Placement: Promote to Homepage

Olivia Corradin

Education

  • PhD, 2015, Case Western Reserve University
  • BS, 2010, Biochemistry, Marquette University

Research Summary

Our lab studies genetic and epigenetic variation that contributes to human disease by disrupting gene expression programs. We utilize biological insights into the mechanisms of gene regulation in order to determine the impact of disease-associated variants on cellular function. We aim to identify actionable insights into disease pathogenesis by studying the confluence of genetic and epigenetic risk factors of human diseases, including multiple sclerosis and opioid use disorder.

Awards

  • NIH Director’s Pioneer Award Program Avenir Award, 2017
Whitehead Institute appoints two new faculty members
Merrill Meadow | Whitehead Institute
May 4, 2021

Whitehead Institute director Ruth Lehmann announced the appointment of two dynamic new Members: Olivia Corradin, currently a Whitehead Fellow, and Sinisa Hrvatin, currently an instructor and postdoctoral fellow at Harvard Medical School. Both will also become assistant professors of biology at Massachusetts Institute of Technology (MIT). Corradin’s joint appointments begin in July 2021, Hrvatin’s in January 2022.

“Both Olivia and Sinisa are creative, collaborative, and highly accomplished early-career scientists,” says Lehmann. “Each has impressed the Whitehead Institute and MIT faculties with their drive, intellect, and their scientific vision. We look forward to their contributions — as researchers, educators, and colleagues — for many years to come.”

Corradin investigates gene variants, small differences in DNA sequence, which can prompt disease-causing changes in gene regulation. During her nearly five years as a Whitehead Fellow, her lab defined the concept of “outside variants,” which helps to explain how genetic variants increase one’s likelihood of developing disease. She also developed a method to identify the cell type affected by a specific disease-linked variant; and then used it to single out oligodendrocytes as one type of brain cell involved in multiple sclerosis. Most recently, Corradin created an approach for defining epigenetic variation — which is caused by factors other than DNA sequence changes — in some individuals with opioid use disorder; this will help researchers’ identify genes associated with the disorder.

Before becoming the Scott Cook and Signe Ostby Fellow at Whitehead Institute in 2016, Corradin earned a PhD at Case Western Reserve University. There her research focused on genetic and epigenetic dysregulation in human disease, and she pioneered approaches to predict gene targets of regulatory DNA sequences associated with variants.

“I’m incredibly excited to be stepping into this new stage at Whitehead Institute and MIT Biology,” Corradin says. “I look forward to continued collaboration and to becoming a part of the rich history that shapes our Institute.”

Hrvatin investigates how organisms enter torpor and hibernation and how their cells adapt and survive in these states. As a postdoctoral research fellow in the lab of Harvard Medical School neurobiologist Michael Greenberg, Hrvatin established an experimental paradigm for studying a hibernation-like behavior in mice — and used this system to discover the neurons that control entry into this state. In addition, he pioneered the Paralleled Enhancer Single Cell Assay platform — a new method to generate cell-type-specific AAV vectors that can be used for targeted human gene therapy, as well as to control defined neuronal cell types across species, including in hibernating animals.

Hrvatin earned a PhD in stem cell and regenerative medicine from Harvard University, where he studied the process of directed differentiation from human embryonic stem cells to pancreatic beta cells. After his graduate work, he served as a postdoctoral associate at MIT in the lab of Daniel Anderson, where he investigated approaches for targeted siRNA delivery to pancreatic beta cells. Hrvatin also founded ReadCube, a startup dedicated to disseminating access to scientific literature and developing reference management tools for research scientists.

“I’ve always been inspired by the exceptional scientists, educators, pioneers, and visionaries at the Whitehead Institute and MIT Biology,” Hrvatin says. “I am absolutely thrilled for the opportunity to learn from and become a part of this extraordinary community.”

Biologists discover a trigger for cell extrusion

Study suggests this process for eliminating unneeded cells may also protect against cancer.

Anne Trafton | MIT News Office
May 5, 2021

For all animals, eliminating some cells is a necessary part of embryonic development. Living cells are also naturally sloughed off in mature tissues; for example, the lining of the intestine turns over every few days.

One way that organisms get rid of unneeded cells is through a process called extrusion, which allows cells to be squeezed out of a layer of tissue without disrupting the layer of cells left behind. MIT biologists have now discovered that this process is triggered when cells are unable to replicate their DNA during cell division.

The researchers discovered this mechanism in the worm C. elegans, and they showed that the same process can be driven by mammalian cells; they believe extrusion may serve as a way for the body to eliminate cancerous or precancerous cells.

“Cell extrusion is a mechanism of cell elimination used by organisms as diverse as sponges, insects, and humans,” says H. Robert Horvitz, the David H. Koch Professor of Biology at MIT, a member of the McGovern Institute for Brain Research and the Koch Institute for Integrative Cancer Research, a Howard Hughes Medical Institute investigator, and the senior author of the study. “The discovery that extrusion is driven by a failure in DNA replication was unexpected and offers a new way to think about and possibly intervene in certain diseases, particularly cancer.”

MIT postdoc Vivek Dwivedi is the lead author of the paper, which appears today in Nature. Other authors of the paper are King’s College London research fellow Carlos Pardo-Pastor, MIT research specialist Rita Droste, MIT postdoc Ji Na Kong, MIT graduate student Nolan Tucker, Novartis scientist and former MIT postdoc Daniel Denning, and King’s College London professor of biology Jody Rosenblatt.

Stuck in the cell cycle

In the 1980s, Horvitz was one of the first scientists to analyze a type of programmed cell suicide called apoptosis, which organisms use to eliminate cells that are no longer needed. He made his discoveries using C. elegans, a tiny nematode that contains exactly 959 cells. The developmental lineage of each cell is known, and embryonic development follows the same pattern every time. Throughout this developmental process, 1,090 cells are generated, and 131 cells undergo programmed cell suicide by apoptosis.

Horvitz’s lab later showed that if the worms were genetically mutated so that they could not eliminate cells by apoptosis, a few of those 131 cells would instead be eliminated by cell extrusion, which appears to be able to serve as a backup mechanism to apoptosis. How this extrusion process gets triggered, however, remained a mystery.

To unravel this mystery, Dwivedi performed a large-scale screen of more than 11,000 C. elegans genes. One by one, he and his colleagues knocked down the expression of each gene in worms that could not perform apoptosis. This screen allowed them to identify genes that are critical for turning on cell extrusion during development.

To the researchers’ surprise, many of the genes that turned up as necessary for extrusion were involved in the cell division cycle. These genes were primarily active during first steps of the cell cycle, which involve initiating the cell division cycle and copying the cell’s DNA.

Further experiments revealed that cells that are eventually extruded do initially enter the cell cycle and begin to replicate their DNA. However, they appear to get stuck in this phase, leading them to be extruded.

Most of the cells that end up getting extruded are unusually small, and are produced from an unequal cell division that results in one large daughter cell and one much smaller one. The researchers showed that if they interfered with the genes that control this process, so that the two daughter cells were closer to the same size, the cells that normally would have been extruded were able to successfully complete the cell cycle and were not extruded.

The researchers also showed that the failure of the very small cells to complete the cell cycle stems from a shortage of the proteins and DNA building blocks needed to copy DNA. Among other key proteins, the cells likely don’t have enough of an enzyme called LRR-1, which is critical for DNA replication. When DNA replication stalls, proteins that are responsible for detecting replication stress quickly halt cell division by inactivating a protein called CDK1. CDK1 also controls cell adhesion, so the researchers hypothesize that when CDK1 is turned off, cells lose their stickiness and detach, leading to extrusion.

Cancer protection

Horvitz’s lab then teamed up with researchers at King’s College London, led by Rosenblatt, to investigate whether the same mechanism might be used by mammalian cells. In mammals, cell extrusion plays an important role in replacing the lining of the intestines, lungs, and other organs.

The researchers used a chemical called hydroxyurea to induce DNA replication stress in canine kidney cells grown in cell culture. The treatment quadrupled the rate of extrusion, and the researchers found that the extruded cells made it into the phase of the cell cycle where DNA is replicated before being extruded. They also showed that in mammalian cells, the well-known cancer suppressor p53 is involved in initiating extrusion of cells experiencing replication stress.

That suggests that in addition to its other cancer-protective roles, p53 may help to eliminate cancerous or precancerous cells by forcing them to extrude, Dwivedi says.

“Replication stress is one of the characteristic features of cells that are precancerous or cancerous. And what this finding suggests is that the extrusion of cells that are experiencing replication stress is potentially a tumor suppressor mechanism,” he says.

The fact that cell extrusion is seen in so many animals, from sponges to mammals, led the researchers to hypothesize that it may have evolved as a very early form of cell elimination that was later supplanted by programmed cell suicide involving apoptosis.

“This cell elimination mechanism depends only on the cell cycle,” Dwivedi says. “It doesn’t require any specialized machinery like that needed for apoptosis to eliminate these cells, so what we’ve proposed is that this could be a primordial form of cell elimination. This means it may have been one of the first ways of cell elimination to come into existence, because it depends on the same process that an organism uses to generate many more cells.”

Dwivedi, who earned his PhD at MIT, was a Khorana scholar before entering MIT for graduate school. This research was supported by the Howard Hughes Medical Institute and the National Institutes of Health.

3 Questions: Sheena Vasquez and Mandana Sassanfar on building an outreach initiative from scratch

Graduate student and outreach director discuss efforts by the Department of Biology’s faculty, students, and staff to engage local community college students in scientific research.

Raleigh McElvery | Department of Biology
May 4, 2021

On June 10 of last year, MIT’s Department of Biology took the day to engage in open conversations about racial bias, diversity, and inclusion in support of the #ShutDownSTEM national initiative. These discussions spurred students, faculty, and staff to come together and form their own initiative. Known as the Community College Partnership, this program hopes to develop strong ties with local community colleges that are within commuting distance and serve diverse, nontraditional students — in order to increase access to MIT’s on-site and online resources. 

The department’s existing outreach programs — including the MIT Summer Research Program in Biology (MSRP-Bio), Quantitative Methods Workshop (QMW), and LEAH Knox Scholars Program — engage local high school students and non-MIT undergraduates from historically underrepresented groups in science. However, as of last year, the department had no research training opportunities geared toward community college students. The Community College Partnership is filling this gap by organizing virtual career panels, workshops, and seminars for students from Bunker Hill Community College and Roxbury Community College. In doing so, the initiative aims to encourage community college students from the Boston area to participate in additional MIT research opportunities, such as MSRP-Bio and QMW. Graduate student Sheena Vasquez, who spearheaded this initiative, and Mandana Sassanfar, the department’s director of outreach, sat down to discuss building a new program from scratch and how to plan for long-term success.

Q: What was your impetus for creating a program geared toward community college outreach?

Vasquez: I consider community college outreach very important for personal reasons. Back when I was applying to college, I couldn’t afford to attend a traditional four-year institution. I was also unsure what I wanted to major in, and I needed to stay close to home to take care of my family. I attended Georgia Perimeter College — a two-year community college — before transferring to the University of Georgia to finish my bachelor’s degree. I was able to participate in programs funded by the National Science Foundation, which led me to MIT for several summers as part of MSRP-Bio.

Looking back, I don’t think I would be a biology graduate student today if I hadn’t attended a community college. It also allowed me to see firsthand the talent, drive, and diversity at community colleges. And yet, at times these students are overlooked and underestimated by the general public. After our #ShutDownSTEM event last summer, it seemed like an ideal time to start engaging local community colleges in MIT’s biology research.

Sassanfar: I agree. It was by admitting bright students like Sheena to programs like MSRP that I realized the lack of initiatives aimed at community colleges. #ShutDownSTEM generated the energy and interest we needed to finally catalyze something like this. It was the missing link.

Q: What are the goals of the program, and how will you measure success?

Sassanfar: Our goals are twofold. First, we want to ensure that these students go far and reach their career goals — and possibly discover new goals that they didn’t realize were possible. Second, we hope to educate our own MIT community about the community college population, and build long-lasting relationships. This way, everyone will benefit.

Vasquez: We’ll be able to gauge the strength of these budding relationships by tracking how many students go on to participate in MSRP-Bio, QMW, and other rigorous research opportunities after attending our events. We also hope to create a team of graduate student mentors who can offer their expertise in grant writing and applying to graduate or other post-secondary schools.

Q: What challenges have you had to overcome in order to launch an outreach program aimed at a new community? How have you surmounted these difficulties?

Vasquez: The first challenge we faced was figuring out which community colleges to reach out to, and establishing points of contact there. We connected with Bunker Hill Community College first because of the diversity of students that attend. In addition, they had an active diversity, equity, and inclusion office, but no formal relationship with MIT Biology yet.

The next challenge was figuring out how to teach lab techniques virtually during our four-day workshop. We experimented with several different platforms before settling on Zoom. We also ended up sharing video recordings of ourselves in lab, and included tutorials on open-source software such as SnapGene and PyMOL — which allowed students to try their hand at procedures like DNA cloning, PCR, and interpreting protein structures. We asked everyone to fill out a survey at the very end, and 82 percent said they enjoyed the workshop and gained new skills. Ninety-six percent said they’d be interested in learning more about applying to graduate school, and some students have even reached out to us individually to continue the discussion.

Sassanfar: As Sheena alluded to, we’ve learned over the years that the secret to success is finding at least one faculty member or administrator at the other institution who is equally passionate about forming a partnership. In the case of Roxbury Community College, it took one meeting with a handful of faculty members to identify a professor who was willing to help make things happen. We do our part and they do their part; there has to be seamless communication.

My last piece of advice is that it’s vital for an outreach initiative to be focused. Go for depth, not breadth. It would be impossible to engage all community colleges in the greater Boston area. Instead, we are working hard to form strong relationships with a few in particular. That’s essential to creating something that’s long-lasting.

Up for a challenge in the lab and on the mat

While exploring a variety of research opportunities, senior Jose Aceves-Salvador has also thrown himself into mentoring, teaching, and cheerleading.

Hannah Meiseles | MIT News Office
April 28, 2021

At 5:30 a.m., his alarm would start blaring. Reluctant to get up, Jose Aceves-Salvador would hear his parents outside his door, bustling to get ready for work. “Ponte las pilas!” they would shout, using a Spanish idiom expressing encouragement to work hard.

The expression would stick with Aceves-Salvador throughout high school as he dreamed of going to college. Although neither of his parents had college degrees, they were both huge supporters of his decision. As Mexican immigrants who had moved to Los Angeles in their youth, their goal was to see their son achieve a better future.

“They didn’t know much about applying to college, but they knew that when you go, you’re set up for life,” explains Aceves-Salvador. “Whenever I’d hit a low, I’d think of how they’d tell me to work hard and keep going.”

To get a first taste of campus life, Aceves-Salvador attended a program at MIT called Minority Introduction to Engineering and Science (MITES) during the summer before his junior year of high school. MITES allowed Aceves-Salvador to take a genomics class at the Broad Institute of MIT and Harvard. The experience exposed him to the exciting and ever-changing world of scientific research.

“After MITES was over, I knew I wanted to go back to MIT. There was so much I still wanted to learn and explore,” Aceves-Salvador says. “In my mind, MIT was a huge reach school. But I couldn’t let go of the goal and figured I’d apply anyway.”

Aceves-Salvador was admitted and is now a senior studying biology with a concentration in education. “I love the learning process, and in biology there’s a never-ending cycle of questions to explore,” he says enthusiastically. “There are also so many opportunities to learn from failures and successes along the way.”

Aceves-Salvador wanted to do research the moment he arrived on campus, but struggled to get a lab position without any prior experience. Fortunately, in his sophomore year an interview with Xun Gong, a postdoc with the Strano Research Group, led to an opportunity. The lab had recently observed a new phenomenon in single-walled carbon nanotubes and wanted to investigate further. Aceves-Salvador joined the group and led the side project with Gong’s mentorship. “The project, and the fact that we were going into the unknown and exploring a new phenomenon perfectly fit my mentality, so I immediately said yes,” says Aceves-Salvador. “I eventually got my first taste of real science and have been hooked ever since.”

Since his first project, Aceves-Salvador has continued to do research, in multiple MIT labs and at the University of California at Los Angeles one summer. He has enjoyed working on everything from modeling protein behavior to developing a gut microphysical system. “As a college student, you come in barely knowing what’s out there to explore. I’ve tried to use my undergraduate degree to learn more about biology as a field before committing to something,” he says.

Across his different lab experiences, Aceves-Salvador has noted the lack of Latinx representation in science. He is devoted to encouraging greater minority representation in STEM and has served as a teaching assistant and mentor for MITES and the MIT Leadership Training Institute. These roles have allowed him to share his empowering story and love for education by teaching others. “I really wouldn’t be here if it weren’t for programs like MITES. I’m so grateful I can give back and be part of its legacy,” Aceves-Salvador says.

For an afterschool program he led in Los Angeles, Aceves-Salvador shaped the science curriculum he teaches to be more exciting to young learners. Students were challenged through hands-on activities, like creating chemical reactions, to make their own observations. “At a young age you’re so curious and curiosity is what science is all about,” says Aceves-Salvador. “But oftentimes, this curiosity gets stifled through outside pressures. In the hands-on activities I help lead, I try to create an open environment that encourages students to feel comfortable asking questions.”

Aceves-Salvador noticed the same approaches being used abroad during his international teaching experiences. Through MISTI Global Teaching Labs, he has traveled to Spain and Mexico to teach biology, math, health sciences, and chemistry. In Spain, Aceves-Salvador got to lead a discussion with local teachers on how to approach and encourage STEM education. “At least in the school I was placed in, I saw greater opportunities for students to explore different corners of science in their projects,” he notes. “The community-centric classrooms were also more focused on discussion among the students and less lecture.”

Outside of teaching and research, Aceves-Salvador enjoys channeling his passionate energy into dance and cheer. He has been part of MIT Cheerleading and DanceTroupe. These activities have pushed him physically, for example training him to lift cheerleaders on his shoulders and throw them into the air. He credits the intense nature of workout routines for creating a deep communal bond between members. “You share a connection with people after they’ve seen you fall on your face,” he jokes. “You can’t really hide anything at that point.”

This fall, Aceves-Salvador will be attending Harvard Medical School to pursue a PhD through the Biological and Biomedical Sciences program. He looks forward to continuing to explore different realms in science, as well as encouraging other young minority students to do the same. “Growing up, I never expected myself to be here in this position today. Even when I actually got into MIT, I faced a lot of pushback. People questioned my abilities and attributed my successes to luck,” Aceves-Salvador explains.

“It took me four years to leave that mentality. Now, I want to be a driving force to change that stigma. I want people to know that the reason we’re here is because we deserve to be here. And we’re going to do big things just like anyone else.”

Using CRISPR as a research tool to develop cancer treatments

KSQ Therapeutics uses technology created at MIT to study the role of every human gene in disease biology.

Zach Winn | MIT News Office
April 23, 2021

CRISPR’s potential to prevent or treat disease is widely recognized. But the gene-editing technology can also be used as a research tool to probe and understand diseases.

That’s the basic insight behind KSQ Therapeutics. The company uses CRISPR to alter genes across millions of cells. By observing the effect of turning on and off individual genes, KSQ can decipher their role in diseases like cancer. The company uses those insights to develop new treatments.

The approach allows KSQ to evaluate the function of every gene in the human genome. It was developed at MIT by co-founder Tim Wang PhD ’17 in the labs of professors Eric Lander and David Sabatini.

“Now we can look at every single gene, which you really couldn’t do before in a human cell system, and therefore there are new aspects of biology and disease to discover, and some of these have clinical value,” says Sabatini, who is also a co-founder.

KSQ’s product pipeline includes small-molecule drugs as well as cell therapies that target genetic vulnerabilities identified from their experiments with cancer and tumor cells. KSQ believes its CRISPR-based methodology gives it a more complete understanding of disease biology than other pharmaceutical companies and thus a better chance of developing effective treatments to cancer and other complex diseases.

A tool for discovery

KSQ’s scientific co-founders had been studying the function of genes for years before advances in CRISPR allowed them to precisely edit genomes about 10 years ago. They immediately recognized CRISPR’s potential to help them understand the role of genes in disease biology.

During his PhD work, Wang and his collaborators developed a way to use CRISPR at scale, knocking out individual genes across millions of cells. By observing the impact of those changes over time, the researchers could tease out the functionality of each gene. If a cell died, they knew the gene they knocked out was essential. In cancer cells, the researchers could add drugs and see if knocking out any of the genes affected drug resistance. More sophisticated screening methods taught the researchers how different genes inhibit or drive tumor growth.

“It’s a tool for discovering human biology at scale that was not possible before CRISPR,” says KSQ co-founder Jonathan Weissman, a professor of biology at MIT and a member of the Whitehead Institute. “You can search for genes or mechanisms that can modulate essentially any disease process.”

Wang credits Sabatini with spearheading the commercialization efforts, speaking with investors, and working with MIT’s Technology Licensing Office. Wang also says MIT’s ecosystem helped him think about bringing the technology out of the lab.

“Being at MIT and in the Cambridge area probably made the leap to commercialization a bit easier than it would have been elsewhere,” Wang says. “A lot of the students are entrepreneurial, there’s that rich tradition, so that helped shape my mindset around commercialization.”

Weissman had developed a complementary, CRISPR-based technology that Wang and Sabatini knew would be useful for KSQ’s discovery platform. Around 2015, as the founders were starting the company, they also brought on co-founder William Hahn, a member of the Broad Institute of MIT and Harvard, a professor at Harvard Medical School, and the chief operating officer of the Dana-Farber Cancer Institute.

Since then, the company has advanced Wang’s method.

“They’re able to scale this to a degree that is not possible in any academic lab, even David’s,” Wang says. “The cell lines I used for my experiments were just what was easy to grow and what was in the lab, whereas KSQ is thinking about what therapies aren’t available in certain cancers and deciding what diseases to go after.”

KSQ’s gene evaluations include tens of millions of cells. The company says the data it collects has been predictive of past successes and failures in cancer drug development. Weissman equates the data to “a roadmap for finding cancer vulnerabilities.”

“Cancers have all these different escape routes,” Weissman says. “This is a way of mapping out those escape routes. If there are too many, it’s not a good target to go after, but if there is a small number, you can now start to develop therapies to block off the escape routes.”

From discovery to impact

KSQ’s lead drug candidate is in preclinical development. It targets a DNA-repair pathway identified using an updated version of Wang’s technique. The drug could treat multiple ovarian cancers as well as a disease called triple-negative breast cancer. KSQ is also currently developing a cell therapy to boost the immune system’s ability to fight tumors.

“I’ve always thought the best biotech companies start with information that other people don’t have,” Sabatini says. “I think biotech companies have to have some discovery to them. That’s enabled KSQ to go in different directions.”

The founders feel KSQ has already validated their approach and stimulated further interest in using CRISPR as a research tool.

“There’s a lot of interest in CRISPR as a therapeutic, and that’s an important aspect,” Weissman says. “But I’d argue equally important both in discovery and in therapeutics will be [using CRISPR] to identify the targets you want to go after to affect disease process. Your ability to engineer genomes or make drugs depends on knowing what genes you want to change.”

Five from MIT elected to American Academy of Arts and Sciences for 2021

Prestigious honor society announces more than 250 new members.

MIT News Office
April 23, 2021

Five MIT faculty members are among more than 250 leaders from academia, business, public affairs, the humanities, and the arts elected to the American Academy of Arts and Sciences, the academy announced Thursday.

One of the nation’s most prestigious honorary societies, the academy is also a leading center for independent policy research. Members contribute to academy publications, as well as studies of science and technology policy, energy and global security, social policy and American institutions, the humanities and culture, and education.

Those elected from MIT this year are:

  • Linda Griffith, the School of Engineering Professor of Teaching Innovation, Biological Engineering, and Mechanical engineering;
  • Muriel Médard, the Cecil H. Green Professor in the Department of Electrical Engineering;
  • Leona Samson, professor of biological engineering and biology;
  • Scott Sheffield, the Leighton Family Professor in the Department of Mathematics; and
  • Li-Huei Tsai, the Picower Professor in the Department of Brain and Cognitive Sciences.

“We are honoring the excellence of these individuals, celebrating what they have achieved so far, and imagining what they will continue to accomplish,” says David Oxtoby, president of the academy. “The past year has been replete with evidence of how things can get worse; this is an opportunity to illuminate the importance of art, ideas, knowledge, and leadership that can make a better world.”

Since its founding in 1780, the academy has elected leading thinkers from each generation, including George Washington and Benjamin Franklin in the 18th century, Maria Mitchell and Daniel Webster in the 19th century, and Toni Morrison and Albert Einstein in the 20th century. The current membership includes more than 250 Nobel and Pulitzer Prize winners.

These worms’ stem cells are developmental shapeshifters
Eva Frederick | Whitehead Institute
April 20, 2021

Planarians are small water-dwelling worms known for their regenerative capacity. If you chop one into ten pieces, you’ll end up with ten fully-formed worms.

While humans have pools of specialized stem cells that can create our regenerative body parts like hair and skin, these worms owe their regenerative superpowers to a special kind of stem cell called a neoblast. At least some of these cells are “pluripotent,” meaning that they can divide to create almost any cell type in a worm’s body at any time. Neoblasts are actually the only dividing cells in planarians — fully committed cells like those in the eyes or intestines cannot divide again.

“The big question for us is, how does a neoblast go from being able to make anything, to making one particular thing?” says Amelie Raz, a postdoctoral researcher at Whitehead Institute who conducted her graduate research in the lab of Whitehead Institute Member Peter Reddien. “How do they go from being able to make anything in the body to being, say, an intestine cell that’s going to stay an intestine cell until it dies?”

Now, in a paper published online April 20 in the journal Cell Stem Cell, researchers at Whitehead Institute lay out a new model for how these stem cells commit to their fates and go on to create fully differentiated cells. The process of cellular differentiation is often viewed as a hierarchy, with one special stem cell at the top which can take a number of potential paths to arrive at a specialized state. This is generally thought to take place over a series of cell divisions in which each generation’s fate is gradually restricted.

“We’re proposing something happens that is very different from the conventional view,” says senior author Reddien, who is also a professor of biology at Massachusetts Institute of Technology and an investigator with the Howard Hughes Medical Institute. “We think that stem cells can make broad jumps in state without going through a series of fate-restricting divisions. We call it the single-step fate model.”

In the new model, neoblasts that are on a path toward creating skin cells or intestine cells can produce progeny cells that can switch fates to create cells of other types. The work is a step in the long road to understanding these worms’ regenerative capacities, and could possibly inform regenerative medicine approaches far in the future.

“The ability of planarian stem cells to essentially switch their fate is really, really powerful,” says Raz, the first author of the paper. “Obviously this is a long way off, but theoretically the concept of stem cell fate switching could be applied to regenerative medicine, with human stem cell programming.”

Upturning the hierarchy

Neoblasts can be sorted into many “classes.” For example, one class of neoblasts contains all the materials to make skin cells, and others have the necessary toolkit to form the worms’ primitive kidneys or their intestines. According to the hierarchical model, these specialized neoblasts are intermediaries between a pluripotent cell at the top of the hierarchy, and the non-dividing body cells.

“You can imagine that the special cell at the top is a blank slate with no predisposition towards any cell type — it can make anything,” says Raz. “This is how we’ve often imagined development works.”

But Raz, Reddien and Omri Wurtzel, a former postdoc in the Reddien lab now at Tel Aviv University, started to question this assumption after noticing a few mysterious properties of planarian cells.

First of all, researchers have observed in the past that when a planarian is treated with radiation to kill all existing stem cells, a single neoblast can rescue the animal by forming a colony containing many different classes of neoblasts. If, as previous theories suggested, there was a single class of neoblast that gave rise to all these types, Raz and Reddien reasoned that that class should be a common resident in every colony that formed. After creating many of these colonies and analyzing their composition, however, the researchers saw that this was not the case. “For every class we looked at, there were plenty of colonies that lacked that class altogether,” says Reddien. “There was no unique class present in all colonies.”

Another sticking point: the researchers began to realize that, when applying the hierarchy model, the math of planarian cell divisions and potency just didn’t add up. In a prior cell transplantation study, the Reddien lab found that many of the neoblasts they tested were pluripotent —in this study they found that proportion to be larger than what they would expect if only non-specialized neoblasts were pluripotent. “When you add up all the different kinds of specialized neoblasts, it’s at least three quarters of the neoblast population, and almost certainly higher than that.” says Raz. Therefore, the researchers wondered if some specialized neoblasts could be pluripotent as well.

Another study from the Reddien lab showed that skin-specialized neoblasts did not retain skin fate through more than one cell division. Also, in about half of all cell divisions in planarians, the two daughter cells will be different from one another. This raised the possibility that specialized neoblasts can divide asymmetrically as a possible route to stem cells changing fate.

Furthermore, the timeline for regeneration was off — the rate at which planarians were able to regrow body parts didn’t allow for several rounds of fate-restricting divisions.

After conducting experiments to study these different situations, Raz, Wurtzel, and Reddien were able to create a case for their new model of cell differentiation. “What we think is happening is that planarians have a ton of plasticity in their general stem cell population, where individual cells can move in and out of different specialized stages through the process of cell division in order to give rise to what is required,” Raz says.

“This is just the beginning of exploring this process, even though we’ve been studying it for many years,” Reddien says. “Focusing on the model, we’re suggesting that the cells can choose one fate, and then through the process of a division with an asymmetric outcome, one of the daughter cells can now divide again and choose a different fate. That fate switching process might be fundamental to explaining pluripotency.”

Reddien’s lab will continue investigating the mechanisms of neoblast fate specification, including how specialization lines up with the timing of the cell cycle.

“Understanding the structure of cell lineage and how fate choices are made is fundamental to understanding adult stem cell biology, and how in the context of injury and repair, new cells can be brought about,” says Reddien. “Do they have to go through long, complex lineage trajectories? Or can they make big jumps in state from stem cells to the final state? How flexible is that? All of these things have potential implications for understanding stem cell biology broadly, and we hope that the work will highlight some of these mechanisms and provide opportunities to explore general principles in the future.”

Two heads are better than one, but two disciplines are even better

How biologists and mathematicians reached across departmental lines to solve a long-standing problem in electron microscopy

Saima Sidik | Department of Biology
April 19, 2021

MIT’s Hockfield Court is bordered on the west by the ultra-modern Stata Center, with its reflective, silver alcoves that jut off at odd angles, and on the east by Building 68, which is a simple, window-lined, cement rectangle. At first glance, Bonnie Berger’s mathematics lab in the Stata Center and Joey Davis’s biology lab in Building 68 are as different as the buildings that house them. And yet, a recent collaboration between these two labs shows how their disciplines complement each other. The partnership started when Ellen Zhong, a graduate student from the Computational and Systems Biology (CSB) Program, decided to use a computational pattern-recognition tool called a neural network to study the shapes of molecular machines. Three years later, Zhong’s project is letting scientists see patterns that run beneath the surface of their data, and deepening their understanding of the molecules that shape life.

Zhong’s work builds on a technique from the 1970s called cryo-electron microscopy (cryo-EM), which lets researchers take high-resolution images of frozen protein complexes. Over the last decade, better microscopes and cameras have led to a “resolution revolution” in cryo-EM that’s allowed scientists to see individual atoms within proteins. But, as good as these images are, they’re still only static snapshots. In reality, many of these molecular machines are constantly changing shape and composition as cells carry out their normal functions and adjust to new situations.

Along with former Berger lab member Tristan Belper, Zhong devised software called cryoDRGN. The tool uses neural nets to combine hundreds of thousands of cryo-EM images, and shows scientists the full range of three-dimensional conformations that protein complexes can take, letting them reconstruct the proteins’ motion as they carry out cellular functions. Understanding the range of shapes that protein complexes can take helps scientists develop drugs that block viruses from entering cells, study how pests kill crops, and even design custom proteins that can cure disease. COVID-19 vaccines, for example, work partly because they include a mutated version of the virus’s spike protein that’s stuck in its active conformation, so vaccinated people produce antibodies that block the virus from entering human cells. Scientists needed to understand the variety of shapes that spike proteins can take in order to figure out how to force spike into its active conformation.

Two women standing by rock wall
Graduate student Ellen Zhong (right), and her co-advisor, Professor of Mathematics Bonnie Berger (left)

Getting off the computer and into the lab

Zhong’s interest in computational biology goes back to 2011 when, as a chemical engineering undergrad at the University of Virginia, she worked with Professor Michael Shirts to simulate how proteins fold and unfold. After college, Zhong took her skills to a company called D. E. Shaw Research, where, as a Scientific Programmer, she took a computational approach to studying how proteins interact with small molecule drugs.

“The research was very exciting,” Zhong says, “but all based on computer simulations. To really understand biological systems, you need to do experiments.”

This goal of combining computation with experimentation motivated Zhong to join MIT’s CSB PhD program, where students often work with multiple supervisors to blend computational work with bench work. Zhong “rotated” in both the Davis and Berger labs, then decided to combine the Davis lab’s goal of understanding how protein complexes form with the Berger lab’s expertise in machine learning and algorithms. Davis was interested in building up the computational side of his lab, so he welcomed the opportunity to co-supervise a student with Berger, who has a long history of collaborating with biologists.

Davis himself holds a dual bachelor’s degree in computer science and biological engineering, so he’s long believed in the power of combining complementary disciplines. “There are a lot of things you can learn about biology by looking in a microscope,” he says. “But as we start to ask more complicated questions about entire systems, we’re going to require computation to manage the high-dimensional data that come back.”

Before rotating in the Davis lab, Zhong had never performed bench work before — or even touched a pipette. She was fascinated to find how streamlined some very powerful molecular biology techniques can be. Still, Zhong realized that physical limitations mean that biology is much slower when it’s done at the bench instead of on a computer. “With computational research, you can automate experiments and run them super quickly, whereas in the wet lab, you only have two hands, so you can only do one experiment at a time,” she says.

Zhong says that synergizing the two different cultures of the Davis and Berger labs is helping her become a well-rounded, adaptable scientist. Working around experimentalists in the Davis lab has shown her how much labor goes into experimental results, and also helped her to understand the hurdles that scientists face at the bench. In the Berger lab, she enjoys having coworkers who understand the challenges of computer programming.

“The key challenge in collaborating across disciplines is understanding each other’s ‘languages’,” Berger says. “Students like Ellen are fortunate to be learning both biology and computing dialects simultaneously.”

Bringing in the community

Man smiling outside
Zhong’s second co-advisor, Professor Joey Davis

Last spring revealed another reason for biologists to learn computational skills: these tools can be used anywhere there’s a computer and an internet connection. When the COVID-19 pandemic hit, Zhong’s colleagues in the Davis lab had to wind down their bench work for a few months, and many of them filled their time at home by using cryo-EM data that’s freely available online to help Zhong test her cryoDRGN software. The difficulty of understanding another discipline’s language quickly became apparent, and Zhong spent a lot of time teaching her colleagues to be programmers. Seeing the problems that non-programmers ran into when they used cryoDRGN was very informative, Zhong says, and helped her create a more user-friendly interface.

Although the paper announcing cryoDRGN was only recently published, the tool created a stir as soon as Zhong posted her code online, many months prior. The cryoDRGN team thinks this is because leveraging knowledge from two disciplines let them visualize the full range of structures that protein complexes can have, and that’s something researchers have wanted to do for a long time. For example, the cryoDRGN team recently collaborated with researchers from Harvard and Washington University to study locomotion of the single-celled organism Chlamydomonas reinhardtii. The mechanisms they uncovered could shed light on human health conditions, like male infertility, that arise when cells lose the ability to move. The team is also using cryoDRGN to study the structure of the SARS-CoV-2 spike protein, which could help scientists design treatments and vaccines to fight coronaviruses.

Zhong, Berger, and Davis say they’re excited to continue using neural nets to improve cryo-EM analysis, and to extend their computational work to other aspects of biology. Davis cited mass spectrometry as “a ripe area to apply computation.” This technique can complement cryo-EM by showing researchers the identities of proteins, how many of them are bound together, and how cells have modified them.

“Collaborations between disciplines are the future,” Berger says. “Researchers focused on a single discipline can take it only so far with existing techniques. Shining a different lens on the problem is how advances can be made.”

Zhong says it’s not a bad way to spend a PhD, either. Asked what she’d say to incoming graduate students considering interdisciplinary projects, she says: “definitely do it.”

Undergraduate students meld biology and art to forge remote collaborations
April 14, 2021

Taught for the first time in 2013, 7.016 (Introductory Biology) introduces MIT undergraduates to fundamental principles of biochemistry, molecular biology, and genetics. While the class has historically packed over 200 students into a lecture hall, the past two iterations have been held over Zoom due to COVID-19 restrictions. In order to incite collaboration and spur creativity in a remote setting, Professor of Biology and Chemistry, Barbara Imperiali, Associate Professor of Biology, Adam Martin, and MITxBio Instructor, Monika Avello, have infused the homework assignments with some whimsey.

One bonus question on a problem set required students to work together in teams to devise a cartoon of the Statue of Liberty. Inspired by a drawing in Chemical & Engineering News that depicted Lady Liberty clad in chemistry gear, Imperiali, Martin, and Avello asked the students to re-imagine the cartoon with a biology theme instead.

“We wanted to create a light-hearted, fun, and rewarding opportunity for 7.016 students to collaborate and connect with each other in our remote class,” Avello says. “We were totally blown away by how creative and talented the students were. So many of them went above and beyond by modifying the cartoon template we provided to showcase their creativity and artistic skills.”
Below is a sampling of responses from the assignment.
Black and white sketch of the Statue of Liberty
Credit: Gary Nguyen and Sandra Tang

This biology-inspired Statue of Liberty features a crown made of deoxyribose (the 5-carbon sugar in DNA). Per lab protocol, she has also donned safety goggles and disposable gloves. She holds some DNA in one hand and a microscope inspecting a cell in the other.

Cartoon of Statue of Liberty
Credit: Cindy Jie and Dion Sukhram

A DNA sash, hydroxyl eyes, and a crown of SARS-CoV-2 spike proteins highlight some of the details that were central to class discussions this semester. With a textbook in hand and her mitochondria torch held high, this cute comic lifted students’ spirits.

Statue of Liberty and a sunset
Credit: Andrew Emmel and Yoni Haile

In one hand, Lady Liberty is holding a microscope to symbolize discovery. She is holding a petri dish in the other hand, indicating that data are absolute. Her crown is a centrifuge, because the experiment is “king.” And the sunglasses? Those are to show that biology is cool.

Cartoon of Statue of Liberty as a red blood cell
Credit: Joanna Cao and Sarah Wei

Here, Lady Liberty takes the form of a red blood cell, which carries oxygen all over the body. As such, she is holding an oxygen molecule in one hand. In the other hand, she holds carbon dioxide.

Sketch of the Statue of Liberty made of molecules
Credit: Savannah Ashley, Katia Pendowski, and Malia Smith

This cartoon features Lady Liberty standing on the lipid bilayer that constitutes the membrane encircling a cell’s internal components. She is holding a DNA molecule and wearing a dress with deoxyribose molecules, which form the “backbone” of DNA. She is also sporting a crown with adenosine triphosphate (ATP) molecules — providing energy to drive cellular processes — and holding a torch of proteins.