Placement: Promote to Homepage

Nanosensors target enzymes to monitor and study cancer

By analyzing enzyme activity at the organism, tissue, and cellular scales, new sensors could provide new tools to clinicians and cancer researchers.

Bendta Schroeder | Erika Reinfeld | Koch Institute
November 2, 2022

Cancer is characterized by a number of key biological processes known as the “hallmarks of cancer,” which remodel cells and their immediate environment so that tumors can form, grow, and thrive. Many of these changes are mediated by specific genes and proteins, working in tandem with other cellular processes, but the specifics vary from cancer type to cancer type, and even from patient to patient.

Sensitive tools for measuring protein or gene expression, even on the single cell level, have helped researchers understand the different cell types present in a tumor’s microenvironment and how this composition changes after treatments. However, these assays don’t necessarily show which proteins are active or relevant to tumor progression, or allow clinicians to noninvasively monitor the progress of the disease or its response to treatment. A protein could be present in a cancer cell as a bystander, for example, but not an active participant in its cellular transformations. Enzymes, which catalyze biochemical reactions inside cells, may give a clearer picture of which genes or proteins to target at a particular time.

In work recently published in Nature Communications, researchers from the MIT Koch Institute for Integrative Cancer Research have developed a set of enzyme-targeting nanoscale tools to monitor cancer progression and treatment response in real time, map enzyme activity to precise locations within a tumor, and isolate relevant cell populations for analysis.

“We hope that this new suite of tools can be useful in the clinic and the lab alike,” says Sangeeta Bhatia, the John J. and Dorothy Wilson Professor of Health Sciences and Technology, professor of electrical engineering the computer science, and senior author of the study. “With further development, the nanosensors could be used by clinicians to tailor treatments to a patient’s specific cancer, and to monitor cancer progression and treatment response, while researchers could use them to better understand the molecular biology of cancer and develop new tools to diagnose, track, and treat the disease.”

Bhatia is also a member of MIT’s Koch Institute for Integrative Cancer Research and Institute for Medical Engineering and Science. The study, conducted in collaboration with the laboratory of Tyler Jacks, was led by Ava Amini (Soleimany) ’16, a former graduate student from the Bhatia laboratory; and postdoc Jesse Kirkpatrick, also from the Bhatia lab.

Tracking tumors in real time

For several years, the Bhatia laboratory has been developing noninvasive urine tests for the detection of cancer, including colon, ovarian, and lung cancer. The tests rely on nanoparticles that interact with tumor proteins called proteases. Proteases are a type of enzyme that act as molecular scissors to cleave proteins and break them down into smaller components. Proteases help cancer cells escape from tumors by cutting through the extracellular network of proteins that holds cells in place.

The nanoparticles are coated with peptides (short protein fragments) that target cancer-linked proteases. When the nanoparticles arrive at the tumor site, the peptides are cut and release biomarkers that can be detected in the urine.

In the current study, the researchers tested whether they could use this technology not just to detect cancer, but to track the development of cancer and its response to treatments accurately and sensitively over time. The team created a panel of 14 nanoparticles designed to target proteases overexpressed in non-small cell lung cancer induced in a mouse model. These nanoparticles had been adapted to release barcoded peptides when they encounter dysregulated enzymes in the tumor microenvironment.

Each nanosensor was able to track different patterns of protease activity, which changed dramatically as the tumor progressed. After treatment with a lung cancer-targeting drug, the researchers were able to find signs tumor regression quickly, within just three days of administering treatment.

Cell maps and populations

While the existing nanosensor technique could be used to track tumor progression and treatment response in general, by itself, it could not shed any light on the specific cellular process at work.

“Like many of the tools available to assess molecular markers for cancer, our urine reporter treats the body like a black box,” says Kirkpatrick. “While we get some information about the state of the disease, we wanted to know more about the cells or proteins that are causing the disease to behave in a particular way.”

Having identified nanosensors of interest, researchers mapped where in the tumor microenvironment the enzymes acting on these sensors were active. They adapted their nanoprobes to leave behind fluorescent tags when they are cleaved from the nanosensor, assigning different tags to different proteases. After applying the nanoprobes to samples of lung tissue, they looked for patterns in how the tags were distributed.

One tag resulted in a curious spindle-like pattern that turned out to belong to the tumor vasculature. Researchers pinpointed the protease activity to specific types of cells: endothelial cells, which line blood vessels, and pericytes, which regulate vascular function and are actively recruited in angiogenesis — one of the archetypal hallmarks of cancer cell growth. Angiogenesis allows tumor cells to recruit existing blood vessels and stimulate new ones to form, in order to obtain the nutrients needed for tumor formation and progression.

Using their nanoprobes to label and sort cells based on their enzymatic activity, the team identified populations of cells associated with vasculature that displayed heightened expression of genes related to angiogenesis. The researchers also found evidence of signaling between pericytes and the endothelial cells that together comprise angiogenic blood vessels in vascular tissue.

Hallmark observations

In future work, the team seeks to identify the specific protease active in pericytes and dissect its role in angiogenesis. With this knowledge, they hope to develop formulations of therapies that can be delivered to patients to disrupt the recruitment and formation of blood vessels associated with tumor growth.

Ultimately, however, the team envisions panels of nanoprobes targeting several important features of cancer simultaneously and noninvasively in patients. Other hallmarks of cancer include proliferative signaling, the evasion of growth suppressors, genome instability, resistance to cell death, deregulated metabolism, and activation of invasion and metastasis. Because cancer alters protease activity across all of these processes, the team’s nanoprobes could be designed to target these different processes, with the aim of providing a comprehensive picture of tumor activity driving the disease. The approach could be used by researchers looking to investigate key biological phenomena in cancer models, as well as by clinicians seeking to monitor cancer progression noninvasively and select treatments for their patients.

The study was supported, in part, by the Virginia and D.K. Ludwig Fund for Cancer Research, the Koch Institute Frontier Research Program through a gift from Upstage Lung Cancer, the Koch Institute’s Marble Center for Cancer Nanomedicine, and Johnson & Johnson.

A career in biochemistry unfolds

In an MIT summer research program, Rita Anoh learned about molecular machines and the value of collaborations.

Sarah Costello | School of Science
November 1, 2022

Rita Anoh’s first exposure to college-level research was not something she recognized as a path she could follow. While in high school, the daughter of Anoh’s Advanced Placement biology teacher presented a poster to her class about what she was working on in graduate school. “At the time, actually, it did not click to me what she was presenting,” Anoh laughs. “Because I didn’t know that you could do research as such, I just didn’t put it together.”

Instead, Anoh traces the start of her journey to science back to her childhood in Ghana, where she enjoyed spending summers assisting in a health clinic run by her grandmother, a nurse. Anoh especially loved the problem-solving and teamwork involved. “Every time, people would leave like, ‘Problem solved!’ or ‘Oh, my problem is not solved, but I know where to go next.’”

Anoh’s enthusiasm for finding solutions to complex problems shifted from medicine to research when she arrived as an undergraduate at Mount Saint Mary’s University (The Mount) in Maryland, and later as a participant in the 2022 Bernard S. and Sophie G. Gould MIT Summer Research Program in Biology (BSG-MSRP-Bio).

As a first-year majoring in biology at The Mount, Anoh applied to a summer research program with the encouragement of Patrick Lombardi, assistant professor of chemistry. She earned an internship to work in his lab exploring how DNA damage in cells is detected and repaired. Then, the summer following her sophomore year, she participated in the Caltech WAVE Fellows program in the lab of Douglas Rees, the Roscoe Gilkey Dickinson Professor of Chemistry, focusing on the structures and mechanisms of complex metalloproteins and integral membrane proteins. Anoh was also awarded a Barry M. Goldwater Scholarship for students intending to pursue research careers in natural science, mathematics, and engineering. “I was the first sophomore to receive at my school, so that was very exciting,” adds Anoh.

“It’s been a blast”

Eager to continue building her science skills and experience a new city, Anoh quickly accepted an offer to join the BSG-MSRP-Bio program at MIT this past summer.

Anoh spent 10 weeks in the lab of assistant professor of biology Joey Davis, whose lab works to uncover how cells construct and degrade complex molecular machines rapidly and efficiently. Anoh also worked with Robert Sauer, the Salvador E. Luria Professor of Biology at MIT, who studies the relationship between protein structure, function, sequence, and folding.

“It’s been a blast,” says Anoh.

Specifically, her project centered on a complex in the cell that helps oversee proteolysis, or the breakdown of proteins into peptides, or strings of amino acids, and further into amino acids for recycling by the cell. Called ClpXP, this molecular machine is made up of two substructures: ClpX and ClpP. First, ClpX identifies and unfolds peptide sequences in the protein substrate to be broken down; then ClpP breaks the unfolded peptides down into smaller fragments.

In her research, Anoh looked at the degradation of a protein RseA by ClpXP bound to another piece of molecular machinery called SspB. This “adapter protein” delivers the targeted protein to ClpXP to begin breaking it down. By degrading RseA, ClpXP plays an essential role in the signaling pathway in bacteria allowing the bacterial cell to respond to stress. Along with her mentor, she examined samples under a cryo‐electron microscope (Cryo-EM) at MIT.nano and collected data to determine its 3D map, shedding light on how ClpXP with the help of SspB breaks down proteins within a cell.

In addition to her gain of technical and research skills, one of Anoh’s takeaways from her summer at MIT was “how collaborative and dynamic science is in general,” she says, especially with mentors such as Alireza Ghanbarpour, a joint postdoc in the Davis and Sauer labs.

“During her time at our lab, she became friends with everyone,” says Ghanbarpour, who mentored Anoh and another undergraduate student whom Anoh befriended. “Rita developed a great relationship with her and, on many occasions, helped her with her project.”

Anoh attended group meetings, lab retreats, and conferences. In MSRP seminars, she heard from MIT researchers about their own experiences solving problems using advice from fellow scientists.

“I talk to my peers about what we’re all doing, and how different people at the same lab work together, or how different labs work together,” Anoh says. “I’ve learned different ways to achieve the same goal.”

Ghanbarpour also assisted Anoh in deepening her understanding of the material beyond the bench. Passionate about structural biology and biochemistry, he provided explanations and connected Anoh with materials to expand her knowledge of relevant researchers and concepts. “I was learning not just stuff in the lab but actually the meaning of what I was doing, so that was pretty cool,” she says.

Now in her senior year back at The Mount, Anoh intends to keep an open mind. An open mind, after all, is why she acted on her professor’s suggestion when she was a first-year student to apply to the program that set her on her current path to a research career. Without a doubt, though, Anoh says she plans to pursue a PhD in biochemistry and mentor young researchers like herself along the way.

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.

Two first-year students named Rise Global Winners for 2022

Now in its second year, the Rise program targets exceptional teenage scholars from around the world for their potential as future change-makers.

Elizabeth Durant | Office of the Vice Chancellor
October 26, 2022

In 2019, former Google CEO Eric Schmidt and his wife, Wendy, launched a $1 billion philanthropic commitment to identify global talent. Part of that effort is the Rise initiative, which selects 100 young scholars, ages 15-17, from around the world who show unusual promise and a drive to serve others. This year’s cohort of 100 Rise Global Winners includes two MIT first-year students, Jacqueline Prawira and Safiya Sankari.

Rise intentionally targets younger-aged students and focuses on identifying what the program terms “hidden brilliance” in any form, anywhere in the world, whether it be in a high school or a refugee camp. Another defining aspect of the program is that Rise winners receive sustained support — not just in secondary school, but throughout their lives.

“We believe that the answers to the world’s toughest problems lie in the imagination of the world’s brightest minds,” says Eric Braverman, CEO of Schmidt Futures, which manages Rise along with the Rhodes Trust. “Rise is an integral part of our mission to create the best, largest, and most enduring pipeline of exceptional talent globally and match it to opportunities to serve others for life.”

The Rise program creates this enduring pipeline by providing a lifetime of benefits, including funding, programming, and mentoring opportunities. These resources can be tailored to each person as they evolve throughout their career. In addition to a four-year college scholarship, winners receive mentoring and career services; networking opportunities with other Rise recipients and partner organizations; technical equipment such as laptops or tablets; courses on topics like leadership and human-centered design; and opportunities to apply for graduate scholarships and for funding throughout their careers to support their innovative ideas, such as grants or seed money to start a social enterprise.

Prawira and Sankari’s winning service projects focus on global sustainability and global medical access, respectively. Prawira invented a way to use upcycled fish-scale waste to absorb heavy metals in wastewater. She first started experimenting with fish-scale waste in middle school to try to find a bio-based alternative to plastic. More recently, she discovered that the calcium salts and collagen in fish scales can absorb up to 82 percent of heavy metals from water, and 91 percent if an electric current is passed through the water. Her work has global implications for treating contaminated water at wastewater plants and in developing countries.

Prawiri published her research in 2021 and has won awards from the U.S. Environmental Protection Agency and several other organizations. She’s planning to major in Course 3 (materials science and engineering), perhaps with an environmentally related minor. “I believe that sustainability and solving environmental problems requires a multifaced approach,” she says. “Creating greener materials for use in our daily lives will have a major impact in solving current environmental issues.”

For Sankari’s service project, she developed an algorithm to analyze data from electronic nano-sensor devices, or e-noses, which can detect certain diseases from a patient’s breath. The devices are calibrated to detect volatile organic compound biosignatures that are indicative of diseases like diabetes and cancer. “E-nose disease detection is much faster and cheaper than traditional methods of diagnosis, making medical care more accessible to many,” she explains. The Python-based algorithm she created can translate raw data from e-noses into a result that the user can read.

Sankari is a lifetime member of the American Junior Academy of Science and has been a finalist in several prestigious science competitions. She is considering a major in Course 6-7 (computer science and molecular biology) at MIT and hopes to continue to explore the intersection between nanotechnology and medicine.

While the 2022 Rise recipients share a desire to tackle some of the world’s most intractable problems, their ideas and interests, as reflected by their service projects, are broad, innovative, and diverse. A winner from Belarus used bioinformatics to predict the molecular effect of a potential Alzheimer’s drug. A Romanian student created a magazine that aims to promote acceptance of transgender bodies. A Vietnamese teen created a prototype of a toothbrush that uses a nano chip to detect cancerous cells in saliva. And a recipient from the United States designed modular, tiny homes for the unhoused that are affordable and sustainable, as an alternative to homeless shelters.

This year’s winners were selected from over 13,000 applicants from 47 countries, from Azerbaijan and Burkina Faso to Lebanon and Paraguay. The selection process includes group interviews, peer and expert review of each applicant’s service project, and formal talent assessments.

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

Providing new pathways for neuroscience research and education

Payton Dupuis finds new scientific interests and career opportunities through MIT summer research program in biology.

Leah Campbell | School of Science
September 29, 2022

Payton Dupuis’s interest in biology research began where it does for many future scientists — witnessing a relative struggling with an incurable medical condition. For Dupuis, that family member was her uncle, who suffered from complications from diabetes. Dupuis, a senior at Montana State University, says that diabetes is prominent on the Flathead Reservation in Montana, where she grew up, and witnessing the impacts of the disease inspired her to pursue a career in scientific research. Since then, that passion has taken Dupuis around the country to participate in various summer research programs in the biomedical sciences.

Most recently, she was a participant in the Bernard S. and Sophie G. Gould MIT Summer Research Program in Biology (BSG-MSRP-Bio). The program, offered by the departments of Biology and Brain and Cognitive Sciences, is designed to encourage students from underrepresented groups to attend graduate school and pursue careers in science research. More than 85 percent of participants have subsequently enrolled in highly ranked graduate programs, many of them returning to MIT, just as Dupuis is considering.

Her journey from witnessing the impacts of her uncle’s diabetes to considering graduate school at MIT was made possible only by Dupuis’s love of science and her ability to “find a positive,” as she says, in every experience.

As a high-schooler, Dupuis made her first trip to the Northeast, participating in the Summer Academy of Math and Sciences at Carnegie Mellon University. For Dupuis, who hadn’t even taken calculus yet, the experience was a welcome challenge. “That definitely made me work hard,” she laughs, comparing herself to other program participants. “But I proved to myself, not for anyone else, that I belonged in that program.”

In addition to being a confidence booster, the Carnegie Mellon program also gave Dupuis her first taste of scientific research working in a biomedical lab on tissue regeneration. She was excited about the possibilities of growing new organs — such as the insulin-producing pancreas that could help regulate her uncle’s diabetes — outside of the body. Dupuis was officially hooked on biology.

Her experience that summer encouraged Dupuis to major in chemical engineering, seeing it as a good pipeline into biomedical research. Unfortunately, the chemical engineering curriculum at Montana State wasn’t what she expected, focusing less on the human body and more on the oil industry. In that context, her ability to see a silver lining served Dupuis well.

“That wasn’t really what I wanted, but it was still interesting because there were ways that I could apply it to the body,” she explains. “Like fluid mechanics — instead of water flowing through a pipe, I was thinking about blood flowing through veins.”

Dupuis adds that the chemical engineering program also gave her problem-solving skills that have been valuable as she’s undertaken biology-focused summer programs to help refine her interests. One summer, she worked in the chemistry department at Montana State, getting hands-on experience in a wet lab. “I didn’t really know any of the chemistry behind what I was doing,” she admits, “but I fell in love with it.” Another summer, she participated in the Tufts Building Diversity in Biomedical Sciences program, exploring the genetic side of research through a project on bone development in mice.

In 2020, a mentor at the local tribal college connected Dupuis with Keith Henry, an associate professor of biomedical sciences at the University of North Dakota. With Henry, Dupuis looked for new binding sites for the neurotransmitter serotonin that could help minimize the side effects that come with long-term use of selective serotonin reuptake inhibitors (SSRIs), the most common class of antidepressants. That summer was Dupuis’s first exposure to brain research, and her first experience modeling biological processes with computers. She loved it. In fact, as soon as she returned to Montana State, Dupuis enrolled as a computer science minor.

Because of the minor, Dupuis needs an extra year to graduate, which left her one more summer for a research program. Her older sister had previously participated in the general MSRP program at MIT, so it was a no-brainer for Dupuis to apply for the biology-specific program.

This summer, Dupuis was placed in the lab of Troy Littleton, the Menicon Professor in Neuroscience at The Picower Institute for Learning and Memory. “I definitely fell in love with the lab,” she says. With Littleton, Dupuis completed a project looking at complexin, a protein that can both inhibit and facilitate the release of neurotransmitters like serotonin. It’s also essential for the fusion of synaptic vesicles, the parts of neurons that store and release neurotransmitters.

A number of human neurological diseases have been linked to a deficiency in complexin, although Dupuis says that scientists are still figuring out what the protein does and how it works.

To that end, Dupuis focused this summer on fruit flies, which have two different types of complexin — humans, in comparison, have four. Using gene editing, she designed an experiment comparing fruit flies possessing various amounts of different subtypes of the protein. There was the positive control group, which was untouched; the negative control group that had no complexin; and two experimental groups, each with one of the subtypes removed. Using fluorescent staining, Dupuis compared how neurons lit up in each group of flies, illuminating how altering the amount of complexin changed how the flies released neurotransmitters and formed new synaptic connections.

After touching on so many different areas of biological research through summer programs, Dupuis says that researching neuronal activity in fruit flies this summer was the perfect fit intellectually, and a formative experience as a researcher.

“I’ve definitely learned how to take an experiment and make it my own and figure out what works best for me, but still produces the results we need,” she says.

As for what’s next, Dupuis says her experience at MIT has sold her on pursuing graduate work in brain sciences. “Boston is really where I want to be and eventually work, with all the biotech and biopharma companies around,” she says. One of the perks of the MSRP-Bio program is professional development opportunities. Though Dupuis had always been interested in industry, she says she appreciated attending career panels this summer that demystified what that career path really looks like and what it takes to get there.

Perhaps the most important aspect of the program for Dupuis, though, was the confidence it provided as she continues to navigate the world of biomedical research. She intends to take that back with her to Montana State to encourage classmates to seek out similar summer opportunities.

“There’s so many people that I know would be a great researcher and love science, but they just don’t either know about it or think they can get it,” she says. “All I’d say is, you just got to apply. You just have to put yourself out there.”