Research Area: Cell Biology

Scientists unveil the functional landscape of essential genes

Researchers harness new pooled, image-based screening method to probe the functions of over 5,000 essential genes in human cells.

Nicole Davis | Whitehead Institute
November 21, 2022

A team of scientists at the Whitehead Institute for Biomedical Research and the Broad Institute of MIT and Harvard has systematically evaluated the functions of over 5,000 essential human genes using a novel, pooled, imaged-based screening method. Their analysis harnesses CRISPR-Cas9 to knock out gene activity and forms a first-of-its-kind resource for understanding and visualizing gene function in a wide range of cellular processes with both spatial and temporal resolution. The team’s findings span over 31 million individual cells and include quantitative data on hundreds of different parameters that enable predictions about how genes work and operate together. The new study appears in the Nov. 7 online issue of the journal Cell.

“For my entire career, I’ve wanted to see what happens in cells when the function of an essential gene is eliminated,” says MIT Professor Iain Cheeseman, who is a senior author of the study and a member of Whitehead Institute. “Now, we can do that, not just for one gene but for every single gene that matters for a human cell dividing in a dish, and it’s enormously powerful. The resource we’ve created will benefit not just our own lab, but labs around the world.”

Systematically disrupting the function of essential genes is not a new concept, but conventional methods have been limited by various factors, including cost, feasibility, and the ability to fully eliminate the activity of essential genes. Cheeseman, who is the Herman and Margaret Sokol Professor of Biology at MIT, and his colleagues collaborated with MIT Associate Professor Paul Blainey and his team at the Broad Institute to define and realize this ambitious joint goal. The Broad Institute researchers have pioneered a new genetic screening technology that marries two approaches — large-scale, pooled, genetic screens using CRISPR-Cas9 and imaging of cells to reveal both quantitative and qualitative differences. Moreover, the method is inexpensive compared to other methods and is practiced using commercially available equipment.

“We are proud to show the incredible resolution of cellular processes that are accessible with low-cost imaging assays in partnership with Iain’s lab at the Whitehead Institute,” says Blainey, a senior author of the study, an associate professor in the Department of Biological Engineering at MIT, a member of the Koch Institute for Integrative Cancer Research at MIT, and a core institute member at the Broad Institute. “And it’s clear that this is just the tip of the iceberg for our approach. The ability to relate genetic perturbations based on even more detailed phenotypic readouts is imperative, and now accessible, for many areas of research going forward.”

Cheeseman adds, “The ability to do pooled cell biological screening just fundamentally changes the game. You have two cells sitting next to each other and so your ability to make statistically significant calculations about whether they are the same or not is just so much higher, and you can discern very small differences.”

Cheeseman, Blainey, lead authors Luke Funk and Kuan-Chung Su, and their colleagues evaluated the functions of 5,072 essential genes in a human cell line. They analyzed four markers across the cells in their screen — DNA; the DNA damage response, a key cellular pathway that detects and responds to damaged DNA; and two important structural proteins, actin and tubulin. In addition to their primary screen, the scientists also conducted a smaller, follow-up screen focused on some 200 genes involved in cell division (also called “mitosis”). The genes were identified in their initial screen as playing a clear role in mitosis but had not been previously associated with the process. These data, which are made available via a companion website, provide a resource for other scientists to investigate the functions of genes they are interested in.

“There’s a huge amount of information that we collected on these cells. For example, for the cells’ nucleus, it is not just how brightly stained it is, but how large is it, how round is it, are the edges smooth or bumpy?” says Cheeseman. “A computer really can extract a wealth of spatial information.”

Flowing from this rich, multi-dimensional data, the scientists’ work provides a kind of cell biological “fingerprint” for each gene analyzed in the screen. Using sophisticated computational clustering strategies, the researchers can compare these fingerprints to each other and construct potential regulatory relationships among genes. Because the team’s data confirms multiple relationships that are already known, it can be used to confidently make predictions about genes whose functions and/or interactions with other genes are unknown.

There are a multitude of notable discoveries to emerge from the researchers’ screening data, including a surprising one related to ion channels. Two genes, AQP7 and ATP1A1, were identified for their roles in mitosis, specifically the proper segregation of chromosomes. These genes encode membrane-bound proteins that transport ions into and out of the cell. “In all the years I’ve been working on mitosis, I never imagined ion channels were involved,” says Cheeseman.

He adds, “We’re really just scratching the surface of what can be unearthed from our data. We hope many others will not only benefit from — but also build upon — this resource.”

This work was supported by grants from the U.S. National Institutes of Health as well as support from the Gordon and Betty Moore Foundation, a National Defense Science and Engineering Graduate Fellowship, and a Natural Sciences and Engineering Research Council Fellowship.

Genome-wide screens could reveal the liver’s secrets

A new technique for studying liver cells within an organism could shed light on the genes required for regeneration.

Anne Trafton | MIT News Office
November 15, 2022

The liver’s ability to regenerate itself is legendary. Even if more than 70 percent of the organ is removed, the remaining tissue can regrow an entire new liver.

Kristin Knouse, an MIT assistant professor of biology, wants to find out how the liver is able to achieve this kind of regeneration, in hopes of learning how to induce other organs to do the same thing. To that end, her lab has developed a new way to perform genome-wide studies of the liver in mice, using the gene-editing system CRISPR.

With this new technique, researchers can study how each of the genes in the mouse genome affects a particular disease or behavior. In a paper describing the technique, the researchers uncovered several genes important for liver cell survival and proliferation that had not been seen before in studies of cells grown in a lab dish.

“If we really want to understand mammalian physiology and disease, we should study these processes in the living organism wherever possible, as that’s where we can investigate the biology in its most native context,” says Knouse, who is also a member of MIT’s Koch Institute for Integrative Cancer Research.

Knouse is the senior author of the new paper, which appears today in Cell Genomics. Heather Keys, director of the Functional Genomics Platform at the Whitehead Institute, is a co-author on the study.

Extracellular context

As a graduate student at MIT, Knouse used regenerating liver tissue as a model to study an aspect of cell division called chromosome segregation. During this study, she observed that cells dividing in the liver did not behave the same way as liver cells dividing in a lab dish.

“What I internalized from that research was the extent to which something as intrinsic to the cell as cell division, something we have long assumed to be independent of anything beyond the cell, is clearly influenced by the extracellular environment,” she says. “When we study cells in culture, we lose the impact of that extracellular context.”

However, many types of studies, including genome-wide screens that use technologies such as CRISPR, are more difficult to deploy at the scale of an entire organism. The CRISPR gene-editing system consists of an enzyme called Cas9 that cuts DNA in a given location, directed by a strand of RNA called a guide RNA. This allows researchers to knock out one gene per cell, in a huge population of cells.

While this approach can reveal genes and proteins involved in specific cellular processes, it has proven difficult to deliver CRISPR components efficiently to enough cells in the body to make it useful for animal studies. In some studies, researchers have used CRISPR to knock out about 100 genes of interest, which is useful if they know which genes they want to study, but this limited approach doesn’t reveal new genes linked to a particular function or disease.

A few research groups have used CRISPR to do genome-wide screens in the brain and in skin cells, but these studies required large numbers of mice to uncover significant hits.

“For us, and I think many other researchers, the limited experimental tractability of mouse models has long hindered our capacity to dive into questions of mammalian physiology and disease in an unbiased and comprehensive manner,” Knouse says. “That’s what I really wanted to change, to bring the experimental tractability that was once restricted to cell culture into the organism, so that we are no longer limited in our ability to explore fundamental principles of physiology and disease in their native context.”

To get guide RNA strands into hepatocytes, the predominant cell type in the liver, Knouse decided to use lentivirus, an engineered nonpathogenic virus that is commonly used to insert genetic material into the genome of cells. She injected the guide RNAs into newborn mice, such that once the guide RNA was integrated into the genome, it would be passed on to future generations of liver cells as the mice grew. After months of effort in the lab, she was able to get guide RNAs consistently expressed in tens of millions of hepatocytes, which is enough to do a genome-wide screen in just a single animal.

Cellular fitness

To test the system, the researchers decided to look for genes that influence hepatocyte fitness — the ability of hepatocytes to survive and proliferate. To do that, they delivered a library of more than 70,000 guide RNAs, targeting more than 13,000 genes, and then determined the effect of each knockout on cell fitness.

The mice used for the study were engineered so that Cas9 can be turned on at any point in their lifetime. Using a group of four mice — two male and two female — the researchers turned on expression of Cas9 when the mice were five days old. Three weeks later, the researchers screened their liver cells and measured how much of each guide RNA was present. If a particular guide RNA is abundant, that means the gene it targets can be knocked out without fatally damaging the cells. If a guide RNA doesn’t show up in the screen, it means that knocking out that gene was fatal to the cells.

This screen yielded hundreds of genes linked to hepatocyte fitness, and the results were very consistent across the four mice. The researchers also compared the genes they identified to genes that have been linked to human liver disease. They found that genes mutated in neonatal liver failure syndromes also caused hepatocyte death in their screen.

The screen also revealed critical fitness genes that had not been identified in studies of liver cells grown in a lab dish. Many of these genes are involved in interactions with immune cells or with molecules in the extracellular matrix that surrounds cells. These pathways likely did not turn up in screens done in cultured cells because they involve cellular interactions with their external environment, Knouse says.

By comparing the results from the male and female mice, the researchers also identified several genes that had sex-specific effects on fitness, which would not have been possible to pick up by studying cells alone.

Renew and regenerate

Knouse now plans to use this system to identify genes that are critical for liver regeneration.

“Many tissues such as the heart are unable to regenerate because they lack stem cells and the differentiated cells are unable to divide. However, the liver is also a highly differentiated tissue that lacks stem cells, yet it retains this amazing capacity to regenerate itself after injury,” she says. “Importantly, the genome of the liver cells is no different from the genome of the heart cells. All of these cells have the same instruction manual in their nucleus, but the liver cells are clearly reading different sentences in this manual in order to regenerate. What we don’t know is, what are those sentences? What are those genes? If we can identify those genes, perhaps someday we can instruct the heart to regenerate.”

This new screening technique could also be used to study conditions such as fatty liver disease and cirrhosis. Knouse’s lab is also working on expanding this approach to organs other than the liver.

“We need to find ways to get guide RNAs into other tissues at high efficiency,” she says. “In overcoming that technical barrier, then we can establish the same experimental tractability that we now have in the liver in the heart or other issues.”

The research was funded by the National Institutes of Health NIH Director’s Early Independence Award, the Koch Institute Support (core) Grant from the National Cancer Institute, and the Scott Cook and Signe Ostby Fund.

Introducing the Amon Award Winners
MIT Koch Institute
October 25, 2022

Cheers to the inaugural winners of the Koch Institute’s Angelika Amon Young Scientist Award, Alejandro Aguilera and Melanie de Almeida. The new award recognizes graduate students in the life sciences or biomedical research from institutions outside the U.S. who embody Dr. Amon’s infectious enthusiasm for discovery science.

Aguilera, a student at the Weizmann Institute of Science in Israel, has developed a platform for studying mammalian embryogenesis. De Almeida, who recently completed her doctoral work at the Research Institute of Molecular Pathology in Austria, develops CRISPR screens to explore cancer vulnerabilities and gene regulatory networks.

Aguilera and de Almeida will visit the Koch Institute in November to deliver scientific presentations to the MIT community and Amon Lab alumni.

A “door” into the mitochondrial membrane

Study finds the protein MTCH2 is responsible for shuttling various other proteins into the membrane of mitochondria. The finding could have implications for cancer treatments and MTCH2-linked conditions.

Eva Frederick | Whitehead Institute
October 25, 2022

Mitochondria — the organelles responsible for energy production in human cells — were once free-living organisms that found their way into early eukaryotic cells over a billion years ago. Since then, they have merged seamlessly with their hosts in a classic example of symbiotic evolution, and now rely on many proteins made in their host cell’s nucleus to function properly.

Proteins on the outer membrane of mitochondria are especially important; they allow the mitochondria to communicate with the rest of the cell, and play a role in immune functions and a type of programmed cell death called apoptosis. Over the course of evolution, cells evolved a specific mechanism by which to insert these proteins — which are made in the cell’s cytoplasm — into the mitochondrial membrane. But what that mechanism was, and what cellular players were involved, has long been a mystery.

A new paper from the labs of MIT Professor Jonathan Weissman and Caltech Professor Rebecca Voorhees provides a solution to that mystery. The work, published Oct. 21 in the journal Science, reveals that a protein called mitochondrial carrier homolog 2, or MTCH2 for short, which has been linked to many cellular processes and even diseases such as cancer and Alzheimer’s, is responsible for acting as a “door” for a variety of proteins to access the mitochondrial membrane.

“Until now, no one knew what MTCH2 was really doing — they just knew that when you lose it, all these different things happen to the cell,” says Weissman, who is also member of the Whitehead Institute for Biomedical Research and an investigator of the Howard Hughes Medical Institute. “It was sort of a mystery why this one protein affects so many different processes. This study gives a molecular basis for understanding why MTCH2 was implicated in Alzheimer’s and lipid biosynthesis and mitochondrial fission and fusion: because it was responsible for inserting all these different types of proteins in the membrane.”

“The collaboration between our labs was essential in understanding the biochemistry of this interaction, and has led to a really exciting new understanding of a fundamental question in cell biology,” Voorhees says.

The search for a door 

In order to find out how proteins from the cytoplasm — specifically a class called tail-anchored proteins — were being inserted into the outer membranes of mitochondria, Weismann Lab postdoc and first author of the study Alina Guna, alongside Voorhees Lab graduate student Taylor Stevens and postdoc Alison Inglis, decided to use a technique called used the CRISPR interference (or CRISPRi) screening approach, which was invented by Weissman and collaborators.

“The CRISPR screen let us systematically get rid of every gene, and then look and see what happened [to one specific tail-anchored protein],” says Guna. “We found one gene, MTCH2, where when we got rid of it there was a huge decrease in how much of our protein got to the mitochondrial membrane. So we thought, maybe this is the doorway to get in.”

To confirm that MTCH2 was acting as a doorway into the mitochondrial membrane, the researchers performed additional experiments to observe what happened when MTCH2 was not present in the cell. They found that MTCH2 was both necessary and sufficient to allow tail-anchored membrane proteins to move from the cytoplasm into the mitochondrial membrane.

MTCH2’s ability to shuttle proteins from the cytoplasm into the mitochondrial membrane is likely due to its specialized shape. The researchers ran the protein’s sequence through Alpha Fold, an artificial intelligence system that predicts a protein’s structure through its amino acid sequence, which revealed that it is a hydrophobic protein — perfect for inserting into the oily membrane — but with a single hydrophilic groove where other proteins could enter.

“It’s basically like a funnel,” Guna says. “Proteins come from the cytosol, they slip into that hydrophilic groove and then move from the protein into the membrane.”

To confirm that this groove was important in the protein’s function, Guna and her colleagues designed another experiment. “We wanted to play around with the structure to see if we could change its behavior, and we were able to do that,” Guna says. “We went in and made a single point mutation, and that point mutation was enough to really change how the protein behaved and how it interacted with substrates. And then we went on and found mutations that made it less active and mutations that made it super active.”

The new study has applications beyond answering a fundamental question of mitochondria research. “There’s a whole lot of things that come out of this,” Guna says.

For one thing, MTCH2 inserts proteins key to a type of programmed cell death called apoptosis, which researchers could potentially harness for cancer treatments. “We can make leukemia cells more sensitive to a cancer treatment by giving them a mutation that changes the activity of MTCH2,” Guna says. “The mutation makes MTCH2 act more ‘greedy’ and insert more things into the membrane, and some of those things that have inserts are like pro-apoptotic factors, so then those cells are more likely to die, which is fantastic in the context of a cancer treatment.”

The work also raises questions about how MTCH2 developed its function over time. MTCH2 evolved from a family of proteins called the solute carriers, which shuttle a variety of substances across cellular membranes. “We’re really interested in this evolution question of, how do you evolve a new function from an old, ubiquitous class of proteins?” Weissman says.

And researchers still have much to learn about how mitochondria interact with the rest of the cell, including how they react to stress and changes within the cell, and how proteins find their way to mitochondria in the first place. “I think that [this paper] is just the first step,” Weissman says. “This only applies to one class of membrane proteins — and it doesn’t tell you all of the steps that happen after the proteins are made in the cytoplasm. For example, how are they ferried to mitochondria? So stay tuned — I think we’ll be learning that we now have a very nice system for opening up this fundamental piece of cell biology.”

Sally Kornbluth is named as MIT’s 18th president

As Duke University’s provost since 2014, she has advocated for faculty excellence and reinforced the institution’s commitment to the student experience.

Steve Bradt | MIT News Office
October 20, 2022

Sally A. Kornbluth, a cell biologist whose eight-year tenure as Duke University’s provost has earned her a reputation as a brilliant administrator, a creative problem-solver, and a leading advocate of academic excellence, has been selected as MIT’s 18th president.

Kornbluth, 61, was elected to the post this morning by a vote of the MIT Corporation. She will assume the MIT presidency on Jan. 1, 2023, succeeding L. Rafael Reif, who last February announced his intention to step down after 10 years leading the Institute.

A distinguished researcher and dedicated mentor, Kornbluth is currently the Jo Rae Wright University Professor of Biology at Duke. She has served on the Duke faculty since 1994, first as a member of the Department of Pharmacology and Cancer Biology in the Duke University School of Medicine and then as a member of the Department of Biology in the Trinity College of Arts and Sciences.

As Duke’s provost since 2014, Kornbluth has served as the chief academic officer of one of the nation’s leading research universities, with broad responsibility for carrying out Duke’s teaching and research missions; developing its intellectual priorities; and partnering with others to achieve wide-ranging gains for the university’s faculty and students. She oversees Duke’s 10 schools and six institutes, and holds ultimate responsibility for admissions, financial aid, libraries, and all other facets of academic and student life.

“The ethos of MIT, where groundbreaking research and education are woven into the DNA of the institution, is thrilling to me,” Kornbluth says. “The primary role of academic leadership is in attracting outstanding scholars and students, and in supporting their important work. And when it comes to the impact of that work, MIT is unparalleled — in the power of its innovations, in its ability to move those innovations into the world, and in its commitment to discovery, creativity, and excellence.”

“My greatest joy as a leader has always been in facilitating and amplifying the work of others,” Kornbluth adds. “I am eager to meet all the brilliant, entrepreneurial people of MIT, and to champion their research, teaching, and learning.”

A broad search with extensive consultation

Kornbluth’s election as MIT’s president is the culmination of an eight-month process in which a 20-member presidential search committee generated a list of approximately 250 possible candidates for the presidency. These candidates brought a broad range of backgrounds in academia and beyond, and included both members of the MIT community and people outside the Institute.

“Dr. Sally Kornbluth is an extraordinary find for MIT,” says MIT Corporation Chair Diane B. Greene SM ’78. “She is decisive and plain-spoken, a powerhouse administrator who has proactively embraced critical issues like free speech and DEI. An accomplished scientist with a liberal arts background, Dr. Kornbluth is a broadly curious, principled leader who deeply understands MIT’s strengths. Her vision and her humanity will inspire our hearts and minds, and her comprehension of the importance of discovery, innovation, and entrepreneurship will serve us well as MIT confronts the challenges of today’s world.”

The presidential search committee was chaired by MIT Corporation Life Member John W. Jarve ’78, SM ’79. Under his leadership, the committee conducted comprehensive outreach with MIT faculty, students, staff, alumni, and individuals beyond MIT.

“Through these exhaustive efforts, we created a list of attributes for MIT’s next president, to ensure our new leader would have a successful tenure at MIT, would be widely embraced by the MIT community, and would maintain MIT’s excellence as the world’s leading science and technology university,” Jarve says. “I am confident that we have found that leader in Sally Kornbluth, who appreciates MIT’s uniqueness, is committed to maintaining its standards of excellence, and is intellectually broad and insatiably curious.”

“Although she is new to MIT, Sally Kornbluth is a scholar who seems cut from our own cloth,” adds Lily L. Tsai, the Ford Professor of Political Science and chair of the MIT faculty, who also served on the search committee. “She is a bold leader with exceptional judgment; an active listener who seeks all viewpoints with a genuinely open-minded approach; a principled, high-integrity individual who is trusted by her community; and a person with experience handling crises with wisdom and calm. I look forward to welcoming her to our community.”

Wide-ranging gains for Duke faculty and students

After becoming Duke’s provost on July 1, 2014, Kornbluth quickly established herself as a transformative leader who partnered eagerly with faculty and others to build upon the university’s strengths. The first woman to serve Duke as its provost, she became a forceful advocate for faculty excellence, advancement, and diversity.

“The presidency of MIT is a wonderful responsibility,” says outgoing President L. Rafael Reif. “Known for her brilliance, wide-ranging curiosity, and collaborative, down-to-earth style, Sally Kornbluth is a terrific choice to lead our distinctive community, and I look forward to seeing MIT continue to flourish under her leadership.”

As provost, Kornbluth prioritized investments to fortify Duke’s faculty, strengthened its leadership in interdisciplinary scholarship and education, and pursued innovations in undergraduate education. She guided the development of a strategic plan, called Together Duke, that engaged faculty from across the university to advance its educational and research mission.

She also spearheaded a concerted effort to cultivate greater strength in science and engineering at Duke, complementing its longstanding prominence in the humanities and social sciences. That effort has led to the addition in recent years of more than two dozen Duke faculty members in the sciences and engineering, with particular focus on quantum computing, data science, materials science, and biological resilience.

Simultaneously, Kornbluth led efforts to develop a pipeline of faculty from underrepresented groups, aiming to make Duke more diverse and inclusive. She created an Office for Faculty Advancement that helped to grow the number of Black faculty members across campus from 67 in 2017 to more than 100 today, and provided seed money for projects aimed at creating a more inclusive environment for underrepresented faculty as well as funding scholarly projects on race and social equity.

As provost, Kornbluth also reinvigorated Duke’s commitment to the student experience, both in and out of the classroom. Her team sought opportunities to make Duke more accessible and affordable, including new scholarships for first-generation students; increases in need-based financial aid; a preorientation program that includes all first-year students; and a new residential system that more closely links living and learning. During her tenure, Duke has also launched university-wide courses that Kornbluth describes as “essential things for every student to understand,” on topics such as race and climate change.

Kornbluth has adapted some of the lessons from those undergraduate-focused initiatives to benefit graduate and professional students, while partnering with Duke’s Graduate School and her vice provosts to improve the quality of mentoring and other support for graduate students.

She oversaw the launch of the undergraduate degree program at Duke Kunshan University, a liberal arts and research university created in partnership with Wuhan University to offer academic programs for students from China and throughout the world. She has sought to extend Duke’s international outreach and has encouraged the development of new partnerships with a focus on social, economic, and environmental issues impacting societies around the world.

Kornbluth also guided many of Duke’s schools, centers, and institutes through significant leadership transitions. She oversaw a number of key leadership hires, including the appointment of new deans for Duke’s Trinity College of Arts and Sciences, the Pratt School of Engineering, Duke Divinity School, the Sanford School of Public Policy, the Nicholas School of the Environment, Duke’s Graduate School, and the Duke University School of Law, as well as the university librarian and a new vice provost for learning innovation and digital education.

“Sally Kornbluth has demonstrated the ability to lead across disciplines, and to catalyze the type of cross-disciplinary initiatives that have been so instrumental to MIT’s ability to contribute advances in technology and engineering for the betterment of the world,” says Kristala L. Jones Prather, the Arthur Dehon Little Professor of Chemical Engineering, who served on the presidential search committee.

From music to political science to genetics

Born in Paterson, New Jersey, Sally Ann Kornbluth grew up in nearby Fair Lawn. Her father, George, was a music-loving accountant; her mother, Myra, was an opera singer who performed regularly at the New York City Opera, the Metropolitan Opera, and elsewhere around the world under the name Marisa Galvany.

Inspired by a high school teacher, Kornbluth studied political science as an undergraduate at Williams College. Early in her undergraduate years, she gave little thought to studying science, until she had to take a course on human biology and social issues as part of distribution requirements needed to graduate.

“I thought it was really interesting, and, once I saw what science was really about, I found it very exciting,” she recalled in a 2014 interview. “I just hadn’t had that opportunity in high school.”

After earning her BA in political science from Williams in 1982, Kornbluth received a scholarship to attend Cambridge University for two years as a Herchel Smith Scholar at Emmanuel College, ultimately earning a BA in genetics from Cambridge in 1984.

Kornbluth returned to the U.S. to pursue a PhD in molecular oncology at Rockefeller University, awarded in 1989, and then went on to postdoctoral training at the University of California at San Diego. She joined the Duke faculty as an assistant professor in the Department of Pharmacology and Cancer Biology in 1994, becoming an associate professor in 2000 and a full professor in 2005.

Research impacts in cellular behavior — and far beyond

At Duke, Kornbluth’s research focused on the biological signals that tell a cell to start dividing or to self-destruct — processes that are key to understanding cancer as well as various degenerative disorders. She has published extensively on cell proliferation and programmed cell death, studying both phenomena in a variety of organisms. Her research has helped to show how cancer cells evade this programmed death, or apoptosis, and how metabolism regulates the cell death process; her work has also clarified the role of apoptosis in regulating the duration of female fertility in vertebrates.

Kornbluth eventually transitioned into administrative roles at Duke for what she describes as “nonaltruistic reasons: I wanted to attract the best possible students, and I wanted better scientific core facilities.” Her first senior administrative position came when she was named vice dean for basic science at the Duke School of Medicine in 2006, a post she held until being named provost in 2014.

In this role, Kornbluth served as a liaison between the dean of medicine and faculty leaders; oversaw biomedical graduate programs; implemented efforts to support research in basic science; allocated laboratory space; oversaw new and existing core laboratories; and worked with department chairs to recruit and retain faculty. From 2009 to 2011, she also oversaw the clinical research enterprise in the Duke School of Medicine.

As Duke’s provost, with a much wider purview, Kornbluth has worked to foster interdisciplinary efforts across campus. “University leaders need to have broad-ranging intellectual curiosity, and interests in a wide range of topics,” she says. “At MIT, I think there is particularly rich potential in the places where science and engineering brush up against the humanities and social sciences. I am eager to soak in the MIT culture, listen, draw out the best from everyone, and do my part to encourage the Institute to grow ever better.”

Members of MIT’s presidential search committee also look forward to Kornbluth’s arrival on campus.

“In our community conversations, we would again and again come back to three important attributes: that the president be someone who embraces MIT’s unique culture, takes care of the people who create it, and is unafraid to improve it,” says committee member Yu Jing Chen ’22, now a graduate student in urban studies and planning. “For these reasons, we couldn’t be more excited to see Sally Kornbluth lead MIT.”

“Sally Kornbluth is someone who cares about people, and she demonstrated at Duke her passion for excellence and her respect for everyone, no matter their role,” says committee member Deborah Liverman, who serves as executive director of MIT Career Advising and Professional Development. “Those are values that are important to the thousands of people who work to keep MIT the extraordinary place it is. I am eager to see what we can accomplish with her leading the way.”​

Among other honors, Kornbluth received the Basic Science Research Mentoring Award from the Duke School of Medicine in 2012 and the Distinguished Faculty Award from the Duke Medical Alumni Association in 2013. She is a member of the National Academy of Medicine, the National Academy of Inventors, and the American Academy of Arts and Sciences.

Kornbluth’s husband, Daniel Lew, is the James B. Duke Professor of Pharmacology and Cancer Biology at the Duke School of Medicine. Their son, Alex, is a PhD student in electrical engineering and computer science at MIT, and their daughter, Joey, is a medical student at the University of California at San Francisco.

Unusual Labmates: How C. elegans Wormed Its Way into Science Stardom
Greta Friar | Whitehead Institute
September 20, 2022

 

Introduction

Michael Stubna, a graduate student in Whitehead Institute Member David Bartel’s lab, peers into his microscope at the Petri dish full of agar gel below. He spots one of his research specimens, a millimeter-long nematode worm known as Caenorhabditis elegans (C. elegans), slithering across the coating of bacteria–the worm’s food source–on the surface of the gel. The worm leaves sinuous tracks in its wake like a skier slaloming down a slope.

 

Four from MIT receive NIH New Innovator Awards for 2022

Awards support high-risk, high-impact research from early-career investigators.

Phie Jacobs | School of Science
October 4, 2022

The National Institutes of Health (NIH) has awarded grants to four MIT faculty members as part of its High-Risk, High-Reward Research program.

The program supports unconventional approaches to challenges in biomedical, behavioral, and social sciences. Each year, NIH Director’s Awards are granted to program applicants who propose high-risk, high-impact research in areas relevant to the NIH’s mission. In doing so, the NIH encourages innovative proposals that, due to their inherent risk, might struggle in the traditional peer-review process.

This year, Lindsay Case, Siniša Hrvatin, Deblina Sarkar, and Caroline Uhler have been chosen to receive the New Innovator Award, which funds exceptionally creative research from early-career investigators. The award, which was established in 2007, supports researchers who are within 10 years of their final degree or clinical residency and have not yet received a research project grant or equivalent NIH grant.

Lindsay Case, the Irwin and Helen Sizer Department of Biology Career Development Professor and an extramural member of the Koch Institute for Integrative Cancer Research, uses biochemistry and cell biology to study the spatial organization of signal transduction. Her work focuses on understanding how signaling molecules assemble into compartments with unique biochemical and biophysical properties to enable cells to sense and respond to information in their environment. Earlier this year, Case was one of two MIT assistant professors named as Searle Scholars.

Siniša Hrvatin, who joined the School of Science faculty this past winter, is an assistant professor in the Department of Biology and a core member at the Whitehead Institute for Biomedical Research. He studies how animals and cells enter, regulate, and survive states of dormancy such as torpor and hibernation, aiming to harness the potential of these states therapeutically.

Deblina Sarkar is an assistant professor and AT&T Career Development Chair Professor at the MIT Media Lab​. Her research combines the interdisciplinary fields of nanoelectronics, applied physics, and biology to invent disruptive technologies for energy-efficient nanoelectronics and merge such next-generation technologies with living matter to create a new paradigm for life-machine symbiosis. Her high-risk, high-reward proposal received the rare perfect impact score of 10, which is the highest score awarded by NIH.

Caroline Uhler is a professor in the Department of Electrical Engineering and Computer Science and the Institute for Data, Systems, and Society. In addition, she is a core institute member at the Broad Institute of MIT and Harvard, where she co-directs the Eric and Wendy Schmidt Center. By combining machine learning, statistics, and genomics, she develops representation learning and causal inference methods to elucidate gene regulation in health and disease.

The High-Risk, High-Reward Research program is supported by the NIH Common Fund, which oversees programs that pursue major opportunities and gaps in biomedical research that require collaboration across NIH Institutes and Centers. In addition to the New Innovator Award, the NIH also issues three other awards each year: the Pioneer Award, which supports bold and innovative research projects with unusually broad scientific impact; the Transformative Research Award, which supports risky and untested projects with transformative potential; and the Early Independence Award, which allows especially impressive junior scientists to skip the traditional postdoctoral training program to launch independent research careers.

This year, the High-Risk, High-Reward Research program is awarding 103 awards, including eight Pioneer Awards, 72 New Innovator Awards, nine Transformative Research Awards, and 14 Early Independence Awards. These 103 awards total approximately $285 million in support from the institutes, centers, and offices across NIH over five years. “The science advanced by these researchers is poised to blaze new paths of discovery in human health,” says Lawrence A. Tabak DDS, PhD, who is performing the duties of the director of NIH. “This unique cohort of scientists will transform what is known in the biological and behavioral world. We are privileged to support this innovative science.”

New players in an essential pathway to destroy microRNAs

In a study from the lab of Whitehead Institute Member David Bartel, researchers have identified genetic sequences that can lead to the degradation of cellular regulators called microRNAs in the fruit fly Drosophila melanogaster.

Eva Frederick | Whitehead Institute
September 26, 2022

In a study from the lab of Whitehead Institute Member David Bartel, researchers have identified genetic sequences that can lead to the degradation of cellular regulators called microRNAs in the fruit fly Drosophila melanogaster. The findings were published September 22 in Molecular Cell.

“This is an exciting study that paves the way for a deeper understanding of the microRNA degradation pathway,” says Bartel, who is also a professor of biology at the Massachusetts Institute of Technology and investigator with the Howard Hughes Medical Institute. “Finding these ‘trigger’ sequences will allow us to more precisely probe the workings of this pathway in the lab, which is likely critical for flies — and possibly other species — to survive to adulthood.”

In order to produce new proteins, cells transcribe their DNA into messenger RNAs (or mRNAs), which provide information required to make the proteins . When a given mRNA has served its purpose, it’s degraded. The process of degradation is often led by tiny RNA sequences called microRNAs.

In previous work, researchers showed that certain mRNA or non coding RNA transcripts, rather than being degraded by microRNAs, can instead turn the tables on the microRNAs and lead to their destruction through a pathway called target-directed microRNA degradation, or TDMD. “This pathway leads to rapid turnover of certain microRNAs within the cell,” says former Bartel Lab graduate student Elena Kingston.

Kingston wanted to further understand the functions of the TDMD pathway in cells. “I wanted to get at the ‘why,’” she said. “Why are microRNAs regulated in this way, and why does it matter in an organism?”

Previous work on the TDMD pathway was primarily conducted in cultured cells. For the new study, the researchers decided to use the fruit fly Drosophila melanogaster.  A fly model could provide more insight into how the pathway worked in a live organism — including whether or not it had an effect on the organism’s fitness or was essential for survival.

The researchers created a model to study TDMD by using flies with mutations in an essential TDMD pathway gene called Dora (the equivalent human gene is called ZSWIM8, as detailed in this paper). Very few flies with mutations in Dora were seen to make it to adulthood. Most died early in development, suggesting the TDMD pathway was likely important for their embryonic viability.

Putting a finger on the triggers of the TDMD pathway

While microRNAs don’t need many complementary base pairs to bind and regulate their mRNA targets, the opposite is true in the TDMD pathway. In order to work properly, the TDMD pathway needs a highly specific trigger, which can either be a mRNA that codes for proteins, or a non-coding RNA. “What’s unique about a trigger is it has a site that the microRNA can bind to that has a lot of complementarity to the microRNA,” Kingston said.

During the isolation of the early Covid-19 pandemic, Kingston set out to write a program that could pick out probable triggers of microRNA degradation in Drosophila based on their sequences. The program returned thousands of hits, and the researchers set to work narrowing down which sites were the best candidates to test in flies.

“As soon as we were able to get back into lab [after the lockdown], I took our top 10 or so candidates and tried perturbing them in flies,” she said. “Fortunately for me, about half of them ended up working out.”

These six new triggers more than double the list of known RNA sequences that can direct degradation of microRNAs. To take this finding a step further, the researchers conducted an analysis of what happened to the flies when a trigger was disrupted.

The researchers found that one of the triggers — a long non-coding RNA — plays a role in proper development of the cuticle, or the waterproof outer shell of a fly embryo. “We noticed that when we perturbed this trigger, the cuticles of fly embryos had altered elasticity,” Kingston said. “When we popped the embryos out of their egg shells, we could see these cuticles expand up and bloat.”

Because of the bloated phenotype, Kingston decided to name the long non-coding RNA marge after Aunt Marge, a character in the Harry Potter series. In “Harry Potter and the Prisoner of Azkaban”, Aunt Marge’s taunts lead Harry to accidentally perform magic on her, causing her to inflate and float away.

In the future, Kingston, who has since graduated and begun a career in the biotech industry, hopes researchers will pick up the torch on learning the roles of other TDMD triggers. “We still have several other triggers [from this paper] where there’s no known biological role for them in the fly,” she said. “I think this opens up the field for others to go in and to ask the questions, ‘Where are these triggers acting? What are they doing? And what’s the phenotype when you lose them?’”

Notes

Elena Kingston, Lianne Blodgett and David Bartel. “Endogenous transcripts direct microRNA degradation in Drosophila, and this targeted degradation is required for proper embryonic development.” Molecular Cell, September 22, 2022. DOI: https://doi.org/10.1016/j.molcel.2022.08.029

MIT biologist Richard Hynes wins Lasker Award

Hynes and two other scientists will share the prize for their discoveries of proteins critical for cellular adhesion.

Anne Trafton | MIT News Office
September 28, 2022

MIT Professor Richard Hynes, a pioneer in studying cellular adhesion, has been named a recipient of the 2022 Albert Lasker Basic Medical Research Award.

Hynes, the Daniel K. Ludwig Professor for Cancer Research and a member of MIT’s Koch Institute for Integrative Cancer Research, was honored for the discovery of integrins, proteins that are key to cell-cell and cell-matrix interactions in the body. He will share the prize with Erkki Ruoslahti of Sanford Burnham Prebys and Timothy Springer of Harvard University.

“I’m delighted, and it’s a pleasure to be sharing it with them,” Hynes says. “It’s great for the field, and for the trainees who did much of the work.”

Hynes’ research focuses on proteins that allow cells to adhere to each other and to the extracellular matrix — a mesh-like network that provides structural support for cells. These proteins include integrins, a type of cell surface receptor, and fibronectins, a family of extracellular adhesive proteins. Integrins are the major adhesion receptors connecting the extracellular matrix to the intracellular cytoskeleton.

During embryonic development, cell adhesion is critical for cells to move to the correct locations in the embryo. Hynes’ work has also revealed that dysregulation of cell-to-matrix contact plays an important role in cancer cells’ ability to detach from a tumor and spread to other parts of the body, in a process known as metastasis.

“Professor Hynes’ contributions to the field of cancer biology, and more broadly, cellular biology, are numerous,” says Nergis Mavalvala, the Curtis and Kathleen Marble Professor of Astrophysics and the dean of the School of Science. “His investigations of fundamental biological questions — How do cells interact? How do they stick together? — changed how scientists approach cancer research and opened up avenues in developing potential therapeutics to disrupt metastatic disease.”

Born in Kenya, Hynes grew up in Liverpool, in the United Kingdom. Both of his parents were scientists: His father was a freshwater ecologist, and his mother a physics teacher. Hynes and all three of his siblings followed their parents into scientific fields.

“We talked science at home, and if we asked questions, we got questions back, not answers. So that conditioned me into being a scientist, for sure,” Hynes says.

After earning his bachelor’s and master’s degrees in biochemistry at Cambridge University, Hynes decided to head to the United States to continue graduate school. Colleagues at Cambridge suggested MIT, so he came to the Institute and earned his PhD in 1971. After doing a postdoc at the Imperial Cancer Research Fund Laboratories in London, he returned to MIT in 1975 as a faculty member in the Department of Biology and a founding member of MIT’s Center for Cancer Research (the predecessor of today’s Koch Institute).

Hynes began his career as a developmental biologist, studying how cells move to the correct locations during embryonic development. As a postdoc, he began studying the differences in the surface landscapes of healthy cells and tumor cells. This led to the discovery of a protein called fibronectin, which is often lost when cells become cancerous.

He and others found that fibronectin is part of the extracellular matrix, the network of proteins and other molecules that support cells and tissues in the body. When fibronectin is lost, cancer cells can more easily free themselves from their original location and metastasize to other sites in the body. Cells bind to the matrix through cell surface receptors known as integrins. In humans, 24 integrin proteins have been identified. These proteins help give tissues their structure, enable blood to clot, and are essential for embryonic development.

“These cell-matrix adhesion proteins hold us all together,” Hynes says. “If we didn’t have them, we’d be a pool of cells on the floor. And they’re contributors to lots of diseases: fibrosis, cancer, thrombosis, immune and autoimmune diseases. So, cell adhesion has become a huge field at both the basic science level and the therapeutic level.”

Since joining the MIT faculty, Hynes has also served as head and associate head of the Department of Biology, and as director of the Center for Cancer Research. He has also served as scientific governor of the Wellcome Trust in the United Kingdom, and as co-chair of National Academy committees establishing guidelines for stem cell and genome editing research.

His many awards include the Gairdner Foundation International Award, the Distinguished Investigator Award from the International Society for Matrix Biology, the Robert and Claire Pasarow Medical Research Award, the E.B. Wilson Medal from the American Society for Cell Biology and the Paget-Ewing Award, Metastasis Research Society. Hynes is also a member of the National Academy of Sciences, the National Academy of Medicine, the Royal Society of London, the American Association for the Advancement of Science, and the American Academy of Arts and Sciences.

The Lasker Award comes with a $250,000 prize, which will be shared between the three recipients.

Yami Acevedo ­Sánchez’s “go for it” attitude leads to MIT
Pamela Ferdinand
September 21, 2022

MIT PHD STUDENT YAMI ACEVEDO-SÁNCHEZ DISCOVERED SHE ENJOYED SCIENCE by watching television at home in Puerto Rico. While a strong student, encouraged by her mentors and parents to do well, she never imagined a science career would be in her future.

Acevedo-Sánchez is the second member of her extended family—her mother has 17 brothers and sisters; her father has 11—to earn a college degree. She didn’t learn about MIT until she began studying at the University of Puerto Rico, and attending the Institute felt like a very big step.

“I remember my thoughts were, ‘I’m never going to make it there.’ It felt really, really out of reach,” she says. “But I don’t say ‘no’ to myself. I just go for it.”

Today at MIT, Acevedo-Sánchez is pursuing her passion for biology, working to understand the basic processes that make all the complexity of life possible. “To me, it seems like a puzzle waiting for someone to assemble the pieces,” she says.

Her research focuses on a fundamental question: How do bacterial pathogens hijack a host? By studying how they travel between cells and spur infection, she hopes to discover more about the diseases they cause and potential therapies.

In particular, she is focused on Listeria monocytogenes, a widespread bacterium that can cause food poisoning. In high-risk populations, such as pregnant women or immunocompromised individuals, it can spread to the liver and then move through the bloodstream into the rest of the body. Listeria infection (listeriosis) has a high mortality rate, killing an estimated 20% to 30% of those infected, according to the US Food and Drug Administration.

Listeria hijacks molecular pathways as it spreads from cell to cell. It typically forces itself into neighboring cells by ramming into cell junctions (spots where cells connect). The force and speed Listeria uses to do this is about 0.2–1 microns per second—the equivalent of 50 feet per second if Listeria were the size of a submarine, Acevedo-Sánchez says: “It’s very impressive to watch!”

What is the mechanism of this action? Is it random, or programmed and regulated by the bacteria or our cells? Working with assistant professor of biology Rebecca Lamason and others in Lamason’s lab, Acevedo-Sánchez hopes to answer such questions through groundbreaking work that visualizes the cell membrane dynamics as Listeria spreads from cell to cell. To do this, the team uses a cellular line with a membrane marker (developed by Lamason) and a confocal microscope, which can capture high-resolution images deep inside cells.

Acevedo-Sánchez is especially interested in exploring how the mechanisms of two proteins, CAV1 and PACSIN2, promote cell-to-cell spread over long distances in a short amount of time. “These pathogens are constantly interacting with their host,” she says. “By understanding the key players that mediate those interactions from the bacteria side as well as the cell side, we can understand more about the microbiology of the bacteria and our own cell biology.”

Mentoring others

Outside the lab, Acevedo-Sánchez is working to support others like her who have not always believed they could pursue careers in science, technology, engineering, and mathematics. “There is tremendous power in having someone believe in your ability,” she says.

She has served as a mentor for the MIT Summer Research Program in Biology and supported first-year biology graduate students through the BioPals Program. Acevedo- Sánchez has also presented her work to middle school students around the world through the video series MIT Abstracts.

“Anyone can be a scientist, regardless of their background,” says Acevedo-Sánchez, who also has served as a graduate diversity ambassador at MIT. “You just need three things: be curious about the world that surrounds you, be willing to ask questions, and do the work yourself. Work smart and hard.”

Pamela Ferdinand is a 2003–2004 MIT Knight Science Journalism Fellow