Author: mantulin

A new way to understand and predict gene splicing

The KATMAP model, developed by researchers in the Department of Biology, can predict alternative cell splicing, which allows cells to create endless diversity from the same sets of genetic blueprints.

Lillian Eden | Department of Biology
November 4, 2025

Although heart cells and skin cells contain identical instructions for creating proteins encoded in their DNA, they’re able to fill such disparate niches because molecular machinery can cut out and stitch together different segments of those instructions to create endlessly unique combinations.

The ingenuity of using the same genes in different ways is made possible by a process called splicing and is controlled by splicing factors; which splicing factors a cell employs determines what sets of instructions that cell produces, which, in turn, gives rise to proteins that allow cells to fulfill different functions.

In an open-access paper published today in Nature Biotechnology, researchers in the MIT Department of Biology outlined a framework for parsing the complex relationship between sequences and splicing regulation to investigate the regulatory activities of splicing factors, creating models that can be applied to interpret and predict splicing regulation across different cell types, and even different species. Called Knockdown Activity and Target Models from Additive regression Predictions, KATMAP draws on experimental data from disrupting the expression of a splicing factor and information on which sequences the splicing factor interacts with to predict its likely targets.

Aside from the benefits of a better understanding of gene regulation, splicing mutations — either in the gene that is spliced or in the splicing factor itself — can give rise to diseases such as cancer by altering how genes are expressed, leading to the creation or accumulation of faulty or mutated proteins. This information is critical for developing therapeutic treatments for those diseases. The researchers also demonstrated that KATMAP can potentially be used to predict whether synthetic nucleic acids, a promising treatment option for disorders including a subset of muscular atrophy and epilepsy disorders, affect splicing.

Perturbing splicing 

In eukaryotic cells, including our own, splicing occurs after DNA is transcribed to produce an RNA copy of a gene, which contains both coding and non-coding regions of RNA. The noncoding intron regions are removed, and the coding exon segments are spliced back together to make a near-final blueprint, which can then be translated into a protein.

According to first author Michael P. McGurk, a postdoc in the lab of MIT Professor Christopher Burge, previous approaches could provide an average picture of regulation, but could not necessarily predict the regulation of splicing factors at particular exons in particular genes.

KATMAP draws on RNA sequencing data generated from perturbation experiments, which alter the expression level of a regulatory factor by either overexpressing it or knocking down its levels. The consequences of overexpression or knockdown are that the genes regulated by the splicing factor should exhibit different levels of splicing after perturbation, which helps the model identify the splicing factor’s targets.

Cells, however, are complex, interconnected systems, where one small change can cause a cascade of effects. KATMAP is also able to distinguish between direct targets from indirect, downstream impacts by incorporating known information about the sequence the splicing factor is likely to interact with, referred to as a binding site or binding motif.

“In our analyses, we identify predicted targets as exons that have binding sites for this particular factor in the regions where this model thinks they need to be to impact regulation,” McGurk says, while non-targets may be affected by perturbation but don’t have the likely appropriate binding sites nearby.

This is especially helpful for splicing factors that aren’t as well-studied.

“One of our goals with KATMAP was to try to make the model general enough that it can learn what it needs to assume for particular factors, like how similar the binding site has to be to the known motif or how regulatory activity changes with the distance of the binding sites from the splice sites,” McGurk says.

Starting simple

Although predictive models can be very powerful at presenting possible hypotheses, many are considered “black boxes,” meaning the rationale that gives rise to their conclusions is unclear. KATMAP, on the other hand, is an interpretable model that enables researchers to quickly generate hypotheses and interpret splicing patterns in terms of regulatory factors while also understanding how the predictions were made.

“I don’t just want to predict things, I want to explain and understand,” McGurk says. “We set up the model to learn from existing information about splicing and binding, which gives us biologically interpretable parameters.”

The researchers did have to make some simplifying assumptions in order to develop the model. KATMAP considers only one splicing factor at a time, although it is possible for splicing factors to work in concert with one another. The RNA target sequence could also be folded in such a way that the factor wouldn’t be able to access a predicted binding site, so the site is present but not utilized.

“When you try to build up complete pictures of complex phenomena, it’s usually best to start simple,” McGurk says. “A model that only considers one splicing factor at a time is a good starting point.”

David McWaters, another postdoc in the Burge Lab and a co-author on the paper, conducted key experiments to test and validate that aspect of the KATMAP model.

Future directions

The Burge lab is collaborating with researchers at Dana-Farber Cancer Institute to apply KATMAP to the question of how splicing factors are altered in disease contexts, as well as with other researchers at MIT as part of an MIT HEALS grant to model splicing factor changes in stress responses. McGurk also hopes to extend the model to incorporate cooperative regulation for splicing factors that work together.

“We’re still in a very exploratory phase, but I would like to be able to apply these models to try to understand splicing regulation in disease or development. In terms of variation of splicing factors, they are related, and we need to understand both,” McGurk says.

Burge, the Uncas (1923) and Helen Whitaker Professor and senior author of the paper, will continue to work on generalizing this approach to build interpretable models for other aspects of gene regulation.

“We now have a tool that can learn the pattern of activity of a splicing factor from types of data that can be readily generated for any factor of interest,” says Burge, who is also an extra-mural member of the Koch Institute for Integrative Cancer Research and an associate member of the Broad Institute of MIT and Harvard. “As we build up more of these models, we’ll be better able to infer which splicing factors have altered activity in a disease state from transcriptomic data, to help understand which splicing factors are driving pathology.”

The joy of life (sciences)

Mary Gallagher’s deeply rooted MIT experience and love of all life supports growth at the MIT Department of Biology.

Samantha Edelen | Department of Biology
November 28, 2025

For almost 30 years, Mary Gallagher has supported award-winning faculty members and their labs in the same way she tends the soil beneath her garden. In both, she pairs diligence and experience with a delight in the way that interconnected ecosystems contribute to the growth of a plant, or an idea, seeded in the right place.

Gallagher, a senior administrative assistant in the Department of Biology, has spent much of her career at MIT. Her mastery in navigating the myriad tasks required by administrators, and her ability to build connections, have supported and elevated everyone she interacts with, at the Institute and beyond.

Oh, the people you’ll know

Gallagher didn’t start her career at MIT. Her first role following graduation from the University of Vermont in the early 1980s was at a nearby community arts center, where she worked alongside a man who would become a household name in American politics.

“This guy had just been elected mayor, shockingly, of Burlington, Vermont, by under 100 votes, unseating the incumbent. He went in and created this arts council and youth office,” Gallagher recalls.

That political newcomer was none other than a young Bernie Sanders, now the longest-serving independent senator in U.S. congressional history.

Gallagher arrived at MIT in 1996, becoming an administrative assistant (aka “lab admin”) in what was then called the MIT Energy Laboratory. Shortly after her arrival, Cecil and Ida Green Professor of Physics and Engineering Systems Ernest Moniz transformed the laboratory into the MIT Energy Initiative (MITEI).

Gallagher quickly learned how versatile the work of an administrator can be. As MITEI rapidly grew, she interacted with people across campus and its vast array of disciplines at the Institute, including mechanical engineering, political science, and economics.

“Admin jobs at MIT are really crazy because of the depth of work that we’re willing to do to support the institution. I was hired to do secretarial work, and next thing I know, I was traveling all the time, and planning a five-day, 5,000-person event down in D.C.,” Gallagher says. “I developed crazy computer and event-planner skills.”

Although such tasks may seem daunting to some, Gallagher has been thrilled with the opportunities she’s had to meet so many people and develop so many new skills. As a lab admin in MITEI for 18 years, she mastered navigating MIT administration, lab finances, and technical support. When Moniz left MITEI to lead the U.S. Department of Energy under President Obama, she moved to the Department of Biology at MIT.

Mutual thriving

Over the years, Gallagher has fostered the growth of students and colleagues at MIT, and vice versa.

Friend and former colleague Samantha Farrell recalls her first days at MITEI as a rather nervous and very “green” temp, when Gallagher offered an excellent cappuccino from Gallagher’s new Nespresso coffee machine.

“I treasure her friendship and knowledge,” Farrell says. “She taught me everything I needed to know about being an admin and working in research.”

Gallagher’s experience has also set faculty across the Institute up for success.

According to one principal investigator she currently supports, Novartis Professor of Biology Leonard Guarente, Gallagher is “extremely impactful and, in short, an ideal administrative assistant.”

Similarly, professor of biology Daniel Lew is grateful that her extensive MIT experience was available as he moved his lab to the Institute in recent years. “Mary was invaluable in setting up and running the lab, teaching at MIT, and organizing meetings and workshops,” Lew says. “She is a font of knowledge about MIT.”

A willingness to share knowledge, resources, and sometimes a cappuccino, is just as critical as a willingness to learn, especially at a teaching institution like MIT. So it goes without saying that the students at MIT have left their mark on Gallagher in turn — including teaching her how to format a digital table of contents on her very first day at MIT.

“Working with undergrads and grad students is my favorite part of MIT. Their generosity leaves me breathless,” says Gallagher. “No matter how busy they are, they’re always willing to help another person.”

Campus community

Gallagher cites the decline in community following the Covid-19 pandemic shutdown as one of her most significant challenges.

Prior to Covid, Gallagher says, “MIT had this great sense of community. Everyone had projects, volunteered, and engaged. The campus was buzzing, it was a hoot!”

She nurtured that community, from active participation in the MIT Women’s League to organizing an award-winning relaunch of Artist Behind the Desk. This subgroup of the MIT Working Group for Support Staff Issues hosted lunchtime recitals and visual art shows to bring together staff artists around campus, for which the group received a 2005 MIT Excellence Award for Creating Connections.

Moreover, Gallagher is an integral part of the smaller communities within the labs she supports.

Professor of biology and American Cancer Society Professor Graham Walker, yet another Department of Biology faculty member Gallagher supports, says, “Mary’s personal warmth and constant smile has lit up my lab for many years, and we are all grateful to have her as such a good colleague and friend.”

She strives to restore the sense of community that the campus used to have, but recognizes that striving for bygone days is futile.

“You can never go back in time and make the future what it was in the past,” she says. “You have to reimagine how we can make ourselves special in a new way.”

Spreading her roots

Gallagher’s life has been inextricably shaped by the Institute, and MIT, in turn, would not be what it is if not for Gallagher’s willingness to share her wisdom on the complexities of administration alongside the “joie de vivre” of her garden’s butterflies.

She recently bought a home in rural New Hampshire, trading the buzzing crowds of campus for the buzzing of local honeybees. Her work ethic is reflected in her ongoing commitment to curiosity, through reading about native plant life and documenting pollinating insects as they wander about her flowers.

Just as she can admire each bug and flower for the role it plays in the larger system, Gallagher has participated in and contributed to a culture of appreciating the role of every individual within the whole.

“At MIT’s core, they believe that everybody brings something to the table,” she says. “I wouldn’t be who I am if I didn’t work at MIT and meet all these people.”

Facundo Batista among MIT affiliates elected to National Academy of Medicine for 2025

Professors Facundo Batista and Dina Katabi, along with three additional MIT alumni, are honored for their outstanding professional achievement and commitment to service.

Lillian Eden | Jane Halpern | Department of Biology | Department of Electrical Engineering and Computer Science
October 22, 2025

On Oct. 20 during its annual meeting, the National Academy of Medicine announced the election of 100 new members, including MIT faculty members Dina Katabi and Facundo Batista, along with three additional MIT alumni.

Election to the National Academy of Medicine (NAM) is considered one of the highest honors in the fields of health and medicine, recognizing individuals who have demonstrated outstanding professional achievement and commitment to service.

Facundo Batista is the associate director and scientific director of the Ragon Institute of MGH, MIT and Harvard, as well as the first Phillip T. and Susan M. Ragon Professor in the MIT Department of Biology. The National Academy of Medicine recognized Batista for “his work unraveling the biology of antibody-producing B cells to better understand how our body’s immune systems responds to infectious disease.” More recently, Facundo’s research has advanced preclinical vaccine and therapeutic development for globally important diseases including HIV, malaria, and influenza.

Batista earned a PhD from the International School of Advanced Studies and established his lab in 2002 as a member of the Francis Crick Institute (formerly the London Research Institute), simultaneously holding a professorship at Imperial College London. In 2016, he joined the Ragon Institute to pursue a new research program applying his expertise in B cells and antibody responses to vaccine development, and preclinical vaccinology for diseases including SARS-CoV-2 and HIV. Batista is an elected fellow or member of the U.K. Academy of Medical Sciences, the American Academy of Microbiology, the Academia de Ciencias de América Latina, and the European Molecular Biology Organization, and he is chief editor of The EMBO Journal.

Dina Katabi SM ’99, PhD ’03 is the Thuan (1990) and Nicole Pham Professor in the Department of Electrical Engineering and Computer Science at MIT. Her research spans digital health, wireless sensing, mobile computing, machine learning, and computer vision. Katabi’s contributions include efficient communication protocols for the internet, advanced contactless biosensors, and novel AI models that interpret physiological signals. The NAM recognized Katabi for “pioneering digital health technology that enables non-invasive, off-body remote health monitoring via AI and wireless signals, and for developing digital biomarkers for Parkinson’s progression and detection. She has translated this technology to advance objective, sensitive measures of disease trajectory and treatment response in clinical trials.”

Katabi is director of the MIT Center for Wireless Networks and Mobile Computing. She is also a member of the Computer Science and Artificial Intelligence Laboratory (CSAIL), where she leads the Networks at MIT Research Group. Katabi received a bachelor’s degree from the University of Damascus and MS and PhD degrees in computer science from MIT. She is a MacArthur Fellow; a member of the American Academy of Arts and Sciences, National Academy of Sciences, and National Academy of Engineering; and a recipient of the ACM Computing Prize.

Additional MIT alumni who were elected to the NAM for 2025 are:

  • Christopher S. Chen SM ’93, PhD ’97, an alumnus of the Department of Mechanical Engineering and the Harvard-MIT Program in Health Sciences and Technology;
  • Michael E. Matheny SM ’06, an alumnus of the Harvard-MIT Program in Health Sciences and Technology; and
  • Rebecca R. Richards-Kortum SM ’87, PhD ’90, and alumna of the Department of Physics and the Harvard-MIT Program in Health Sciences and Technology.

Established originally as the Institute of Medicine in 1970 by the National Academy of Sciences, the National Academy of Medicine addresses critical issues in health, science, medicine, and related policy, and inspires positive actions across sectors.

“I am deeply honored to welcome these extraordinary health and medicine leaders and researchers into the National Academy of Medicine,” says NAM President Victor J. Dzau. “Their demonstrated excellence in tackling public health challenges, leading major discoveries, improving health care, advancing health policy, and addressing health equity will critically strengthen our collective ability to tackle the most pressing health challenges of our time.”

Department of Biology welcomes new faculty Yunha Hwang in shared position with EECS, Schwarzman College of Computing

Hwang is one of 11 new faculty members that occupy core computing and shared positions, bringing varied backgrounds and expertise to the MIT community.

Amanda Diehl | MIT Schwarzman College of Computing
October 17, 2025

The MIT Schwarzman College of Computing welcomes 11 new faculty members in core computing and shared positions to the MIT community. They bring varied backgrounds and expertise spanning sustainable design, satellite remote sensing, decision theory, and the development of new algorithms for declarative artificial intelligence programming, among others.

“I warmly welcome this talented group of new faculty members. Their work lies at the forefront of computing and its broader impact in the world,” says Dan Huttenlocher, dean of the MIT Schwarzman College of Computing and the Henry Ellis Warren Professor of Electrical Engineering and Computer Science.

College faculty include those with appointments in the Department of Electrical Engineering and Computer Science (EECS) or in the Institute for Data, Systems, and Society (IDSS), which report into both the MIT Schwarzman College of Computing and the School of Engineering. There are also several new faculty members in shared positions between the college and other MIT departments and sections, including Political Science, Linguistics and Philosophy, History, and Architecture.

“Thanks to another successful year of collaborative searches, we have hired six additional faculty in shared positions, bringing the total to 20,” says Huttenlocher.

The new shared faculty include:

Bailey Flanigan is an assistant professor in the Department of Political Science, holding an MIT Schwarzman College of Computing shared position with EECS. Her research combines tools from social choice theory, game theory, algorithms, statistics, and survey methods to advance political methodology and strengthen democratic participation. She is interested in sampling algorithms, opinion measurement, and the design of democratic innovations like deliberative minipublics and participatory budgeting. Flanigan was a postdoc at Harvard University’s Data Science Initiative, and she earned her PhD in computer science from Carnegie Mellon University.

Brian Hedden PhD ’12 is a professor in the Department of Linguistics and Philosophy, holding an MIT Schwarzman College of Computing shared position with EECS. His research focuses on how we ought to form beliefs and make decisions. His works span epistemology, decision theory, and ethics, including ethics of AI. He is the author of “Reasons without Persons: Rationality, Identity, and Time” (Oxford University Press, 2015) and articles on topics such as collective action problems, legal standards of proof, algorithmic fairness, and political polarization. Prior to joining MIT, he was a faculty member at the Australian National University and the University of Sydney, and a junior research fellow at Oxford University. He received his BA from Princeton University and his PhD from MIT, both in philosophy.

Yunha Hwang is an assistant professor in the Department of Biology, holding an MIT Schwarzman College of Computing shared position with EECS. She is also a member of the Laboratory for Information and Decision Systems. Her research interests span machine learning for sustainable biomanufacturing, microbial evolution, and open science. She serves as the co-founder and chief scientist at Tatta Bio, a scientific nonprofit dedicated to advancing genomic AI for biological discovery. She holds a BS in computer science from Stanford University and a PhD in biology from Harvard University.

Ben Lindquist is an assistant professor in the History Section, holding an MIT Schwarzman College of Computing shared position with EECS. Through a historical lens, his work observes the ways that computing has circulated with ideas of religion, emotion, and divergent thinking. His book, “The Feeling Machine” (University of Chicago Press, forthcoming), follows the history of synthetic speech to examine how emotion became a subject of computer science. He was a postdoc in the Science in Human Culture Program at Northwestern University and earned his PhD in history from Princeton University.

Mariana Popescu is an assistant professor in the Department of Architecture, holding an MIT Schwarzman College of Computing shared position with EECS. She is also a member of the Computer Science and Artificial Intelligence Laboratory (CSAIL). A computational architect and structural designer, Popescu has a strong interest and experience in innovative ways of approaching the fabrication process and use of materials in construction. Her area of expertise is computational and parametric design, with a focus on digital fabrication and sustainable design. Popescu earned her doctorate at ETH Zurich.

Paris Smaragdis SM ’97, PhD ’01 is a professor in the Music and Theater Arts Section, holding an MIT Schwarzman College of Computing shared position with EECS. His research focus lies at the intersection of signal processing and machine learning, especially as it relates to sound and music. Prior to coming to MIT, he worked as a research scientist at Mitsubishi Electric Research Labs, a senior research scientist at Adobe Research, and an Amazon Scholar with Amazon’s AWS. He spent 15 years as a professor at the University of Illinois Urbana Champaign in the Computer Science Department, where he spearheaded the design of the CS+Music program, and served as an associate director of the School of Computer and Data Science. He holds a BMus from Berklee College of Music and earned his PhD in perceptual computing from MIT.

Daniel Varon is an assistant professor in the Department of Aeronautics and Astronautics, holding an MIT Schwarzman College of Computing shared position with IDSS. His work focuses on using satellite observations of atmospheric composition to better understand human impacts on the environment and identify opportunities to reduce them. An atmospheric scientist, Varon is particularly interested in greenhouse gasses, air pollution, and satellite remote sensing. He holds an MS in applied mathematics and a PhD in atmospheric chemistry, both from Harvard University.

In addition, the School of Engineering has adopted the shared faculty search model to hire its first shared faculty member:

Mark Rau is an assistant professor in the Music and Theater Arts Section, holding a School of Engineering shared position with EECS. He is involved in developing graduate programming focused on music technology. He has an interest in musical acoustics, vibration and acoustic measurement, audio signal processing, and physical modeling synthesis. His work focuses on musical instruments and creative audio effects. He holds an MA in music, science, and technology from Stanford, as well as a BS in physics and BMus in jazz from McGill University. He earned his PhD at Stanford’s Center for Computer Research in Music and Acoustics.

The new core faculty are:

Mitchell Gordon is an assistant professor in EECS. He is also a member of CSAIL. In his research, Gordon designs interactive systems and evaluation approaches that bridge principles of human-computer interaction with the realities of machine learning. His work has won awards at conferences in human-computer interaction and artificial intelligence, including a best paper award at CHI and an Oral at NeurIPS. Gordon received a BS from the University of Rochester, and MS and PhD from Stanford University, all in computer science.

Omar Khattab is an assistant professor in EECS. He is also a member of CSAIL. His work focuses on natural language processing, information retrieval, and AI systems. His research includes developing new algorithms and abstractions for declarative AI programming and for composing retrieval and reasoning. He received his BS from Carnegie Mellon University and his PhD from Stanford University, both in computer science.

Rachit Nigam will join EECS as an assistant professor in January 2026. He will also be a member of CSAIL and the Microsystems Technology Laboratories. He works on programming languages and computer architecture to address the design, verification, and usability challenges of specialized hardware. He was previously a visiting scholar at MIT. Nigam earned an MS and PhD in computer science from Cornell University.

Biologists identify targets for new pancreatic cancer treatments

Research from MIT and Dana-Farber Cancer Institute yielded hundreds of “cryptic” peptides that are found only on pancreatic tumor cells and could be targeted by vaccines or engineered T cells.

Anne Trafton | MIT News
May 7, 2025

Researchers from MIT and Dana-Farber Cancer Institute have discovered that a class of peptides expressed in pancreatic cancer cells could be a promising target for T-cell therapies and other approaches that attack pancreatic tumors.

Known as cryptic peptides, these molecules are produced from sequences in the genome that were not thought to encode proteins. Such peptides can also be found in some healthy cells, but in this study, the researchers identified about 500 that appear to be found only in pancreatic tumors.

The researchers also showed they could generate T cells targeting those peptides. Those T cells were able to attack pancreatic tumor organoids derived from patient cells, and they significantly slowed down tumor growth in a study of mice.

“Pancreas cancer is one of the most challenging cancers to treat. This study identifies an unexpected vulnerability in pancreas cancer cells that we may be able to exploit therapeutically,” says Tyler Jacks, the David H. Koch Professor of Biology at MIT and a member of the Koch Institute for Integrative Cancer Research.

Jacks and William Freed-Pastor, a physician-scientist in the Hale Family Center for Pancreatic Cancer Research at Dana-Farber Cancer Institute and an assistant professor at Harvard Medical School, are the senior authors of the study, which appears today in Science. Zackery Ely PhD ’22 and Zachary Kulstad, a former research technician at Dana-Farber Cancer Institute and the Koch Institute, are the lead authors of the paper.

Cryptic peptides

Pancreatic cancer has one of the lowest survival rates of any cancer — about 10 percent of patients survive for five years after their diagnosis.

Most pancreatic cancer patients receive a combination of surgery, radiation treatment, and chemotherapy. Immunotherapy treatments such as checkpoint blockade inhibitors, which are designed to help stimulate the body’s own T cells to attack tumor cells, are usually not effective against pancreatic tumors. However, therapies that deploy T cells engineered to attack tumors have shown promise in clinical trials.

These therapies involve programming the T-cell receptor (TCR) of T cells to recognize a specific peptide, or antigen, found on tumor cells. There are many efforts underway to identify the most effective targets, and researchers have found some promising antigens that consist of mutated proteins that often show up when pancreatic cancer genomes are sequenced.

In the new study, the MIT and Dana-Farber team wanted to extend that search into tissue samples from patients with pancreatic cancer, using immunopeptidomics — a strategy that involves extracting the peptides presented on a cell surface and then identifying the peptides using mass spectrometry.

Using tumor samples from about a dozen patients, the researchers created organoids — three-dimensional growths that partially replicate the structure of the pancreas. The immunopeptidomics analysis, which was led by Jennifer Abelin and Steven Carr at the Broad Institute, found that the majority of novel antigens found in the tumor organoids were cryptic antigens. Cryptic peptides have been seen in other types of tumors, but this is the first time they have been found in pancreatic tumors.

Each tumor expressed an average of about 250 cryptic peptides, and in total, the researchers identified about 1,700 cryptic peptides.

“Once we started getting the data back, it just became clear that this was by far the most abundant novel class of antigens, and so that’s what we wound up focusing on,” Ely says.

The researchers then performed an analysis of healthy tissues to see if any of these cryptic peptides were found in normal cells. They found that about two-thirds of them were also found in at least one type of healthy tissue, leaving about 500 that appeared to be restricted to pancreatic cancer cells.

“Those are the ones that we think could be very good targets for future immunotherapies,” Freed-Pastor says.

Programmed T cells

To test whether these antigens might hold potential as targets for T-cell-based treatments, the researchers exposed about 30 of the cancer-specific antigens to immature T cells and found that 12 of them could generate large populations of T cells targeting those antigens.

The researchers then engineered a new population of T cells to express those T-cell receptors. These engineered T cells were able to destroy organoids grown from patient-derived pancreatic tumor cells. Additionally, when the researchers implanted the organoids into mice and then treated them with the engineered T cells, tumor growth was significantly slowed.

This is the first time that anyone has demonstrated the use of T cells targeting cryptic peptides to kill pancreatic tumor cells. Even though the tumors were not completely eradicated, the results are promising, and it is possible that the T-cells’ killing power could be strengthened in future work, the researchers say.

Freed-Pastor’s lab is also beginning to work on a vaccine targeting some of the cryptic antigens, which could help stimulate patients’ T cells to attack tumors expressing those antigens. Such a vaccine could include a collection of the antigens identified in this study, including those frequently found in multiple patients.

This study could also help researchers in designing other types of therapy, such as T cell engagers — antibodies that bind an antigen on one side and T cells on the other, which allows them to redirect any T cell to kill tumor cells.

Any potential vaccine or T cell therapy is likely a few years away from being tested in patients, the researchers say.

The research was funded in part by the Hale Family Center for Pancreatic Cancer Research, the Lustgarten Foundation, Stand Up To Cancer, the Pancreatic Cancer Action Network, the Burroughs Wellcome Fund, a Conquer Cancer Young Investigator Award, the National Institutes of Health, and the National Cancer Institute.

Dopamine signals when a fear can be forgotten

Study shows how a dopamine circuit between two brain regions enables mice to extinguish fear after a peril has passed.

David Orenstein | The Picower Institute for Learning and Memory
May 7, 2025

Dangers come but dangers also go, and when they do, the brain has an “all-clear” signal that teaches it to extinguish its fear. A new study in mice by MIT neuroscientists shows that the signal is the release of dopamine along a specific interregional brain circuit. The research therefore pinpoints a potentially critical mechanism of mental health, restoring calm when it works, but prolonging anxiety or even post-traumatic stress disorder when it doesn’t.

“Dopamine is essential to initiate fear extinction,” says Michele Pignatelli di Spinazzola, co-author of the new study from the lab of senior author Susumu Tonegawa, Picower Professor of biology and neuroscience at the RIKEN-MIT Laboratory for Neural Circuit Genetics within The Picower Institute for Learning and Memory at MIT, and a Howard Hughes Medical Institute (HHMI) investigator.

In 2020, Tonegawa’s lab showed that learning to be afraid, and then learning when that’s no longer necessary, result from a competition between populations of cells in the brain’s amygdala region. When a mouse learns that a place is “dangerous” (because it gets a little foot shock there), the fear memory is encoded by neurons in the anterior of the basolateral amygdala (aBLA) that express the gene Rspo2. When the mouse then learns that a place is no longer associated with danger (because they wait there and the zap doesn’t recur), neurons in the posterior basolateral amygdala (pBLA) that express the gene Ppp1r1b encode a new fear extinction memory that overcomes the original dread. Notably, those same neurons encode feelings of reward, helping to explain why it feels so good when we realize that an expected danger has dwindled.

In the new study, the lab, led by former members Xiangyu Zhang and Katelyn Flick, sought to determine what prompts these amygdala neurons to encode these memories. The rigorous set of experiments the team reports in the Proceedings of the National Academy of Sciences show that it’s dopamine sent to the different amygdala populations from distinct groups of neurons in the ventral tegmental area (VTA).

“Our study uncovers a precise mechanism by which dopamine helps the brain unlearn fear,” says Zhang, who also led the 2020 study and is now a senior associate at Orbimed, a health care investment firm. “We found that dopamine activates specific amygdala neurons tied to reward, which in turn drive fear extinction. We now see that unlearning fear isn’t just about suppressing it — it’s a positive learning process powered by the brain’s reward machinery. This opens up new avenues for understanding and potentially treating fear-related disorders, like PTSD.”

Forgetting fear

The VTA was the lab’s prime suspect to be the source of the signal because the region is well known for encoding surprising experiences and instructing the brain, with dopamine, to learn from them. The first set of experiments in the paper used multiple methods for tracing neural circuits to see whether and how cells in the VTA and the amygdala connect. They found a clear pattern: Rspo2 neurons were targeted by dopaminergic neurons in the anterior and left and right sides of the VTA. Ppp1r1b neurons received dopaminergic input from neurons in the center and posterior sections of the VTA. The density of connections was greater on the Ppp1r1b neurons than for the Rspo2 ones.

The circuit tracing showed that dopamine is available to amygdala neurons that encode fear and its extinction, but do those neurons care about dopamine? The team showed that indeed they express “D1” receptors for the neuromodulator. Commensurate with the degree of dopamine connectivity, Ppp1r1b cells had more receptors than Rspo2 neurons.

Dopamine does a lot of things, so the next question was whether its activity in the amygdala actually correlated with fear encoding and extinction. Using a method to track and visualize it in the brain, the team watched dopamine in the amygdala as mice underwent a three-day experiment. On Day One, they went to an enclosure where they experienced three mild shocks on the feet. On Day Two, they went back to the enclosure for 45 minutes, where they didn’t experience any new shocks — at first, the mice froze in anticipation of a shock, but then relaxed after about 15 minutes. On Day Three they returned again to test whether they had indeed extinguished the fear they showed at the beginning of Day Two.

The dopamine activity tracking revealed that during the shocks on Day One, Rspo2 neurons had the larger response to dopamine, but in the early moments of Day Two, when the anticipated shocks didn’t come and the mice eased up on freezing, the Ppp1r1b neurons showed the stronger dopamine activity. More strikingly, the mice that learned to extinguish their fear most strongly also showed the greatest dopamine signal at those neurons.

Causal connections

The final sets of experiments sought to show that dopamine is not just available and associated with fear encoding and extinction, but also actually causes them. In one set, they turned to optogenetics, a technology that enables scientists to activate or quiet neurons with different colors of light. Sure enough, when they quieted VTA dopaminergic inputs in the pBLA, doing so impaired fear extinction. When they activated those inputs, it accelerated fear extinction. The researchers were surprised that when they activated VTA dopaminergic inputs into the aBLA they could reinstate fear even without any new foot shocks, impairing fear extinction.

The other way they confirmed a causal role for dopamine in fear encoding and extinction was to manipulate the amygdala neurons’ dopamine receptors. In Ppp1r1b neurons, over-expressing dopamine receptors impaired fear recall and promoted extinction, whereas knocking the receptors down impaired fear extinction. Meanwhile in the Rspo2 cells, knocking down receptors reduced the freezing behavior.

“We showed that fear extinction requires VTA dopaminergic activity in the pBLA Ppp1r1b neurons by using optogenetic inhibition of VTA terminals and cell-type-specific knockdown of D1 receptors in these neurons,” the authors wrote.

The scientists are careful in the study to note that while they’ve identified the “teaching signal” for fear extinction learning, the broader phenomenon of fear extinction occurs brainwide, rather than in just this single circuit.

But the circuit seems to be a key node to consider as drug developers and psychiatrists work to combat anxiety and PTSD, Pignatelli di Spinazzola says.

“Fear learning and fear extinction provide a strong framework to study generalized anxiety and PTSD,” he says. “Our study investigates the underlying mechanisms suggesting multiple targets for a translational approach, such as pBLA and use of dopaminergic modulation.”

Marianna Rizzo is also a co-author of the study. Support for the research came from the RIKEN Center for Brain Science, the HHMI, the Freedom Together Foundation, and The Picower Institute.

Staff Spotlight: Lighting up biology’s basement lab

Senior Technical Instructor Vanessa Cheung ’02 brings the energy, experience, and excitement needed to educate students in the biology teaching lab.

Samantha Edelen | Department of Biology
April 29, 2025

For more than 30 years, Course 7 (Biology) students have descended to the expansive, windowless basement of Building 68 to learn practical skills that are the centerpiece of undergraduate biology education at the Institute. The lines of benches and cabinets of supplies that make up the underground MIT Biology Teaching Lab could easily feel dark and isolated.

In the corner of this room, however, sits Senior Technical Instructor Vanessa Cheung ’02, who manages to make the space seem sunny and communal.

“We joke that we could rig up a system of mirrors to get just enough daylight to bounce down from the stairwell,” Cheung says with a laugh. “It is a basement, but I am very lucky to have this teaching lab space. It is huge and has everything we need.”

This optimism and gratitude fostered by Cheung is critical, as MIT undergrad students enrolled in classes 7.002 (Fundamentals of Experimental Molecular Biology) and 7.003 (Applied Molecular Biology Laboratory) spend four-hour blocks in the lab each week, learning the foundations of laboratory technique and theory for biological research from Cheung and her colleagues.

Running toward science education

Cheung’s love for biology can be traced back to her high school cross country and track coach, who also served as her second-year biology teacher. The sport and the fundamental biological processes she was learning about in the classroom were, in fact, closely intertwined.

“He told us about how things like ATP [adenosine triphosphate] and the energy cycle would affect our running,” she says. “Being able to see that connection really helped my interest in the subject.”

That inspiration carried her through a move from her hometown of Pittsburgh, Pennsylvania, to Cambridge, Massachusetts, to pursue an undergraduate degree at MIT, and through her thesis work to earn a PhD in genetics at Harvard Medical School. She didn’t leave running behind either: To this day, she can often be found on the Charles River Esplanade, training for her next marathon.

She discovered her love of teaching during her PhD program. She enjoyed guiding students so much that she spent an extra semester as a teaching assistant, outside of the one required for her program.

“I love research, but I also really love telling people about research,” Cheung says.

Cheung herself describes lab instruction as the “best of both worlds,” enabling her to pursue her love of teaching while spending every day at the bench, doing experiments. She emphasizes for students the importance of being able not just to do the hands-on technical lab work, but also to understand the theory behind it.

“The students can tend to get hung up on the physical doing of things — they are really concerned when their experiments don’t work,” she says. “We focus on teaching students how to think about being in a lab — how to design an experiment and how to analyze the data.”

Although her talent for teaching and passion for science led her to the role, Cheung doesn’t hesitate to identify the students as her favorite part of the job.

“It sounds cheesy, but they really do keep the job very exciting,” she says.

Using mind and hand in the lab

Cheung is the type of person who lights up when describing how much she “loves working with yeast.”

“I always tell the students that maybe no one cares about yeast except me and like three other people in the world, but it is a model organism that we can use to apply what we learn to humans,” Cheung explains.

Though mastering basic lab skills can make hands-on laboratory courses feel “a bit cookbook,” Cheung is able to get the students excited with her enthusiasm and clever curriculum design.

“The students like things where they can get their own unique results, and things where they have a little bit of freedom to design their own experiments,” she says. So, the lab curriculum incorporates opportunities for students to do things like identify their own unique yeast mutants and design their own questions to test in a chemical engineering module.

Part of what makes theory as critical as technique is that new tools and discoveries are made frequently in biology, especially at MIT. For example, there has been a shift from a focus on RNAi to CRISPR as a popular lab technique in recent years, and Cheung muses that CRISPR itself may be overshadowed within only a few more years — keeping students learning at the cutting edge of biology is always on Cheung’s mind.

“Vanessa is the heart, soul, and mind of the biology lab courses here at MIT, embodying ‘mens et manus’ [‘mind and hand’],” says technical lab instructor and Biology Teaching Lab Manager Anthony Fuccione.

Support for all students

Cheung’s ability to mentor and guide students earned her a School of Science Dean’s Education and Advising Award in 2012, but her focus isn’t solely on MIT undergraduate students.

In fact, according to Cheung, the earlier students can be exposed to science, the better. In addition to her regular duties, Cheung also designs curriculum and teaches in the LEAH Knox Scholars Program. The two-year program provides lab experience and mentorship for low-income Boston- and Cambridge-area high school students.

Paloma Sanchez-Jauregui, outreach programs coordinator who works with Cheung on the program, says Cheung has a standout “growth mindset” that students really appreciate.

“Vanessa teaches students that challenges — like unexpected PCR results — are part of the learning process,” Sanchez-Jauregui says. “Students feel comfortable approaching her for help troubleshooting experiments or exploring new topics.”

Cheung’s colleagues report that they admire not only her talents, but also her focus on supporting those around her. Technical Instructor and colleague Eric Chu says Cheung “offers a lot of help to me and others, including those outside of the department, but does not expect reciprocity.”

Professor of biology and co-director of the Department of Biology undergraduate program Adam Martin says he “rarely has to worry about what is going on in the teaching lab.” According to Martin, Cheung is ”flexible, hard-working, dedicated, and resilient, all while being kind and supportive to our students. She is a joy to work with.”

Staff Spotlight: Always looking to home

Mingmar Sherpa, a researcher in the Martin Lab in the Department of Biology, has remained connected to his home in Nepal at every step of his career.

Ekaterina Khalizeva | Department of Biology
April 29, 2025

For Mingmar Sherpa, a senior research support associate in the Martin Lab in the Department of Biology, community is more than just his colleagues in the lab, where he studies how mechanical forces affect cell division timing during embryogenesis. On his long and winding path to MIT, he never left behind the people he grew up among in Nepal. Sherpa has been dedicated, every step of his career — from rural Solukhumbu to Kathmandu to Alabama to Cambridge — to advancing education and health care among his people in any way he can.

Despite working more than 7,000 miles away from home, Mingmar Sherpa makes every effort to keep himself connected to his community in Nepal. Every month, for example, he sends home money to support a computer lab that he established in his hometown in rural Solukhumbu, the district of Nepal that houses Mount Everest — just $250 a month covers the costs of a teacher’s salary, electricity, internet, and a space to teach. In this lab, almost 250 students thus far have learned computer skills essential to working in today’s digitally driven world. In college, Sherpa also started The Bright Vision Foundation (The Bright Future), an organization to support health and education in Nepal, and during the pandemic raised funds to provide personal protective equipment (PPE) and health care services across his home country.

While Sherpa’s ambition to help his home can be traced back to his childhood, he didn’t have it all figured out from the start, and found inspiration at each step of his career.

“This mindset of giving back to the community, helping policymakers or establishing an organization to help people do science, helping the scientific community to find cures for diseases — all these ideas came to me along the way,” Sherpa says. “It is the journey that matters.”

A journey driven by hope and optimism

“Sherpa” is a reference to the ethnic group native to the mountainous regions of Nepal and Tibet, whose members are well-known for their mountaineering skills, which they use to guide and assist tourists who want to climb Mount Everest. Growing up in rural Solukhumbu, Sherpa was surrounded by people working in the tourism industry; few other occupations appeared feasible. There was just one hospital for the whole district, requiring locals to walk for days to get medical assistance.

The youngest of seven siblings, Sherpa went to an English-language middle school, which he had to walk for over an hour to get to. He excelled there, soon becoming the top student in his class and passing the national exam with distinction — success that allowed him to both dream of and accomplish a move to Kathmandu, the capital city of Nepal, to study in the best school in the country.

It was an overwhelming transition, surrounded as he was for the first time by people from a very different social class, privileged with far more technological resources. The gaps between this well-equipped community and the one he left back home became increasingly obvious and left a strong impression on Sherpa.

There, he started thinking about how to use his newly acquired access to education and technology to uplift his community at home. He was especially fascinated by questions surrounding biology and human health, and next set his sights on attending college in the United States.

“If I came to the U.S., I could learn skills which I could not learn in Nepal,” he says. “I could prepare myself to solve the problems that I want to solve.”

At the University of Alabama in Birmingham, Sherpa continued to deepen his passion for biological science and joined a research lab. Through that work, he discovered the joys of basic research and the diverse set of skills it fosters.

“I joined the lab to learn science, but to do science, you need other skills, like research communication,” he says. “I was learning unintentionally from being in a research position.”

When Covid-19 spread around the globe, Sherpa wanted to apply the expertise and resources he had gained to help his people address the crisis. It was then that he started The Bright Vision Foundation, an organization aiming to raise the standards of health care and education in underserved communities in Nepal. Through the foundation, he raised funds to distribute PPE, provide health care services, and set up the computer lab in his childhood home.

“Today’s world is all about technology and innovation, but here are good people in my community who don’t even know about computers,” he says.

With the help of his brother, who serves as the lab instructor, and his parents, who provide the space and support the lab, and Sherpa’s own fundraising, he aims to help youths from backgrounds similar to his own be better prepared for the technologically advanced, globalized world of today.

The MIT chapter

Now, at MIT, Sherpa speaks with deep appreciation of the opportunities that the university has opened up for him — the people he has been meeting here, and the skills he has been learning.

Professor of biology Adam C. Martin, Sherpa’s principal investigator, views making sure that international trainees like Mingmar are aware of the wide range of opportunities MIT offers — whether it be workshops, collaborations, networking and funding possibilities, or help with the pathway toward graduate school — as a key part of creating a supportive environment.

Understanding the additional burdens on international trainees gives Martin extra appreciation for Sherpa’s perseverance, motivation, and desire to share his culture with the lab, sharing Nepalese food and providing context for Nepalese customs.

Being at such a research-intensive institution as MIT has helped Sherpa further clarify his goals and his view of the paths he can take to achieve them. Since college, his three passions have been intertwined: leadership, research, and human health.

Sherpa will pursue a PhD in biomedical and biological sciences with a focus in cancer biology at Cornell University in the fall. In the longer term, he plans to focus on developing policy to improve public health.

Although Sherpa recognizes that Nepal is not the only place that might need his help, he has a sharp focus and an acute sense of what he is best positioned to do now. Sherpa is gearing up to organize a health camp in the spring to bring doctors to rural areas in Nepal, not only to provide care, but also to gather data on nutrition and health in different regions of the country.

“I cannot, in a day, or even a year, bring the living conditions of people in vulnerable communities up to a higher level, but I can slowly increase the living standard of people in less-developed communities, especially in Nepal,” he says. “There might be other parts of the world which are even more vulnerable than Nepal, but I haven’t explored them yet. But I know my community in Nepal, so I want to help improve people’s lives there.”

New study reveals how cleft lip and cleft palate can arise

MIT biologists have found that defects in some transfer RNA molecules can lead to the formation of these common conditions.

Anne Trafton | MIT News
April 17, 2025

Cleft lip and cleft palate are among the most common birth defects, occurring in about one in 1,050 births in the United States. These defects, which appear when the tissues that form the lip or the roof of the mouth do not join completely, are believed to be caused by a mix of genetic and environmental factors.

In a new study, MIT biologists have discovered how a genetic variant often found in people with these facial malformations leads to the development of cleft lip and cleft palate.

Their findings suggest that the variant diminishes cells’ supply of transfer RNA, a molecule that is critical for assembling proteins. When this happens, embryonic face cells are unable to fuse to form the lip and roof of the mouth.

“Until now, no one had made the connection that we made. This particular gene was known to be part of the complex involved in the splicing of transfer RNA, but it wasn’t clear that it played such a crucial role for this process and for facial development. Without the gene, known as DDX1, certain transfer RNA can no longer bring amino acids to the ribosome to make new proteins. If the cells can’t process these tRNAs properly, then the ribosomes can’t make protein anymore,” says Michaela Bartusel, an MIT research scientist and the lead author of the study.

Eliezer Calo, an associate professor of biology at MIT, is the senior author of the paper, which appears today in the American Journal of Human Genetics.

Genetic variants

Cleft lip and cleft palate, also known as orofacial clefts, can be caused by genetic mutations, but in many cases, there is no known genetic cause.

“The mechanism for the development of these orofacial clefts is unclear, mostly because they are known to be impacted by both genetic and environmental factors,” Calo says. “Trying to pinpoint what might be affected has been very challenging in this context.”

To discover genetic factors that influence a particular disease, scientists often perform genome-wide association studies (GWAS), which can reveal variants that are found more often in people who have a particular disease than in people who don’t.

For orofacial clefts, some of the genetic variants that have regularly turned up in GWAS appeared to be in a region of DNA that doesn’t code for proteins. In this study, the MIT team set out to figure out how variants in this region might influence the development of facial malformations.

Their studies revealed that these variants are located in an enhancer region called e2p24.2. Enhancers are segments of DNA that interact with protein-coding genes, helping to activate them by binding to transcription factors that turn on gene expression.

The researchers found that this region is in close proximity to three genes, suggesting that it may control the expression of those genes. One of those genes had already been ruled out as contributing to facial malformations, and another had already been shown to have a connection. In this study, the researchers focused on the third gene, which is known as DDX1.

DDX1, it turned out, is necessary for splicing transfer RNA (tRNA) molecules, which play a critical role in protein synthesis. Each transfer RNA molecule transports a specific amino acid to the ribosome — a cell structure that strings amino acids together to form proteins, based on the instructions carried by messenger RNA.

While there are about 400 different tRNAs found in the human genome, only a fraction of those tRNAs require splicing, and those are the tRNAs most affected by the loss of DDX1. These tRNAs transport four different amino acids, and the researchers hypothesize that these four amino acids may be particularly abundant in proteins that embryonic cells that form the face need to develop properly.

When the ribosomes need one of those four amino acids, but none of them are available, the ribosome can stall, and the protein doesn’t get made.

The researchers are now exploring which proteins might be most affected by the loss of those amino acids. They also plan to investigate what happens inside cells when the ribosomes stall, in hopes of identifying a stress signal that could potentially be blocked and help cells survive.

Malfunctioning tRNA

While this is the first study to link tRNA to craniofacial malformations, previous studies have shown that mutations that impair ribosome formation can also lead to similar defects. Studies have also shown that disruptions of tRNA synthesis — caused by mutations in the enzymes that attach amino acids to tRNA, or in proteins involved in an earlier step in tRNA splicing — can lead to neurodevelopmental disorders.

“Defects in other components of the tRNA pathway have been shown to be associated with neurodevelopmental disease,” Calo says. “One interesting parallel between these two is that the cells that form the face are coming from the same place as the cells that form the neurons, so it seems that these particular cells are very susceptible to tRNA defects.”

The researchers now hope to explore whether environmental factors linked to orofacial birth defects also influence tRNA function. Some of their preliminary work has found that oxidative stress — a buildup of harmful free radicals — can lead to fragmentation of tRNA molecules. Oxidative stress can occur in embryonic cells upon exposure to ethanol, as in fetal alcohol syndrome, or if the mother develops gestational diabetes.

“I think it is worth looking for mutations that might be causing this on the genetic side of things, but then also in the future, we would expand this into which environmental factors have the same effects on tRNA function, and then see which precautions might be able to prevent any effects on tRNAs,” Bartusel says.

The research was funded by the National Science Foundation Graduate Research Program, the National Cancer Institute, the National Institute of General Medical Sciences, and the Pew Charitable Trusts.

Restoring healthy gene expression with programmable therapeutics

CAMP4 Therapeutics is targeting regulatory RNA, whose role in gene expression was first described by co-founder and MIT Professor Richard Young.

Zach Winn | MIT News
April 16, 2025

Many diseases are caused by dysfunctional gene expression that leads to too much or too little of a given protein. Efforts to cure those diseases include everything from editing genes to inserting new genetic snippets into cells to injecting the missing proteins directly into patients.

CAMP4 is taking a different approach. The company is targeting a lesser-known player in the regulation of gene expression known as regulatory RNA. CAMP4 co-founder and MIT Professor Richard Young has shown that by interacting with molecules called transcription factors, regulatory RNA plays an important role in controlling how genes are expressed. CAMP4’s therapeutics target regulatory RNA to increase the production of proteins and put patients’ levels back into healthy ranges.

The company’s approach holds promise for treating diseases caused by defects in gene expression, such as metabolic diseases, heart conditions, and neurological disorders. Targeting regulatory RNAs as opposed to genes could also offer more precise treatments than existing approaches.

“If I just want to fix a single gene’s defective protein output, I don’t want to introduce something that makes that protein at high, uncontrolled amounts,” says Young, who is also a core member of the Whitehead Institute. “That’s a huge advantage of our approach: It’s more like a correction than sledgehammer.”

CAMP4’s lead drug candidate targets urea cycle disorders (UCDs), a class of chronic conditions caused by a genetic defect that limits the body’s ability to metabolize and excrete ammonia. A phase 1 clinical trial has shown CAMP4’s treatment is safe and tolerable for humans, and in preclinical studies the company has shown its approach can be used to target specific regulatory RNA in the cells of humans with UCDs to restore gene expression to healthy levels.

“This has the potential to treat very severe symptoms associated with UCDs,” says Young, who co-founded CAMP4 with cancer genetics expert Leonard Zon, a professor at Harvard Medical School. “These diseases can be very damaging to tissues and causes a lot of pain and distress. Even a small effect in gene expression could have a huge benefit to patients, who are generally young.”

Mapping out new therapeutics

Young, who has been a professor at MIT since 1984, has spent decades studying how genes are regulated. It’s long been known that molecules called transcription factors, which orchestrate gene expression, bind to DNA and proteins. Research published in Young’s lab uncovered a previously unknown way in which transcription factors can also bind to RNA. The finding indicated RNA plays an underappreciated role in controlling gene expression.

CAMP4 was founded in 2016 with the initial idea of mapping out the signaling pathways that govern the expression of genes linked to various diseases. But as Young’s lab discovered and then began to characterize the role of regulatory RNA in gene expression around 2020, the company pivoted to focus on targeting regulatory RNA using therapeutic molecules known as antisense oligonucleotides (ASOs), which have been used for years to target specific messenger RNA sequences.

CAMP4 began mapping the active regulatory RNAs associated with the expression of every protein-coding gene and built a database, which it calls its RAP Platform, that helps it quickly identify regulatory RNAs to target  specific diseases and select ASOs that will most effectively bind to those RNAs.

Today, CAMP4 is using its platform to develop therapeutic candidates it believes can restore healthy protein levels to patients.

“The company has always been focused on modulating gene expression,” says CAMP4 Chief Financial Officer Kelly Gold MBA ’09. “At the simplest level, the foundation of many diseases is too much or too little of something being produced by the body. That is what our approach aims to correct.”

Accelerating impact

CAMP4 is starting by going after diseases of the liver and the central nervous system, where the safety and efficacy of ASOs has already been proven. Young believes correcting genetic expression without modulating the genes themselves will be a powerful approach to treating a range of complex diseases.

“Genetics is a powerful indicator of where a deficiency lies and how you might reverse that problem,” Young says. “There are many syndromes where we don’t have a complete understanding of the underlying mechanism of disease. But when a mutation clearly affects the output of a gene, you can now make a drug that can treat the disease without that complete understanding.”

As the company continues mapping the regulatory RNAs associated with every gene, Gold hopes CAMP4 can eventually minimize its reliance on wet-lab work and lean more heavily on machine learning to leverage its growing database and quickly identify regRNA targets for every disease it wants to treat.

In addition to its trials in urea cycle disorders, the company plans to launch key preclinical safety studies for a candidate targeting seizure disorders with a genetic basis, this year. And as the company continues exploring drug development efforts around the thousands of genetic diseases where increasing protein levels are can have a meaningful impact, it’s also considering collaborating with others to accelerate its impact.

“I can conceive of companies using a platform like this to go after many targets, where partners fund the clinical trials and use CAMP4 as an engine to target any disease where there’s a suspicion that gene upregulation or downregulation is the way to go,” Young says.