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Why cancer cells waste so much energy

MIT study sheds light on the longstanding question of why cancer cells get their energy from fermentation.

Anne Trafton | MIT News Office
January 19, 2021

In the 1920s, German chemist Otto Warburg discovered that cancer cells don’t metabolize sugar the same way that healthy cells usually do. Since then, scientists have tried to figure out why cancer cells use this alternative pathway, which is much less efficient.

MIT biologists have now found a possible answer to this longstanding question. In a study appearing in Molecular Cell, they showed that this metabolic pathway, known as fermentation, helps cells to regenerate large quantities of a molecule called NAD+, which they need to synthesize DNA and other important molecules. Their findings also account for why other types of rapidly proliferating cells, such as immune cells, switch over to fermentation.

“This has really been a hundred-year-old paradox that many people have tried to explain in different ways,” says Matthew Vander Heiden, an associate professor of biology at MIT and associate director of MIT’s Koch Institute for Integrative Cancer Research. “What we found is that under certain circumstances, cells need to do more of these electron transfer reactions, which require NAD+, in order to make molecules such as DNA.”

Vander Heiden is the senior author of the new study, and the lead authors are former MIT graduate student and postdoc Alba Luengo PhD ’18 and graduate student Zhaoqi Li.

Inefficient metabolism

Fermentation is one way that cells can convert the energy found in sugar to ATP, a chemical that cells use to store energy for all of their needs. However, mammalian cells usually break down sugar using a process called aerobic respiration, which yields much more ATP. Cells typically switch over to fermentation only when they don’t have enough oxygen available to perform aerobic respiration.

Since Warburg’s discovery, scientists have put forth many theories for why cancer cells switch to the inefficient fermentation pathway. Warburg originally proposed that cancer cells’ mitochondria, where aerobic respiration occurs, might be damaged, but this turned out not to be the case. Other explanations have focused on the possible benefits of producing ATP in a different way, but none of these theories have gained widespread support.

In this study, the MIT team decided to try to come up with a solution by asking what would happen if they suppressed cancer cells’ ability to perform fermentation. To do that, they treated the cells with a drug that forces them to divert a molecule called pyruvate from the fermentation pathway into the aerobic respiration pathway.

They saw, as others have previously shown, that blocking fermentation slows down cancer cells’ growth. Then, they tried to figure out how to restore the cells’ ability to proliferate, while still blocking fermentation. One approach they tried was to stimulate the cells to produce NAD+, a molecule that helps cells to dispose of the extra electrons that are stripped out when cells make molecules such as DNA and proteins.

When the researchers treated the cells with a drug that stimulates NAD+ production, they found that the cells started rapidly proliferating again, even though they still couldn’t perform fermentation. This led the researchers to theorize that when cells are growing rapidly, they need NAD+ more than they need ATP. During aerobic respiration, cells produce a great deal of ATP and some NAD+. If cells accumulate more ATP than they can use, respiration slows and production of NAD+ also slows.

“We hypothesized that when you make both NAD+ and ATP together, if you can’t get rid of ATP, it’s going to back up the whole system such that you also cannot make NAD+,” Li says.

Therefore, switching to a less efficient method of producing ATP, which allows the cells to generate more NAD+, actually helps them to grow faster. “If you step back and look at the pathways, what you realize is that fermentation allows you to generate NAD+ in an uncoupled way,” Luengo says.

Solving the paradox

The researchers tested this idea in other types of rapidly proliferating cells, including immune cells, and found that blocking fermentation but allowing alternative methods of NAD+ production enabled cells to continue rapidly dividing. They also observed the same phenomenon in nonmammalian cells such as yeast, which perform a different type of fermentation that produces ethanol.

“Not all proliferating cells have to do this,” Vander Heiden says. “It’s really only cells that are growing very fast. If cells are growing so fast that their demand to make stuff outstrips how much ATP they’re burning, that’s when they flip over into this type of metabolism. So, it solves, in my mind, many of the paradoxes that have existed.”

The findings suggest that drugs that force cancer cells to switch back to aerobic respiration instead of fermentation could offer a possible way to treat tumors. Drugs that inhibit NAD+ production could also have a beneficial effect, the researchers say.

The research was funded by the Ludwig Center for Molecular Oncology, the National Science Foundation, the National Institutes of Health, the Howard Hughes Medical Institute, the Medical Research Council, NHS Blood and Transplant, the Novo Nordisk Foundation, the Knut and Alice Wallenberg Foundation, Stand Up 2 Cancer, the Lustgarten Foundation, and the MIT Center for Precision Cancer Medicine.

Through my Viewfinder: savoring the little things
Irene Shih | MindHandHeart
January 13, 2021
window in a house

If the coronavirus pandemic has taught me (and probably many of you) anything, it is that time is of the essence. Funnily enough, when campus and research were shut down, I had too much time that I didn’t know what to do with. In the beginning, I was glad that I could sleep in as much as I wanted but after a month of doing just that, I was so bored of staying indoors. One of the ways to get myself out of the house was the anticipation of witnessing something I would find endearing. I’ve always loved people watching and being observant of random details that most others miss. These little quiet acts, signs that life was happening inside these still, quiet facades, I say to them: I see you, I acknowledge your existence. I spent much of the spring and summer taking long walks around Cambridge, sometimes with a friend but mostly on my own. I feel happy that I managed to capture some of my favorite moments on these walks with my film camera.

My favorite part of photography is that I get to share how I see life, how I am able to note what matters to me. It has never been about creating a pretty image. What I find interesting, sad, beautiful, I take pictures of.

 

girl holding a cake

I made a chocolate dairy-free cake for my awesome labmate who defended her PhD thesis during the pandemic.

food cans on a table

In East Cambridge, free food laid out on a table outside a house.

 

wall with names
a blue house

I enjoyed walking around my neighborhood and seeing signs like these.

window in a house
window in a house
Neuroscientists identify brain circuit that encodes timing of events

Findings suggest this hippocampal circuit helps us to maintain our timeline of memories.

Anne Trafton | MIT News Office
January 12, 2021

When we experience a new event, our brain records a memory of not only what happened, but also the context, including the time and location of the event. A new study from MIT neuroscientists sheds light on how the timing of a memory is encoded in the hippocampus, and suggests that time and space are encoded separately.

In a study of mice, the researchers identified a hippocampal circuit that the animals used to store information about the timing of when they should turn left or right in a maze. When this circuit was blocked, the mice were unable to remember which way they were supposed to turn next. However, disrupting the circuit did not appear to impair their memory of where they were in space.

The findings add to a growing body of evidence suggesting that when we form new memories, different populations of neurons in the brain encode time and place information, the researchers say.

“There is an emerging view that ‘place cells’ and ‘time cells’ organize memories by mapping information onto the hippocampus. This spatial and temporal context serves as a scaffold that allows us to build our own personal timeline of memories,” says Chris MacDonald, a research scientist at MIT’s Picower Institute for Learning and Memory and the lead author of the study.

Susumu Tonegawa, the Picower Professor of Biology and Neuroscience at the RIKEN-MIT Laboratory of Neural Circuit Genetics at the Picower Institute, is the senior author of the study, which appears this week in the Proceedings of the National Academy of Sciences.

Time and place

About 50 years ago, neuroscientists discovered that the brain’s hippocampus contains neurons that encode memories of specific locations. These cells, known as place cells, store information that becomes part of the context of a particular memory.

The other critical piece of context for any given memory is the timing. In 2011, MacDonald and the late Howard Eichenbaum, a professor of psychological and brain sciences at Boston University, discovered cells that keep track of time, in a part of the hippocampus called CA1.

In that study, MacDonald, who was then a postdoc at Boston University, found that these cells showed specific timing-related firing patterns when mice were trained to associate two stimuli — an object and an odor — that were presented with a 10-second delay between them. When the delay was extended to 20 seconds, the cells reorganized their firing patterns to last 20 seconds instead of 10.

“It’s almost like they’re forming a new representation of a temporal context, much like a spatial context,” MacDonald says. “The emerging view seems to be that both place and time cells organize memory by mapping experience to a representation of context that is defined by time and space.”

In the new study, the researchers wanted to investigate which other parts of the brain might be feeding CA1 timing information. Some previous studies had suggested that a nearby part of the hippocampus called CA2 might be involved in keeping track of time. CA2 is a very small region of the hippocampus that has not been extensively studied, but it has been shown to have strong connections to CA1.

To study the links between CA2 and CA1, the researchers used an engineered mouse model in which they could use light to control the activity of neurons in the CA2 region. They trained the mice to run a figure-eight maze in which they would earn a reward if they alternated turning left and right each time they ran the maze. Between each trial, they ran on a treadmill for 10 seconds, and during this time, they had to remember which direction they had turned on the previous trial, so they could do the opposite on the upcoming trial.

When the researchers turned off CA2 activity while the mice were on the treadmill, they found that the mice performed very poorly at the task, suggesting that they could no longer remember which direction they had turned in the previous trial.

“When the animals are performing normally, there is a sequence of cells in CA1 that ticks off during this temporal coding phase,” MacDonald says. “When you inhibit the CA2, what you see is the temporal coding in CA1 becomes less precise and more smeared out in time. It becomes destabilized, and that seems to correlate with them also performing poorly on that task.”

Memory circuits

When the researchers used light to inhibit CA2 neurons while the mice were running the maze, they found little effect on the CA1 “place cells” that allow the mice to remember where they are. The findings suggest that spatial and timing information are encoded preferentially by different parts of the hippocampus, MacDonald says.

“One thing that’s exciting about this work is this idea that spatial and temporal information can operate in parallel and might merge or separate at different points in the circuit, depending on what you need to accomplish from a memory standpoint,” he says.

MacDonald is now planning additional studies of time perception, including how we perceive time under different circumstances, and how our perception of time influences our behavior. Another question he hopes to pursue is whether the brain has different mechanisms for keeping track of events that are separated by seconds and events that are separated by much longer periods of time.

“Somehow the information that we store in memory preserves the sequential order of events across very different timescales, and I’m very interested in how it is that we’re able to do that,” he says.

The research was funded by the RIKEN Center for Brain Science, the Howard Hughes Medical Institute, and the JPB Foundation.

Turning microbiome research into a force for health

A diverse group of researchers is working to turn new discoveries about the trillions of microbes in the body into treatments for a range of diseases.

Zach Winn | MIT News Office
January 8, 2021

The microbiome comprises trillions of microorganisms living on and inside each of us. Historically, some researchers have guessed at its role in human health, but in the last decade or so genetic sequencing techniques have illuminated this galaxy of microorganisms enough to study it in detail.

As researchers unravel the complex interplay between our bodies and microbiomes, they are beginning to appreciate the full scope of the field’s potential for treating disease and promoting health.

For instance, the growing list of conditions that correspond with changes in the microbes of our gut includes type 2 diabetes, inflammatory bowel disease, Alzheimer’s disease, and a variety of cancers.

“In almost every disease context that’s been investigated, we’ve found different types of microbial communities, divergent between healthy and sick patients,” says professor of biological engineering Eric Alm. “The promise [of these findings] is that some of those differences are going to be causal, and intervening to change the microbiome is going to help treat some of these diseases.”

Alm’s lab, in conjunction with collaborators at the Broad Institute of MIT and Harvard, did some of the early work characterizing the gut microbiome and showing its relationship to human health. Since then, microbiome research has exploded, pulling in researchers from far-flung fields and setting new discoveries in motion. Startups are now working to develop microbiome-based therapies, and nonprofit organizations have also sprouted up to ensure these basic scientific advances turn into treatments that benefit the maximum number of people.

“The first chapter in this field, and our history, has been validating this modality,” says Mark Smith PhD ’14, a co-founder of OpenBiome, which processes stool donations for hospitals to conduct stool transplants for patients battling gut infection. Smith is also currently CEO of the startup Finch Therapeutics, which is developing microbiome-based treatments. “Until now, it’s been about the promise of the microbiome. Now I feel like we’ve delivered on the first promise. The next step is figuring out how big this gets.”

An interdisciplinary foundation

MIT’s prominent role in microbiome research came, in part, through its leadership in a field that may at first seem unrelated. For decades, MIT has made important contributions to microbial ecology, led by work in the Parsons Laboratory in the Department of Civil and Environmental Engineering and by scientists including Institute Professor Penny Chisholm.

Ecologists who use complex statistical techniques to study the relationships between organisms in different ecosystems are well-equipped to study the behavior of different bacterial strains in the microbiome.

Not that ecologists — or anyone else — initially had much to study involving the human microbiome, which was essentially a black box to researchers well into the 2000s. But the Human Genome Project led to faster, cheaper ways to sequence genes at scale, and a group of researchers including Alm and visiting professor Martin Polz began using those techniques to decode the genomes of environmental bacteria around 2008.

Those techniques were first pointed at the bacteria in the gut microbiome as part of the Human Microbiome Project, which began in 2007 and involved research groups from MIT and the Broad Institute.

Alm first got pulled into microbiome research by the late biological engineering professor David Schauer as part of a research project with Boston Children’s Hospital. It didn’t take much to get up to speed: Alm says the number of papers explicitly referencing the microbiome at the time could be read in an afternoon.

The collaboration, which included Ramnik Xavier, a core institute member of the Broad Institute, led to the first large-scale genome sequencing of the gut microbiome to diagnose inflammatory bowel disease. The research was funded, in part, by the Neil and Anna Rasmussen Family Foundation.

The study offered a glimpse into the microbiome’s diagnostic potential. It also underscored the need to bring together researchers from diverse fields to dig deeper.

Taking an interdisciplinary approach is important because, after next-generation sequencing techniques are applied to the microbiome, a large amount of computational biology and statistical methods are still needed to interpret the resulting data — the microbiome, after all, contains more genes than the human genome. One catalyst for early microbiome collaboration was the Microbiology Graduate PhD Program, which recruited microbiology students to MIT and introduced them to research groups across the Institute.

As microbiology collaborations increased among researchers from different department and labs, Neil Rasmussen, a longtime member of the MIT Corporation and a member of the visiting committees for a number of departments, realized there was still one more component needed to turn microbiome research into a force for human health.

“Neil had the idea to find all the clinical researchers in the [Boston] area studying diseases associated with the microbiome and pair them up with people like [biological engineers, mathematicians, and ecologists] at MIT who might not know anything about inflammatory bowel disease or microbiomes but had the expertise necessary to solve big problems in the field,” Alm says.

In 2014, that insight led the Rasmussen Foundation to support the creation of the Center for Microbiome Informatics and Therapeutics (CMIT), one of the first university-based microbiome research centers in the country.

Tami Lieberman, the Hermann L. F. von Helmholtz Career Development Professor at MIT, whose background is in ecology, says CMIT was a big reason she joined MIT’s faculty in 2018. Lieberman has developed new genomic approaches to study how bacteria mutate in healthy and sick individuals, with a particular focus on the skin microbiome.

Laura Kiessling, a chemist who has been recognized for contributions to our understanding of cell surface interactions, was also quick to joint CMIT. Kiessling, the Novartis Professor of Chemistry, has made discoveries relating to microbial mechanisms that influence immune function. Both Lieberman and Kiessling are also members of the Broad Institute.

Today, CMIT, co-directed by Alm and Xavier, facilitates collaborations between researchers and clinicians from hospitals around the country in addition to supporting research groups in the area. That work has led to hundreds of ongoing clinical trials that promise to further elucidate the microbiome’s connection to a broad range of diseases.

Fulfilling the promise of the microbiome

Researchers don’t yet know what specific strains of bacteria can improve the health of people with microbiome-associated diseases. But they do know that fecal matter transplants, which carry the full spectrum of gut bacteria from a healthy donor, can help patients suffering from certain diseases.

The nonprofit organization OpenBiome, founded by a group from MIT including Smith and Alm, launched in 2012 to help expand access to fecal matter transplants by screening donors for stool collection then processing, storing, and shipping samples to hospitals. Today OpenBiome works with more than 1,000 hospitals, and its success in the early days of the field shows that basic microbiome research, when paired with clinical trials like those happening at CMIT, can quickly lead to new treatments.

“You start with a disease, and if there’s a microbiome association, you can start a small trial to see if fecal transplants can help patients right away,” Alm explains. “If that becomes an effective treatment, while you’re rolling it out you can be doing the genomics to figure out how to make it better. So you can translate therapeutics into patients more quickly than when you’re developing small-molecule drugs.”

Another nonprofit project launched out of MIT, the Global Microbiome Conservancy, is collecting stool samples from people living nonindustrialized lifestyles around the world, whose guts have much different bacterial makeups and thus hold potential for advancing our understanding of host-microbiome interactions.

A number of private companies founded by MIT alumni are also trying to harness individual microbes to create new treatments, including, among others, Finch Therapeutics founded by Mark Smith; Concerto Biosciences, co-founded by Jared Kehe PhD ’20 and Bernardo Cervantes PhD ’20; BiomX, founded by Associate Professor Tim Lu; and Synlogic, founded by Lu and Jim Collins, the Termeer Professor of Medical Engineering and Science at MIT.

“There’s an opportunity to more precisely change a microbiome,” explains CMIT’s Lieberman. “But there’s a lot of basic science to do to figure out how to tweak the microbiome in a targeted way. Once we figure out how to do that, the therapeutic potential of the microbiome is quite limitless.”

Endowed funds to support MSRP-Bio
December 22, 2020

Dear colleagues,

I’m writing to share some really good news about our MIT’s Summer Research Program in Biology, or as most of us know it, MSRP-Bio. The simple take-home message: we now have endowed funds from Mike Gould and Sara Moss that will support about a dozen MSRP-Bio students each summer, for a very long time!

In 2015, Mike and Sara established the Bernard S. and Sophie G. Gould Fund to support students participating in MSRP-Bio. This gift was to provide opportunities to deserving students and to honor the memory of Mike’s parents.

Mike’s parents were both MIT alumni, and his father Bernie was a professor in the Biology Department from 1934 – 1987. Bernie and Sophie both committed their lives to supporting and counseling young students, and Mike and Sara chose to establish this fund to honor Mike’s parents and their deep and shared commitment to mentorship. Indeed, Mike and Sara share that commitment to support students and provide them with opportunities that could change their lives.

Mike and Sara have been remarkably dedicated to MSRP-Bio. Beginning with the first cohort of Gould Fellows in 2016, they visited each summer to meet and get to know these talented students. The first four meetings were in person, and then in the summer of 2020, the meeting was virtual due to the pandemic. Mike and Sara insisted on having the meeting, and even attended all of the student talks that summer. They have kept in touch with several of the Gould Fellow alumni and have gotten together with those who are in their hometown (NYC).

Mike and Sara have been so touched by the impact of their initial gift that they decided recently to provide additional support. To acknowledge this support and their commitment to our students and program, we are renaming MSRP-Bio the Bernard S. and Sophie G. Gould MIT Summer Research Program in Biology: BSG-MSRP-Bio, in honor of Mike’s parents.

We are deeply grateful to Mike and Sara for their commitment to and support for our community, their willingness to enable opportunities for students, irrespective of their specific research interests, and for the many talented individuals who will benefit from the experiences afforded by their generous gift. 

This gift is a great way to end the year. Wishing everyone a wonderful holiday season and a Happy Healthy New Year!

Best wishes,
Alan Grossman, Department Head

Ruth Lehmann receives 2020 Francis Amory Prize
Greta Friar | Whitehead Institute
December 21, 2020

Whitehead Institute Director Ruth Lehmann has been awarded the 2020 Francis Amory Prize in Reproductive Medicine and Reproductive Physiology by the American Academy of Arts & Sciences. Lehmann shares the prize with geneticist Gertrud M. Schüpbach, emeritus professor at Princeton University and a longtime friend and colleague. The Amory Prize recognizes outstanding achievements in medicine and reproductive physiology, and Lehmann and Schüpbach are being recognized for their contributions to areas including DNA repair, embryonic development, RNA regulation, and stem cell research. Lehmann, who is also a professor at the Massachusetts Institute of Technology, studies the biological origins of germ cells, the sex cells that produce eggs and sperm. Her research has shed light on many aspects of the germ cell life cycle, including how germ cells first form and become set apart from the rest of the body’s cells, how they migrate to the gonads during embryonic development, and how they remain protected in order to produce the next generation, preserving and passing on the complex instructions to construct a new life. Lehmann and Schüpbach will accept the Amory Prize at a virtual American Academy of Arts & Sciences event on February 3, 2021. To learn more, click here.

Disarming cancer
Greta Friar | Whitehead Institute
December 21, 2020

Cancer is at its most deadly when two things occur: the cancer cells metastasize, spreading to new sites in the body, and the cells become resistant to treatment. The epithelial-mesenchymal transition (EMT) is a process that cancer cells may undergo that enables them to do both of these things. Cells that undergo this process are called “quasi-mesenchymal” cancer cells, and they are mobile, aggressive, and harder to kill. They can resist attacks launched both by the body’s own immune system as well as immune checkpoint blockade therapy (ICB), an increasingly employed clinical treatment that works by liberating cells of the immune system from certain constraints, thereby allowing them to attack cancer cells. Anushka Dongre, a postdoctoral researcher in the lab of Whitehead Institute Founding Member Robert Weinberg, had previously found that even a small population of quasi-mesenchymal cells within a mouse breast cancer tumor—as little as 10% amongst a majority of cells that had not gone through the EMT—could protect the entire tumor from a version of ICB called anti-CTLA4 therapy. Most breast cancers in humans contain some minority populations of quasi-mesenchymal cells, as do many other types of human tumors, likely contributing to ICB therapy’s mixed success rates in the clinic.

Because cells that have been through the EMT process play such a large role in making cancers more deadly and less responsive to treatment, Dongre set out to understand how to defang them. Her first step was to figure out how minority populations of quasi-mesenchymal cells within a breast tumor make the tumors as a whole resistant to immune therapy. Then she studied how to disable those mechanisms. The work, described in a paper published in Cancer Discovery on December 16, includes studies in mice showing that disabling those resistance mechanisms can sensitize otherwise-resistant tumors to anti-CTLA4 checkpoint blockade immunotherapy and reduce the severity of metastasis.

Dongre had previously studied how quasi-mesenchymal cells alter the area in and around a tumor to render it more favorable for the outgrowth of a cancer. They keep out of the core of the tumor the type of immune cells that can destroy cancers, and instead let in other types of immune cells that the tumor is able to co-opt to its benefit, thereby protecting it from immune attack. 

In her latest research, Dongre identified six molecules that quasi-mesenchymal cells produce and release that help them perturb the tumor’s surroundings, protecting cells throughout the tumor from immune attack and elimination. She then tested what happened when the release of each of the protective molecules was suppressed. She discovered that eliminating release of either of two molecules, CSF1 and SPP1, made the tumors significantly more susceptible to the immune attack and thus elimination by ICB therapy. However, the strongest therapeutic benefit came when she prevented production of CD73, an enzyme usually made by the quasi-mesenchymal cells that produces the immunosuppressive molecule adenosine. In mice, anti-CTLA4 therapy was very effective against tumors in which CD73 and thus adenosine had been eliminated from the quasi-mesenchymal cells, in some cases, succeeding in eliminating the tumors entirely. These findings are consistent with previous research that identified CD73 as a good complementary target for immunotherapy. Furthermore, the experiments demonstrated the utility of combining anti-CD73 therapy with anti-CTLA4 immunotherapy in order to successfully treat tumors that would usually not respond to treatment by ICB therapy alone. Dongre was particularly excited to see the combination of anti-CD73 and anti-CTLA4 reduce the number and size of metastatic tumors.

Dongre hopes that these insights will prove useful for patients.

“There is this minority population of mesenchymal cells present in many patient tumors, creating a big barrier to therapy. I’m hopeful that by identifying the drivers that can sensitize this population to treatment, our work can one day help patients suffering from cancers that are resistant to current therapies,” Dongre says.

Weathering the storm

Professors Heald and Li provide stellar advising in challenging times.

Ellie Immerman | Office of Graduate Education
December 19, 2020

Professors Colette Heald and Gene-Wei Li have been honored as “Committed to Caring” for crafting inclusive laboratory environments, as well as continually empowering their students. A hurdle like the Covid-19 pandemic can easily throw student well-being and research off-kilter. Having such caring advisors can help students persevere amid uncertainty.

Colette Heald: an inspirational advocate

Colette Heald is a professor in the Department of Civil and Environmental Engineering as well as a professor of earth, atmospheric, and planetary sciences. Through her research, Heald investigates global atmospheric composition and chemistry, focusing on how this impacts air quality, climate, and environmental health. Heald’s research has significantly advanced discussions of the combined effects of climate change and air pollution on diminishing crop yields and global food insecurity.

Heald emphasizes that a PhD is an arduous process that “inevitably [has] personal and professional bumps.” Most of all, Heald wants to “create an environment where members of [her] group can rely on [her] for research guidance and for support whenever they need it, while feeling empowered to lead their own research.”

To achieve this balance, Heald provides a forum for regular, clear communication and mutually agreeable expectations. Writes one advisee on speaking with Heald: “I know that I will be heard no matter what the case may be.” Heald meets with each member of her lab weekly, finding that individual needs for these meetings vary greatly. Consistently and empathetically engaging with advisees is a Committed to Caring (C2C) Mentoring Guidepost.

In the midst of the Covid-19 pandemic, Heald is keenly aware of the ways isolation hampers positivity and productivity. She devotes extra time to meeting with students and creating informal Zoom breaks where students share “stories about how we are all adapting to this [shifting] normal.” She looks forward to the time when it will be safe to return to an in-person “vibrant back-and-forth on research and technical questions.”

Structural and individual support

Navigating an academic field is often rife with obstacles. Heald supports her students by communicating with them about the norms of the field, as well as advocating for them in inequitable situations and when dealing with challenging personalities.

In one instance, a postdoc lost their funding, and Heald found financial support for them. According to a nominator, she also “fought to remove potentially discriminatory practices in funding [maternity] leave, that might bias professors away from hiring women postdocs.” Heald’s advocacy spans both individual situations and work on structural reform.

Heald developed conscientious and considerate advising practices over time, through observing what was effective in her and others’ mentoring relationships. As a postdoc, she attended three laboratory groups’ meetings and observed the professors’ differing approaches. She emphasizes the development of an advising style that works for both the individual mentee and the advisor.

Describing Heald concisely, one advisee opts for “#mentorgoals.”

Gene-Wei Li: amplifying diverse voices

Gene-Wei Li is an assistant professor of biology. He joined the MIT faculty in 2015, after completing a PhD at Harvard University and a postdoc at the University of California at San Francisco. A biophysicist, Li studies how bacteria optimize the proteins they produce. His laboratory focuses on design principles of transcription, translation, and RNA maturation in the face of competing cellular processes.

“Metaphorically an endlessly deep vessel,” according to a student nominator, Li “nurture[s] everyone around him both in scien[ce] and, more importantly, personal development.”

Harmonious support

Intrinsically attuned to students’ needs, Li often notices when students could use academic or personal support without being prompted. When one student was feeling burnt out, Li listened closely to understand their individual experience of burnout and what could help them recuperate. The student returned refreshed, “engaged and motivated to work on a day-to-day basis.” Li prioritizes mental health and makes clear that he values students.

Setbacks are inevitable in experimental work. Li works with students to build resilience to research impediments, as well as to collaboratively problem-solve. This emphasis on learning, development, and practice over achievement is a Mentoring Guidepost.

In thinking about guidance during the Covid-19 pandemic, Li offers a thoughtful framework. Being “proactive” amid uncertainty is central. Li’s lab started preparing to work from home in February. He writes, “Acting early is important to both ensure research continuity and reduce emotional impact when an avalanche of restrictions are implemented.”

Li has developed individualized plans with students based on two key principles: “safety cannot be sacrificed,” and “[the student’s] career must advance.” A lingering challenge that many faculty including Li face is how to find ways to interact regularly and informally with lab members while simultaneously homeschooling their own kids.

Building an inclusive community

Li works to intentionally craft a caring laboratory environment. According to Li, he purposefully seeks out “a team with diverse viewpoints and [an] eagerness to help each other.” Students are grateful for this effort, feeling supported by their colleagues. Writes one student nominator, “I’ve always come out of chats with my labmates feeling like my thoughts were heard and that people were genuinely invested in giving me good feedback.”

Being adaptable and requesting feedback in ways that enable students to comfortably share their candid views is a strong skill of Li’s. Referencing how Li solicits feedback and his genuine interest in students’ lives, students describe it as “refreshing to have an advisor who treats us as equals.”

Li also knows how to gracefully guide others in crafting inclusive environments. One student writes that Li “always corrects my implicit biases … Thanks to his awareness, I have been able to start correcting these biases.” This is vital, challenging, and delicate work. Having courageous conversations and fostering inclusivity are Mentoring Guideposts identified by the C2C program.

Nurturing and perceptive, Li is dedicated to the personal and scientific growth of all those around him.

More on Committed to Caring

The Committed to Caring program is an initiative of the Office of Graduate Education and contributes to its mission of making graduate education at MIT “empowering, exciting, holistic, and transformative.”

Since 2014, C2C has invited graduate students from across MIT’s campus to nominate professors whom they believe to be outstanding mentors. Selection criteria for the honor include the scope and reach of advisor impact on graduate students’ experience, excellence in scholarship, and demonstrated commitment to diversity and inclusion.

The most recent outgrowth in 2019 took the form of a Faculty Peer Mentorship Program (FPMP) in which C2C faculty act as peer mentors to incoming MIT professors. The program provides one-to-one matches with the goal of fostering strong mentorship practices and providing a network of support.

By recognizing the human element of graduate education, C2C seeks to encourage excellent advising and mentorship across MIT’s campus.

Harvey Lodish receives two international honors
Merrill Meadow | Whitehead Institute
December 16, 2020

Founding Member Harvey Lodish has been twice honored by the international science community for his path-breaking scientific accomplishments and intellectual leadership.

The Royal Academy of Medicine of Belgium has elected Lodish as a Foreign Member, recognizing his pioneering role in the field of molecular cell biology, his seminal contributions to understanding protein translation and protein traffic processes, and his discovery and cloning of cell surface receptors for many hormones and cytokines. Collectively, Lodish’s work has helped to explain key aspects of hematopoiesis, obesity, and diabetes.

In addition, the Chinese University of Hong Kong has conferred on Lodish an honorary Doctor of Science degree, recognizing both his research achievements and his long-term efforts to help build Hong Kong’s biotechnology ecosystem.

In nominating him for Royal Academy membership, former Lodish-lab fellow Stefan Constantinescu—now Head of the Cell Signaling and Molecular Hematology at Brussels’ Ludwig Institute for Cancer Research—noted that beyond making discoveries that led to effective treatments, Lodish was “one of the pioneers of modern biotechnology, being a founder of Genzyme Inc., [plus] Arris Pharmaceuticals, Inc., Millennium Pharmaceuticals, Inc., Allozyne, Inc, and most recently Rubius Therapeutics.”

RNA molecules are masters of their own destiny
Eva Frederick | Whitehead Institute
December 16, 2020

At any given moment in the human body, in about 30 trillion cells, DNA is being “read” into molecules of messenger RNA, the intermediary step between DNA and proteins, in a process called transcription.

Scientists have a pretty good idea of how transcription gets started: proteins called RNA polymerases are recruited to specific regions of the DNA molecules and begin skimming their way down the strand, synthesizing mRNA molecules as they go. But part of this process is less well understood: how does the cell know when to stop transcribing?

Now, new work from the labs of Whitehead Institute Member Richard Young, also a professor of biology at Massachusetts Institute of Technology (MIT), and Arup K. Chakraborty, professor of chemical engineering, physics and chemistry at MIT, suggests that RNA molecules themselves are responsible for regulating their formation through a feedback loop. Too few RNA molecules, and the cell initiates transcription to create more. Then, at a certain threshold, too many RNA molecules cause transcription to draw to a halt.

The research, published in Cell on December 16, represents a collaboration between biologists and physicists, and provides some insight into the potential roles of the thousands of RNAs that are not translated into any proteins, called noncoding RNAs, which are common in mammals and have mystified scientists for decades.

A question of condensates

Previous work in Young’s lab has focused on transcriptional condensates, small cellular droplets that bring together the molecules needed to transcribe DNA to RNA. Scientists in the lab discovered the transcriptional droplets in 2018, noticing that they typically formed when transcription began and dissolved a few seconds or minutes later when the process was finished.

The researchers wondered if the force that governed the dissolution of the transcriptional condensates could be related to the chemical properties of the RNA they produced — specifically, its highly negative charge. If this were the case, it would be the latest example of cellular processes being regulated via a feedback mechanism — an elegant, efficient system used in the cell to control biological functions such as red blood cell production and DNA repair.

As an initial test, the researchers used an in vitro experiment to test whether the amount of RNA had an effect on condensate formation. They found that within the range of physiological levels observed in cells, low levels of RNA encouraged droplet formation and high levels of RNA discouraged it.

Thinking outside the biology box 

With these results in mind, Young Lab postdocs and co-first authors Ozgur Oksuz and Jon Henninger teamed up with physicist and co-first author Krishna Shrinivas, a graduate student in Arup Chakraborty’s lab, to investigate what physical forces were at play.

Shrinivas proposed that the team build a computational model to study the physical and chemical interactions between actively transcribed RNA and condensates formed by transcriptional proteins. The goal of the model was not to simply reproduce existing results, but to create a platform with which to test a variety of situations.

“The way most people study these kinds of problems is to take mixtures of molecules in a test tube, shake it and see what happens,” Shrinivas said. “That is as far away from what happens in a cell as one can imagine. Our thought was, ‘Can we try to study this problem in its biological context, which is this out-of-equilibrium, complex process?’”

Studying the problem from a physics perspective allowed the researchers to take a step back from traditional biology methods. “As a biologist, it’s difficult to come up with new hypotheses, new approaches to understanding how things work from available data,” Henninger said. “You can do screens, you can identify new players, new proteins, new RNAs that may be involved in a process, but you’re still limited by our classical understanding of how all these things interact. Whereas when talking with a physicist, you’re in this theoretical space extending beyond what the data can currently give you. Physicists love to think about how something would behave, given certain parameters.”

Once the model was complete, the researchers could ask it questions about situations that may arise in cells — for instance, what happens to condensates when RNAs of different lengths are produced at different rates as time ensues? — and then follow it up with an experiment at the lab bench. “We ended up with a very nice convergence of model and experiment,” Henninger said. “To me, it’s like the model helps distill the simplest features of this type of system, and then you can do more predictive experiments in cells to see if it fits that model.”

The charge is in charge

Through a series of modeling and experiments at the lab bench, the researchers were able to confirm their hypothesis that the effect of RNA on transcription is due to RNAs molecules’ highly negative charge. Furthermore, it was predicted that initial low levels of RNA enhance and subsequent higher levels dissolve condensates formed by transcriptional proteins. Because the charge is carried by the RNAs’ phosphate backbone, the effective charge of a given RNA molecule is directly proportional to its length.

In order to test this finding in a living cell, the researchers engineered mouse embryonic stem cells to have glowing condensates, then treated them with a chemical to disrupt the elongation phase of transcription. Consistent with the model’s predictions, the resulting dearth of condensate-dissolving RNA molecules increased the size and lifetime of condensates in the cell. Conversely, when the researchers engineered cells to induce the production of extra RNAs, transcriptional condensates at these sites dissolved. “These results highlight the importance of understanding how non-equilibrium feedback mechanisms regulate the functions of the biomolecular condensates present in cells,” said Chakraborty.

Confirmation of this feedback mechanism might help answer a long-standing mystery of the mammalian genome: the purpose of non-coding RNAs, which make up a large portion of genetic material. “While we know a lot about how proteins work, there are tens of thousands of noncoding RNA species, and we don’t know the functions of most of these molecules,” said Young. “The finding that RNA molecules can regulate transcriptional condensates makes us wonder if many of the noncoding species just function locally to tune gene expression throughout the genome. Then this giant mystery of what all these RNAs do has a potential solution.”

The researchers are optimistic that understanding this new role for RNA in the cell could inform therapies for a wide range of diseases. “Some diseases are actually caused by increased or decreased expression of a single gene,” said Oksuz, a co-first author. “We now know that if you modulate the levels of RNA, you have a predictable effect on condensates. So you could hypothetically tune up or down the expression of a disease gene to restore the expression — and possibly restore the phenotype — that you want, in order to treat a disease.”

Young added that a deeper understanding of RNA behavior could inform therapeutics more generally. In the last 10 years, a variety of drugs have been developed that directly target RNA successfully. “RNA is an important target,” Young said. “Understanding mechanistically how RNA molecules regulate gene expression bridges the gap between gene dysregulation in disease and new therapeutic approaches that target RNA.”