Author: mantulin

Alana gift to MIT launches Down syndrome research center, technology program for disabilities

Foundation’s $28.6 million gift will fund science, innovation, and education to advance understanding, ability, and inclusion.

David Orenstein | Picower Institute for Learning and Memory
March 21, 2019

As part of its continued mission to help build a better world, MIT is establishing the Alana Down Syndrome Center, an innovative new research endeavor, technology development initiative, and fellowship program launched with a $28.6 million gift from Alana Foundation, a nonprofit organization started by Ana Lucia Villela of São Paulo, Brazil.

In addition to multidisciplinary research across neuroscience, biology, engineering, and computer science labs, the gift will fund a four-year program with MIT’s Deshpande Center for Technological Innovation called “Technology to Improve Ability,” in which creative minds around the Institute will be encouraged and supported in designing and developing technologies that can improve life for people with different intellectual abilities or other challenges.

The Alana Down Syndrome Center, based out of MIT’s Picower Institute for Learning and Memory, will engage the expertise of scientists and engineers in a research effort to increase understanding of the biology and neuroscience of Down syndrome. The center will also provide new training and educational opportunities for early career scientists and students to become involved in Down syndrome research. Together, the center and technology program will work to accelerate the generation, development, and clinical testing of novel interventions and technologies to improve the quality of life for people with Down syndrome.

“At MIT, we value frontier research, particularly when it is aimed at making a better world,” says MIT President L. Rafael Reif. “The Alana Foundation’s inspiring gift will position MIT’s researchers to investigate new pathways to enhance and extend the lives of those with Down syndrome. We are grateful to the foundation’s leadership — President Ana Lucia Villela and Co-President Marcos Nisti — for entrusting our community with this critical challenge.”

With a $1.7 million gift to MIT in 2015, Alana funded studies to create new laboratory models of Down syndrome and to improve understanding of the mechanisms of the disorder and potential therapies. In creating the new center, MIT and the Alana Foundation officials say they are building on that partnership to promote discovery and technology development aimed at helping people with different abilities gain greater social and practical skills to enhance their participation in the educational system, in the workforce, and in community life.

“We couldn’t be happier and more hopeful as to the size of the impact this center can generate,” Villela says. “It’s an innovative approach that doesn’t focus on the disability but, instead, focuses on the barriers that can prevent people with Down syndrome from thriving in life in their own way.”

Marcos Nisti, co-president of Alana, adds, “This grant represents all the trust we have in MIT especially because the values our family hold are so aligned with MIT’s own values and its mission.”

Villela and Nisti have two daughters, one with Down syndrome. MIT Executive Vice President and Treasurer Israel Ruiz has had a personal connection to the foundation.

“It is an extraordinary day,” Ruiz says. “It has been a pleasure getting to know Ana Lucia, Marcos and their family over the past few years. Their work to advance the needs of the Down syndrome community is truly exemplary, and I look forward to future collaborations. Today, MIT celebrates their generosity in recognizing all abilities and working to provide opportunities to all.”

Down syndrome, also known as trisomy 21, is characterized by extra genetic material from some or all of chromosome 21 in many or all of an individual’s cells and occurs in one out of every 700 babies in the United States. Though the chromosomal hallmark of Down syndrome has been well known for decades, and advances in research, health care and social services have doubled lifespans over the past 25 years, significant challenges remain for individuals with different abilities and their families because the underlying neurobiology of the disorder is complex.

The center will be co-directed by Angelika Amon, the Kathleen and Curtis Marble Professor in Cancer Research, and Li-Huei Tsai, the Picower Professor of Neuroscience. Amon is an expert in understanding the health impacts of chromosomal instability and aneuploidy, the presence of an abnormal chromosome number, while Tsai is renowned for her work in the field of neurodegenerative disorders, including Alzheimer’s disease, which shares important underlying similarities with Down syndrome.

In the first four years, the new center will employ cutting-edge techniques to study Down syndrome in the brain with two main focuses: systems and circuits as well as genes and cells.

With the support of the previous Alana Foundation gift, Hiruy Meharena, senior fellow in Tsai’s neuroscience lab, has already been deeply engaged in studying Down syndrome’s impact in the brain at the cellular and genomic level, examining key differences in gene expression in cultures of neurons and glia created from patient-derived induced pluripotent stem cells.

To further advance research at that molecular scale, Tsai’s lab will collaborate with computer science Professor Manolis Kellis, director of MIT’s Computational Biology Group and a leader in creating sophisticated methods for big-data integration and analysis of genomic and gene expression data.

At the systems and circuits level, Ed Boyden, the Y. Eva Tan Professor in Neurotechnology will lead efforts to conduct high-resolution 3-D brain mapping and will collaborate with Tsai to examine the potential of using her emerging non-invasive, sensory-based therapy for Alzheimer’s in Down syndrome.

Amon’s lab will bring its deep expertise from their study of cancer to the new center. Researchers there have made important discoveries about how aneuploidy may undermine overall health, for instance by causing stresses within cells. It is their hope that identifying genetic alterations that suppress the stresses associated with trisomy 21 could lead to the development of therapeutics that improve cell function in individuals with Down syndrome.

To further support these research endeavors and to increase the long-term global pipeline of scientists trained in the study of Down syndrome, the Alana Down Syndrome Center will fund postdoctoral Alana Fellowships and graduate fellowships.

The Alana Center will also convene an annual symposium on Down syndrome research, the first of which is tentatively scheduled for this fall.

The Alana Foundation gift supports the MIT Campaign for a Better World, which was publicly launched in 2016 with a mission to advance MIT’s work in education, research, and innovation to address humanity’s urgent challenges. A joint statement guiding the gift’s purpose is available at alana.mit.edu/statement.

How tumors behave on acid

Acidic environment triggers genes that help cancer cells metastasize.

Anne Trafton | MIT News Office
March 21, 2019

Scientists have long known that tumors have many pockets of high acidity, usually found deep within the tumor where little oxygen is available. However, a new study from MIT researchers has found that tumor surfaces are also highly acidic, and that this acidity helps tumors to become more invasive and metastatic.

The study found that the acidic environment helps tumor cells to produce proteins that make them more aggressive. The researchers also showed that they could reverse this process in mice by making the tumor environment less acidic.

“Our findings reinforce the view that tumor acidification is an important driver of aggressive tumor phenotypes, and it indicates that methods that target this acidity could be of value therapeutically,” says Frank Gertler, an MIT professor of biology, a member of MIT’s Koch Institute for Integrative Cancer Research, and the senior author of the study.

Former MIT postdoc Nazanin Rohani is the lead author of the study, which appears in the journal Cancer Research.

Mapping acidity

Scientists usually attribute a tumor’s high acidity to the lack of oxygen, or hypoxia, that often occurs in tumors because they don’t have an adequate blood supply. However, until now, it has been difficult to precisely map tumor acidity and determine whether it overlaps with hypoxic regions.

In this study, the MIT team used a probe called pH (Low) Insertion Peptide (pHLIP), originally developed by researchers at the University of Rhode Island, to map the acidic regions of breast tumors in mice. This peptide is floppy at normal pH but becomes more stable at low, acidic pH. When this happens, the peptide can insert itself into cell membranes. This allows the researchers to determine which cells have been exposed to acidic conditions, by identifying cells that have been tagged with the peptide.

To their surprise, the researchers found that not only were cells in the oxygen-deprived interior of the tumor acidic, there were also acidic regions at the boundary of the tumor and the structural tissue that surrounds it, known as the stroma.

“There was a great deal of tumor tissue that did not have any hallmarks of hypoxia that was quite clearly exposed to acidosis,” Gertler says. “We started looking at that, and we realized hypoxia probably wouldn’t explain the majority of regions of the tumor that were acidic.”

Further investigation revealed that many of the cells at the tumor surface had shifted to a type of cell metabolism known as aerobic glycolysis. This process generates lactic acid as a byproduct, which could account for the high acidity, Gertler says. The researchers also discovered that in these acidic regions, cells had turned on gene expression programs associated with invasion and metastasis. Nearly 3,000 genes showed pH-dependent changes in activity, and close to 300 displayed changes in how the genes are assembled, or spliced.

“Tumor acidosis gives rise to the expression of molecules involved in cell invasion and migration. This reprogramming, which is an intracellular response to a drop in extracellular pH, gives the cancer cells the ability to survive under low-pH conditions and proliferate,” Rohani says.

Those activated genes include Mena, which codes for a protein that normally plays a key role in embryonic development. Gertler’s lab had previously discovered that in some tumors, Mena is spliced differently, producing an alternative form of the protein known as MenaINV (invasive). This protein helps cells to migrate into blood vessels and spread though the body.

Another key protein that undergoes alternative splicing in acidic conditions is CD44, which also helps tumor cells to become more aggressive and break through the extracellular tissues that normally surround them. This study marks the first time that acidity has been shown to trigger alternative splicing for these two genes.

Reducing acidity

The researchers then decided to study how these genes would respond to decreasing the acidity of the tumor microenvironment. To do that, they added sodium bicarbonate to the mice’s drinking water. This treatment reduced tumor acidity and shifted gene expression closer to the normal state. In other studies, sodium bicarbonate has also been shown to reduce metastasis in mouse models.

Sodium bicarbonate would not be a feasible cancer treatment because it is not well-tolerated by humans, but other approaches that lower acidity could be worth exploring, Gertler says. The expression of new alternative splicing genes in response to the acidic microenvironment of the tumor helps cells survive, so this phenomenon could be exploited to reverse those programs and perturb tumor growth and potentially metastasis.

“Other methods that would more focally target acidification could be of great value,” he says.

The research was funded by the Koch Institute Support (core) Grant from the National Cancer Institute, the Howard Hughes Medical Institute, the National Institutes of Health, the KI Quinquennial Cancer Research Fellowship, and MIT’s Undergraduate Research Opportunities Program.

Other authors of the paper include Liangliang Hao, a former MIT postdoc; Maria Alexis and Konstantin Krismer, MIT graduate students; Brian Joughin, a lead research modeler at the Koch Institute; Mira Moufarrej, a recent graduate of MIT; Anthony Soltis, a recent MIT PhD recipient; Douglas Lauffenburger, head of MIT’s Department of Biological Engineering; Michael Yaffe, a David H. Koch Professor of Science; Christopher Burge, an MIT professor of biology; and Sangeeta Bhatia, the John and Dorothy Wilson Professor of Health Sciences and Technology and Electrical Engineering and Computer Science.

Meenakshi Chakraborty named 2019 Churchill Scholar

Senior majoring in computer science and molecular biology will pursue an MPhil at Cambridge University.

Office of Distinguished Fellowships
March 18, 2019

Meenakshi Chakraborty, a senior from Cambridge, Massachusetts, has been named a 2019 Churchill Scholar and will pursue an MPhil at Cambridge University.

Chakraborty is expected to graduate this spring with a BS in computer science and molecular biology. As a Churchill scholar she aims to pursue a master’s degree in genetics at Cambridge. When she returns to the U.S. she plans to pursue a PhD in biology with a focus on genetics.

Chakraborty realized a passion for scientific research when still in high school. After a trip to a South African hospital, she realized the devastation caused by the AIDS epidemic, and discovered a desire to participate in scientific research that could lead to medical breakthroughs. Upon her return, she learned of the work of Bruce Walker, director of the Ragon Institute of MGH, MIT, and Harvard, and a professor at MIT’s Institute for Medical Engineering and Science. Despite the fact that Chakraborty was still in high school, Walker agreed to mentor her work on a study of epidemiology of HIV.

Chakraborty next began research under the tutelage of Institute Professor Phil Sharp. Jeremy Wilusz, a former Sharp Lab postdoc and current professor of biochemistry at the University of Pennsylvania, says, “It was clear long ago that Meena was a superstar in the making. As a 15-year-old, she reached out to Phil about writing an independent report on RNA over the summer. (I believe you had to be at least 16 to do actual research in a lab at MIT, so this was her way of getting her feet wet.) She asked to meet with one of the postdocs in the lab every couple of weeks to make sure she was heading in the right direction, and I became that postdoc. We decided to have her write a report on the history and functions of circular RNAs, which had recently been the subject of several prominent papers in Nature. She would go off, read a ton of papers, write extensive outlines, and bring very thoughtful questions to my attention that we would talk about. This effort ultimately resulted in the first Wikipedia page on circular RNAs (completely her idea) that others have built upon as the field has evolved.”

When Chakraborty matriculated at MIT, she began conducting research in the Sharp Lab at the Koch Institute for Integrative Cancer Research, as an Undergraduate Research Opportunities Program (UROP) student. During her time in the lab, she has investigated cell states, and how cells with identical genetic information and the same differentiation state vary. This issue is at the center of problems in developmental biology and the mechanisms of cancer. She has worked closely with research scientist Salil Garg on this work, who says, “Meena makes everything around her more fun. Her endless enthusiasm and positivity rub off on everyone in lab. Working with her has been an absolute joy. It’s hard to imagine what the lab will be like without her.”

Chakraborty has also participated in competitive summer research programs including MIT’s Johnson and Johnson UROP Scholars Program, which aims to support and increase the number of women in STEM, manufacturing, and design fields. With funding from Johnson and Johnson as part of its Women in Science, Technology, Engineering, Math, Manufacturing and Design (WiSTEM2D) initiative, Johnson and Johnson UROP Scholars conduct full-time summer research, in addition to attending faculty presentations, workshops, and networking events. Sarah Nelson, senior program coordinator of UROP and Johnson and Johnson UROP Scholars, says, “Meena was a great addition to this program not only because she is an outstanding student and researcher, but she is a true advocate for women in STEM.”

Chakraborty received a Goldwater scholarship last year due to her exceptional work as a student and researcher. She has continued to work in the Sharp lab while she finishes her degree at MIT.

During her time at MIT, she has also worked on science advocacy with MIT Effective Altruism (EA) Club. Chakraborty plans to explore working with Cambridge EA while studying in the U.K. She hopes to use this opportunity to develop her multidisciplinary approach to research and developing treatments for life-threatening conditions.

Chakraborty was advised in her application by Kim Benard in the Office of Distinguished Fellowships and by the Presidential Committee for Distinguished Fellowships, co-chaired by Professors William Broadhead and Rebecca Saxe. The Churchill Scholarship is a competitive program that annually offers 16 students an opportunity to pursue a funded graduate degree in science, mathematics or engineering at Churchill College within Cambridge University.

Committed to service and science

When senior Julia Ginder isn’t investigating the mystery of her own allergies, she’s volunteering to help young people reach their goals.

Gina Vitale | MIT News correspondent
February 25, 2019

Julia Ginder has to avoid a lot of foods due to allergies. From a young age, she got used to bringing her own snacks to birthday parties and group outings. But she didn’t really know the science behind her allergies until high school, when she read a chapter for class on immunology.

“I read it, and then I read it again, and I went running downstairs to tell my mom, ‘This is what’s wrong with me!’” she recalls.

From them on, Ginder was driven to learn about what made her body react so severely to certain stimuli. Now a biology major, she does research in the lab of Christopher Love, in the Koch Institute for Integrative Cancer Research, where she studies peanut allergies — one of the few food allergies she actually doesn’t have.

“I really enjoy figuring out, what’s the perspective from the biology side? What is the contributing chemistry? And how do those fit together?” she says. “And then, when you take a step back, how do you use that knowledge and perhaps the technology that comes out of it, and actually apply that in the real world?”

Nuts about research

In the Love lab, researchers look at how individual immune cells from people with peanut allergies react when stimulated with peanut extracts. More recently, they’ve been analyzing how the stimulated cells change over the course of treatment, evolving from one state to the next.

“You can watch the activation signals change over time in individual cells from peanut-allergic patients compared to healthy ones,” Ginder explains. “You can then dig deeper and look at distinct populations of cells at a single time point. With all of this information, you can start to get a sense of what critical cell types and signals are making the allergic person maintain a reaction.”

The researchers aim to figure out which cell types are associated with the development of tolerance so that more effective treatments can be developed. For instance, allergic people are sometimes given peanuts in small doses as a sort of biological exposure therapy, but perhaps if more key cell states are identified, targeted drug treatments can be added on top of that to induce those cell states.

Further pursuing her interest in health, Ginder spent the Independent Activities Period of her sophomore year volunteering for Boston Medical Center. The program she worked for helped families learn how to be advocates for their children with autism. For instance, it provided guidance on how to negotiate an appropriate accommodations agreement with their child’s school for their individual needs.

“It [the BMC experience] made it clear to me that for a child to succeed, they need to have support from both the educational side and the health side,” she says. “And it might seem obvious, but, especially for a child who might be coming from a less privileged background, those are two really important angles for ensuring that they are given the opportunity to reach their full potential.”

“The most helpful thing you can do is simply be there.”

Ginder became a swim coach and tutor for Amphibious Achievement in the fall of her first year, almost immediately after arriving at MIT. It’s a program that aims to help high schoolers reach both their athletic and academic goals. The high schoolers, often known as Achievers, are assigned a mentor like Ginder who helps with the academic and the athletic activities.

Local students come to MIT early Sunday morning to practice swimming or rowing, head to the Maseeh dining hall for lunch, participate in an afternoon academics lesson, reflect on their goals, and then spend a half an hour one-on-one with their mentor. It’s a big commitment for both the Achievers and mentors to spend almost six hours every Sunday with the program, but Ginder, who completed her two-year term as one of the co-executive directors this fall, has seen the importance of showing up week after week.

“The most helpful thing you can do is simply be there. Listen if they want to tell you anything, but really just being consistent — every single Sunday, being there.”

Ginder played on the field hockey team during her first year. However, when a practice during her sophomore year left her with a concussion and unable to play, she used the newfound spare time to start volunteering for Camp Kesem (CK). Having really enjoyed her experience at Amphibious Achievement, she was eager to be a counselor for the camp, which serves children whose parents are affected by cancer.

“Being there for someone, whether they are having a tough time or a great day, is really important to me. I felt that CK really aligned with that value I hold, and I hoped to meet even more people at MIT who felt that way. And so I joined, and I’ve loved it,” she says.

Management and moving west

Eventually, Ginder would like to become a physician, possibly in the fields of pediatrics and allergies. However, with a minor in public policy, she’s interested in developing areas outside of science as well. So, for the next couple of years, she’ll be moving westward to work as an associate consultant for Bain and Company in San Francisco.

“The reason I’m most interested in consulting is that there is this strong culture of learning and feedback. I want to improve my ability to be a strong team member, leader, and persuader. I think these are areas where I can continue to grow a lot,” she says. “It may sound silly, but I think for me, as someone who is 5’2” and hoping to become a pediatrician, it’s important to cultivate those professional skills early. I want to also serve as a leader and advocate outside of the clinic.”

As Ginder admits, the move is quite the geographic leap. Right now, her entire family is between a 20-minute and two-hour drive away. Moving to the opposite side of the country will be difficult, but she isn’t one to shy away from a challenge.

“I think it’ll be a bit sad because I’m not going to be as close to my family, but I think that it’ll really push me to be as independent as possible. I’ll need to look for my own opportunities, meet new people, build my network, and be my own person,” she says. “I’m really excited about that.”

Predicting sequence from structure

Researchers have devised a faster, more efficient way to design custom peptides and perturb protein-protein interactions.

Raleigh McElvery | Department of Biology
February 15, 2019

One way to probe intricate biological systems is to block their components from interacting and see what happens. This method allows researchers to better understand cellular processes and functions, augmenting everyday laboratory experiments, diagnostic assays, and therapeutic interventions. As a result, reagents that impede interactions between proteins are in high demand. But before scientists can rapidly generate their own custom molecules capable of doing so, they must first parse the complicated relationship between sequence and structure.

Small molecules can enter cells easily, but the interface where two proteins bind to one another is often too large or lacks the tiny cavities required for these molecules to target. Antibodies and nanobodies bind to longer stretches of protein, which makes them better suited to hinder protein-protein interactions, but their large size and complex structure render them difficult to deliver and unstable in the cytoplasm. By contrast, short stretches of amino acids, known as peptides, are large enough to bind long stretches of protein while still being small enough to enter cells.

The Keating lab at the MIT Department of Biology is hard at work developing ways to quickly design peptides that can disrupt protein-protein interactions involving Bcl-2 proteins, which promote cancer growth. Their most recent approach utilizes a computer program called dTERMen, developed by Keating lab alumnus, Gevorg Grigoryan PhD ’07, currently an associate professor of computer science and adjunct associate professor of biological sciences and chemistry at Dartmouth College. Researchers simply feed the program their desired structures, and it spits out amino acid sequences for peptides capable of disrupting specific protein-protein interactions.

“It’s such a simple approach to use,” says Keating, an MIT professor of biology and senior author on the study. “In theory, you could put in any structure and solve for a sequence. In our study, the program came up with new sequence combinations that aren’t like anything found in nature — it deduced a completely unique way to solve the problem. It’s exciting to be uncovering new territories of the sequence universe.”

Former postdoc Vincent Frappier and Justin Jenson PhD ’18 are co-first authors on the study, which appears in the latest issue of Structure.

Same problem, different approach

Jenson, for his part, has tackled the challenge of designing peptides that bind to Bcl-2 proteins using three distinct approaches. The dTERMen-based method, he says, is by far the most efficient and general one he’s tried yet.

Standard approaches for discovering peptide inhibitors often involve modeling entire molecules down to the physics and chemistry behind individual atoms and their forces. Other methods require time-consuming screens for the best binding candidates. In both cases, the process is arduous and the success rate is low.

dTERMen, by contrast, necessitates neither physics nor experimental screening, and leverages common units of known protein structures, like alpha helices and beta strands — called tertiary structural motifs or “TERMs” — which are compiled in collections like the Protein Data Bank. dTERMen extracts these structural elements from the data bank and uses them to calculate which amino acid sequences can adopt a structure capable of binding to and interrupting specific protein-protein interactions. It takes a single day to build the model, and mere seconds to evaluate a thousand sequences or design a new peptide.

“dTERMen allows us to find sequences that are likely to have the binding properties we’re looking for, in a robust, efficient, and general manner with a high rate of success,” Jenson says. “Past approaches have taken years. But using dTERMen, we went from structures to validated designs in a matter of weeks.”

Of the 17 peptides they built using the designed sequences, 15 bound with native-like affinity, disrupting Bcl-2 protein-protein interactions that are notoriously difficult to target. In some cases, their designs were surprisingly selective and bound to a single Bcl-2 family member over the others. The designed sequences deviated from known sequences found in nature, which greatly increases the number of possible peptides.

“This method permits a certain level of flexibility,” Frappier says. “dTERMen is more robust to structural change, which allows us to explore new types of structures and diversify our portfolio of potential binding candidates.”

Probing the sequence universe

Given the therapeutic benefits of inhibiting Bcl-2 function and slowing tumor growth, the Keating lab has already begun extending their design calculations to other members of the Bcl-2 family. They intend to eventually develop new proteins that adopt structures that have never been seen before.

“We have now seen enough examples of various local protein structures that computational models of sequence-structure relationships can be inferred directly from structural data, rather than having to be rediscovered each time from atomistic interaction principles,” says Grigoryan, dTERMen’s creator. “It’s immensely exciting that such structure-based inference works and is accurate enough to enable robust protein design. It provides a fundamentally different tool to help tackle the key problems of structural biology — from protein design to structure prediction.”

Frappier hopes one day to be able to screen the entire human proteome computationally, using methods like dTERMen to generate candidate binding peptides. Jenson suggests that using dTERMen in combination with more traditional approaches to sequence redesign could amplify an already powerful tool, empowering researchers to produce these targeted peptides. Ideally, he says, one day developing peptides that bind and inhibit your favorite protein could be as easy as running a computer program, or as routine as designing a DNA primer.

According to Keating, although that time is still in the future, “our study is the first step towards demonstrating this capacity on a problem of modest scope.”

This research was funded the National Institute of General Medical Sciences, National Science Foundation, Koch Institute for Integrative Cancer Research, Natural Sciences and Engineering Research Council of Canada, and Fonds de Recherche du Québec.

Why too much DNA repair can injure tissue

Overactive repair system promotes cell death following DNA damage by certain toxins, study shows.

Anne Trafton | MIT News Office
February 14, 2019

DNA-repair enzymes help cells survive damage to their genomes, which arises as a normal byproduct of cell activity and can also be caused by environmental toxins. However, in certain situations, DNA repair can become harmful to cells, provoking an inflammatory response that produces severe tissue damage.

MIT Professor Leona Samson has now determined that inflammation is a key component of the way this damage occurs in photoreceptor cells in the retinas of mice. About 10 years ago, she and her colleagues discovered that overactive initiation of DNA-repair systems can lead to retinal damage and blindness in mice. The key enzyme in this process, known as Aag glycosylase, can also cause harm in other tissues when it becomes hyperactive.

“It’s another case where despite the fact that inflammation is there to protect you, in some circumstances it can actually be harmful, when it’s overactive,” says Samson, a professor emerita of biology and biological engineering and the senior author of the study.

Aag glycosylase helps to repair DNA damage caused by a class of drugs known as alkylating agents, which are commonly used as chemotherapy drugs and are also found in pollutants such as tobacco smoke and fuel exhaust. Retinal damage from these drugs has not been seen in human patients, but alkylating agents may produce similar damage in other human tissues, Samson says. The new study, which reveals how Aag overactivity leads to cell death, suggest possible targets for drugs that could prevent such damage.

Mariacarmela Allocca, a former MIT postdoc, is the lead author of the study, which appears in the Feb. 12 issue of Science Signaling. MIT technical assistant Joshua Corrigan, former postdoc Aprotim Mazumder, and former technical assistant Kimberly Fake are also authors of the paper.

A vicious cycle

In a 2009 study, Samson and her colleagues found that a relatively low level of exposure to an alkylating agent led to very high rates of retinal damage in mice. Alkylating agents produce specific types of DNA damage, and Aag glycosylase normally initiates repair of such damage. However, in certain types of cells that have higher levels of Aag, such as mouse photoreceptors, the enzyme’s overactivity sets off a chain of events that eventually leads to cell death.

In the new study, the researchers wanted to find exactly out how this happens. They knew that Aag was overactive in the affected cells, but they didn’t know exactly how it was leading to cell death or what type of cell death was occurring. The researchers initially suspected it was apoptosis, a type of programmed cell death in which a dying cell is gradually broken down and absorbed by other cells.

However, they soon found evidence that another type of cell death called necrosis accounts for most of the damage. When Aag begins trying to repair the DNA damage caused by the alkylating agent, it cuts out so many damaged DNA bases that it hyperactivates an enzyme called PARP, which induces necrosis. During this type of cell death, cells break apart and spill out their contents, which alerts the immune system that something is wrong.

One of the proteins secreted by the dying cells, known as HMGB1, stimulates production of chemicals that attract immune cells called macrophages, which specifically penetrate the photoreceptor layer of the retina. These macrophages produce highly reactive oxygen species — molecules that create more damage and make the environment even more inflammatory. This in turn causes more DNA damage, which is  recognized by Aag.

“That makes the situation worse, because the Aag glycosylase will act on the lesions produced from the inflammation, so you get a vicious cycle, and the DNA repair drives more and more degeneration and necrosis in the photoreceptor layer,” Samson says.

None of this happens in mice that lack Aag or PARP, and it does not occur in other cells of the eye or in most other body tissues.

“It amazes me how segmented this is. The other cells in the retina are not affected at all, and they must experience the same amount of DNA damage. So, one possibility is maybe they don’t express Aag, while the  photoreceptor cells do,” Samson says.

“These molecular studies are exciting, as they have helped define the underlying pathophysiology associated with retinal damage,” says Ben Van Houten, a professor of pharmacology and chemical biology at the University of Pittsburgh, who was not involved in the study. “DNA repair is essential for the faithful inheritance of a cell’s genetic material. However, the very action of some DNA repair enzymes can result in the production of toxic intermediates that exacerbate exposures to genotoxic agents.”

Varying effects

The researchers also found that retinal inflammation and necrosis were more severe in male mice than in female mice. They suspect that estrogen, which can interfere with PARP activity, may help to suppress the pathway that leads to inflammation and cell death.

Samson’s lab has previously found that Aag activity can also exacerbate damage to the brain during a stroke, in mice. The same study revealed that Aag activity also worsens inflammation and tissue damage in the liver and kidney following oxygen deprivation. Aag-driven cell death has also been seen in the mouse cerebellum and some pancreatic and bone marrow cells.

The effects of Aag overactivity have been little studied in humans, but there is evidence that healthy individuals have widely varying levels of the enzyme, suggesting that it could have different effects in different people.

“Presumably there are some cell types in the human body that would respond the same way as the mouse photoreceptors,” Samson says. “They may just not be the same set of cells.”

The research was funded by the National Institutes of Health.

Biologists answer fundamental question about cell size

The need to produce just the right amount of protein is behind the striking uniformity of sizes.

Anne Trafton | MIT News Office
February 7, 2019

MIT biologists have discovered the answer to a fundamental biological question: Why are cells of a given type all the same size?

In humans, cell size can vary more than 100-fold, ranging from tiny red blood cells to large neurons. However, within each cell type, there is very little deviation from a standard size. In studies of yeast, MIT researchers grew cells to 10 times their normal size and found that their DNA could not keep up with the demands of producing enough protein to maintain normal cell functions.

Furthermore, the researchers found that this protein shortage leads the cells into a nondividing state known as senescence, suggesting a possible explanation for how cells become senescent as they age.

“There are so many hypotheses out there that try to explain why senescence happens, and I think this data provides a beautiful and simple explanation for senescence,” says Angelika Amon, the Kathleen and Curtis Marble Professor in Cancer Research in the Department of Biology and a member of the Koch Institute for Integrative Cancer Research.

Amon is the senior author of the study, which appears in the Feb. 7 online edition of Cell. Gabriel Neurohr, an MIT postdoc, is the lead author of the paper.

Excessive size

To explore why cell size is so tightly controlled, the researchers prevented yeast cells from dividing by modifying a gene critical for cell division, so that it could be turned off at a certain temperature. These cells continued to grow, but they could not divide and they did not replicate their DNA.

The researchers discovered that as the cells expanded, their DNA and their protein-building machinery could not keep pace with the needs of such a large cell. This failure to produce enough protein led to the dilution of the cytoplasm and disruption of cell division. The researchers believe that many other fundamental cell processes that rely on cellular molecules finding and interacting with each other may also be impaired when cells are too big.

“Theoretical models predict that diluting the cytoplasm will decrease reaction rates. Every chemical reaction would occur more slowly, and some threshold concentrations of certain proteins may not be reached, so certain reactions would never happen because the concentrations are lower,” Neurohr says.

The researchers showed that yeast cells with two sets of chromosomes were able to grow to twice the size of yeast cells with just one set of chromosomes before becoming senescent, suggesting that the amount of DNA in the cells is the limiting factor in the cells’ ability to grow.

Experiments with human cells yielded similar results: In a study of human fibroblast cells, the researchers found that forcing the cells to grow to excessive sizes (eight times their normal size) disrupted many functions, including cell division.

“It’s been clear for some time that cells do control their size, but it’s been unclear what the various physiological reasons are for why they do so,” says Jan Skotheim, an associate professor of biology at Stanford University, who was not involved in the research. “What’s nice about this work is it really shows how things go wrong when cells get too big.”

Age-related disease

Amon says excessive growth likely plays a major role in the development of senescence, which occurs in many types of mammalian cells and is thought to contribute to age-related organ dysfunction and chronic age-related diseases.

Senescent cells are often larger than younger cells, and this study, which showed that unchecked cell growth leads to senescence, offers a possible explanation for this observation. Human cells tend to grow slightly larger throughout their lifetimes, because every time a cell divides, it checks for DNA damage, and if any is found, division is halted while repairs are made. During each of these delays, the cell grows slightly larger.

“Over the lifetime of a cell, the more divisions you make, the higher your probability is of having that damage, and over time cells will get larger,” Amon says. “Eventually they get so large that they start diluting critical factors that are important for proliferation.”

A difficult question that remains unanswered is how different types of cells maintain the appropriate size for their cell type, which the researchers now hope to study further.

The research was funded, in part, by the National Institutes of Health, the Howard Hughes Medical Institute, the Paul F. Glenn Center for Biology of Aging Research at MIT, a National Science Foundation graduate research fellowship, the William Bowes Fellows program, and the Vilcek Foundation.

Biologist Adam Martin studies the mechanics of tissue folding

The dynamic process is critical to embryonic development and other cellular phenomena.

Anne Trafton | MIT News Office
February 1, 2019

Embryonic development is tightly regulated by genes that control how body parts form. One of the key responsibilities of these genes is to make sure that tissues fold into the correct shapes, forming structures that will become the spine, brain, and other body parts.

During the 1970s and ’80s, the field of embryonic development focused mainly on identifying the genes that control this process. More recently, many biologists have shifted toward investigating the physics behind the tissue movements that occur during development, and how those movements affect the shape of tissues, says Adam Martin, an MIT associate professor of biology.

Martin, who recently earned tenure, has made key discoveries in how tissue folding is controlled by the movement of cells’ internal scaffolding, known as the cytoskeleton. Such discoveries can not only shed light on how tissues form, including how birth defects such as spina bifida occur, but may also help guide scientists who are working on engineering artificial human tissues.

“We’d like to understand the molecular mechanisms that tune how forces are generated by cells in a tissue, such that the tissue then gets into a proper shape,” Martin says. “It’s important that we understand fundamental mechanisms that are in play when tissues are getting sculpted in development, so that we can then harness that knowledge to engineer tissues outside of the body.”

Cellular forces

Martin grew up in Rochester, New York, where both of his parents were teachers. As a biology major at nearby Cornell University, he became interested in genetics and development. He went on to graduate school at the University of California at Berkeley, thinking he would study the genes that control embryonic development.

However, while in his PhD program, Martin became interested in a different phenomenon — the role of the cytoskeleton in a process called endocytosis. Cells use endocytosis to absorb many different kinds of molecules, such as hormones or growth factors.

“I was interested in what generates the force to promote this internalization,” Martin says.

He discovered that the force is generated by the assembly of arrays of actin filaments. These filaments tug on a section of the cell membrane, pulling it inward so that the membrane encloses the molecule being absorbed. He also found that myosin, a protein that can act as a motor and controls muscle contractions, helps to control the assembly of actin filaments.

After finishing his PhD, Martin hoped to find a way to combine his study of cytoskeleton mechanics with his interest in developmental biology. As a postdoc at Princeton University, he started to study the phenomenon of tissue folding in fruit fly embryonic development, which is now one of the main research areas of his lab at MIT. Tissue folding is a ubiquitous shape change in tissues to convert a planar sheet of cells into a three-dimensional structure, such as a tube.

In developing fruit fly embryos, tissue folding invaginates cells that will form internal structures in the fly. This folding process is similar to tissue folding events in vertebrates, such as neural tube formation. The neural tube, which is the precursor to the vertebrate spinal cord and brain, begins as a sheet of cells that must fold over and “zip” itself up along a seam to form a tube. Problems with this process can lead to spina bifida, a birth defect that results from an incomplete closing of the backbone.

When Martin began working in this area, scientists had already discovered many of the transcription factors (proteins that turn on networks of specific genes) that control the folding of the neural tube. However, little was known about the mechanics of this folding.

“We didn’t know what types of forces those transcription factors generate, or what the mechanisms were that generated the force,” he says.

He discovered that the accumulation of myosin helps cells lined up in a row to become bottle-shaped, causing the top layer of the tissue to pucker inward and create a fold in the tissue. More recently, he found that myosin is turned on and off in these cells in a dynamic way, by a protein called RhoA.

“What we found is there’s essentially an oscillator running in the cells, and you get a cycle of this signaling protein, RhoA, that’s being switched on and off in a cyclical manner,” Martin says. “When you don’t have the dynamics, the tissue still tries to contract, but it falls apart.”

He also found that the dynamics of this myosin activity can be disrupted by depleting genes that have been linked to spina bifida.

Breaking free

Another important cellular process that relies on tissue folding is the epithelial-mesenchymal transition (EMT). This occurs during embryonic development when cells gain the ability to break free and move to a new location. It is also believed to occur when cancer cells metastasize from tumors to seed new tumors in other parts of the body.

During embryonic development, cells lined up in a row need to orient themselves so that when they divide, both daughter cells remain in the row. Martin has shown that when the mechanism that enables the cells to align correctly is disrupted, one of the daughter cells will be squeezed out of the tissue.

“This has been proposed as one way you can get an epithelial-to-mesenchymal transition, where you have cells dissociate from native tissue,” Martin says.  He now plans to further study what happens to the cells that get squeezed out during the EMT.

In addition to these projects, he is also collaborating with Jörn Dunkel, an MIT associate professor of mathematics, to map the network connections between the myosin proteins that control tissue folding during development. “That project really highlights the benefits of getting people from diverse backgrounds to analyze a problem,” Martin says.

Bacteria promote lung tumor development, study suggests

Antibiotics or anti-inflammatory drugs may help combat lung cancer.

Anne Trafton | MIT News Office
January 31, 2019

MIT cancer biologists have discovered a new mechanism that lung tumors exploit to promote their own survival: These tumors alter bacterial populations within the lung, provoking the immune system to create an inflammatory environment that in turn helps the tumor cells to thrive.

In mice that were genetically programmed to develop lung cancer, those raised in a bacteria-free environment developed much smaller tumors than mice raised under normal conditions, the researchers found. Furthermore, the researchers were able to greatly reduce the number and size of the lung tumors by treating the mice with antibiotics or blocking the immune cells stimulated by the bacteria.

The findings suggest several possible strategies for developing new lung cancer treatments, the researchers say.

“This research directly links bacterial burden in the lung to lung cancer development and opens up multiple potential avenues toward lung cancer interception and treatment,” says Tyler Jacks, director of MIT’s Koch Institute for Integrative Cancer Research and the senior author of the paper.

Chengcheng Jin, a Koch Institute postdoc, is the lead author of the study, which appears in the Jan. 31 online edition of Cell.

Linking bacteria and cancer

Lung cancer, the leading cause of cancer-related deaths, kills more than 1 million people worldwide per year. Up to 70 percent of lung cancer patients also suffer complications from bacterial infections of the lung. In this study, the MIT team wanted to see whether there was any link between the bacterial populations found in the lungs and the development of lung tumors.

To explore this potential link, the researchers studied genetically engineered mice that express the oncogene Kras and lack the tumor suppressor gene p53. These mice usually develop a type of lung cancer called adenocarcinoma within several weeks.

Mice (and humans) typically have many harmless bacteria growing in their lungs. However, the MIT team found that in the mice engineered to develop lung tumors, the bacterial populations in their lungs changed dramatically. The overall population grew significantly, but the number of different bacterial species went down. The researchers are not sure exactly how the lung cancers bring about these changes, but they suspect one possibility is that tumors may obstruct the airway and prevent bacteria from being cleared from the lungs.

This bacterial population expansion induced immune cells called gamma delta T cells to proliferate and begin secreting inflammatory molecules called cytokines. These molecules, especially IL-17 and IL-22, create a progrowth, prosurvival environment for the tumor cells. They also stimulate activation of neutrophils, another kind of immune cell that releases proinflammatory chemicals, further enhancing the favorable environment for the tumors.

“You can think of it as a feed-forward loop that forms a vicious cycle to further promote tumor growth,” Jin says. “The developing tumors hijack existing immune cells in the lungs, using them to their own advantage through a mechanism that’s dependent on local bacteria.”

However, in mice that were born and raised in a germ-free environment, this immune reaction did not occur and the tumors the mice developed were much smaller.

Blocking tumor growth

The researchers found that when they treated the mice with antibiotics either two or seven weeks after the tumors began to grow, the tumors shrank by about 50 percent. The tumors also shrank if the researchers gave the mice drugs that block gamma delta T cells or that block IL-17.

The researchers believe that such drugs may be worth testing in humans, because when they analyzed human lung tumors, they found altered bacterial signals similar to those seen in the mice that developed cancer. The human lung tumor samples also had unusually high numbers of gamma delta T cells.

“If we can come up with ways to selectively block the bacteria that are causing all of these effects, or if we can block the cytokines that activate the gamma delta T cells or neutralize their downstream pathogenic factors, these could all be potential new ways to treat lung cancer,” Jin says.

Many such drugs already exist, and the researchers are testing some of them in their mouse model in hopes of eventually testing them in humans. The researchers are also working on determining which strains of bacteria are elevated in lung tumors, so they can try to find antibiotics that would selectively kill those bacteria.

The research was funded, in part, by a Lung Cancer Concept Award from the Department of Defense, a Cancer Center Support (core) grant from the National Cancer Institute, the Howard Hughes Medical Institute, and a Margaret A. Cunningham Immune Mechanisms in Cancer Research Fellowship Award.

Sallie “Penny” Chisholm awarded the 2019 Crafoord Prize

Institute Professor honored for discovering <i>Prochlorococcus,</i> the most abundant photosynthesizing organism on Earth.

Allison Dougherty | Department of Civil and Environmental Engineering
January 22, 2019

MIT Institute Professor Sallie “Penny” Chisholm of the departments of Civil and Environmental Engineering and Biology is the recipient of the 2019 Crafoord Prize.

Announced on Jan. 17, Chisholm was awarded the prize “for the discovery and pioneering studies of the most abundant photosynthesizing organism on Earth, Prochlorococcus.”

Prochlorococcus is a type of phytoplankton found in the ocean that is able to photosynthesize like plants on land.  The process of photosynthesis is responsible for the oxygen humans breathe, which makes it critical to life on Earth. Prochlorococcus accounts for approximately 10 percent of all ocean photosynthesis, which draws carbon dioxide out of the atmosphere, provides it with oxygen, and forms the base of the food chain.

While the organism is the most abundant photosynthesizer on the planet (the total amount of Prochlorococcus on Earth has been estimated to be 3*1027, or 3,000,000,000,000,000,000,000,000,000), it wasn’t until the mid-1980’s that Prochlorococcus was discovered by Chisholm and colleagues at the Woods Hole Oceanographic Institution. The reason the organism remained unknown for so long can be attributed to its small size. The tiny bacteria is half of a micrometer in size, 1/100 the width of a human hair, making it the smallest photosynthesizing organism.

Since its discovery, Chisholm and her team have found that although each cell has only 2,000 genes, the species as a whole has more than 80,000 different genes in its gene pool, which is four times more than the genetic makeup of humans. This vast diversity of genes distributed among the global population contributes to why Prochlorococcus is able to exist prominently in various environments containing different levels of light, heat, and nutrients.

Chisholm, who has been at MIT since 1976, now studies how Prochlorococcus interacts with various components of seawater and other microorganisms found in the ocean; its role in shaping the ocean ecosystem over evolutionary time; and how its populations may shift in response to climate change.

In April, Chisholm delivered a TED Talk that dove deeper into the properties of Prochlorococcus, comparing the organism’s genetic diversity to iPhone apps, and expanded on the the beauty of this microorganism as the smallest living thing that can convert solar energy and carbon dioxide into fuel through photosynthesis. Understanding its simple design could aid in efforts to engineer artificial photosynthesis machines — reducing our dependency on fossil fuels.

Prochlorococcus has even inspired Chisholm to educate future generations of scientists through a series of children’s books called the “Sunlight Series,” with co-author and illustrator Molly Bang. The series describes the Earth’s natural processes in layman’s terms and through imagery. While none of Chisholm’s books mention Prochlorococcus by name, Chisholm says the simplicity of Prochlorococcus compelled her to create the series.

Chisholm will present her prize lecture in Sweden at Lund University on May 13, and will receive her prize at the Royal Swedish Academy of Sciences prize award ceremony on May 15, in the presence of H. M. King Carl XVI Gustaf and H. M. Queen Silvia of Sweden.

The Crafoord Prize is awarded in partnership between the Royal Swedish Academy of Sciences and the Crafoord Foundation, with the academy responsible for selecting the Crafoord Laureates. Awards are presented in one of four disciplines each year: mathematics and astronomy, geosciences, biosciences, or polyarthritis (such as rheumatoid arthritis).