Author: mantulin

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.

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.

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.”

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.”

Through mentorship, a deeper understanding of brain cancer metabolism grows

As an MSRP-Bio student in the Vander Heiden lab, Alejandra Rosario helped to reveal how cancer cells maintain access to materials they need to grow.

Grace van Deelen | Department of Biology
September 22, 2022

Alejandra Rosario’s enthusiasm for research is infectious. When she talks about studying cancer cells, or the possibility of getting a PhD, her face lights up. “It’s something I’m really passionate about,” she says.

As a Bernard S. and Sophie G. Gould MIT Summer Research Program in Biology (BSG-MSRP-Bio) student this past summer in the lab of Matt Vander Heiden, MIT’s Lester Wolfe (1919) Professor of Molecular Biology, Rosario worked to understand cancer metabolism. MSRP-Bio is a 10-week, research-intensive summer program intended to introduce non-MIT undergraduates to a research career. Rosario, who is a senior at the University of Puerto Rico at Cayey this fall, was one of two MSRP-Bio students this year who were the first from their campus to attend the program. “It’s a really great opportunity for us,” she says.

Rosario had always been interested in research and understanding natural systems. As a child growing up in San Lorenzo, Puerto Rico, she was surrounded by nature, and got involved at a young age in environmental activism. She also has a special passion for the beach, which contributed to her eventual interest in science and, more specifically, in biology.

Medical connections

When her mother developed thyroid cancer, she focused on cancer research. To support her mother, Rosario tried to learn as much as possible about the type of cancer she was fighting, as well as the treatments available. She noticed the impact of basic cancer research on the therapies her mother was receiving.

As a result of her experience watching her mother battle cancer, too, Rosario has a special interest in translational medicine: working to determine how fundamental discoveries can have specific relevance to human disease treatment. “In cancer research,” she says, “small strides can be huge strides.”

Delving into a career in cancer research became a focus for Rosario, who sought out opportunities to advance her connections to the field. During a virtual conference held by the Society for the Advancement of Chicanos/Hispanics and Native Americans in Science, Rosario met MIT Department of Biology lecturer and science outreach director Mandana Sassanfar, who invited Rosario to visit MIT for a January workshop on computational skills. During the workshop, she met MIT professors, explored possible research ideas, and decided to apply to the MSRP-Bio program.

Rosario, who would like eventually to pursue a PhD or MD/PhD, was especially drawn to the Vander Heiden lab because of its focus on connecting research to medical applications. “I’m really fascinated about that connection, and how that works,” she says.

She especially liked the diversity of research happening in the lab, where projects range from cancer metabolism to genetics to stem cell research. “They’re all exploring different questions,” she says. “But at the end of the day, they all have conversations with each other and help each other out in a collaborative way.”

New insights into brain cancer

This summer, Rosario contributed to that diversity of research by continuing some of the core experiments of the Vander Heiden lab with a new cell line: glioblastoma, a type of brain cancer with a poor prognosis. The lab had never worked with this type of cancer before, so Rosario worked to understand its metabolism and process of cell division.

The main characteristic of cancer cells is that they divide very quickly. In order to do so, they need a lot of new material, like proteins, lipids, and nucleotides. A cancer cell has two options to obtain this new material: it can take it from the environment, or it can produce that new material itself. Glioblastoma occurs in the brain, a microenvironment that provides very little access to the materials necessary for cell division. In order to divide, then, glioblastoma cells must reprogram themselves in order to produce the materials necessary for growth.

Rosario’s research this summer sought to determine how glioblastoma cells survive in the environment of the brain by limiting the cells’ access to certain substances, like certain proteins or amino acids, and then measuring how the cells react. Understanding the cell’s reactions to such changes in the microenvironment could eventually inform cancer therapies.

“Our goal is to understand metabolically how these brain cancer cells are surviving everything we throw at them in order to possibly find a more specific target for treatment,” she says. Rosario presented her research in August in the MSRP-Bio poster session.

Shaped by mentorship

Overall, Rosario really enjoyed her experience as a summer researcher. The collaborative and open atmosphere in the lab, says Rosario, has helped her grow. For example, the lab holds occasional meetings called “Idea Club,” where researchers in the lab bring a question they’re struggling with or an idea they’re excited about, and other lab members give their input. “There’s a lot of scientific independence and curiosity,” says Rosario.

Rosario has especially enjoyed getting to know the graduate students in the lab, like Ryan Elbashir, a rising third-year doctoral student. Elbashir was also an MSRP-Bio student in 2018 and was one of the reasons Rosario chose the Vander Heiden lab. After a discussion with Elbashir about the importance of diversity in research, they formed a connection. “Alejandra is very inquisitive and comfortable around other people in the lab,” says Elbashir.

Rosario’s formal mentor, fourth-year MD/PhD student Sarah Chang, has also supported Rosario’s research goals by helping Rosario design research protocols and understand lab jargon. “Sarah’s been nothing but amazing,” says Rosario. “She’s teaching me how to think like a scientist.”

Rosario plans to build on the research she completed this summer in an MD/PhD program. She’d love to return to MIT or the Vander Heiden lab to carry out her future research and would like to continue to find ways to contribute to the development of cancer therapies. She’s very committed to studying cancer biology and wants to continue exploring the different sub-fields of cancer research during her senior year.

She plans to be a mentor to other young scientists, as well, and “pay it forward” to a new generation of underrepresented researchers. Mentoring, she says, creates a “chain reaction” of scientists supporting other scientists, which leads to better advances in research.

“By doing research and pursuing a question to the best of my abilities, I can impact as many people as possible,” she says.

Biologists glean insight into repetitive protein sequences

A computational analysis reveals that many repetitive sequences are shared across proteins and are similar in species from bacteria to humans.

Anne Trafton | MIT News Office
September 13, 2022

About 70 percent of all human proteins include at least one sequence consisting of a single amino acid repeated many times, with a few other amino acids sprinkled in. These “low-complexity regions” are also found in most other organisms.

The proteins that contain these sequences have many different functions, but MIT biologists have now come up with a way to identify and study them as a unified group. Their technique allows them to analyze similarities and differences between LCRs from different species, and helps them to determine the functions of these sequences and the proteins in which they are found.

Using their technique, the researchers have analyzed all of the proteins found in eight different species, from bacteria to humans. They found that while LCRs can vary between proteins and species, they often share a similar role — helping the protein in which they’re found to join a larger-scale assembly such as the nucleolus, an organelle found in nearly all human cells.

“Instead of looking at specific LCRs and their functions, which might seem separate because they’re involved in different processes, our broader approach allows us to see similarities between their properties, suggesting that maybe the functions of LCRs aren’t so disparate after all,” says Byron Lee, an MIT graduate student.

The researchers also found some differences between LCRs of different species and showed that these species-specific LCR sequences correspond to species-specific functions, such as forming plant cell walls.

Lee and graduate student Nima Jaberi-Lashkari are the lead authors of the study, which appears today in eLife. Eliezer Calo, an assistant professor of biology at MIT, is the senior author of the paper.

Large-scale study

Previous research has revealed that LCRs are involved in a variety of cellular processes, including cell adhesion and DNA binding. These LCRs are often rich in a single amino acid such as alanine, lysine, or glutamic acid.

Finding these sequences and then studying their functions individually is a time-consuming process, so the MIT team decided to use bioinformatics — an approach that uses computational methods to analyze large sets of biological data — to evaluate them as a larger group.

“What we wanted to do is take a step back and instead of looking at individual LCRs, to try to take a look at all of them and to see if we could observe some patterns on a larger scale that might help us figure out what the ones that have assigned functions are doing, and also help us learn a bit about what the ones that don’t have assigned functions are doing,” Jaberi-Lashkari says.

To do that, the researchers used a technique called dotplot matrix, which is a way to visually represent amino acid sequences, to generate images of each protein under study. They then used computational image processing methods to compare thousands of these matrices at the same time.

Using this technique, the researchers were able to categorize LCRs based on which amino acids were most frequently repeated in the LCR. They also grouped LCR-containing proteins by the number of copies of each LCR type found in the protein. Analyzing these traits helped the researchers to learn more about the functions of these LCRs.

As one demonstration, the researchers picked out a human protein, known as RPA43, that has three lysine-rich LCRs. This protein is one of many subunits that make up an enzyme called RNA polymerase 1, which synthesizes ribosomal RNA. The researchers found that the copy number of lysine-rich LCRs is important for helping the protein integrate into the nucleolus, the organelle responsible for synthesizing ribosomes.

Biological assemblies

In a comparison of the proteins found in eight different species, the researchers found that some LCR types are highly conserved between species, meaning that the sequences have changed very little over evolutionary timescales. These sequences tend to be found in proteins and cell structures that are also highly conserved, such as the nucleolus.

“These sequences seem to be important for the assembly of certain parts of the nucleolus,” Lee says. “Some of the principles that are known to be important for higher order assembly seem to be at play because the copy number, which might control how many interactions a protein can make, is important for the protein to integrate into that compartment.”

The researchers also found differences between LCRs seen in two different types of proteins that are involved in nucleolus assembly. They discovered that a nucleolar protein known as TCOF contains many glutamine-rich LCRs that can help scaffold the formation of assemblies, while nucleolar proteins with only a few of these glutamic acid-rich LCRs could be recruited as clients (proteins that interact with the scaffold).

Another structure that appears to have many conserved LCRs is the nuclear speckle, which is found inside the cell nucleus. The researchers also found many similarities between LCRs that are involved in forming larger-scale assemblies such as the extracellular matrix, a network of molecules that provides structural support to cells in plants and animals.

The research team also found examples of structures with LCRs that seem to have diverged between species. For example, plants have distinctive LCR sequences in the proteins that they use to scaffold their cell walls, and these LCRs are not seen in other types of organisms.

The researchers now plan to expand their LCR analysis to additional species.

“There’s so much to explore, because we can expand this map to essentially any species,” Lee says. “That gives us the opportunity and the framework to identify new biological assemblies.”

The research was funded by the National Institute of General Medical Sciences, National Cancer Institute, the Ludwig Center at MIT, a National Institutes of Health Pre-Doctoral Training Grant, and the Pew Charitable Trusts.

Scientists identify a plant molecule that sops up iron-rich heme

The peptide is used by legumes to control nitrogen-fixing bacteria; it may also offer leads for treating patients with too much heme in their blood.

Anne Trafton | MIT News Office
August 11, 2022

Symbiotic relationships between legumes and the bacteria that grow in their roots are critical for plant survival. Without those bacteria, the plants would have no source of nitrogen, an element that is essential for building proteins and other biomolecules, and they would be dependent on nitrogen fertilizer in the soil.

To establish that symbiosis, some legume plants produce hundreds of peptides that help bacteria live within structures known as nodules within their roots. A new study from MIT reveals that one of these peptides has an unexpected function: It sops up all available heme, an iron-containing molecule. This sends the bacteria into an iron-starvation mode that ramps up their production of ammonia, the form of nitrogen that is usable for plants.

“This is the first of the 700 peptides in this system for which a really detailed molecular mechanism has been worked out,” says Graham Walker, the American Cancer Society Research Professor of Biology at MIT, a Howard Hughes Medical Institute Professor, and the senior author of the study.

This heme-sequestering peptide could have beneficial uses in treating a variety of human diseases, the researchers say. Removing free heme from the blood could help to treat diseases caused by bacteria or parasites that need heme to survive, such as P. gingivalis (periodontal disease) or toxoplasmosis, or diseases such as sickle cell disease or sepsis that release too much heme into the bloodstream.

“This study demonstrates that basic research in plant-microbe interactions also has potential to be translated to therapeutic applications,” says Siva Sankari, an MIT research scientist and the lead author of the study, which appears today in Nature Microbiology.

Other authors of the paper include Vignesh Babu, an MIT research scientist; Kevin Bian and Mary Andorfer, both MIT postdocs; Areej Alhhazmi, a former KACST-MIT Ibn Khaldun Fellowship for Saudi Arabian Women scholar; Kwan Yoon and Dante Avalos, MIT graduate students; Tyler Smith, an MIT instructor in biology; Catherine Drennan, an MIT professor of chemistry and biology and a Howard Hughes Medical Institute investigator; Michael Yaffe, a David H. Koch Professor of Science and a member of MIT’s Koch Institute for Integrative Cancer Research; and Sebastian Lourido, the Latham Family Career Development Professor of Biology at MIT and a member of the Whitehead Institute for Biomedical Research.

Iron control

For nearly 40 years, Walker’s lab has been studying the symbiosis between legumes and rhizobia, a type of nitrogen-fixing bacteria. These bacteria convert nitrogen gas to ammonia, a critical step of the Earth’s nitrogen cycle that makes the element available to plants (and to animals that eat the plants).

Most of Walker’s work has focused on a clover-like plant called Medicago truncatula. Nitrogen-fixing bacteria elicit the formation of nodules on the roots of these plants and eventually end up inside the plant cells, where they convert to their symbiotic form called bacteroids.

Several years ago, plant biologists discovered that Medicago truncatula produces about 700 peptides that contribute to the formation of these bacteroids. These peptides are generated in waves that help the bacteria make the transition from living freely to becoming embedded into plant cells where they act as nitrogen-fixing machines.

Walker and his students picked one of these peptides, known as NCR247, to dig into more deeply. Initial studies revealed that when nitrogen-fixing bacteria were exposed to this peptide, 15 percent of their genes were affected. Many of the genes that became more active were involved in importing iron.

The researchers then found that when they fused NCR247 to a larger protein, the hybrid protein was unexpectedly reddish in color. This serendipitous observation led to the discovery that NCR247 binds heme, an organic ring-shaped iron-containing molecule that is an important component of hemoglobin, the protein that red blood cells use to carry oxygen.

Further studies revealed that when NCR247 is released into bacterial cells, it sequesters most of the heme in the cell, sending the cells into an iron-starvation mode that triggers them to begin importing more iron from the external environment.

“Usually bacteria fine-tune their iron metabolism, and they don’t take up more iron when there is already enough,” Sankari says. “What’s cool about this peptide is that it overrides that mechanism and indirectly regulates the iron content of the bacteria.”

Nitrogenase, the main enzyme that bacteria use to fix nitrogen, requires 24 to 32 atoms of iron per enzyme molecule, so the influx of extra iron likely helps those enzymes to become more active, the researchers say. This influx is timed to coincide with nitrogen fixation, they found.

“These peptides are produced in a wave in the nodules, and the production of this particular peptide is higher when the bacteria are preparing to fix nitrogen. If this peptide was secreted throughout the whole process, then the cell would have too much iron all the time, which is bad for the cell,” Sankari says.

Without the NCR247 peptide, Medicago truncatula and rhizobium cannot form an effective nitrogen-fixing symbiosis, the researchers showed.

“Many possible directions”

The peptide that the researchers studied in this work may have potential therapeutic uses. When heme is incorporated into hemoglobin, it performs a critical function in the body, but when it’s loose in the bloodstream, it can kill cells and promote inflammation. Free heme can accumulate in stored blood, so having a way to filter out the heme before the blood is transfused into a patient could be potentially useful.

A variety of human diseases lead to free heme circulating in the bloodstream, including sickle cell anemia, sepsis, and malaria. Additionally, some infectious parasites and bacteria depend on heme for their survival but cannot produce it, so they scavenge it from their environment. Treating such infections with a protein that takes up all available heme could help prevent the parasitic or bacterial cells from being able to grow and reproduce.

In this study, Lourido and members of his lab showed that treating the parasite Toxoplasma gondii with NCR427 prevented the parasite from forming plaques on human cells.

The researchers are now pursuing collaborations with other labs at MIT to explore some of these potential applications, with funding from a Professor Amar G. Bose Research Grant.

“There are many possible directions, but they’re all at a very early stage,” Walker says. “The number of potential clinical applications is very broad. You can place more than one bet in this game, which is an intriguing thing.”

Currently, the human protein hemopexin, which also binds to heme, is being explored as a possible treatment for sickle cell anemia. The NCR247 peptide could provide an easier to deploy alternative, the researchers say, because it is much smaller and could be easier to manufacture and deliver into the body.

The research was funded in part by the MIT Center for Environmental Health Sciences, the National Science Foundation, and the National Institutes of Health.

New findings reveal how neurons build and maintain their capacity to communicate

Nerve cells regulate and routinely refresh the collection of calcium channels that enable them to send messages across circuit connections.

David Orenstein | Picower Institute for Learning and Memory
July 21, 2022

The nervous system works because neurons communicate across connections called synapses. They “talk” when calcium ions flow through channels into “active zones” that are loaded with vesicles carrying molecular messages. The electrically charged calcium causes vesicles to “fuse” to the outer membrane of presynaptic neurons, releasing their communicative chemical cargo to the postsynaptic cell. In a new study, scientists at The Picower Institute for Learning and Memory at MIT provide several revelations about how neurons set up and sustain this vital infrastructure.

“Calcium channels are the major determinant of calcium influx, which then triggers vesicle fusion, so it is a critical component of the engine on the presynaptic side that converts electrical signals to chemical synaptic transmission,” says Troy Littleton, senior author of the new study in eLife and Menicon Professor of Neuroscience in MIT’s departments of Biology and Brain and Cognitive Sciences. “How they accumulate at active zones was really unclear. Our study reveals clues into how active zones accumulate and regulate the abundance of calcium channels.”

Neuroscientists have wanted these clues. One reason is that understanding this process can help reveal how neurons change how they communicate, an ability called “plasticity” that underlies learning and memory and other important brain functions. Another is that drugs such as gabapentin, which treats conditions as diverse as epilepsy, anxiety, and nerve pain, binds a protein called alpha2delta that is closely associated with calcium channels. By revealing more about alpha2delta’s exact function, the study better explains what those treatments affect.

“Modulation of the function of presynaptic calcium channels is known to have very important clinical effects,” Littleton says. “Understanding the baseline of how these channels are regulated is really important.”

MIT postdoc Karen Cunningham led the study, which was her doctoral thesis work in Littleton’s lab. Using the model system of fruit fly motor neurons, she employed a wide variety of techniques and experiments to show for the first time the step-by-step process that accounts for the distribution and upkeep of calcium channels at active zones.

A cap on Cac

Cunningham’s first question was whether calcium channels are necessary for active zones to develop in larvae. The fly calcium channel gene (called “cacophony,” or Cac) is so important, flies literally can’t live without it. So rather than knocking out Cac across the fly, Cunningham used a technique to knock it out in just one population of neurons. By doing so, she was able to show that even without Cac, active zones grow and mature normally.

Using another technique that artificially prolongs the larval stage of the fly she was also able to see that given extra time the active zone will continue to build up its structure with a protein called BRP, but that Cac accumulation ceases after the normal six days. Cunningham also found that moderate increases or decreases in the supply of available Cac in the neuron did not affect how much Cac ended up at each active zone. Even more curious, she found that while Cac amount did scale with each active zone’s size, it barely budged if she took away a lot of the BRP in the active zone. Indeed, for each active zone, the neuron seemed to enforce a consistent cap on the amount of Cac present.

“It was revealing that the neuron had very different rules for the structural proteins at the active zone like BRP that continued to accumulate over time, versus the calcium channel that was tightly regulated and had its abundance capped” Cunningham says.

Regular refresh

The findings showed there must be factors other than Cac supply or changes in BRP that regulate Cac levels so tightly. Cunningham turned to alpha2delta. When she genetically manipulated how much of that was expressed, she found that alpha2delta levels directly determined how much Cac accumulated at active zones.

In further experiments, Cunningham was also able to show that alpha2delta’s ability to maintain Cac levels depended on the neuron’s overall Cac supply. That finding suggested that rather than controlling Cac amount at active zones by stabilizing it, alpha2delta likely functioned upstream, during Cac trafficking, to supply and resupply Cac to active zones.

Cunningham used two different techniques to watch that resupply happen, producing measurements of its extent and its timing. She chose a moment after a few days of development to image active zones and measure Cac abundance to ascertain the landscape. Then she bleached out that Cac fluorescence to erase it. After 24 hours, she visualized Cac fluorescence anew to highlight only the new Cac that was delivered to active zones over that 24 hours. She saw that over that day there was Cac delivery across virtually all active zones, but that one day’s work was indeed only a fraction compared to what had built up over several days before. Moreover, she could see that the larger active zones accrued more Cac than smaller ones. And in flies with mutated alpha2delta, there was very little new Cac delivery at all.

If Cac channels were indeed constantly being resupplied, then Cunningham wanted to know at what pace Cac channels are removed from active zones. To determine that, she used a staining technology with a photoconvertible protein called Maple tagged to the Cac protein that allowed her to change the color with a flash of light at the time of her choosing. That way she could first see how much Cac accumulated by a certain time (shown in green) and then flash the light to turn that Cac red. When she checked back five days later, about 30 percent of the red Cac had been replaced with new green Cac, suggesting 30 percent turnover. When she reduced Cac delivery levels by mutating alpha2 delta or reducing Cac biosynthesis, Cac turnover stopped. That means a significant amount of Cac is turned over each day at active zones and that the turnover is prompted by new Cac delivery.

Littleton says his lab is eager to build on these results. Now that the rules of calcium channel abundance and replenishment are clear, he wants to know how they differ when neurons undergo plasticity — for instance, when new incoming information requires neurons to adjust their communication to scale up or down synaptic communication. He says he is also eager to track individual calcium channels as they are made in the cell body and then move down the neural axon to the active zones, and he wants to determine what other genes may affect Cac abundance.

In addition to Cunningham and Littleton, the paper’s other authors are Chad Sauvola and Sara Tavana.

The National Institutes of Health and the JPB Foundation provided support for the research.