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Scaffolding the nursery of pollen development
Nicole Giese Rura | Whitehead Institute
April 2, 2019

Cambridge, MA — Increased temperatures and decreased precipitation associated with climate change could threaten the world’s crops. Seed and pollen production in particular are vulnerable to shifts in temperature or rainfall. For example, in heat- or drought-stressed wheat and rice, the tissue responsible for nourishing pollen, called the tapetum, is compromised, causing the plants to not generate pollen. Without pollen, these staples are unable to bear the grains that billions of people rely on for food. In research described this week in the journal Plant Cell, Whitehead Institute Member Jing-Ke Weng and his lab have identified the components of a critical scaffold system that supports the tapetum. With a better understanding of the tapetum, scientists may be able to adapt plants to produce pollen even in hot, arid conditions.

Within a flower bud, pollen-filled anthers perch atop stalk-like filaments. Lining the anther’s inner chamber is a tissue called the tapetum, which nurtures the developing pollen. To better understand pollen and anther formation, Joseph Jacobowitz, a graduate student in Weng’s lab and first author of the Plant Cell paper, analyzed genes active in the anther during early flower development in the Arabidopsis plant. Two practically unknown genes stood out because they likely contribute to pollen maturation: PRX9 and PRX40. After further investigation, Jacobowitz determined that the two genes encode enzymes that work in conjunction with another type of protein called extensin and together they form the supportive walls that act like a scaffold in the tapetum.

Weng, who is also an assistant professor of biology at Massachusetts Institute of Technology, likens extensins to bricks in a wall and the PRX9 and PRX40 proteins to the mortar. Pushing against a wall can easily compromise its structure unless mortar bonds the bricks together. The same seems to be true with extensins and PRX9 and PRX40. The extensins and PRX9/PRX40 wall in the tapetum remained intact until Jacobowitz genetically “knocked out” the mortar genes. With the mortar gone, the scaffolding loses its integrity, and the tapetum collapses into the space where the pollen develops, either crushing or starving it. The result appears similar to what occurs in the tapetum of stressed wheat and rice plants, and the final effects are similar as well: Both the stressed crops and Arabidopsis lacking PRX9 and PRX40 are male sterile and do not produce pollen.

After further investigation, Jacobowitz and colleagues determined that the PRX9 and PRX40 genes are closely related and first appeared at pivotal moments in plant history. PRX40 is highly conserved among land plants and originated about 470 million years ago, when plants first emerged onto land from the seas and rivers. PRX9 seems to have evolved from PRX40 as a redundant backup when flowering plants diverged from nonflowering plants.

Pollen creation is a delicate process that plants have evolved over millions of years. Insights such as these into how plants maintain the integrity of their reproductive system are invaluable toward understanding how we might be able to generate crops capable of withstanding environmental stresses like heat and drought that could threaten our food supply.

This work was supported by Pew Scholars Program in the Biomedical Sciences (27345), the Searle Scholars Program (15-SSP-162), and the National Science Foundation (CHE-1709616 and 1122374).

Written by Nicole Giese Rura

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Jing-Ke Weng’s primary affiliation is with Whitehead Institute for Biomedical Research, where his laboratory is located and all his research is conducted. He is also an assistant professor of biology at Massachusetts Institute of Technology.

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Citation:

“PRX9 and PRX40 are extensin peroxidases essential for maintaining tapetum and microspore cell wall integrity during Arabidopsis anther development”

Plant Cell, online March 18, 2019, DOI: https://doi.org/10.1105/tpc.18.00907

Joseph R. Jacobowitz, William C. Doyle, and Jing-Ke Weng.

Pulin Li joins Whitehead Institute
Whitehead Institute
April 2, 2019

Whitehead Institute announced today that the developmental and synthetic biologist Pulin Li will join the Institute in May as its newest Member. Li will also be appointed an assistant professor of biology at Massachusetts Institute of Technology (MIT). At Whitehead Institute, she will pursue studies that could, ultimately, lead to methods for programming cells to form replacement tissues and prosthetic cells for regenerative medicine.

During her Ph.D. work at Harvard University, Li worked in the lab of Leonard Zon on hematopoietic stem cells using zebrafish as a model. Trained as a chemical biologist, netbet sports bettingshe was interested in programming stem cells with chemicals to improve their engraftment efficiency upon transplantation. Working with zebrafish embryos, she discovered her passion for the fundamental molecular and cellular aspects of developmental biology. In particular, she wanted to understand how circuits of interacting genes, running as an automated program in individual cells, generate highly dynamic and yet choreographed multicellular behavior.

For her postdoctoral research at California Institute of Technology with Michael B. Elowitz, Li chose to study morphogen-mediated tissue patterning, a key process in embryo development and tissue regeneration. To directly test the relationship between the architecture of the genetic circuits and precision of tissue patterning, she reconstituted morphogen gradients in a petri dish. This system allows researchers to systematically rewire genetic circuits, finely tune the key parameters, and quantitatively analyze the resulting spatiotemporal patterning dynamics. This cell-based multiscale reconstitution approach, from genetic circuits to single cells to multicellular behavior, provides an important new methodology for studying developmental and evolutionary questions. It could also offer a quantitative framework and molecular tools for tissue engineering.

“Pulin’s insightful work has demonstrated that she is just the kind of pathbreaking scientist we prize at Whitehead Institute: brilliant, creative, and passionately dedicated to fundamental biomedical discovery,” says David Page, Whitehead Institute Director and Member. “She has taken a bottom‐up approach to understanding tissue patterning. As a result, for the first time, scientists are able to take a pathway apart, rebuild it, and analyze the role of each of its design features in a multicellular patterning process.”

Whitehead Institute Member and associate director Peter Reddien — who studies tissue regeneration in model organisms — chaired the search committee that recommended Li’s appointment. “Pulin’s research elegantly dissects the key principles of signaling pathways, and has great future potential,” Reddien notes. “By engineering genetic circuits and functional modules in single cells, she can start to understand how genetic circuits enable multicellular behavior and address myriad developmental questions.”

Li earned a Ph.D. in Chemical Biology at Harvard University, and a bachelor’s degree in Life Sciences from Peking University. Recipient of an American Cancer Society Postdoctoral Fellowship and Santa Cruz Developmental Biology Young Investigator Award, Li currently holds a prestigious National Institutes of Health “Pathway to Independence” (K99) award from NICHD. She is a lead author on peer-reviewed studies that have appeared in the journals Nature and Science.

“It is a very exciting time to apply quantitative and engineering approaches to developmental biology questions,” says Li. “Whitehead Institute provides such a supportive and intellectually stimulating environment. I am thrilled to be back to Cambridge and be part of the research community of Whitehead, MIT, and the greater Boston area.”

School of Science announces 2019 Infinite Mile Awards

Ten staff members in the School of Science are recognized for going above and beyond their job descriptions to support a better Institute.

School of Science
April 2, 2019

The MIT School of Science has announced the winners of the 2019 Infinite Mile Award, which is presented annually to staff members within the school who demonstrate exemplary dedication to making MIT a better place.

Nominated by their colleagues, these winners are notable for their unrelenting and extraordinary hard work in their positions, which can include mentoring fellow community members, innovating new solutions to problems big and small, building their communities, or going far above and beyond their job descriptions to support the goals of their home departments, labs, and research centers.

The 2019 Infinite Mile Award winners are:

Christine Brooks, an administrative assistant in the Department of Chemistry, nominated by Mircea Dincă and several members of the Dincă, Schrock, and Cummins groups;

Annie Cardinaux, a research specialist in the Department of Brain and Cognitive Sciences, nominated by Pawan Sinha;

Kimberli DeMayo, a human resources consultant in the Department of Mathematics, nominated by Nan Lin, Dennis Porche, and Paul Seidel, with support from several other faculty members;

Arek Hamalian, a technical associate at the Picower Institute for Learning and Memory, nominated by Susumu Tonegawa;

Jonathan Harmon, an administrative assistant in the Department of Mathematics, nominated by Pavel Etingof and Kimberli DeMayo, with support from several other faculty members;

Tanya Khovanova, a lecturer in the Department of Mathematics, nominated by Pavel Etingof, David Jerison, and Slava Gerovitch;

Kelley Mahoney, an SRS financial staff member in the Kavli Institute for Astrophysics and Space Research, nominated by Sarah Brady, Michael McDonald, Anna Frebel, Jacqueline Hewitt, Jack Defandorf, and Stacey Sullaway;

Walter Massefski, the director of instrumentation facility in the Department of Chemistry, nominated by Timothy Jamison and Richard Wilk;

Raleigh McElvery, a communications coordinator in the Department of Biology, nominated by Vivian Siegel with support from Amy Keating, Julia Keller, and Erika Reinfeld; and

Kate White, an administrative officer in the Department of Brain and Cognitive Sciences, nominated by Jim DiCarlo, Michale Fee, Sara Cody-Larnard, Rachel Donahue, Federico Chiavazza, Matthew Regan, Gayle Lutchen, and William Lawson.

The recipients will receive a monetary award in addition to being honored at a celebratory reception, along with their peers, family and friends, and the recipients of the 2019 Infinite Kilometer Award this month.

Biologists find a way to boost intestinal stem cell populations

Study suggests that stimulating stem cells may protect the gastrointestinal tract from age-related disease.

Anne Trafton | MIT News Office
March 28, 2019

Cells that line the intestinal tract are replaced every few days, a high rate of turnover that relies on a healthy population of intestinal stem cells. MIT and University of Tokyo biologists have now found that aging takes a toll on intestinal stem cells and may contribute to increased susceptibility to disorders of the gastrointestinal tract.

The researchers also showed that they could reverse this effect in aged mice by treating them with a compound that helps boost the population of intestinal stem cells. The findings suggest that this compound, which appears to stimulate a pathway that involves longevity-linked proteins known as sirtuins, could help protect the gut from age-related damage, the researchers say.

“One of the issues with aging is organ dysfunction, accompanied by a decline in the activity of the netbet sports bettingstem cells that nurture and replenish that organ, so this is a potentially very useful intervention point to either slow or reverse aging,” says Leonard Guarente, the Novartis Professor of Biology at MIT.

Guarente and Toshimasa Yamauchi, a professor at the University of Tokyo, are the senior authors of the study, which appears online in the journal Aging Cell on March 28. The lead author of the paper is Masaki Igarashi, a former MIT postdoc who is now at the University of Tokyo.

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Guarente’s lab has long studied the link between aging and sirtuins, a class of proteins found in nearly all animals. Sirtuins, which have been shown to protect against the effects of aging, can also be stimulated by calorie restriction.

In a paper published in 2016, Guarente and Igarashi found that in mice, low-calorie diets activate sirtuins in intestinal stem cells, helping the cells to proliferate. In their new study, they set out to investigate whether aging contributes to a decline in stem cell populations, and whether that decline could be reversed.

By comparing young (aged 3 to 5 months) and older (aged 2 years) mice, the researchers found that intestinal stem cell populations do decline with age. Furthermore, when these stem cells are removed from the mice and grown in a culture dish, they are less able to generate intestinal organoids, which mimic the structure of the intestinal lining, compared to stem cells from younger mice. The researchers also found reduced sirtuin levels in stem cells from the older mice.

Once the effects of aging were established, the researchers wanted to see if they could reverse the effects using a compound called nicotinamide riboside (NR). This compound is a precursor to NAD, a coenzyme that activates the sirtuin SIRT1. They found that after six weeks of drinking water spiked with NR, the older mice had normal levels of intestinal stem cells, and these cells were able to generate organoids as well as stem cells from younger mice could.

To determine if this stem cell boost actually has any health benefits, the researchers gave the older, NR-treated mice a compound that normally induces colitis. They found that NR protected the mice from the inflammation and tissue damage usually produced by this compound in older animals.

“That has real implications for health because just having more stem cells is all well and good, but it might not equate to anything in the real world,” Guarente says. “Knowing that the guts are actually more stress-resistant if they’re NR- supplemented is pretty interesting.”

Protective effects

Guarente says he believes that NR is likely acting through a pathway that his lab previously identified, in which boosting NAD turns on not only SIRT1 but another gene called mTORC1, which stimulates protein synthesis in cells and helps them to proliferate.

“What we would hypothesize is that the NAD replenishment in old mice is driving this pathway of growth that’s working through SIRT1 and TOR to reverse the decline that has occurred with aging,” he says.

The findings suggest that NAD might have a protective effect against diseases of the gut, such as colitis, in older people, he says. Guarente and his colleagues have previously found that NAD precursors can also stimulate the growth of blood vessels and muscles and boost endurance in aged mice, and a 2016 study from researchers in Switzerland found that boosting NAD can help replenish muscle stem cell populations in aged mice.

In 2014, Guarente started a company called Elysium Health, which sells a dietary supplement containing NR combined with another natural compound called pterostilbene, which is an activator of SIRT1.

The research was funded, in part, by the National Institutes of Health and the Glenn Foundation for Medical Research.

Whitehead Institute’s David Page to conclude term as director

Search committee chaired by MIT President Emerita Susan Hockfield will identify new director for eminent biomedical institute.

Lisa Girard | Whitehead Institute
March 27, 2019

Whitehead Institute, the world-renowned nonprofit research institution dedicated to improving human health through basic biomedical research, has announced that Institute Director David C. Page — a Whitehead Institute member since 1988 and director since 2004 — will complete his current term as director and president in summer 2020. An international search has been launched for Page’s successor.

“David’s tenure as director has been a period of incredible richness for Whitehead Institute,” says Charles D. Ellis, chair of the Whitehead Institute Board of Directors. “It has been rich in the path-breaking science that our researchers have done; in the intellectual ferment and creative environment that Whitehead members have fostered; and in the sense of community and common purpose that David has nurtured. He has led us with great skill and vision through a dynamic period of growth and continuous exploration, and he will pass to his successor an organization primed to tackle the challenges offered by a swiftly evolving bioscience landscape.”

Since its founding in 1982, Whitehead Institute has been one of the world’s most influential biomedical research centers — producing a continual stream of significant discoveries and new research tools and approaches. Whitehead Institute is a legally and financially independent organization closely affiliated with MIT, and Whitehead Institute members hold MIT faculty appointments. The 17 Whitehead Institute members include two National Medal of Science winners, nine National Academy of Sciences members, four National Academy of Medicine members, and four Investigators of the Howard Hughes Medical Institute. In addition, the institute’s prestigious Whitehead Fellows Program has fostered generations of biomedical science leaders — including Harvard Medical School Dean George Daley, celebrated MIT cancer researcher and professor of biology Angelika Amon, Broad Institute President and Founding Director Eric Lander, and NASA astronaut and space biologist Kate Rubins.

Whitehead Institute and MIT have been Page’s professional home since he earned an MD from Harvard Medical School and the Harvard-MIT Health Sciences and Technology Program and completed research in David Botstein’s lab at MIT in 1984. After serving as the institute’s first Whitehead Fellow, he became a Whitehead member and MIT faculty member in 1988. Page was appointed associate director of the institute in 2002, interim director in 2004, and director in 2005.

Throughout his 35 years at Whitehead Institute, Page has run a thriving and productive research lab. His groundbreaking studies on the Y chromosome changed the way biomedical science views the function of sex chromosomes. That work earned him wide recognition, including a Macarthur netbet online sports bettingFoundation Fellowship and a Searle Scholar Award; and he has been an Investigator of the Howard Hughes Medical Institute since 1990. His research twice earned inclusion in Science magazine’s “Top 10 Breakthroughs of the Year,” first for mapping a human chromosome and then for sequencing the human Y chromosome. Today, his lab is pursuing a deep understanding of the role of sex chromosomes in health and disease — work with the potential to fundamentally change the practice of medicine and improve the quality of care for women and men alike.

As director, Page has made a mark on all facets of the Whitehead Institute organization. During his tenure, he oversaw the creation of the Institute’s Intellectual Property Office; strengthened its core facilities; and established new platforms, such as the Metabolomics Center. He also enhanced the leadership structure by appointing three associate directors; and he supported the creation of the child care center. Perhaps most important for the long run, Page has guided a robust renewal of faculty and has helped to prepare the organization for the eventual retirement of the Institute’s founding generation of members.

The search for Page’s successor will be guided by a committee of noted leaders in education, biomedical research, and nonprofit organizations, including Susan Hockfield (chair), MIT professor of neuroscience and president emerita; Laurie H. Glimcher, president and CEO of the Dana-Farber Cancer Institute and former dean of Weill Cornell Medical College; Alan Grossman, the Praecis Professor of Biology and head of the MIT Department of Biology; Paul L. Joskow, former president and CEO of Alfred P. Sloan Foundation and the Elizabeth and James Killian Professor of Economics Emeritus at MIT; Amy E. Keating, professor in the departments of Biology and Biological Engineering at MIT; David Sabatini, Whitehead Institute member and associate director, and professor of biology at MIT; Phillip A. Sharp, Nobel laureate and MIT Institute professor and professor of biology; and Sarah Williamson, CEO of FCLT Global and former partner at Wellington Management Company (Joskow, Sharp, and Williamson are also members of the Whitehead Institute Board of Directors.)

The committee will be assisted by global executive search firm Russell Reynolds Associates.

“Whitehead Institute is one of the world’s premier research institutions,” says Hockfield. “It possesses an innovative and collaborative culture; rich talent and intellectual capital; a robust relationship with MIT; and a place at the heart of the Kendall Square innovation community. These factors make it an ideal opportunity for a director with vision, scientific courage, and a passion to address basic biomedical science’s most significant challenges.”

“The scientists of Whitehead Institute have helped to drive biomedical research forward and onto exciting new paths,” says Page. “In coming years, the Institute itself will experience a generational evolution, and my successor will help define the organization’s future — and by extension, help shape the direction of biomedical research for decades to come.”

The new director will have an impressive line of predecessors: Whitehead Institute’s founding director was Nobel laureate and former Caltech president David Baltimore; he was succeeded by globally respected researcher and science enterprise leader Gerald Fink, and then by National Medal of Science recipient Susan Lindquist — Page’s immediate predecessor.

Life unfolding

Graduate student Marlis Denk-Lobnig investigates the biological forces that shape developing tissue to dictate form and function.

Raleigh McElvery
March 22, 2019

A few hours after fertilization, the fruit fly embryo is just a hollow sphere, slightly oblong in shape, until a band of cells on its surface furrows inward to form a new layer. This folding process takes only 15 minutes, but it’s critical for determining where the cells will go and what roles they will eventually play. In humans, errors in tissue folding can result in diseases like spina bifida, where the spine never fully closes.

Fourth-year graduate student Marlis Denk-Lobnig watches this gastrulation process occurring in fly embryos in real time, tagging molecules with fluorescent proteins to probe the forces that eventually shape a fully-formed organism. Every day, she gets to witness new life unfold — literally.

Denk-Lobnig spends most of her time with her eye to a microscope or generating genetic crosses in the “fly room” where she keeps her stocks — rows of tubes containing light brown insect food that emits an unmistakable odor, despite being corked with cotton swabs. Inside each neatly labeled container, scores of tiny flies mill around as they lay eggs and feast.

Given that her mother trained in chemistry and her father in physics, “it didn’t take much creativity to get into science early on.” Denk-Lobnig enjoyed physics throughout high school, but also maintained a keen interest in biology, which became more pronounced after she was diagnosed with an autoimmune disease affecting her thyroid and adrenal glands.

“In some ways, the question of how your own body works is the most tangible question to ask,” she says. “It’s fascinating to connect everyday experiences with mechanisms, and studying biology and medicine seemed like a powerful way to have a direct impact on life.”

She majored in molecular medicine at Georg August University in Göttingen, Germany, located several hours from her childhood home in Heidelberg. Inspired by a summer internship with MIT Biology alum and Rockefeller professor Cori Bargmann PhD ’87, Denk-Lobnig centered her undergraduate thesis on the role glial cells play in disease.

She graduated after only three years, the typical duration in Germany, and spent the next several months traveling and applying to graduate schools. She also visited Nepal, where she taught visual and performing arts — and a bit of gymnastics — at a local boarding school.

When she began at MIT in 2015, Denk-Lobnig took the opportunity to blend her expertise in biology with a renewed enthusiasm for physics. Although she is a full-fledged member of the Department of Biology, she is simultaneously enrolled in the interdepartmental Biophysics Certificate Program.

“Not many people know that MIT has a thriving biophysics community,” she says. “It’s a mix of mechanical engineers, chemists, biologists, and physicists. There are specific course requirements, and we go on retreats and participate in seminars to share our research and discuss collaborations.”

As a member of Adam Martin’s lab, Denk-Lobnig studies the cellular forces that shape tissue form and function. Martin is also affiliated with the certificate NetBet sportprogram, and was one of the faculty members who initially interviewed Denk-Lobnig for the graduate program.

“Biophysics is all about finding elegant explanations for everyday phenomena, and I really enjoy thinking about physical principles and how they apply to biological problems,” Denk-Lobnig says. “The methods we use in the Martin lab are also incredibly visual. You can literally see a fruit fly embryo fold, and watch as a sheet of cells furrows inside the embryo to form a second layer, which is important for development. It’s both informative and aesthetically pleasing.”

Denk-Lobnig began by focusing on a single molecule called Cumberland-GAP (C-GAP), which regulates one of the many proteins in charge of tissue folding: myosin. Myosin is responsible for muscle contraction, among other duties. With its characteristic forked shape — two “heads” protruding from string-like “tail” domain — myosin can appear to walk along the cell’s scaffolding, sometimes transporting cargo. Denk-Lobnig, though, is most interested in myosin’s ability to pull on developing tissue and create a fold.

Right before graduating, one of Denk-Lobnig’s former labmates noticed that depleting C-GAP seemed to alter the concentration (or “gradient”) of myosin across the tissue. Since this finding pertained to the very regulator she was studying, it piqued Denk-Lobnig’s interest. She wanted to know how molecules like C-GAP might influence myosin and impact folding, and her scope widened from the molecular level to include the entire tissue.

It’s unlikely, she says, that myosin is pulling with equal force across the tissue — “that wouldn’t constrict the sheet of cells very efficiently.” Instead, there’s probably more myosin in middle and less towards the edges, which contracts the cells in the middle of the sheet to a greater degree and creates the curvature that forms the crease of the fold. In the fruit fly, gastrulation occurs just three hours after the eggs are laid. Because the folding happens at the surface of the embryo, there’s no need for dissection to witness the entire event through a microscope.

Denk-Lobnig has begun exploring other regulators besides C-GAP to analyze their effects on the myosin gradient and cell curvature. She was one of the first members of the lab to introduce CRISPR-Cas9 into their testing protocol, and is currently the only one experimenting with optogenetic techniques. She also regularly participates in the lab book club, which features classics like The Bell Jar and One Hundred Years of Solitude.

Outside of lab, Denk-Lobnig serves as the president of MIT’s women’s club gymnastics team, volunteers to help run weekly Gymnastics Special Olympics events, and sings in a graduate student choir. She is also a member of the department’s peer support program, bioREFs.

Long-term, she plans to stay in academia and delve further into physics-based methods, like modeling and coding. If she could find a project that’s just as visual as her current work in the Martin lab, “that would definitely be a plus.”

Posted 3.21.19
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 NetBet sportall 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, NetBet sportproducing 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.