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Childhood hobbies jump-start a research career

MIT Biology junior Eduardo Canto tinkered with science long before he started studying Treacher Collins syndrome in the Calo lab.

Saima Sidik | Department of Biology
May 19, 2021

In seventh grade, Eduardo Canto wanted a dog. His mom said no, though. She didn’t want to spend her days vacuuming fur. They reached a compromise: Canto was allowed to have pet fish. Soon Canto’s disappointment with his new pets turned to curiosity. While he couldn’t train the fish to sit or roll over, he decided that breeding the fish could be a fun pastime.

An internet search told Canto that some aquarists use dried Indian almond leaves, a traditional Asian herbal remedy, to stimulate fish breeding, although no one is quite sure how the leaves do this. However, finding Indian almond leaves presented a problem for a kid without an Amazon account living far from the tree’s native habitat. On a whim, Canto picked up some similar-looking leaves in a park near his house in Puerto Rico. He knew they weren’t from an Indian almond tree, but he put them in the tank anyhow, just to see what would happen. A few days later, he noticed a collection of eggs attached to the bottom of a leaf!

Canto often took on little experiments like this, which caused his grandfather to predict early on that he would have a scientific career. Eight years after the breeding endeavor, Canto is fulfilling his grandfather’s prediction by studying Course 7 (Biology) at MIT, where he’s currently in his third year of a bachelor’s degree. Once again, fish have come into Canto’s life — he’s working in Eliezer Calo’s lab, where researchers use zebrafish to study a genetic disorder called Treacher Collins syndrome, which causes deformities in eyes, ears, cheekbones, and chins.

Throughout middle school and high school, Canto dipped his toes into many scientific disciplines. School science fairs motivated him to build a dry ice-powered trolley, a solar-powered water heater, and start a vegetable garden.

Sometimes, he admits, his motivation for joining science clubs wasn’t lofty. “I joined the math club because I got to miss a day of school every year for their annual competition,” he says with a laugh. But he also talks excitedly about his early experiments, particularly in biology. “I’ve always loved working with my hands,” he says.

Canto’s father, a medical doctor, encouraged his son’s interest by letting Canto shadow him at work. He also started a molecular biology summer program at Canto’s high school that taught students how to pipette and do simple experiments. By the time Canto applied to college, he was convinced he wanted to study biology, and MIT drew his attention because of its reputation as a top science school with excellent biology teachers. He knew it was the right choice for him when he attended Campus Preview Weekend, and found a large Puerto Rican community ready to welcome him. Even far from the island, he felt at home.

Canto has kept up with his roots since joining MIT by playing on a soccer team for Puerto Rican students. He’s also become part of a new community in a lab run by Eliezer Calo — who is a Puerto Rican himself. The lab is interested in ribosomes, the molecular machines that build proteins. Treacher Collins syndrome arises when cells can’t make ribosomes properly, and Canto wants to understand why that is.

Before Canto joined the Calo lab, the group had already started studying a protein called DDX21 that’s involved in making ribosomes in both humans and zebrafish. When genetic mutations in zebrafish cause DDX21 to go to the wrong part of the cell, the fish develop jaw deformations that mirror Treacher Collins syndrome. The Calo lab thinks cells with mislocalized DDX21 probably don’t produce ribosomes as well as normal cells, but they’re still testing this hypothesis.

Canto wants to probe the relationship between DDX21 and Treacher Collins syndrome further, but fish reproduce slowly, so they’re not ideal organisms for his research. Instead, he’s built a strain of Escherichia coli bacteria that carry DDX21 in place of the equivalent bacterial gene. DDX21 helps these bacteria survive the stress associated with cold temperatures, so without it, the bacteria will die in the cold. Canto hopes to take advantage of this trait by finding small molecules that stop the bacteria from growing at low temperatures — just like a DDX21 mutation would. Studying how these molecules bind DDX21 will help him understand which parts of this protein are important for its function.

The possibility that this work will one day reveal how Treacher Collins syndrome develops in patients is rewarding to Canto, and in fact he hopes helping patients will soon become his life’s focus. He wants to attend medical school, and eventually become a doctor. The human physiology class he took last semester was one of his favorites, even though it was over Zoom due to the COVID-19 pandemic. Becoming a doctor will let him help others while studying topics he finds fascinating. “Medicine is like biology on steroids!” he says.

And who knows — one day after he’s a doctor, maybe he’ll even get that pet he’s always wanted. But unlike Canto’s interest in biology, some of his interests have evolved over time. These days, he prefers cats over dogs.

Photo credit: Saima Sidik
Posted: 5.19.21
Kristin Knouse

Education

  • PhD, 2017, MIT; MD, 2018, Harvard Medical School
  • Undergraduate: BS, 2010, Biology, Duke University

Research Summary

We aim to understand how tissues sense and respond to damage with the goal of developing novel treatments for diverse human diseases. We focus on the mammalian liver, which has the unique ability to completely regenerate itself, in order to identify the molecular requirements for effective organ repair. To this end, we innovate genetic, molecular, and cellular tools that allow us to investigate and modulate organ injury and regeneration directly within living organisms.

Awards

  • NIH Director’s Early Independence Award, 2018
  • Henry Asbury Christian Award, 2018
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.”