident that he would get in. Nevertheless, an acquaintance encouraged him to apply to UMBC. 

“It was the only school I applied to, and I couldn’t believe that I got in,” says Lasekan. 

At UMBC, Lasekan discovered the pre-med track he’d signed up for was not a good fit for him either — many of the fundamental questions he was curious about were beyond the scope of his courses. A friend who was working in a research lab on campus suggested that Lasekan should try to find a lab to work in, too. 

“They told me I might like what they’re doing there because of the level of questions that I ask,” Lasekan says. “Sometimes people didn’t have answers for me, and maybe I could find some of those answers through research.” 

After he emailed PIs in biology and chemistry labs around campus, Lasekan was eventually accepted into the lab of Dr. Erin Green, Associate Professor of Biological Sciences at UMBC — his first experience doing research in the lab. 

Dr. Green focuses on trying to understand how post-translational modifications of proteins regulate functions, such as the establishment of proper states of gene expression and the ability of cells to respond to stress. 

“Dr. Green took a chance with me,” Lasekan says. “I am forever grateful to her for that.” 

MIT: A Destination for Scientific Discovery

When considering summer research programs, Praise applied to MIT, one institution he’d always remembered from his childhood textbooks as the birthplace of many great inventions and scientific discoveries. It’s also one of the few programs in the U.S. that accepts international students. 

“I’ve always had MIT at the back of my mind, but I didn’t think they’re looking for people like me,” Lasekan says. When he saw the notification for his acceptance to the program pop up on his smartwatch, he screamed, startling some students walking by him in the hallway.

“This is one of the best institutions in the world, and I just got an opportunity to go there for ten weeks, actually do a project of my own under the mentorship of my PI,” Lasekan recalls thinking. “This was a dream come true for me.”

In the Vos lab, Lasekan’s interest in the fundamental questions of biology was not only acceptable but encouraged, especially by his mentor, Su.

“Bonnie always had the patience to sit down with me, explain concepts to me, and write out the math with me if I need her to,” Lasekan says, “and sometimes I need it 25 times, but she’s there for me.” 

Now that the BSG-MSRP-Bio program has wrapped up, Praise has the confidence to set his sights higher than ever before — on the “big guys,” the universities and institutions doing the sort of cutting-edge research that first caught his eye in the textbooks back home. Praise is eagerly preparing his graduate school applications for fall 2025, including MIT.

“After being here, surrounded by people from everywhere driven by the same purpose, I know there’s an exciting future in science for me.” 

Want to know more about our BSG-MSRP-Bio Students? Read more testimonials and stories here.

From open education learners to MIT coders

MIT Digital Learning Lab’s high school interns gain professional experience working on the backend of open online MITx courses. The program emerged after Mary Ellen Wiltrout, PhD '09, digital learning scientist at MIT Open Learning, connected with the executive director and founder of Empowr, a nonprofit that serves low-income communities by creating a school-to-career pipeline through software development skills.

Katherine Ouellette | MIT Open Learning
August 26, 2024

Switching programming languages is not as simple as switching word processors. Yet high schooler Thomas Esayas quickly adapted from Swift to Python during his 2023 internship with the MIT Digital Learning Lab, a joint program between MIT Open Learning and the Institute’s academic departments. One year later, Esayas returns to the Institute for a second internship and as a new undergraduate student.

“I felt thoroughly challenged and learned a lot of new skills,” says Esayas.

Through this remote opportunity, interns gain real-world coding experience and practice professional skills by collaborating on MIT’s open online courses. The four interns from Digital Learning Lab’s 2023 and 2024 cohorts also participate in Empowr, a four-year program for low-income high school students that teaches in-demand software development skills and helps them secure paid internships.

The Digital Learning Lab program emerged after Mary Ellen Wiltrout PhD ’09, digital learning scientist at MIT Open Learning, connected with Adrian Devezin, executive director and founder of Empowr, at a conference about making education more accessible and equitable.

“It was affirming to have someone else see what Empowr is trying to do,” says Devezin about the organization’s goal to strengthen the school-to-career pipeline. “Being able to collaborate was beautiful for me, and more importantly, to the students.”

Building technical skills and self-confidence

The Digital Learning Lab internship empowers students to build confidence in their technical abilities, career skills, and the college application process. Interns assist the lab’s digital learning scientists with their work developing and maintaining online MITx courses at Open Learning across multiple academic areas.

“I found myself always busy with something interesting to work on,” says Esayas.

The interactive open education resources that Esayas produced last summer are now being used in live courses. He also helped find and fix bugs on the platform that hosts the MITx courses.

The internship’s flexible design allows projects to be adapted based on the student’s personal progress and interests.

“The students became co-creators of their educational experiences,” says Wiltrout, noting this is beneficial from a pedagogical standpoint.

Devezin adds, “I definitely saw a big improvement in their problem-solving abilities. Having to switch their mindset to a new language, work in new frameworks, and work on teams solving real problems enhanced their ability to adapt to new situations.”

The students’ also strengthened their professional repertoire in areas such as collaboration, communication, and project management. The 2023 cohort, Devezin says, developed the initiative to help other students and take on leadership roles.

Now that Esayas has completed his 2024 internship, he says, “I’m glad that I got to collaborate with more people and work on more projects. Overall, I’m very happy I was able to return.”

two people smiling, standing in front of a colorful wall.
Adrian Devezin, executive director and founder of Empowr (left), and Mary Ellen Wiltrout, digital learning scientist at MIT Open Learning (right), presented their takeaways from the first year of the MIT Digital Learning Lab internship at the 2024 Open edX conference. Photo courtesy of Empowr.

Learning from both sides

Learning occurred for both students and educators alike. Wiltrout says that the Digital Learning Lab values the opportunity to see the interns’ growth day-to-day and week-to-week, since digital learning scientists rarely follow the trajectory of individual learners who are using the course materials they create. Having instant feedback informs how they can adjust their teaching approaches for various problems.

The positive impact of the Digital Learning Lab internship’s hands-on learning experiences has made Devezin rethink the way he teaches class moving forward, and “the problems I want them to be solving,” he says.

Now, Devezin tries to emulate the real-world experience of working on a project for his Empowr students. Instead of assigning coding exercises where he provides the exact methods to solve the problems, he started asking students to determine the correct approach on their own.

The fact that Wiltrout and Devezin are open to adapting their teaching methods based on student feedback is indicative of a key factor to the internship’s success — active participation in students’ growth. It was mutually beneficial for the students and the educators to have determined stakeholders at both Digital Learning Lab and Empowr.

“A lot of dedicated educators understand that there’s a lot of inequities in education, and we need to come together to solve them,” Devezin says.

The Digital Learning Lab internship shows how open source learning materials can make educational and professional opportunities more accessible. The 2024 cohort has been able to increase their annual household income by an average of 75%, a recent Empowr report revealed. Wiltrout says that the two new Empowr students seem more confident with coding and showed enthusiasm and dedication to their tasks as they also consider colleges.

Wiltrout and Devezin presented their takeaways from the internship’s first year at the 2024 Open edX conference.

“I think it’s important to try making sure that more people are aware of tools and resources that are out there,” Wiltrout says. “Then giving people opportunities where they may not have otherwise had that chance.”

Now, Devezin is thinking about how Empowr students can come full circle with their relationship to open educational materials. He’s asking, “How can I help my students contribute to the open source world to give back to others?”