Author: mantulin

Matthew Vander Heiden among those elected to National Academy of Medicine for 2024

Professor Matthew Vander Heiden and Biology alum Konstantina M. Stankovic are honored for their outstanding professional achievement and commitment to service.

Nina Tamburello | Koch Institute
October 22, 2024

The National Academy of Medicine recently announced the election of more than 90 members during its annual meeting, including MIT faculty members Matthew Vander Heiden and Fan Wang, along with five MIT alumni.

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

Matthew Vander Heiden is the director of the Koch Institute for Integrative Cancer Research at MIT, a Lester Wolfe Professor of Molecular Biology, and a member of the Broad Institute of MIT and Harvard. His research explores how cancer cells reprogram their metabolism to fuel tumor growth and has provided key insights into metabolic pathways that support cancer progression, with implications for developing new therapeutic strategies. The National Academy of Medicine recognized Vander Heiden for his contributions to “the development of approved therapies for cancer and anemia” and his role as a “thought leader in understanding metabolic phenotypes and their relations to disease pathogenesis.”

Vander Heiden earned his MD and PhD from the University of Chicago and completed  his clinical training in internal medicine and medical oncology at the Brigham and Women’s Hospital and the Dana-Farber Cancer Institute. After postdoctoral research at Harvard Medical School, Vander Heiden joined the faculty of the MIT Department of Biology and the Koch Institute in 2010. He is also a practicing oncologist and instructor in medicine at Dana-Farber Cancer Institute and Harvard Medical School.

Fan Wang is a professor of brain and cognitive sciences, an investigator at the McGovern Institute, and director of the K. Lisa Yang and Hock E. Tan Center for Molecular Therapeutics at MIT.  Wang’s research focuses on the neural circuits governing the bidirectional interactions between the brain and body. She is specifically interested in the circuits that control the sensory and emotional aspects of pain and addiction, as well as the sensory and motor circuits that work together to execute behaviors such as eating, drinking, and moving. The National Academy of Medicine has recognized her body of work for “providing the foundational knowledge to develop new therapies to treat chronic pain and movement disorders.”

Before coming to MIT in 2021, Wang obtained her PhD from Columbia University and received her postdoctoral training at the University of California at San Francisco and Stanford University. She became a faculty member at Duke University in 2003 and was later appointed the Morris N. Broad Professor of Neurobiology. Wang is also a member of the American Academy of Arts and Sciences and she continues to make important contributions to the neural mechanisms underlying general anesthesia, pain perception, and movement control.

MIT alumni who were elected to the NAM for 2024 include:

  • Leemore Dafny PhD ’01 (Economics);
  • David Huang ’85 MS ’89  (Electrical Engineering and Computer Science) PhD ’93 Medical Engineering and Medical Physics);
  • Nola M. Hylton ’79 (Chemical Engineering);
  • Mark R. Prausnitz PhD ’94 (Chemical Engineering); and
  • Konstantina M. Stankovic ’92 (Biology and Physics) PhD ’98 (Speech and Hearing Bioscience 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.

“This class of new members represents the most exceptional researchers and leaders in health and medicine, who have made significant breakthroughs, led the response to major public health challenges, and advanced health equity,” said National Academy of Medicine President Victor J. Dzau. “Their expertise will be necessary to supporting NAM’s work to address the pressing health and scientific challenges we face today.”

Cancer biologists discover a new mechanism for an old drug

Study reveals the drug, 5-fluorouracil, acts differently in different types of cancer — a finding that could help researchers design better drug combinations.

Anne Trafton | MIT News
October 7, 2024

Since the 1950s, a chemotherapy drug known as 5-fluorouracil has been used to treat many types of cancer, including blood cancers and cancers of the digestive tract.

Doctors have long believed that this drug works by damaging the building blocks of DNA. However, a new study from MIT has found that in cancers of the colon and other gastrointestinal cancers, it actually kills cells by interfering with RNA synthesis.

The findings could have a significant effect on how doctors treat many cancer patients. Usually, 5-fluorouracil is given in combination with chemotherapy drugs that damage DNA, but the new study found that for colon cancer, this combination does not achieve the synergistic effects that were hoped for. Instead, combining 5-FU with drugs that affect RNA synthesis could make it more effective in patients with GI cancers, the researchers say.

“Our work is the most definitive study to date showing that RNA incorporation of the drug, leading to an RNA damage response, is responsible for how the drug works in GI cancers,” says Michael Yaffe, a David H. Koch Professor of Science at MIT, the director of the MIT Center for Precision Cancer Medicine, and a member of MIT’s Koch Institute for Integrative Cancer Research. “Textbooks implicate the DNA effects of the drug as the mechanism in all cancer types, but our data shows that RNA damage is what’s really important for the types of tumors, like GI cancers, where the drug is used clinically.”

Yaffe, the senior author of the new study, hopes to plan clinical trials of 5-fluorouracil with drugs that would enhance its RNA-damaging effects and kill cancer cells more effectively.

Jung-Kuei Chen, a Koch Institute research scientist, and Karl Merrick, a former MIT postdoc, are the lead authors of the paper, which appears today in Cell Reports Medicine.

An unexpected mechanism

Clinicians use 5-fluorouracil (5-FU) as a first-line drug for colon, rectal, and pancreatic cancers. It’s usually given in combination with oxaliplatin or irinotecan, which damage DNA in cancer cells. The combination was thought to be effective because 5-FU can disrupt the synthesis of DNA nucleotides. Without those building blocks, cells with damaged DNA wouldn’t be able to efficiently repair the damage and would undergo cell death.

Yaffe’s lab, which studies cell signaling pathways, wanted to further explore the underlying mechanisms of how these drug combinations preferentially kill cancer cells.

The researchers began by testing 5-FU in combination with oxaliplatin or irinotecan in colon cancer cells grown in the lab. To their surprise, they found that not only were the drugs not synergistic, in many cases they were less effective at killing cancer cells than what one would expect by simply adding together the effects of 5-FU or the DNA-damaging drug given alone.

“One would have expected that these combinations to cause synergistic cancer cell death because you are targeting two different aspects of a shared process: breaking DNA, and making nucleotides,” Yaffe says. “Karl looked at a dozen colon cancer cell lines, and not only were the drugs not synergistic, in most cases they were antagonistic. One drug seemed to be undoing what the other drug was doing.”

Yaffe’s lab then teamed up with Adam Palmer, an assistant professor of pharmacology at the University of North Carolina School of Medicine, who specializes in analyzing data from clinical trials. Palmer’s research group examined data from colon cancer patients who had been on one or more of these drugs and showed that the drugs did not show synergistic effects on survival in most patients.

“This confirmed that when you give these combinations to people, it’s not generally true that the drugs are actually working together in a beneficial way within an individual patient,” Yaffe says. “Instead, it appears that one drug in the combination works well for some patients while another drug in the combination works well in other patients. We just cannot yet predict which drug by itself is best for which patient, so everyone gets the combination.”

These results led the researchers to wonder just how 5-FU was working, if not by disrupting DNA repair. Studies in yeast and mammalian cells had shown that the drug also gets incorporated into RNA nucleotides, but there has been dispute over how much this RNA damage contributes to the drug’s toxic effects on cancer cells.

Inside cells, 5-FU is broken down into two different metabolites. One of these gets incorporated into DNA nucleotides, and other into RNA nucleotides. In studies of colon cancer cells, the researchers found that the metabolite that interferes with RNA was much more effective at killing colon cancer cells than the one that disrupts DNA.

That RNA damage appears to primarily affect ribosomal RNA, a molecule that forms part of the ribosome — a cell organelle responsible for assembling new proteins. If cells can’t form new ribosomes, they can’t produce enough proteins to function. Additionally, the lack of undamaged ribosomal RNA causes cells to destroy a large set of proteins that normally bind up the RNA to make new functional ribosomes.

The researchers are now exploring how this ribosomal RNA damage leads cells to under programmed cell death, or apoptosis. They hypothesize that sensing of the damaged RNAs within cell structures called lysosomes somehow triggers an apoptotic signal.

“My lab is very interested in trying to understand the signaling events during disruption of ribosome biogenesis, particularly in GI cancers and even some ovarian cancers, that cause the cells to die. Somehow, they must be monitoring the quality control of new ribosome synthesis, which somehow is connected to the death pathway machinery,” Yaffe says.

New combinations

The findings suggest that drugs that stimulate ribosome production could work together with 5-FU to make a highly synergistic combination. In their study, the researchers showed that a molecule that inhibits KDM2A, a suppressor of ribosome production, helped to boost the rate of cell death in colon cancer cells treated with 5-FU.

The findings also suggest a possible explanation for why combining 5-FU with a DNA-damaging drug often makes both drugs less effective. Some DNA damaging drugs send a signal to the cell to stop making new ribosomes, which would negate 5-FU’s effect on RNA. A better approach may be to give each drug a few days apart, which would give patients the potential benefits of each drug, without having them cancel each other out.

“Importantly, our data doesn’t say that these combination therapies are wrong. We know they’re effective clinically. It just says that if you adjust how you give these drugs, you could potentially make those therapies even better, with relatively minor changes in the timing of when the drugs are given,” Yaffe says.

He is now hoping to work with collaborators at other institutions to run a phase 2 or 3 clinical trial in which patients receive the drugs on an altered schedule.

“A trial is clearly needed to look for efficacy, but it should be straightforward to initiate because these are already clinically accepted drugs that form the standard of care for GI cancers. All we’re doing is changing the timing with which we give them,” he says.

The researchers also hope that their work could lead to the identification of biomarkers that predict which patients’ tumors will be more susceptible to drug combinations that include 5-FU. One such biomarker could be RNA polymerase I, which is active when cells are producing a lot of ribosomal RNA.

The research was funded by the Damon Runyon Cancer Research Fund, a Ludwig Center at MIT Fellowship, the National Institutes of Health, the Ovarian Cancer Research Fund, the Holloway Foundation, and the STARR Cancer Consortium.

Victor Ambros ’75, PhD ’79 and Gary Ruvkun share Nobel Prize in Physiology or Medicine

The scientists, who worked together as postdocs at MIT, are honored for their discovery of microRNA — a class of molecules that are critical for gene regulation.

Anne Trafton | MIT News
October 7, 2024

MIT alumnus Victor Ambros ’75, PhD ’79 and Gary Ruvkun, who did his postdoctoral training at MIT, will share the 2024 Nobel Prize in Physiology or Medicine, the Royal Swedish Academy of Sciences announced this morning in Stockholm.

Ambros, a professor at the University of Massachusetts Chan Medical School, and Ruvkun, a professor at Harvard Medical School and Massachusetts General Hospital, were honored for their discovery of microRNA, a class of tiny RNA molecules that play a critical role in gene control.

“Their groundbreaking discovery revealed a completely new principle of gene regulation that turned out to be essential for multicellular organisms, including humans. It is now known that the human genome codes for over one thousand microRNAs. Their surprising discovery revealed an entirely new dimension to gene regulation. MicroRNAs are proving to be fundamentally important for how organisms develop and function,” the Nobel committee said in its announcement today.

During the late 1980s, Ambros and Ruvkun both worked as postdocs in the laboratory of H. Robert Horvitz, a David H. Koch Professor at MIT, who was awarded the Nobel Prize in 2002.

While in Horvitz’s lab, the pair began studying gene control in the roundworm C. elegans — an effort that laid the groundwork for their Nobel discoveries. They studied two mutant forms of the worm, known as lin-4 and lin-14, that showed defects in the timing of the activation of genetic programs that control development.

In the early 1990s, while Ambros was a faculty member at Harvard University, he made a surprising discovery. The lin-4 gene, instead of encoding a protein, produced a very short RNA molecule that appeared in inhibit the expression of lin-14.

At the same time, Ruvkun was continuing to study these C. elegans genes in his lab at MGH and Harvard. He showed that lin-4 did not inhibit lin-14 by preventing the lin-14 gene from being transcribed into messenger RNA; instead, it appeared to turn off the gene’s expression later on, by preventing production of the protein encoded by lin-14.

The two compared results and realized that the sequence of lin-4 was complementary to some short sequences of lin-14. Lin-4, they showed, was binding to messenger RNA encoding lin-14 and blocking it from being translated into protein — a mechanism for gene control that had never been seen before. Those results were published in two articles in the journal Cell in 1993.

In an interview with the Journal of Cell Biology, Ambros credited the contributions of his collaborators, including his wife, Rosalind “Candy” Lee ’76, and postdoc Rhonda Feinbaum, who both worked in his lab, cloned and characterized the lin-4 microRNA, and were co-authors on one of the 1993 Cell papers.

In 2000, Ruvkun published the discovery of another microRNA molecule, encoded by a gene called let-7, which is found throughout the animal kingdom. Since then, more than 1,000 microRNA genes have been found in humans.

“Ambros and Ruvkun’s seminal discovery in the small worm C. elegans was unexpected, and revealed a new dimension to gene regulation, essential for all complex life forms,” the Nobel citation declared.

Ambros, who was born in New Hampshire and grew up in Vermont, earned his PhD at MIT under the supervision of David Baltimore, then an MIT professor of biology, who received a Nobel Prize in 1973. Ambros was a longtime faculty member at Dartmouth College before joining the faculty at the University of Massachusetts Chan Medical School in 2008.

Ruvkun is a graduate of the University of California at Berkeley and earned his PhD at Harvard University before joining Horvitz’s lab at MIT.

Improving biology education here, there, and everywhere

At the cutting edge of pedagogy, Mary Ellen Wiltrout has shaped blended and online learning at MIT and beyond.

Samantha Edelen | Department of Biology
September 18, 2024

When she was a child, Mary Ellen Wiltrout PhD ’09 didn’t want to follow in her mother’s footsteps as a K-12 teacher. Growing up in southwestern Pennsylvania, Wiltrout was studious with an early interest in science — and ended up pursuing biology as a career.

But following her doctorate at MIT, she pivoted toward education after all. Now, as the director of blended and online initiatives and a lecturer with the Department of Biology, she’s shaping biology pedagogy at MIT and beyond.

Establishing MOOCs at MIT

To this day, E.C. Whitehead Professor of Biology and Howard Hughes Medical Institute (HHMI) investigator emeritus Tania Baker considers creating a permanent role for Wiltrout one of the most consequential decisions she made as department head.

Since launching the very first MITxBio massive online open course 7.00x (Introduction to Biology – the Secret of Life) with professor of biology Eric Lander in 2013, Wiltrout’s team has worked with MIT Open Learning and biology faculty to build an award-winning repertoire of MITxBio courses.

MITxBio is part of the online learning platform edX, established by MIT and Harvard University in 2012, which today connects 86 million people worldwide to online learning opportunities. Within MITxBio, Wiltrout leads a team of instructional staff and students to develop online learning experiences for MIT students and the public while researching effective methods for learner engagement and course design.

“Mary Ellen’s approach has an element of experimentation that embodies a very MIT ethos: applying rigorous science to creatively address challenges with far-reaching impact,” says Darcy Gordon, instructor of blended and online initiatives.

Mentee to motivator

Wiltrout was inspired to pursue both teaching and research by the late geneticist Elizabeth “Beth” Jones at Carnegie Mellon University, where Wiltrout earned a degree in biological sciences and served as a teaching assistant in lab courses.

“I thought it was a lot of fun to work with students, especially at the higher level of education, and especially with a focus on biology,” Wiltrout recalls, noting she developed her love of teaching in those early experiences.

Though her research advisor at the time discouraged her from teaching, Jones assured Wiltrout that it was possible to pursue both.

Jones, who received her postdoctoral training with late Professor Emeritus Boris Magasanik at MIT, encouraged Wiltrout to apply to the Institute and join American Cancer Society and HHMI Professor Graham Walker’s lab. In 2009, Wiltrout earned a PhD in biology for thesis work in the Walker lab, where she continued to learn from enthusiastic mentors.

“When I joined Graham’s lab, everyone was eager to teach and support a new student,” she reflects. After watching Walker aid a struggling student, Wiltrout was further affirmed in her choice. “I knew I could go to Graham if I ever needed to.”

After graduation, Wiltrout taught molecular biology at Harvard for a few years until Baker facilitated her move back to MIT. Now, she’s a resource for faculty, postdocs, and students.

“She is an incredibly rich source of knowledge for everything from how to implement the increasingly complex tools for running a class to the best practices for ensuring a rigorous and inclusive curriculum,” says Iain Cheeseman, the Herman and Margaret Sokol Professor of Biology and associate head of the biology department.

Stephen Bell, the Uncas and Helen Whitaker Professor of Biology and instructor of the Molecular Biology series of MITxBio courses, notes Wiltrout is known for staying on the “cutting edge of pedagogy.”

“She has a comprehensive knowledge of new online educational tools and is always ready to help any professor to implement them in any way they wish,” he says.

Gordon finds Wiltrout’s experiences as a biologist and learning engineer instrumental to her own professional development and a model for their colleagues in science education.

“Mary Ellen has been an incredibly supportive supervisor. She facilitates a team environment that centers on frequent feedback and iteration,” says Tyler Smith, instructor for pedagogy training and biology.

Prepared for the pandemic, and beyond

Wiltrout believes blended learning, combining in-person and online components, is the best path forward for education at MIT. Building personal relationships in the classroom is critical, but online material and supplemental instruction are also key to providing immediate feedback, formative assessments, and other evidence-based learning practices.

“A lot of people have realized that they can’t ignore online learning anymore,” Wiltrout noted during an interview on The Champions Coffee Podcast in 2023. That couldn’t have been truer than in 2020, when academic institutions were forced to suddenly shift to virtual learning.

“When Covid hit, we already had all the infrastructure in place,” Baker says. “Mary Ellen helped not just our department, but also contributed to MIT education’s survival through the pandemic.”

For Wiltrout’s efforts, she received a COVID-19 Hero Award, a recognition from the School of Science for staff members who went above and beyond during that extraordinarily difficult time.

“Mary Ellen thinks deeply about how to create the best learning opportunities possible,” says Cheeseman, one of almost a dozen faculty members who nominated her for the award.

Recently, Wiltrout expanded beyond higher education and into high schools, taking on several interns in collaboration with Empowr, a nonprofit organization that teaches software development skills to Black students to create a school-to-career pipeline. Wiltrout is proud to report that one of these interns is now a student at MIT in the class of 2028.

Looking forward, Wiltrout aims to stay ahead of the curve with the latest educational technology and is excited to see how modern tools can be incorporated into education.

“Everyone is pretty certain that generative AI is going to change education,” she says. “We need to be experimenting with how to take advantage of technology to improve learning.”

Ultimately, she is grateful to continue developing her career at MIT biology.

“It’s exciting to come back to the department after being a student and to work with people as colleagues to produce something that has an impact on what they’re teaching current MIT students and sharing with the world for further reach,” she says.

As for Wiltrout’s own daughter, she’s declared she would like to follow in her mother’s footsteps — a fitting symbol of Wiltrout’s impact on the future of education.

No detail too small

For Sarah Sterling, the new director of the Cryo-Electron Microscopy facility at MIT.nano, better planning and more communication leads to better science.

Nikole L. Fendler | Department of Biology
September 6, 2024

Sarah Sterling, director of the Cryo-Electron Microscopy, or Cryo-EM, core facility, often compares her job to running a small business. Each day brings a unique set of jobs ranging from administrative duties and managing facility users to balancing budgets and maintaining equipment.

Although one could easily be overwhelmed by the seemingly never-ending to-do list, Sterling finds a great deal of joy in wearing so many different hats. One of her most essential tasks involves clear communication with users when the delicate instruments in the facility are unusable because of routine maintenance and repairs.

“Better planning allows for better science,” Sterling says. “Luckily, I’m very comfortable with building and fixing things. Let’s troubleshoot. Let’s take it apart. Let’s put it back together.”

Out of all her duties as a core facility director, she most looks forward to the opportunities to teach, especially helping students develop research projects.

“Undergraduate or early-stage graduate students ask the best questions,” she says. “They’re so curious about the tiny details, and they’re always ready to hit the ground running on their projects.”

A non-linear scientific journey

When Sterling enrolled in Russell Sage College, a women’s college in New York, she was planning to pursue a career as a physical therapist. However, she quickly realized she loved her chemistry classes more than her other subjects. She graduated with a bachelor of science degree in chemistry and immediately enrolled in a master’s degree program in chemical engineering at the University of Maine.

Sterling was convinced to continue her studies at the University of Maine with a dual PhD in chemical engineering and biomedical sciences. That decision required the daunting process of taking two sets of core courses and completing a qualifying exam in each field.

“I wouldn’t recommend doing that,” she says with a laugh. “To celebrate after finishing that intense experience, I took a year off to figure out what came next.”

Sterling chose to do a postdoc in the lab of Eva Nogales, a structural biology professor at the University of California at Berkeley. Nogales was looking for a scientist with experience working with lipids, a class of molecules that Sterling had studied extensively in graduate school.

At the time Sterling joined, the Nogales Lab was at the forefront of implementing an exciting structural biology approach: cryo-EM.

“When I was interviewing, I’d never even seen the type of microscope required for cryo-EM, let alone performed any experiments,” Sterling says. “But I remember thinking ‘I’m sure I can figure this out.’”

Cryo-EM is a technique that allows researchers to determine the three-dimensional shape, or structure, of the macromolecules that make up cells. A researcher can take a sample of their macromolecule of choice, suspend it in a liquid solution, and rapidly freeze it onto a grid to capture the macromolecules in random positions — the “cryo” part of the name. Powerful electron microscopes then collect images of the macromolecule — the EM part of cryo-EM.

The two-dimensional images of the macromolecules from different angles can be combined to produce a three-dimensional structure. Structural information like this can reveal the macromolecule’s function inside cells or inform how it differs in a disease state. The rapidly expanding use of cryo-EM has unlocked so many mechanistic insights that the researchers who developed the technology were awarded the 2017 Nobel Prize in Chemistry.

The MIT.nano facility opened its doors in 2018. The open-access, state-of-the-art facility now has more than 160 tools and more than 1,500 users representing nearly every department at MIT. The Cryo-EM facility lives in the basement of the MIT.nano building and houses multiple electron microscopes and laboratory space for cryo-specimen preparation.

Thanks to her work at UC Berkeley, Sterling’s career trajectory has long been intertwined with the expanding use of cryo-EM in research. Sterling anticipated the need for experienced scientists to run core facilities in order to maintain the electron microscopes needed for cryo-EM, which range in cost from a staggering $1 million to $10 million each.

After completing her postdoc, Sterling worked at the Harvard University cryo-EM core facility for five years. When the director position for the MIT.nano Cryo-EM facility opened, she decided to apply.

“I like that the core facility at MIT was smaller and more frequently used by students,” Sterling says. “There’s a lot more teaching, which is a challenge sometimes, but it’s rewarding to impact someone’s career at such an early stage.”

A focus on users

When Sterling arrived at MIT, her first initiative was to meet directly with all the students in research labs that use the core facility to learn what would make using the facility a better experience. She also implemented clear and standard operating procedures for cryo-EM beginners.

“I think being consistent and available has really improved users’ experiences,” Sterling says.

The users themselves report that her initiatives have proven highly successful — and have helped them grow as scientists.

“Sterling cultivates an environment where I can freely ask questions about anything to support my learning,” says Bonnie Su, a frequent Cryo-EM facility user and graduate student from the Vos lab.

But Sterling does not want to stop there. Looking ahead, she hopes to expand the facility by acquiring an additional electron microscope to allow more users to utilize this powerful technology in their research. She also plans to build a more collaborative community of cryo-EM scientists at MIT with additional symposia and casual interactions such as coffee hours.

Under her management, cryo-EM research has flourished. In the last year, the Cryo-EM core facility has supported research resulting in 12 new publications across five different departments at MIT. The facility has also provided access to 16 industry and non-MIT academic entities. These studies have revealed important insights into various biological processes, from visualizing how large protein machinery reads our DNA to the protein aggregates found in neurodegenerative disorders.

If anyone wants to conduct cryo-EM experiments or learn more about the technique, Sterling encourages anyone in the MIT community to reach out.

“Come visit us!” she says. “We give lots of tours, and you can stop by to say hi anytime.”

Pursuing the secrets of a stealthy parasite

By unraveling the genetic pathways that help Toxoplasma gondii persist in human cells, Sebastian Lourido hopes to find new ways to treat toxoplasmosis.

Anne Trafton | MIT News
August 25, 2024

Toxoplasma gondii, the parasite that causes toxoplasmosis, is believed to infect as much as one-third of the world’s population. Many of those people have no symptoms, but the parasite can remain dormant for years and later reawaken to cause disease in anyone who becomes immunocompromised.

Why this single-celled parasite is so widespread, and what triggers it to reemerge, are questions that intrigue Sebastian Lourido, an associate professor of biology at MIT and member of the Whitehead Institute for Biomedical Research. In his lab, research is unraveling the genetic pathways that help to keep the parasite in a dormant state, and the factors that lead it to burst free from that state.

“One of the missions of my lab to improve our ability to manipulate the parasite genome, and to do that at a scale that allows us to ask questions about the functions of many genes, or even the entire genome, in a variety of contexts,” Lourido says.

There are drugs that can treat the acute symptoms of Toxoplasma infection, which include headache, fever, and inflammation of the heart and lungs. However, once the parasite enters the dormant stage, those drugs don’t affect it. Lourido hopes that his lab’s work will lead to potential new treatments for this stage, as well as drugs that could combat similar parasites such as a tickborne parasite known as Babesia, which is becoming more common in New England.

“There are a lot of people who are affected by these parasites, and parasitology often doesn’t get the attention that it deserves at the highest levels of research. It’s really important to bring the latest scientific advances, the latest tools, and the latest concepts to the field of parasitology,” Lourido says.

A fascination with microbiology

As a child in Cali, Colombia, Lourido was enthralled by what he could see through the microscopes at his mother’s medical genetics lab at the University of Valle del Cauca. His father ran the family’s farm and also worked in government, at one point serving as interim governor of the state.

“From my mom, I was exposed to the ideas of gene expression and the influence of genetics on biology, and I think that really sparked an early interest in understanding biology at a fundamental level,” Lourido says. “On the other hand, my dad was in agriculture, and so there were other influences there around how the environment shapes biology.”

Lourido decided to go to college in the United States, in part because at the time, in the early 2000s, Colombia was experiencing a surge in violence. He was also drawn to the idea of attending a liberal arts college, where he could study both science and art. He ended up going to Tulane University, where he double-majored in fine arts and cell and molecular biology.

As an artist, Lourido focused on printmaking and painting. One area he especially enjoyed was stone lithography, which involves etching images on large blocks of limestone with oil-based inks, treating the images with chemicals, and then transferring the images onto paper using a large press.

“I ended up doing a lot of printmaking, which I think attracted me because it felt like a mode of expression that leveraged different techniques and technical elements,” he says.

At the same time, he worked in a biology lab that studied Daphnia, tiny crustaceans found in fresh water that have helped scientists learn about how organisms can develop new traits in response to changes to their environment. As an undergraduate, he helped develop ways to use viruses to introduce new genes into Daphnia. By the time he graduated from Tulane, Lourido had decided to go into science rather than art.

“I had really fallen in love with lab science as an undergrad. I loved the freedom and the creativity that came from it, the ability to work in teams and to build on ideas, to not have to completely reinvent the entire system, but really be able to develop it over a longer period of time,” he says.

After graduating from college, Lourido spent two years in Germany, working at the Max Planck Institute for Infection Biology. In Arturo Zychlinksy’s lab, Lourido studied two bacteria known as Shigella and Salmonella, which can cause severe illnesses, including diarrhea. His studies there helped to reveal how these bacteria get into cells and how they modify the host cells’ own pathways to help them replicate inside cells.

As a graduate student at Washington University in St. Louis, Lourido worked in several labs focusing on different aspects of microbiology, including virology and bacteriology, but eventually ended up working with David Sibley, a prominent researcher specializing in Toxoplasma.

“I had not thought much about Toxoplasma before going to graduate school,” Lourido recalls. “I was pretty unaware of parasitology in general, despite some undergrad courses, which honestly very superficially treated the subject. What I liked about it was here was a system where we knew so little — organisms that are so different from the textbook models of eukaryotic cells.”

Toxoplasma gondii belongs to a group of parasites known as apicomplexans — a type of protozoans that can cause a variety of diseases. After infecting a human host, Toxoplasma gondii can hide from the immune system for decades, usually in cysts found in the brain or muscles. Lourido found the organism especially intriguing because as a 17-year-old, he had been diagnosed with toxoplasmosis. His only symptom was swollen glands, but doctors found that his blood contained antibodies against Toxoplasma.

“It is really fascinating that in all of these people, about a quarter to a third of the world’s population, the parasite persists. Chances are I still have live parasites somewhere in my body, and if I became immunocompromised, it would become a big problem. They would start replicating in an uncontrolled fashion,” he says.

A transformative approach

One of the challenges in studying Toxoplasma is that the organism’s genetics are very different from those of either bacteria or other eukaryotes such as yeast and mammals. That makes it harder to study parasitic gene functions by mutating or knocking out the genes.

Because of that difficulty, it took Lourido his entire graduate career to study the functions of just a couple of Toxoplasma genes. After finishing his PhD, he started his own lab as a fellow at the Whitehead Institute and began working on ways to study the Toxoplasma genome at a larger scale, using the CRISPR genome-editing technique.

With CRISPR, scientists can systematically knock out every gene in the genome and then study how each missing gene affects parasite function and survival.

“Through the adaptation of CRISPR to Toxoplasma, we’ve been able to survey the entire parasite genome. That has been transformative,” says Lourido, who became a Whitehead member and MIT faculty member in 2017. “Since its original application in 2016, we’ve been able to uncover mechanisms of drug resistance and susceptibility, trace metabolic pathways, and explore many other aspects of parasite biology.”

Using CRISPR-based screens, Lourido’s lab has identified a regulatory gene called BFD1 that appears to drive the expression of genes that the parasite needs for long-term survival within a host. His lab has also revealed many of the molecular steps required for the parasite to shift between active and dormant states.

“We’re actively working to understand how environmental inputs end up guiding the parasite in one direction or another,” Lourido says. “They seem to preferentially go into those chronic stages in certain cells like neurons or muscle cells, and they proliferate more exuberantly in the acute phase when nutrient conditions are appropriate or when there are low levels of immunity in the host.”

Uphill battles: Across the country in 75 days

Amulya Aluru ’23, MEng ’24 and the MIT Spokes have spent the summer spreading science, over 3,000 miles on two wheels.

Lillian Eden | Department of Biology
August 22, 2024

Amulya Aluru ’23, MEng ’24, will head to the University of California at Berkeley for a PhD in molecular and cell biology PhD this fall. Aluru knows her undergraduate 6-7 major and MEng program, where she worked on a computational project in a biology lab, have prepared her for the next step of her academic journey.

“I’m a lot more comfortable with the unknown in terms of research — and also life,” she says. “While I’ve enjoyed what I’ve done so far, I think it’s equally valuable to try and explore new topics. I feel like there’s still a lot more for me to learn in biology.”

Unlike many of her peers, however, Aluru won’t reach the San Francisco Bay Area by car, plane, or train. She will arrive by bike — a journey she began in Washington just a few days after receiving her master’s degree.

Showing that science is accessible

Spokes is an MIT-based nonprofit that each year sends students on a transcontinental bike ride. Aluru worked for months with seven fellow MIT students on logistics and planning. Since setting out, the team has bonded over their love of memes and cycling-themed nicknames: Hank “Handlebar Hank” Stennes, Clelia “Climbing Cleo” Lacarriere, Varsha “Vroom Vroom Varsha” Sandadi, Rebecca “Railtrail Rebecca” Lizarde, JD “JDerailleur Hanger” Hagood, Sophia “Speedy Sophia” Wang, Amulya “Aero Amulya” Aluru, and Jessica “Joyride Jess” Xu. The support minivan, carrying food, luggage, and occasionally injured or sick cyclists, even earned its own nickname: “Chrissy”, short for Chrysler Pacifica.

“I really wanted to do something to challenge myself, but not in a strictly academic sense,” Aluru says of her decision to join the team and bike more than 3,000 miles this summer.

The Spokes team is not biking across the country solely to accomplish such a feat. Throughout their journey, they’ll be offering a variety of science demonstrations, including making concrete with Rice Krispies, demonstrating the physics of sound, using 3D printers, and, in Aluru’s case, extracting DNA from strawberries.

“We’re going to be in a lot of really different learning environments,” she says. “I hope to demonstrate that science can be accessible, even if you don’t have a lab at your disposal.”

These demonstrations have been held in venues such as a D.C. jail, a space camp, and libraries and youth centers across the country; their learning festivals were even featured on a local news channel in Kentucky.

Some derailments

The team was beset with challenges from the first day they started their journey. Aluru’s first day on the road involved driving to every bike shop and REI store in the D.C. metro area to purchase bike computers for navigation because the ones the team had already purchased would only display maps of Europe.

Four days in and four Chrysler Pacificas later — the first was unsafe due to bald tires, the second made a weird sound as they pulled out of the rental lot, and the third’s gas pedal stopped working over 50 miles away from the nearest rental agency — the team was back together again in Waynesboro, Virginia, for the first time since they’d set out.

Since then, they’ve had run-ins with local fauna — including mean dogs and a meaner turtle — attempted to repair a tubeless bike that was not, in fact, tubeless, and slept in Chrissy the minivan after their tents got soaked and blew away.

Although it hasn’t all been smooth riding, the team has made time for fun. They’ve perfected the art of eating a Clif bar while on two wheels, played around on monkey bars in Colorado, met up with Stanford Spokes, enjoyed pounds of ice cream, and downed gallons of lattes.

The team prioritized routes on bike trails, rather than highways, as much as possible. Their teaching activities are scheduled between visits to National Parks like Tahoe, Zion, Bryce Canyon, Arches, and touring and hiking places like Breaks Interstate Park, Mammoth Cave, and the Collegiate Peaks.

Aluru says she’s excited to see parts of the country she’s never visited before, and experience the terrain under her own power — except for breaks when it’s her turn to drive Chrissy.

Rolling with the ups and downs

Aluru was only a few weeks into her first Undergraduate Research Opportunities Program project in the late professor Angelika Amon’s lab when the Covid-19 pandemic hit, quickly transforming her wet lab project into a computational one. David Waterman, her postdoc mentor in the Amon Lab, was trained as a biologist, not a computational scientist. Luckily, Aluru had just taken two computer science classes.

“I was able to have a big hand in formulating my project and bouncing ideas off of him,” she recalls. “That helped me think about scientific questions, which I was able to apply when I came back to campus and started doing wet lab research again.”

When Aluru returned to campus, she began work in the Page Lab at the Whitehead Institute for Biomedical Research. She continued working there for the rest of her time at MIT, first as an undergraduate student and then as an MEng student.

The Page Lab’s work primarily concerns sex differences and how those differences play out in genetics, development, and disease — and the Department of Electronic Engineering and Computer Science, which oversees the MEng program, allows students to pursue computational projects across disciplines, no matter the department.

For her MEng work, Aluru looked at sex differences in human height, a continuation of a paper that the Page Lab published in 2019. Height is an easily observable human trait and, from previous research, is known to be sex-biased across at least five species. Genes that have sex-biased expression patterns, or expression patterns that are higher or lower in males compared to females, may play a role in establishing or maintaining these sex differences. Through statistical genetics, Aluru replicated the findings of the earlier paper and expanded them using newly published datasets.

“Amulya has had an amazing journey in our department,” says David Page, professor of biology and core member of the Whitehead Institute. “There is simply no stopping her insatiable curiosity and zest for life.”

Working with the lab as a graduate student came with more day-to-day responsibility and independence than when she was an undergrad.

“It was a shift I quite appreciated,” Aluru says. “At times it was challenging, but I think it was a good challenge: learning how to structure my research on my own, while still getting a lot of support from lab members and my PI [principal investigator].”

Gearing up for the future

Since departing MIT, Aluru and the rest of the Spokes team have spent their nights camping, sleeping in churches, and staying with hosts. They enjoyed the longest day of the year in a surprisingly “Brooklyn chic” house, spent a lazy afternoon on a river, and pinky-promised to be in each other’s weddings. The team has also been hosted by, met up with, and run into MIT alums as they’ve crossed the country.

As Aluru looks to the future, she admits she’s not exactly sure what she’ll study — but when she reaches the West Coast, she knows she’s not leaving what she’s built through MIT far behind.

“There’s going to be a small MIT community even there — a lot of my friends are in San Francisco, and a few people I know are also going to be at Berkeley,” she says. “I have formed a community at MIT that I know will support me in all my future endeavors.”

Study reveals the benefits and downside of fasting

Fasting helps intestinal stem cells regenerate and heal injuries but also leads to a higher risk of cancer in mice, MIT researchers report.

Anne Trafton | MIT News
August 21, 2024

Low-calorie diets and intermittent fasting have been shown to have numerous health benefits: They can delay the onset of some age-related diseases and lengthen lifespan, not only in humans but many other organisms.

Many complex mechanisms underlie this phenomenon. Previous work from MIT has shown that one way fasting exerts its beneficial effects is by boosting the regenerative abilities of intestinal stem cells, which helps the intestine recover from injuries or inflammation.

In a study of mice, MIT researchers have now identified the pathway that enables this enhanced regeneration, which is activated once the mice begin “refeeding” after the fast. They also found a downside to this regeneration: When cancerous mutations occurred during the regenerative period, the mice were more likely to develop early-stage intestinal tumors.

“Having more stem cell activity is good for regeneration, but too much of a good thing over time can have less favorable consequences,” says Omer Yilmaz, an MIT associate professor of biology, a member of MIT’s Koch Institute for Integrative Cancer Research, and the senior author of the new study.

Yilmaz adds that further studies are needed before forming any conclusion as to whether fasting has a similar effect in humans.

“We still have a lot to learn, but it is interesting that being in either the state of fasting or refeeding when exposure to mutagen occurs can have a profound impact on the likelihood of developing a cancer in these well-defined mouse models,” he says.

MIT postdocs Shinya Imada and Saleh Khawaled are the lead authors of the paper, which appears today in Nature.

Driving regeneration

For several years, Yilmaz’s lab has been investigating how fasting and low-calorie diets affect intestinal health. In a 2018 study, his team reported that during a fast, intestinal stem cells begin to use lipids as an energy source, instead of carbohydrates. They also showed that fasting led to a significant boost in stem cells’ regenerative ability.

However, unanswered questions remained: How does fasting trigger this boost in regenerative ability, and when does the regeneration begin?

“Since that paper, we’ve really been focused on understanding what is it about fasting that drives regeneration,” Yilmaz says. “Is it fasting itself that’s driving regeneration, or eating after the fast?”

In their new study, the researchers found that stem cell regeneration is suppressed during fasting but then surges during the refeeding period. The researchers followed three groups of mice — one that fasted for 24 hours, another one that fasted for 24 hours and then was allowed to eat whatever they wanted during a 24-hour refeeding period, and a control group that ate whatever they wanted throughout the experiment.

The researchers analyzed intestinal stem cells’ ability to proliferate at different time points and found that the stem cells showed the highest levels of proliferation at the end of the 24-hour refeeding period. These cells were also more proliferative than intestinal stem cells from mice that had not fasted at all.

“We think that fasting and refeeding represent two distinct states,” Imada says. “In the fasted state, the ability of cells to use lipids and fatty acids as an energy source enables them to survive when nutrients are low. And then it’s the postfast refeeding state that really drives the regeneration. When nutrients become available, these stem cells and progenitor cells activate programs that enable them to build cellular mass and repopulate the intestinal lining.”

Further studies revealed that these cells activate a cellular signaling pathway known as mTOR, which is involved in cell growth and metabolism. One of mTOR’s roles is to regulate the translation of messenger RNA into protein, so when it’s activated, cells produce more protein. This protein synthesis is essential for stem cells to proliferate.

The researchers showed that mTOR activation in these stem cells also led to production of large quantities of polyamines — small molecules that help cells to grow and divide.

“In the refed state, you’ve got more proliferation, and you need to build cellular mass. That requires more protein, to build new cells, and those stem cells go on to build more differentiated cells or specialized intestinal cell types that line the intestine,” Khawaled says.

Too much of a good thing

The researchers also found that when stem cells are in this highly regenerative state, they are more prone to become cancerous. Intestinal stem cells are among the most actively dividing cells in the body, as they help the lining of the intestine completely turn over every five to 10 days. Because they divide so frequently, these stem cells are the most common source of precancerous cells in the intestine.

In this study, the researchers discovered that if they turned on a cancer-causing gene in the mice during the refeeding stage, they were much more likely to develop precancerous polyps than if the gene was turned on during the fasting state. Cancer-linked mutations that occurred during the refeeding state were also much more likely to produce polyps than mutations that occurred in mice that did not undergo the cycle of fasting and refeeding.

“I want to emphasize that this was all done in mice, using very well-defined cancer mutations. In humans it’s going to be a much more complex state,” Yilmaz says. “But it does lead us to the following notion: Fasting is very healthy, but if you’re unlucky and you’re refeeding after a fasting, and you get exposed to a mutagen, like a charred steak or something, you might actually be increasing your chances of developing a lesion that can go on to give rise to cancer.”

Yilmaz also noted that the regenerative benefits of fasting could be significant for people who undergo radiation treatment, which can damage the intestinal lining, or other types of intestinal injury. His lab is now studying whether polyamine supplements could help to stimulate this kind of regeneration, without the need to fast.

“This fascinating study provides insights into the complex interplay between food consumption, stem cell biology, and cancer risk,” says Ophir Klein, a professor of medicine at the University of California at San Francisco and Cedars-Sinai Medical Center, who was not involved in the study. “Their work lays a foundation for testing polyamines as compounds that may augment intestinal repair after injuries, and it suggests that careful consideration is needed when planning diet-based strategies for regeneration to avoid increasing cancer risk.”

The research was funded, in part, by a Pew-Stewart Trust Scholar award, the Marble Center for Cancer Nanomedicine, the Koch Institute-Dana Farber/Harvard Cancer Center Bridge Project, and the MIT Stem Cell Initiative.

MIT affiliates named 2024 HHMI Investigators

Four faculty members and four others with MIT ties are recognized for pushing the boundaries of science and for creating highly inclusive and collaborative research environments.

School of Science
July 23, 2024

The Howard Hughes Medical Institute (HHMI) today announced its 2024 investigators, four of whom hail from the School of Science at MIT: Steven Flavell, Mary Gehring, Mehrad Jazayeri, and Gene-Wei Li.

Four others with MIT ties were also honored: Jonathan Abraham, graduate of the Harvard/MIT MD-PhD Program; Dmitriy Aronov PhD ’10; Vijay Sankaran, graduate of the Harvard/MIT MD-PhD Program; and Steven McCarroll, institute member of the Broad Institute of MIT and Harvard.

Every three years, HHMI selects roughly two dozen new investigators who have significantly impacted their chosen disciplines to receive a substantial and completely discretionary grant. This funding can be reviewed and renewed indefinitely. The award, which totals roughly $11 million per investigator over the next seven years, enables scientists to continue working at their current institution, paying their full salary while providing financial support for researchers to be flexible enough to go wherever their scientific inquiries take them.

Of the almost 1,000 applicants this year, 26 investigators were selected for their ability to push the boundaries of science and for their efforts to create highly inclusive and collaborative research environments.

“When scientists create environments in which others can thrive, we all benefit,” says HHMI president Erin O’Shea. “These newest HHMI Investigators are extraordinary, not only because of their outstanding research endeavors but also because they mentor and empower the next generation of scientists to work alongside them at the cutting edge.”

Steven Flavell

Steven Flavell, associate professor of brain and cognitive sciences and investigator in the Picower Institute for Learning and Memory, seeks to uncover the neural mechanisms that generate the internal states of the brain, for example, different motivational and arousal states. Working in the model organism, the C. elegans worm, the lab has used genetic, systems, and computational approaches to relate neural activity across the brain to precise features of the animal’s behavior. In addition, they have mapped out the anatomical and functional organization of the serotonin system, mapping out how it modulates the internal state of C. elegans. As a newly named HHMI Investigator, Flavell will pursue research that he hopes will build a foundational understanding of how internal states arise and influence behavior in nervous systems in general. The work will employ brain-wide neural recordings, computational modeling, expansive research on neuromodulatory system organization, and studies of how the synaptic wiring of the nervous system constrains an animal’s ability to generate different internal states.

“I think that it should be possible to define the basis of internal states in C. elegans in concrete terms,” Flavell says. “If we can build a thread of understanding from the molecular architecture of neuromodulatory systems, to changes in brain-wide activity, to state-dependent changes in behavior, then I think we’ll be in a much better place as a field to think about the basis of brain states in more complex animals.”

Mary Gehring

Mary Gehring, professor of biology and core member and David Baltimore Chair in Biomedical Research at the Whitehead Institute for Biomedical Research, studies how plant epigenetics modulates plant growth and development, with a long-term goal of uncovering the essential genetic and epigenetic elements of plant seed biology. Ultimately, the Gehring Lab’s work provides the scientific foundations for engineering alternative modes of seed development and improving plant resiliency at a time when worldwide agriculture is in a uniquely precarious position due to climate changes.

The Gehring Lab uses genetic, genomic, computational, synthetic, and evolutionary approaches to explore heritable traits by investigating repetitive sequences, DNA methylation, and chromatin structure. The lab primarily uses the model plant A. thaliana, a member of the mustard family and the first plant to have its genome sequenced.

“I’m pleased that HHMI has been expanding its support for plant biology, and gratified that our lab will benefit from its generous support,” Gehring says. “The appointment gives us the freedom to step back, take a fresh look at the scientific opportunities before us, and pursue the ones that most interest us. And that’s a very exciting prospect.”

Mehrad Jazayeri

Mehrdad Jazayeri, a professor of brain and cognitive sciences and an investigator at the McGovern Institute for Brain Research, studies how physiological processes in the brain give rise to the abilities of the mind. Work in the Jazayeri Lab brings together ideas from cognitive science, neuroscience, and machine learning with experimental data in humans, animals, and computer models to develop a computational understanding of how the brain creates internal representations, or models, of the external world.

Before coming to MIT in 2013, Jazayeri received his BS in electrical engineering, majoring in telecommunications, from Sharif University of Technology in Tehran, Iran. He completed his MS in physiology at the University of Toronto and his PhD in neuroscience at New York University.

With his appointment to HHMI, Jazayeri plans to explore how the brain enables rapid learning and flexible behavior — central aspects of intelligence that have been difficult to study using traditional neuroscience approaches.

“This is a recognition of my lab’s past accomplishments and the promise of the exciting research we want to embark on,” he says. “I am looking forward to engaging with this wonderful community and making new friends and colleagues while we elevate our science to the next level.”

Gene-Wei Li,

Gene-Wei Li, associate professor of biology, has been working on quantifying the amount of proteins cells produce and how protein synthesis is orchestrated within the cell since opening his lab at MIT in 2015.

Li, whose background is in physics, credits the lab’s findings to the skills and communication among his research team, allowing them to explore the unexpected questions that arise in the lab.

For example, two of his graduate student researchers found that the coordination between transcription and translation fundamentally differs between the model organisms E. coli and B. subtilis. In B. subtilis, the ribosome lags far behind RNA polymerase, a process the lab termed “runaway transcription.” The discovery revealed that this kind of uncoupling between transcription and translation is widespread across many species of bacteria, a study that contradicted the long-standing dogma of molecular biology that the machinery of protein synthesis and RNA polymerase work side-by-side in all bacteria.

The support from HHMI enables Li and his team the flexibility to pursue the basic research that leads to discoveries at their discretion.

“Having this award allows us to be bold and to do things at a scale that wasn’t possible before,” Li says. “The discovery of runaway transcription is a great example. We didn’t have a traditional grant for that.”

CHARMed collaboration creates a potent therapy candidate for fatal prion diseases

A new gene-silencing tool shows promise as a future therapy against prion diseases and paves the way for new approaches to treating disease.

Greta Friar | Whitehead Institute
June 27, 2024

Drug development is typically slow: The pipeline from basic research discoveries that provide the basis for a new drug to clinical trials and then production of a widely available medicine can take decades. But decades can feel impossibly far off to someone who currently has a fatal disease. Broad Institute of MIT and Harvard Senior Group Leader Sonia Vallabh is acutely aware of that race against time, because the topic of her research is a neurodegenerative and ultimately fatal disease — fatal familial insomnia, a type of prion disease — that she will almost certainly develop as she ages.

Vallabh and her husband, Eric Minikel, switched careers and became researchers after they learned that Vallabh carries a disease-causing version of the prion protein gene and that there is no effective therapy for fatal prion diseases. The two now run a lab at the Broad Institute, where they are working to develop drugs that can prevent and treat these diseases, and their deadline for success is not based on grant cycles or academic expectations but on the ticking time bomb in Vallabh’s genetic code.

That is why Vallabh was excited to discover, when she entered into a collaboration with Whitehead Institute for Biomedical Research member Jonathan Weissman, that Weissman’s group likes to work at full throttle. In less than two years, Weissman, Vallabh, and their collaborators have developed a set of molecular tools called CHARMs that can turn off disease-causing genes such as the prion protein gene — as well as, potentially, genes coding for many other proteins implicated in neurodegenerative and other diseases — and they are refining those tools to be good candidates for use in human patients. Although the tools still have many hurdles to pass before the researchers will know if they work as therapeutics, the team is encouraged by the speed with which they have developed the technology thus far.

“The spirit of the collaboration since the beginning has been that there was no waiting on formality,” Vallabh says. “As soon as we realized our mutual excitement to do this, everything was off to the races.”

Co-corresponding authors Weissman and Vallabh and co-first authors Edwin Neumann, a graduate student in Weissman’s lab, and Tessa Bertozzi, a postdoc in Weissman’s lab, describe CHARM — which stands for Coupled Histone tail for Autoinhibition Release of Methyltransferase — in a paper published today in the journal Science.

“With the Whitehead and Broad Institutes right next door to each other, I don’t think there’s any better place than this for a group of motivated people to move quickly and flexibly in the pursuit of academic science and medical technology,” says Weissman, who is also a professor of biology at MIT and a Howard Hughes Medical Institute Investigator. “CHARMs are an elegant solution to the problem of silencing disease genes, and they have the potential to have an important position in the future of genetic medicines.”

To treat a genetic disease, target the gene

Prion disease, which leads to swift neurodegeneration and death, is caused by the presence of misshapen versions of the prion protein. These cause a cascade effect in the brain: the faulty prion proteins deform other proteins, and together these proteins not only stop functioning properly but also form toxic aggregates that kill neurons. The most famous type of prion disease, known colloquially as mad cow disease, is infectious, but other forms of prion disease can occur spontaneously or be caused by faulty prion protein genes.

Most conventional drugs work by targeting a protein. CHARMs, however, work further upstream, turning off the gene that codes for the faulty protein so that the protein never gets made in the first place. CHARMs do this by epigenetic editing, in which a chemical tag gets added to DNA in order to turn off or silence a target gene. Unlike gene editing, epigenetic editing does not modify the underlying DNA — the gene itself remains intact. However, like gene editing, epigenetic editing is stable, meaning that a gene switched off by CHARM should remain off. This would mean patients would only have to take CHARM once, as opposed to protein-targeting medications that must be taken regularly as the cells’ protein levels replenish.

Research in animals suggests that the prion protein isn’t necessary in a healthy adult, and that in cases of disease, removing the protein improves or even eliminates disease symptoms. In a person who hasn’t yet developed symptoms, removing the protein should prevent disease altogether. In other words, epigenetic editing could be an effective approach for treating genetic diseases such as inherited prion diseases. The challenge is creating a new type of therapy.

Fortunately, the team had a good template for CHARM: a research tool called CRISPRoff that Weissman’s group previously developed for silencing genes. CRISPRoff uses building blocks from CRISPR gene editing technology, including the guide protein Cas9 that directs the tool to the target gene. CRISPRoff silences the targeted gene by adding methyl groups, chemical tags that prevent the gene from being transcribed, or read into RNA, and so from being expressed as protein. When the researchers tested CRISPRoff’s ability to silence the prion protein gene, they found that it was effective and stable.

Several of its properties, though, prevented CRISPRoff from being a good candidate for a therapy. The researchers’ goal was to create a tool based on CRISPRoff that was just as potent but also safe for use in humans, small enough to deliver to the brain, and designed to minimize the risk of silencing the wrong genes or causing side effects.

From research tool to drug candidate

Led by Neumann and Bertozzi, the researchers began engineering and applying their new epigenome editor. The first problem that they had to tackle was size, because the editor needs to be small enough to be packaged and delivered to specific cells in the body. Delivering genes into the human brain is challenging; many clinical trials have used adeno-associated viruses (AAVs) as gene-delivery vehicles, but these are small and can only contain a small amount of genetic code. CRISPRoff is way too big; the code for Cas9 alone takes up most of the available space.

The Weissman lab researchers decided to replace Cas9 with a much smaller zinc finger protein (ZFP). Like Cas9, ZFPs can serve as guide proteins to direct the tool to a target site in DNA. ZFPs are also common in human cells, meaning they are less likely to trigger an immune response against themselves than the bacterial Cas9.

Next, the researchers had to design the part of the tool that would silence the prion protein gene. At first, they used part of a methyltransferase, a molecule that adds methyl groups to DNA, called DNMT3A. However, in the particular configuration needed for the tool, the molecule was toxic to the cell. The researchers focused on a different solution: Instead of delivering outside DNMT3A as part of the therapy, the tool is able to recruit the cell’s own DNMT3A to the prion protein gene. This freed up precious space inside of the AAV vector and prevented toxicity.

The researchers also needed to activate DNMT3A. In the cell, DNMT3A is usually inactive until it interacts with certain partner molecules. This default inactivity prevents accidental methylation of genes that need to remain turned on. Neumann came up with an ingenious way around this by combining sections of DNMT3A’s partner molecules and connecting these to ZFPs that bring them to the prion protein gene. When the cell’s DNMT3A comes across this combination of parts, it activates, silencing the gene.

“From the perspectives of both toxicity and size, it made sense to recruit the machinery that the cell already has; it was a much simpler, more elegant solution,” Neumann says. “Cells are already using methyltransferases all of the time, and we’re essentially just tricking them into turning off a gene that they would normally leave turned on.”

Testing in mice showed that ZFP-guided CHARMs could eliminate more than 80 percent of the prion protein in the brain, while previous research has shown that as little as 21 percent elimination can improve symptoms.

Once the researchers knew that they had a potent gene silencer, they turned to the problem of off-target effects. The genetic code for a CHARM that gets delivered to a cell will keep producing copies of the CHARM indefinitely. However, after the prion protein gene is switched off, there is no benefit to this, only more time for side effects to develop, so they tweaked the tool so that after it turns off the prion protein gene, it then turns itself off.

Meanwhile, a complementary project from Broad Institute scientist and collaborator Benjamin Deverman’s lab, focused on brain-wide gene delivery and published in Science on May 17, has brought the CHARM technology one step closer to being ready for clinical trials. Although naturally occurring types of AAV have been used for gene therapy in humans before, they do not enter the adult brain efficiently, making it impossible to treat a whole-brain disease like prion disease. Tackling the delivery problem, Deverman’s group has designed an AAV vector that can get into the brain more efficiently by leveraging a pathway that naturally shuttles iron into the brain. Engineered vectors like this one make a therapy like CHARM one step closer to reality.

Thanks to these creative solutions, the researchers now have a highly effective epigenetic editor that is small enough to deliver to the brain, and that appears in cell culture and animal testing to have low toxicity and limited off-target effects.

“It’s been a privilege to be part of this; it’s pretty rare to go from basic research to therapeutic application in such a short amount of time,” Bertozzi says. “I think the key was forming a collaboration that took advantage of the Weissman lab’s tool-building experience, the Vallabh and Minikel lab’s deep knowledge of the disease, and the Deverman lab’s expertise in gene delivery.”

Looking ahead

With the major elements of the CHARM technology solved, the team is now fine-tuning their tool to make it more effective, safer, and easier to produce at scale, as will be necessary for clinical trials. They have already made the tool modular, so that its various pieces can be swapped out and future CHARMs won’t have to be programmed from scratch. CHARMs are also currently being tested as therapeutics in mice.

The path from basic research to clinical trials is a long and winding one, and the researchers know that CHARMs still have a way to go before they might become a viable medical option for people with prion diseases, including Vallabh, or other diseases with similar genetic components. However, with a strong therapy design and promising laboratory results in hand, the researchers have good reason to be hopeful. They continue to work at full throttle, intent on developing their technology so that it can save patients’ lives not someday, but as soon as possible.