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Whitehead Institute receives $10 million to study sex chromosomes’ impact on women’s health

Gift establishes the Brit Jepson d’Arbeloff Center on Women's Health.

Whitehead Institute
January 15, 2020

The Whitehead Institute has announced that Brit Jepson d’Arbeloff SM ’61 — a pioneering engineer, advocate for women in science, and philanthropic leader — has made a $10 million gift to support research uncovering the biological consequences of the sex chromosomes on women’s health and disease. The gift, one of the largest contributions ever made to the Whitehead Institute, will underwrite the establishment of the Brit Jepson d’Arbeloff Center on Women’s Health within the institute’s Sex Differences in Health and Disease Initiative.

The overall initiative is a comprehensive effort to understand sex differences at the molecular level — a long-neglected area of biomedical research — by building a fundamental understanding of how the female and male genome, transcriptome, epigenome, proteome, and metabolome differ. In the long run, determining the practical implications of those differences should lead to better, more effective treatments for both women and men.

The initiative holds particular promise for understanding health and treating disease in women. The d’Arbeloff Center is designed to drive progress toward that promise: catalyzing basic and translational research studies and collaborations that transform health care for women.

“Brit d’Arbeloff has been a trailblazer in science, research, and education,” says David C. Page, Whitehead Institute director and MIT professor of biology, who leads the sex differences initiative. “This is just the latest example of her determination to help drive biomedical research forward in significant ways. She is a staunch supporter of our work to understand the effects of the sex chromosomes on human health and disease, and her leadership and generosity have enabled us to build a solid research foundation.

“With this extraordinary new gift, she empowers us to build on that base by pursuing and translating discoveries that address the gaps in knowledge about health and disease in women,” Page says.

D’Arbeloff, a member of the Whitehead Institute’s board of directors since 2008, says, “I have long marveled at the stream of scientific discoveries and technical advances by Whitehead Institute researchers. For me, the most exciting of that work is being done within the sex differences initiative — exciting for both the imperative task it is taking on and the invaluable knowledge it is creating. The initiative will help to redress the longstanding inadequacy of research into women’s health and disease, and to catalyze development of therapeutics that are demonstrated effective for women.

“I believe that this is an essential biomedical quest, one as challenging today as the Human Genome Project was in 1991,” d’Arbeloff says. “No institution is better positioned to lead it than Whitehead Institute. And, in creating the Center for Women’s Health, I cannot make a more important investment in the health of my grandchildren and their children.”

D’Arbeloff is known for her enduring commitment to advancing biomedical research and to ensuring opportunities for women scientists and engineers. It is a commitment born of her own experience. She was the first woman to earn a mechanical engineering degree from Stanford University, graduating at the top of her class, but she had difficulty finding a job. When she earned a master’s degree at MIT in 1961, she was the sole woman in the school’s mechanical engineering department. She went on to become part of pioneering industries — contributing to the design of the Redstone missile in the 1960s, then programming software for Digital Equipment Corporation and Teradyne. For decades since, she has supported the efforts of women to succeed in science and engineering by offering her energy and leadership, her knowledge and experience, and her philanthropy.

While d’Arbeloff has provided substantial philanthropic support to a range of nonprofit organizations, she has had a particular impact in education, science, and technology. For example, beyond her decades of support for the Whitehead Institute, she established an MIT-based summer program to introduce female high school students to engineering careers, founded the Women in Science Committee of the Museum of Science, Boston, and supported the MGH Research Scholars Program to advance the careers of emerging clinical researchers.

The d’Arbeloff Center will create synergies and collaborations among Whitehead Institute investigators and facilities and those at biomedical research organizations throughout the Boston, Massachusetts region, across the nation, and around the world. Leveraging the knowledge gained by the initiative’s investigations into the molecular mechanisms through which the X and Y chromosomes give rise to sex-specific differences in cells, tissues, and organs, the center will delve into the ways that those differences contribute to conditions of health and of disease in women.

It will bring together experts in sex chromosome biology and sex hormones, computational biology and cutting-edge analytics, and proteomics, epigenetics, and metabolomics — fostering the kinds of researcher collaborations never before undertaken and spurring new approaches to the many-variable problem inherent in sex differences research. The center will also pursue partnerships to translate and develop meaningful discoveries into clinical applications for diagnosing, preventing, and treating disease in women. Ultimately, Page envisions, center-driven collaborations and partnerships will include university or medical school-based and independent research organizations, pharmaceutical and medical device manufacturers, and federal agencies.

Page, who will conclude his term as director in June, is also an investigator of the Howard Hughes Medical Institute. He has run a thriving research lab throughout his 35 years at Whitehead Institute, and is globally renowned for his groundbreaking research on sex chromosomes: His studies on the Y chromosome changed the way biomedical science views the function of sex chromosomes, and the work of his laboratory was cited twice in Science magazine’s “Top 10 Breakthroughs of the Year” — first for mapping a human chromosome and then for sequencing the human Y chromosome.

D’Arbeloff observes, “I have very concrete hopes for the center: I want it to help ensure that biomedical research reflects and benefits all of humanity — women and men, young and old. And I believe it is not hyperbole to say that David Page’s sex differences initiative truly has the potential to change the future of health care — for everyone.”

MIT and Sierra Leone professors collaborate on education strategy
Greta Friar | Whitehead Institute
January 13, 2020

Whitehead Member Hazel Sive, also a professor of biology at the Massachusetts Institute of Technology (MIT), is passionate about sharing MIT’s educational strategy for producing skilled, innovative problem-solvers with other educators. Sive, who was born in South Africa and is the founder and faculty director of the MIT-Africa initiative, also cares deeply about strengthening MIT’s connections to Africa—a goal that MIT shares. MIT-Africa has the tagline ‘Collaborating for Impact’ and has the goal to promote mutually beneficial engagement in research, education and innovation with African countries. The university made the African continent a global priority region for its international efforts in 2017. Consequently, Sive was thrilled by the opportunities for exchange that arose when Sierra Leone’s new president, Julius Maada Bio, selected MIT alumnus Moinina David Sengeh (SM ’12, PhD ’16) as his chief innovation officer. Sengeh, who heads the country’s Directorate of Science, Technology, and Innovation, used his MIT ties to catalyze connections between leaders at MIT and in Sierra Leone, including working with MIT-Africa to do so.

Bio and Sengeh visited MIT in March 2019 to officially launch the MIT-Sierra Leone Program.  The program’s early connections with MIT include Njala University membership in the MIT Abdul Latif Jameel World Education Lab, MIT student internships and faculty visits to Sierra Leone, and an ongoing discourse on higher education strategy. Njala University also participated in the summer 2019 launch of the MIT-Africa Short Course.

MIT-Africa Short Courses are 2- to 5-day-long, collegial workshops or lecture series, on topics of interest in research or education. MIT faculty will bring the courses to African colleagues at their home institutions. Sive led the first Short Course series, a three-day program titled, “Educating with Problem-solving Approaches,” in July and August at Njala University, the Central University of Technology in South Africa, and the Dar es Salaam Institute of Technology in Tanzania.

Sive and the three African universities selected the course topic as one of great interest. MIT has a philosophy of educating students in a problem-solving framework, where students practice problem-solving not only in class, but also in their homework, research, and independent projects.

“The great thing that we give our students at MIT, in terms of employability and flexibility to respond to shifts in careers, is the ability to solve problems, a training that is applicable across every field,” Sive said.

That skillset is one that Sierra Leone’s education leaders likewise want to foster in their students.

Sive brought two MIT students with her to each iteration of the Short Course to speak about their experiences at the Institute, six in total, including Michelle Huang, Jia-Hui Lee, Alice Li, Ashwin Narayan, Keith Puthi, and Michal Reda.

When Sive and the students ran the course in Sierra Leone, it was attended by university, technical college and higher education policy leaders. Discussion ranged from exploring MIT approaches, to considering which may be useful in Sierra Leone, to big-picture higher education strategy.

Sive is excited about connections being made between MIT and Sierra Leone, and the possibilities for important projects that can be carried out together.

“It’s outstanding to make connections with colleagues in higher education across the world,” Sive said. “The frameworks of universities across the world overlap enormously, making it easy to connect and work together toward the same goals.”

Written by Greta Friar

Pushing the field of chemical biology in a new direction
Lucy Jackub
January 8, 2020

n 1996, Virginia Cornish had the idea that would define her career in synthetic biology. She had been working in chemistry labs that were trying to imitate, in test tubes, the complex chemistry that occurs in living organisms. Inside a cell, genes code for hundreds of enzymes that are produced to catalyze different chemical reactions. But what if a cell’s natural machinery could be co-opted to do new chemistry, even chemistry that doesn’t occur in nature? She saw the potential for living cells to become tools.

Stuart Schreiber, now at the Broad Institute of MIT and Harvard, discovered early in his career that a certain immunosuppressant drug worked by allowing proteins in the cell to dimerize, or link together, with proteins they wouldn’t normally interact with strongly. These new protein-protein interactions led to new reactions in the cell. He suggested that other small molecules, or “chemical dimerizers,” could be synthesized that would cause other novel protein-protein interactions, with therapeutic potential to trigger a range of biological functions in the cell, such as gene expression, protein degradation, and apoptosis. But it struck Cornish that chemical dimzerizers could instead be used to screen for specific enzymes in a cell’s genetic library, by dimerizing transcription factors so that they would only activate gene expression in the presence of a specific enzyme. Paired with molecular engineering, this could guide directed evolution in the lab. “I called this chemical complementation,” she says.

She brought the idea to professor Bob Sauer, who had just admitted her as a postdoc to his lab in MIT’s Department of Biology. Only three months after she’d begun working with him, Cornish received an unexpected invitation to interview for an assistant professorship in the Department of Chemistry at Columbia University, where she’d gotten her undergraduate degree in biochemistry. She bused down to New York with the plans for chemical complementation in her pocket. By the end of the day she’d been offered her own laboratory.

The offer was tempting, but Cornish asked Columbia if they’d wait for her to finish her postdoc, and ended up staying in the Sauer lab for two years. Those years turned out to be vital, she says. “I had a lot of biology to learn.”

A Changing Field

Cornish came to Columbia from Savannah, Georgia in 1987, and joined the lab of Ronald Breslow, who had been chair of the committee that had urged the university to begin admitting female students in 1983. Columbia was renowned for organic chemistry, and Breslow’s work in biomimetic chemistry — synthesizing molecules in round-bottomed flasks that resemble molecules found in living systems — was laying the groundwork for the nascent field of chemical biology.

After graduating from Columbia, Cornish took her rigorous training in organic chemistry West to do her PhD in the lab of Peter Schultz at the University of California, Berkeley. Schultz’s lab had just succeeded in synthesizing unnatural amino acids that could be encoded into a cell’s DNA and fed into its translational machinery to create novel proteins. This was an unconventional project for a chemistry lab, but Schultz was interested in bringing together organic chemistry and molecular biology to manipulate large molecules, even ones as large and complex as those of the ribosome.

Cornish’s thesis used Schultz’s method of unnatural amino acid mutagenesis to introduce a chemical group called a ketone, rather than an amino acid, into the cell. The ketone could then be tagged with a fluorescent label, and serve as a biosensor for certain chemicals. This was early work in what would later become the field of bio-orthogonal chemistry.

Excited by the molecular engineering she’d learned in the Schultz lab, Cornish wanted to explore it further in living cells. That meant joining a biology laboratory. She’d heard that MIT’s Department of Biology was a great place to be a postdoc, and was drawn to the molecular engineering Bob Sauer’s lab was doing with bacteria. Then the idea for chemical complementation came to her as she was getting coffee with a friend from the Schreiber lab, and she knew exactly what she wanted to do with her postdoc.

“The main thing I remember about Virginia is that she was just fearless,” Sauer recalls. Cornish’s project, to synthesize a small molecule that could be easily adapted to dimerize a large variety of proteins, was a problem the Sauer lab had never taken on before. “As biochemists, we were interested in protein-protein interactions, and how those mediated networks of genetic regulation, because a lot of the proteins that bind DNA specifically do so as dimers or tetramers,” says Sauer. “She took it to a different level by thinking about how you can use chemical biology to actually dimerize things.”

Cornish remembers the “intellectually vibrant environment” at MIT and the cross-fertilization between labs in the department, and learned as much from other postdocs as from faculty. Petra Levin, a postdoc in professor Alan Grossman’s lab, spent hours patiently teaching her genetics. At that time, Sauer’s lab held joint group meetings to discuss their research in protein folding and transcription with two other labs in the department at that time, headed by Peter Kim and Carl Pabo. It was the genesis of a larger collaboration, informally known as “the structural biology supergroup.”

“I still remember the first time I presented my idea of chemical complementation to this group,” Cornish says. “Peter Kim grilled me for a good fifteen to twenty minutes, going so far as to ask me what my transcription factor was.”

Sauer’s lab works with Escherichia coli, but Cornish decided that her model organism of choice chemical complementation wasn’t a bacterium. It was a yeast, Saccharomyces cerevisiae. Researchers at Johns Hopkins had just found a method for chemically dimerizing proteins in yeast, and it had “all the right parts and pieces” that Cornish needed for her own experiment. She began spending more and more time in Chris Kaiser’s lab next door, borrowing their media to culture yeast. She was introduced to a postdoc in Gerald Fink’s lab, Hiten Madhani, who taught her the fundamentals of yeast genetics. She still has the pieces of paper from their meetings, where Madhani sketched out the yeast plasmids and genetic markers.

“She was down the hall learning stuff from the Kaiser lab, over in the Chemistry Department learning stuff from them,” says Sauer. “I provided a bench for her.”

Synthetic Solutions

When Cornish finished her postdoc and finally took her position at Columbia in 1999, chemical complementation became the foundation for the research in her lab. Working in yeast distinguished Cornish from other scientists who came out of MIT and were doing similar experiments in bacteria in the early 2000s, synthesizing molecules to work together in living cells — the first forays in what is now known as synthetic biology.

Cornish is now the Helena Rubinstein Professor in the departments of Chemistry and Systems Biology at Columbia. She has become a leader in her field, serving on the executive committee of Genome Project-Write, a group of synthetic biologists that has come together to establish ethical standards and self-regulation of new technologies to edit and synthesize genetic information.

She stays focused on how synthetic biology can advance medicine and make products that solve real problems. In 2017, the Cornish Group engineered baker’s yeast to detect fungal pathogens and react by turning red, creating a cheap biosensor with the potential to save lives in regions without medical access. Synthetic biologists have, up until now, focused on engineering individual cells, but Cornish’s next project is to engineer entire communities of yeast cells to work together, like our microbiome does, by taking advantage of the complex communication networks between them. Cornish says that in the lab, “the most exciting moment really is when you’re doing something that you can’t quite articulate.”

She credits her mentors — Breslow, Schultz, and Sauer — with instilling that creative drive in her. All of them were “pushing the field in a new direction,” as she puts it. She pays that mentorship forward to her students. “Sometimes there’s a sense that great science and mentorship are at odds with one another,” she says, but she’s found that the opposite is true. “I think the best way to do great science is just to enable your students to be everything that they can be. And then it really becomes an exciting collaboration.”

Images courtesy of Virginia Cornish
Bose grants for 2019 reward bold ideas across disciplines

Three innovative research projects in literature, plant epigenetics, and chemical engineering will be supported by Professor Amar G. Bose Research Grants.

MIT Resource Development
December 30, 2019

Now in its seventh year, the Professor Amar G. Bose Research Grants support visionary projects that represent intellectual curiosity and a pioneering spirit. Three MIT faculty members have each been awarded one of these prestigious awards for 2019 to pursue diverse questions in the humanities, biology, and engineering.

At a ceremony hosted by MIT President L. Rafael Reif on Nov. 25 and attended by past awardees, Provost Martin Schmidt, the Ray and Maria Stata Professor of Electrical Engineering and Computer Science, formally announced this year’s Amar G. Bose Research Fellows: Sandy Alexandre, Mary Gehring, and Kristala L.J. Prather.

The fellowships are named for the late Amar G. Bose ’51, SM ’52, ScD ’56, a longtime MIT faculty member and the founder of the Bose Corporation. Speaking at the event, President Reif expressed appreciation for the Bose Fellowships, which enable highly creative and unusual research in areas that can be hard to fund through traditional means. “We are tremendously grateful to the Bose family for providing the support that allows bold and curious thinkers at MIT to dream big, challenge themselves, and explore.”

Judith Bose, widow of Amar’s son, Vanu ’87, SM ’94, PhD ’99, congratulated the fellows on behalf of the Bose family. “We talk a lot at this event about the power of a great innovative idea, but I think it was a personal mission of Dr. Bose to nurture the ability, in each individual that he met along the way, to follow through — not just to have the great idea but the agency that comes with being able to pursue your idea, follow it through, and actually see where it leads,” Bose said. “And Vanu was the same way. That care that was epitomized by Dr. Bose not just in the idea itself, but in the personal investment, agency, and nurturing necessary to bring the idea to life — that care is a large part of what makes true change in the world.”

The relationship between literature and engineering

Many technological innovations have resulted from the influence of literature, one of the most notable being the World Wide Web. According to many sources, Sir Tim Berners-Lee, the web’s inventor, found inspiration from a short story by Arthur C. Clarke titled “Dial F for Frankenstein.” Science fiction has presaged a number of real-life technological innovations, including the defibrillator, noted in Mary Shelley’s “Frankenstein;” the submarine, described in Jules Verne’s “20,000 Leagues Under the Sea;” and earbuds, described in Ray Bradbury’s “Fahrenheit 451.” But the data about literature’s influence on STEM innovations are spotty, and these one-to-one relationships are not always clear-cut.

Sandy Alexandre, associate professor of literature, intends to change that by creating a large-scale database of the imaginary inventions found in literature. Alexandre’s project will enact the step-by-step mechanics of STEM innovation via one of its oft-unsung sources: literature. “To deny or sever the ties that bind STEM and literature is to suggest — rather disingenuously — that the ideas for many of the STEM devices that we know and love miraculously just came out of nowhere or from an elsewhere where literature isn’t considered relevant or at all,” she says.

During the first phase of her work, Alexandre will collaborate with students to enter into the database the imaginary inventions as they are described verbatim in a selection of books and other texts that fall under the category of speculative fiction—a category that includes but is not limited to the subgenres of fantasy, Afrofuturism, and science fiction. This first phase will, of course, require that students carefully read these texts in general, but also read for these imaginary inventions more specifically. Additionally, students with drawing skills will be tasked with interpreting the descriptions by illustrating them as two-dimensional images.

From this vast inventory of innovations, Alexandre, in consultation with students involved in the project, will decide on a short list of inventions that meet five criteria: they must be feasible, ethical, worthwhile, useful, and necessary. This vetting process, which constitutes the second phase of the project, is guided by a very important question: what can creating and thinking with a vast database of speculative fiction’s imaginary inventions teach us about what kinds of ideas we should (and shouldn’t) attempt to make into a reality? For the third and final phase, Alexandre will convene a team to build a real-life prototype of one of the imaginary inventions. She envisions this prototype being placed on exhibit at the MIT Museum.

The Bose research grant, Alexandre says, will allow her to take this project from a thought experiment to lab experiment. “This project aims to ensure that literature no longer play an overlooked role in STEM innovations. Therefore, the STEM innovation, which will be the culminating prototype of this research project, will cite a work of literature as the main source of information used in its invention.”

Nature’s role in chemical production

Kristala L.J. Prather ’94, the Arthur D. Little Professor of Chemical Engineering, has been focused on using biological systems for chemical production during the 15 years she’s been at the Institute. Biology as a medium for chemical synthesis has been successfully exploited to commercially produce molecules for uses that range from food to pharmaceuticals — ethanol is a good example. However, there is a range of other molecules with which scientists have been trying to work, but they have faced challenges around an insufficient amount of material being produced and a lack of defined steps needed to make a specific compound.

Prather’s research is rooted in the fact that there are a number of naturally (and unnaturally) occurring chemical compounds in the environment, and cells have evolved to be able to consume them. These cells have evolved or developed a protein that will sense a compound’s presence — a biosensor — and in response will make other proteins that help the cells utilize that compound for its benefit.

“We know biology can do this,” Prather says, “so if we can put together a sufficiently diverse set of microorganisms, can we just let nature make these regulatory molecules for anything that we want to be able to sense or detect?” Her hypothesis is that if her team exposes cells to a new compound for a long enough period of time, the cells will evolve the ability to either utilize that carbon source or develop an ability to respond to it. If Prather and her team can then identify the protein that’s now recognizing what that new compound is, they can isolate it and use it to improve the production of that compound in other systems. “The idea is to let nature evolve specificity for particular molecules that we’re interested in,” she adds.

Prather’s lab has been working with biosensors for some time, but her team has been limited to sensors that are already well characterized and that were readily available. She’s interested in how they can get access to a wider range of what she knows nature has available through the incremental exposure of new compounds to a more comprehensive subset of microorganisms.

“To accelerate the transformation of the chemical industry, we must find a way to create better biological catalysts and to create new tools when the existing ones are insufficient,” Prather says. “I am grateful to the Bose Fellowship Committee for allowing me to explore this novel idea.”

Prather’s findings as a result of this project hold the possibility of broad impacts in the field of metabolic engineering, including the development of microbial systems that can be engineered to enhance degradation of both toxic and nontoxic waste.

Adopting orphan crops to adapt to climate change

In the context of increased environmental pressure and competing land uses, meeting global food security needs is a pressing challenge. Although yield gains in staple grains such as rice, wheat, and corn have been high over the last 50 years, these have been accompanied by a homogenization of the global food supply; only 50 crops provide 90% of global food needs.

However, there are at least 3,000 plants that can be grown and consumed by humans, and many of these species thrive in marginal soils, at high temperatures, and with little rainfall. These “orphan” crops are important food sources for farmers in less developed countries but have been the subject of little research.

Mary Gehring, associate professor of biology at MIT, seeks to bring orphan crops into the molecular age through epigenetic engineering. She is working to promote hybridization, increase genetic diversity, and reveal desired traits for two orphan seed crops: an oilseed crop, Camelina sativa (false flax), and a high-protein legume, Cajanus cajan (pigeon pea).

C. sativa, which produces seeds with potential for uses in food and biofuel applications, can grow on land with low rainfall, requires minimal fertilizer inputs, and is resistant to several common plant pathogens. Until the mid-20th century, C. sativa was widely grown in Europe but was supplanted by canola, with a resulting loss of genetic diversity. Gehring proposes to recover this genetic diversity by creating and characterizing hybrids between C. sativa and wild relatives that have increased genetic diversity.

“To find the best cultivars of orphan crops that will withstand ever increasing environmental insults requires a deeper understanding of the diversity present within these species. We need to expand the plants we rely on for our food supply if we want to continue to thrive in the future,” says Gehring. “Studying orphan crops represents a significant step in that direction. The Bose grant will allow my lab to focus on this historically neglected but vitally important field.”

Human-human and protein-protein interactions.

A change in fields and a two-body problem ultimately led Biology and BE Professor Amy Keating to MIT to study coiled-coils and other protein interactions.

J. Carota | CSB Grad Office
December 17, 2019

About 330 miles west of Cambridge lies the small academic town of Ithaca, New York: the location of Cornell University and the hometown of Professor Amy Keating. Surrounded by academics (her father is a professor of computer science at Cornell), Keating was eager to continue her education after high school—just not in Ithaca.

“I could have stayed at Cornell, which is obviously an extremely good school in my hometown, but my family and I agreed that it was important that I go away,” recounts Keating. The scholar/athlete set her sights on Harvard University based on the excellent rowing team and outstanding academics. Physics particularly appealed to her, because it involved using math to explain mechanical and electrical phenomena, and she chose this as her major. She likes to tell people that she also “attempted pure math but failed miserably.” Keating admits that she was not very good at the abstract subject material, and tackling it side-by-side with math whizzes was a harsh awakening after performing well throughout high school. She switched to studying applied math, which was easier for her to manage and also more useful for a physics major.

With an intense rowing schedule, Keating often found herself working late into the night, struggling to solve problems alone. It took a year or two and a serious injury for her to realize that that most of the physics majors were working together in the library many afternoons while she was on the river. “That was very eye-opening. Now I’m a strong advocate of students teaching each other and learning from each other,” explains Keating.

Graduate study gridlock

As she approached the end of her senior year, she had no doubt that she would pursue a PhD, but she did face a crisis about what to study. Initially, she thought she would go to graduate school for physics and applied to and visited many schools. However, she was troubled by the fact that she had tried out a number of areas of physics but never found one that truly captured her interest. In addition to this, Keating began dating a young man, now her husband, who was majoring in chemistry and not set to graduate for another year. “I learned a lot of organic chemistry from him and got very interested in the subject.”

With the decision made to stay in Cambridge for an additional year, she picked up part time work at a Harvard student residence hall cooking, baking, and cleaning in exchange for room and board. Keating also took a few chemistry courses for credit, coached adult rowing, and spent the rest of her time working in the lab of Harvard Physics Professor Mara Prentiss. By the end of that year, she had developed a keen interest in the field of computational chemistry. Having faced difficult decisions about her own post-college plans, she has “a lot of empathy for students who are twenty-one and trying to decide what they want to do in the world.”

Keating and her future husband applied to the same chemistry PhD program at UCLA, where they were both admitted and joined separate labs. She looks back at the interview weekend at UCLA and remembers one faculty interviewer who pointed out the lack of chemistry in her background. “We were talking about cooking, and I told him I like to cook and had been cooking for a job. He said ‘if you can cook, you can do chemistry’, and there is some truth to that, of course.”  Keating acknowledges that the first few months of graduate school were traumatic. “I had exactly two undergrad chemistry classes under my belt. I didn’t really know much chemistry and then I was thrown into this PhD program with chemistry majors. And I was taking graduate level courses with my husband, who is a brilliant chemist. But I caught up and managed to learn a lot in a short time.”

Graduate life smoothed out when Keating joined the lab of Ken Houk, a leader in computational physical organic chemistry. Later in her doctoral studies, she added co-advisor Miguel Garcia-Garibay, an expert in experimental photochemistry. Having the two advisors worked out well and led to several joint publications over Keating’s graduate school career. After her husband’s advisor left UCLA for a company, the couple “had to decide what to do. So, we decided we should graduate quickly.” Now married, Keating and her husband earned their PhDs in under five years, but they would continue to be challenged by the “two-body problem” as they formulated a plan for after graduation.

Further afield

The couple knew they both wanted to find postdoc positions, so they looked in cities like San Diego, San Francisco, and Boston, where positions were abundant. Of that time, Keating says: “I was thinking about different problems or fields where my background might apply. I was reading a lot, just to find out what was out there.” This also marks the first time that she started thinking about problems in biology. “I was actually interested in two areas: material science, and biochemistry, both of which are exciting and rapidly growing areas where chemical principles are centrally important.” Keating’s hard work landed her a position back in Cambridge, where she was again co-advised, this time by former MIT Biology Professor Peter Kim at the Whitehead Institute and MIT Professor of Chemistry  Bruce Tidor(who was later the founding director of the CSB PhD Program).

The postdoc transition was another time in Keating’s life that she good-naturedly describes as “traumatic,” as she once again had to work to understand all-new vocabulary and experimental methods. Her postdoc provided Keating with her first exposure to large molecules; it was also when she first started working on protein interactions, which would become the crux of her future research.  It was in the Kim Lab that she was introduced to coiled-coil proteins. With her background in physics and chemistry, the simplified repeating interactions in these molecules appealed to her. A principle the Keating Lab continues to follow to this day is that they try not to study the most complicated interactions in biology, but rather simpler interactions that they seek to understand in fine detail.

More two-body problems

After four years, Keating hit the academic job market, but she wasn’t sure if she would be accepted as a biochemist because of her change in fields as a postdoc . Her concerns were short-lived as she ended up with a number of exciting offers, including one from MIT. Keating’s husband decided he would go into industry in Boston and with this decision she accepted MIT’s offer to join the Biology faculty in 2002. Later, she added a joint appointment in Biological Engineering.

Keating offers advice to students who are dealing with the two-body problem as she once did.“I think something that helped me and my husband is that we stayed in sync. So, we never had one person make a decision without knowing how that would impact the options of the other person. Of course, that’s not possible for everybody. But that did make our trajectory easier. We would collect our options, put them on the table, look for overlap, and then try to figure out what decision would work best for both of us. And we were very fortunate that we had good options. People have to be flexible to make this work out.” She also recommends looking in cities where there is a high density of opportunities.

The general interest of the Keating lab is in protein-protein interactions, how they work in nature, and how they can be re-engineered using computational and experimental methods. Her group studies proteins that regulate critical processes but are also relatively simple. For example, a system the Keating lab is attracted to is the Bcl-2 family of proteins that control cell death. They have developed a variety of methods that can be used to reprogram the interaction between proteins, and applying these methods to Bcl-2 proteins has generated short peptide molecules that inhibit processes that keep cancer cells alive. Recently the lab has been investigating other types of interactions in cells that are structurally different from the Bcl-2 family. Switching protein families challenges them to develop new methods and allows them to continue to change and evolve their research.

Students and postdocs from the Keating lab have gone on a wide variety of jobs where they study proteins and their interactions in both academia and industry. Keating is happy that young scientists today have so many options. She reflects: “When I was finishing my postdoc, the range of jobs in industry was nothing like it is today. It has been fun to watch my trainees apply their skills to antibody engineering, cancer biology, immuno-oncology and even to start their own companies.” She marvels at how many paths are open to young biologists and likes to tell them that they can’t possibly forsee where they will end up, given the myriad exciting possibilities. Certainly, as a young rower and physics student at Harvard, she had no idea she would end up as a Professor of Biology at MIT.

Hazel Sive named dean of Northeastern University College of Science

Professor and Whitehead Institute member has conducted wide-ranging research in vertebrate developmental biology.

Whitehead Institute
December 16, 2019

Hazel Sive, a globally respected developmental biologist and educator, will become dean of the Northeastern University College of Science, beginning in June 2020. Sive, a member of the Whitehead Institute who has also been on the faculty of the MIT Department of Biology since 1991, is a much-lauded teacher and academic leader at MIT.

“The greatest professional honor of my life has been to be a member of Whitehead Institute and a professor of biology at MIT. To be part of the extraordinary research landscape, to educate our outstanding MIT students, and to have had opportunities to contribute to governance and international activities, has been quite wonderful,” says Sive.

“At the same time, this is an exciting next step in my career,” Sive says. “Northeastern has a fantastic, innovative ethos that meshes with my deep interest in the future of higher education. I look forward to leading the Northeastern College of Science toward even greater excellence in research and education.”

“Hazel has long been committed to teaching and academic leadership, and Northeastern will benefit from her broad experience and expertise,” says David C. Page, Whitehead Institute director and member. “Although we will miss her wit, energy, incisive intelligence, and passionate commitment to outstanding science research, we congratulate her on this wonderful new endeavor.”

Sive, who is also an associate member of Broad Institute of MIT and Harvard, is recognized for her groundbreaking research in vertebrate developmental biology. Her contributions have been wide-ranging, encompassing molecular definition of anterior position, development of the brain ventricular system, and identifying novel cell biological processes, including “epithelial relaxation” and “basal constriction.” Her group defined the extreme anterior domain that gives rise to the mouth and that is a crucial craniofacial signaling center. Sive developed the zebrafish as a tool to analyze human neurodevelopmental disorders, most recently focusing on the metabolic underpinnings of disorders such as autism and 16p11.2 deletion syndrome. She has also been a pioneer in use of the frog Xenopus and zebrafish model systems; indeed, she created the Cold Spring Harbor Laboratory Course on Early Development of Xenopus — which has run for more than 25 years — and she is editor-in-chief of a new two-volume “Xenopus Lab Manual.”

A highly effective educator, Sive has been named a MacVicar Faculty Fellow — MIT’s highest undergraduate teaching accolade — and has twice received the MIT School of Science Teaching Prize. She has taught the undergraduate introductory biology course for 18 years; co-teaches the graduate developmental neuroscience course; and recently created the innovative course Building with Cells for undergraduate and graduate students.

Among her myriad leadership roles, Sive chaired the MIT biology department undergraduate program and has chaired an array of faculty committees. She was the first associate dean of science — where she led the school’s education strategy, promoted diversity in graduate student and faculty recruitment, and devised programs for postdoctoral and junior faculty training. Notably, in 2011 Sive initiated the groundbreaking “Report on the Status of Women Faculty in Science at MIT”.

A native of South Africa — where she earned bachelor’s degrees in chemistry and zoology from the University of Witwatersrand, Johannesburg — Sive has engaged in building connections between MIT and Africa. In 2014, Sive founded the MIT-Africa Initiative, where she serves as faculty director. With the tagline “Collaborating for Impact,” MIT-Africa promotes mutually beneficial engagements in research, education, and innovation. She is founder and faculty director of MISTI-Africa Internships, sending students to multiple African countries. Sive has also focused globally on education, and is founding director of higher education for the MIT Abdul Latif Jameel World Education Lab (J-WEL), located in the Office of Open Learning, started in 2017, that promotes excellence in education across the world. From her leadership, J-WEL Higher Education has built a strong membership across five continents.

Mary Gehring: Using flowering plants to explore epigenetic inheritance

Biologist’s studies illuminate a control system that influences how traits are passed along to new generations.

Anne Trafton | MIT News Office
December 16, 2019

Genes passed down from generation to generation play a significant role in determining the traits of every organism. In recent decades, scientists have discovered that another layer of control, known as epigenetics, is also critically important in shaping those characteristics.

Those added controls often work through chemical modifications of genes or other sections of DNA, which influence how easily those genes can be expressed by a cell. Many of those modifications are similar across species, allowing scientists to use plants as an experimental model to uncover how epigenetic processes work.

“Many of the epigenetic phenomena we know about were first discovered in plants, and in terms of understanding the molecular mechanisms, work on plants has also led the way,” says Mary Gehring, an associate professor of biology and a member of MIT’s Whitehead Institute for Biomedical Research.

Gehring’s studies of the small flowering plant Arabidopsis thaliana have revealed many of the mechanisms that underlie epigenetic control, shedding light on how these modifications can be passed from generation to generation.

“We’re trying to understand how epigenetic information is used during plant growth and development, and looking at the dynamics of epigenetic information through development within a single generation, between generations, and on an evolutionary timescale,” she says.

Seeds of discovery

Gehring, who grew up in a rural area of northern Michigan, became interested in plant biology as a student at Williams College, where she had followed her older sister. During her junior year at Williams, she took a class in plant growth and development and ended up working in the lab of the professor who taught the course. There, she studied how development of Arabidopsis is influenced by plant hormones called auxins.

After graduation, Gehring went to work for an environmental consulting company near Washington, but she soon decided that she wanted to go to graduate school to continue studying plant biology. She enrolled at the University of California at Berkeley, where she joined a lab that was studying how different genetic mutations affect the development of seeds.

That lab, led by Robert Fischer, was one of the first to discover an epigenetic phenomenon called gene imprinting in plants. Gene imprinting occurs when an organism expresses only the maternal or paternal version of particular gene. This phenomenon has been seen in flowering plants and mammals.

Gehring’s task was to try to figure out the mechanism behind this phenomenon, focusing on an Arabidopsis imprinted gene called MEDEA. She found that this type of imprinting is achieved by DNA demethylation, a process of removing chemical modifications from the maternal version of the gene, effectively turning it on.

After finishing her PhD in 2005, she worked as a postdoc at the Fred Hutchinson Cancer Research Center, in the lab of Steven Henikoff. There, she began doing larger, genome-scale studies in which she could examine epigenetic markers for many genes at once, instead of one at a time.

During that time, she began studying some of the topics she continues to investigate now, including regulation of the enzymes that control DNA methylation, as well as regulation of “transposable elements.” Also known as “jumping genes,” these sequences of DNA can change their position within the genome, sometimes to promote their own expression at the expense of the organism. Cells often use methylation to silence these genes if they generate harmful mutations.

Patterns of inheritance

After her postdoc, Gehring was drawn to MIT by “how passionate people are about what they’re working on, whether that’s biology or another subject.”

“Boston, especially MIT and Whitehead, is a great environment for science,” she says. “It seemed like there were a lot of opportunities to get really smart and talented students in the lab and have interesting colleagues to talk with.”

When Gehring joined the Whitehead Institute in 2010, she was the only plant biologist on the faculty, but she has since been joined by Associate Professor Jing-Ke Weng.

Her lab now focuses primarily on questions such as how maternal and paternal parents contribute to reproduction, and how their differing interests can lead to genetic conflicts. Gene imprinting is one way that this conflict is played out. Gehring has also discovered that small noncoding RNA molecules play an important role in imprinting and other aspects of inheritance by directing epigenetic modifications such as DNA methylation.

“One thing we’ve found is that this noncoding RNA pathway seems to control the transcriptional dosage of seeds, that is, how many of the transcripts are from the maternally inherited genome and how many from the paternally inherited genome. Not just for imprinted genes, but also more broadly for genes that aren’t imprinted,” Gehring says.

She has also identified a genetic circuit that controls an enzyme that is required to help patterns of DNA methylation get passed from parent to offspring. When this circuit is disrupted, the methylation state changes and unusual traits can appear. In one case, she found that the plants’ leaves become curled after a few generations of disrupted methylation.

“You need this genetic circuit in order to maintain stable methylation patterns. If you don’t, then what you start to see is that the plants develop some phenotypes that get worse over generational time,” she says.

Many of the epigenetic phenomena that Gehring studies in plants are similar to those seen in animals, including humans. Because of those similarities, plant biology has made significant contributions to scientists’ understanding of epigenetics. The phenomenon of epigenomic imprinting was first discovered in plants, in the 1970s, and many other epigenetic phenomena first seen in plants have also been found in mammals, although the molecular details often vary.

“There are a lot of similarities among epigenetic control in flowering plants and mammals, and fungi as well,” Gehring says. “Some of the pathways are plant-specific, like the noncoding RNA pathway that we study, where small noncoding RNAs direct DNA methylation, but small RNAs directing silencing via chromatin is something that happens in many other systems as well.”

A new way to regulate gene expression

Biologists uncover an evolutionary trick to control gene expression that reverses the flow of genetic information from RNA splicing back to transcription.

Raleigh McElvery | Department of Biology
December 9, 2019

Sometimes, unexpected research results are simply due to experimental error. Other times, it’s the opposite — the scientists have uncovered a new phenomenon that reveals an even more accurate portrayal of our bodies and our universe, overturning well-established assumptions. Indeed, many great biological discoveries are made when results defy expectation.

A few years ago, researchers in the Burge lab were comparing the genomic evolution of several different mammals when they noticed a strange pattern. Whenever a new nucleotide sequence appeared in the RNA of one lineage, there was generally an increase in the total amount of RNA produced from the gene in that lineage. Now, in a new paper, the Burge lab finally has an explanation, which redefines our understanding of how genes are expressed.

Once DNA is transcribed into RNA, the RNA transcript must be processed before it can be translated into proteins or go on to serve other roles within the cell. One important component of this processing is splicing, during which certain nucleotide sequences (introns) are removed from the newlymade RNA transcript, while others (the exons) remain. Depending on how the RNA is spliced, a single gene can give rise to a diverse array of transcripts.

Given this order of operations, it makes sense that transcription affects splicing. After all, splicing cannot occur without an RNA transcript. But the inverse theory — that splicing can affect transcription — is now gaining traction. In a recent study, the Burge lab showed that splicing in an exon near the beginning of a gene impacts transcription and increases gene expression, offering an explanation for the patterns in their previous findings.

“Rather than Step A impacting Step B, what we found here is that Step B, splicing, actually feeds back to influence Step A, transcription,” says Christopher Burge, senior author and professor of biology. “It seems contradictory, since splicing requires transcription, but there is actually no contradiction if — as in our model — the splicing of one transcript from a gene influences the transcription of subsequent transcripts from the same gene.”

The study, published on Nov. 28 in Cell, was led by Burge lab postdoc Ana Fiszbein.

Promoting gene expression

In order for transcription to begin, molecular machines must be recruited to a special sequence of DNA, known as the promoter. Some promoters are better at recruiting this machinery than others, and therefore initiate transcription more often. However, having different promoters available to produce slightly different transcripts from a gene helps boost expression and generates transcript diversity, even before splicing occurs mere seconds or minutes later. ​

At first, Fiszbein wasn’t sure how the new exons were enhancing gene expression, but she theorized that new promoters were involved. Based on evolutionary data available and her experiments at the lab bench, she could see that wherever there was a new exon, there was usually a new promoter nearby. When the exon was spliced in, the new promoter became more active.

The researchers named this phenomenon “exon-mediated activation of transcription starts” (EMATS). They propose a model in which the splicing machinery associated with the new exon recruits transcription machinery to the vicinity, activating transcription from nearby promoters. This process, the researchers predict, likely helps to regulate thousands of mammalian genes across species.

A more flexible genome

Fiszbein believes that EMATS has increased genome complexity over the course of evolution, and may have contributed to species-specific differences. For instance, the mouse and rat genomes are quite similar, but EMATS could have helped produce new promoters, leading to regulatory changes that drive differences in structure and function between the two. EMATS may also contribute to differences in expression between tissues in the same organism.

“EMATS adds a new layer of complexity to gene expression regulation,” Fiszbein says. “It gives the genome more flexibility, and introduces the potential to alter the amount of RNA produced.”

Juan Valcárcel, a research professor at the Catalan Institution for Research and Advanced Studies in the Center for Genomic Regulation in Barcelona, Spain, says understanding the mechanisms behind EMATS could also have biotechnological and therapeutic implications. “A number of human conditions, including genetic diseases and cancer, are caused by a defect or an excess of particular genes,” he says. “Reverting these anomalies through modulation of EMATS might provide innovative therapies.”

Researchers have already begun to tinker with splicing to control transcription. According to Burge, pharmaceutical companies like Ionis, Novartis, and Roche are concocting drugs to regulate splicing and treat diseases like spinal muscular atrophy. There are many ways to decrease gene expression, but it’s much harder to increase it in a targeted manner. “Tweaking splicing might be one way to do that,” he says.

“We found a way in which our cells change gene expression,” Fiszbein adds. “And we can use that to manipulate transcript levels as we want. I think that’s the most exciting part.”

This research was funded by the National Institutes of Health and the Pew Latin American Fellows Program in the Biomedical Sciences.

The surprising individuality of miRNAs
Greta Friar | Whitehead Institute
December 5, 2019

In order for the instructions contained within a gene to ultimately execute some function in the body, the nucleotides, or letters, that make up the gene’s DNA sequence must be “read” and used to produce a messenger RNA (mRNA). This mRNA must then be translated into a functional protein. A number of different pathways within the cell influence this essential biological process, informing whether, when, and to what extent a gene is expressed. A major class of such regulators are microRNAs (miRNAs). These minute RNAs—they are, on average, 22 nucleotides long—join with a protein called Argonaute to cause certain mRNAs to be degraded, which in turn decreases the amount of translation of those mRNAs into their functional protein forms. Scientists have identified hundreds of miRNAs that are common amongst mammals and other vertebrate animals, and most mammalian mRNAs are targeted by at least one of these miRNAs—an indication of their pervasive importance to our biology. Accurately predicting how any particular miRNA will affect gene expression in a cell is important for understanding our own biology, and might facilitate the design of therapeutic drugs that affect or utilize miRNAs, but the complexity of the miRNA pathway makes this sort of prediction difficult.

The success rate with which a miRNA is able to repress a specific gene (by degrading its mRNA) is called its targeting efficacy, and researchers have used a variety of models to calculate it, with mixed results. In the past, researchers have treated miRNAs as a group and looked at average behavior in order to make predictions, because there simply wasn’t enough data specific to individual miRNAs available to do otherwise. However, Whitehead Institute Member David Bartel, who is also a professor of biology at the Massachusetts Institute of Technology and a Howard Hughes Medical Institute investigator, graduate student Sean McGeary, and former graduate student Kathy Lin collected a massive amount of data on six miRNAs, and from that foundation developed an improved predictive model for all individual miRNAs. Their findings, published online in Science on December 5, provide unprecedented accuracy and granularity in miRNA targeting prediction.

“We used to focus our attention on microRNA targeting patterns that were consistent, because that consistency gave us confidence in what we were seeing,” Bartel says, “but with the robust results of this research, we can now pay attention to differences between individual miRNAs.”

Bartel and the Whitehead Institute Bioinformatics and Research Computing group operate one of the go-to resources for prediction of miRNAs’ targets and target efficacy, known as TargetScan. This latest research will be used to update TargetScan, giving scientists around the world an even more useful reference tool for research involving miRNA-mediated regulation of gene expression.

To understand miRNA targeting, researchers need to identify the particular sites within an mRNA sequence where the miRNA can bind, and they additionally need to know how strong the interaction will be at each site—the binding affinity. In general, a miRNA will bind to an mRNA when there is a match between at least six of the first eight nucleotides of the miRNA and a complementary sequence of nucleotides somewhere on the mRNA. The two sequences are like rows of puzzle pieces being pushed together: if each puzzle piece slots into the corresponding piece, the rows combine into one locked puzzle—the miRNA binds its target. If the pieces don’t fit together, the rows can’t connect. These sorts of binding sites, perfect matches within the first eight nucleotides of the miRNA, are called canonical site types, and researchers used to think that there was a clear hierarchy between them, with each individual site type conferring a similar amount of repression regardless of the miRNA identity. But that’s not what McGeary observed.

McGeary looked at six miRNAs and developed a method to measure, for each miRNA, relative binding affinities to a massive collection of RNA sequences.

“I performed experiments that provide vast numbers of measurements, which collectively inform us on how well a miRNA will bind to an mRNA,” McGeary says.

These measurements, as well as further calculations that McGeary made from them, formed a novel, rich pool of data with which to improve miRNA targeting prediction. From their experiments, the researchers found that the expected targeting hierarchy of canonical sites did not apply to all miRNAs. An individual miRNA might actually have a stronger affinity to one of the canonical sites lower in the expected hierarchy than another. Furthermore, the group discovered that the miRNAs each had unique noncanonical binding sites, some of which were sites that contained at least one mismatch but were still able to bind miRNA. The researchers found many instances in which a miRNA bound more strongly to one of its noncanonical sites than to some of its canonical sites, despite the imperfect or unusual pairing of the noncanonical sites.

“As humans, we like to classify things into discrete buckets with discrete characteristics,” Lin says. “But to build a model that is quantitative, you have to recognize that each miRNA and target interaction is different.”

Factors in a target site’s environment contribute to the individuality of target interactions, as they can affect the structural accessibility of the site for binding. In particular, the researchers found that the four nucleotides closest to a target site could have a huge, even 100-fold combined impact on affinity.

With their high-resolution data, the researchers were able to rigorously verify a supposition within the miRNA research community: that the strength with which a miRNA binds to a target site is the major determinant for how effective that miRNA will be at degrading that mRNA. This striking correlation between site affinity and targeting efficacy also allowed them to create a biochemical model of miRNA targeting that used the vast collection of affinity measurements to predict the efficacy of repression of every mRNA in cell, significantly out-performing all existing models of miRNA targeting. They then used machine learning, in the form of a convolutional neural network developed by Lin, to extend the improved predictions to all miRNAs without the need to generate additional data.

Altogether, these findings paint a much richer picture of miRNA-mediated gene repression. The new level of specificity in miRNA targeting prediction will provide all researchers working on the subject with better information about the impact of a given miRNA in a cell.

This work was supported by the NIH and Howard Hughes Medical Institute.

Written by Greta Friar

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David Bartel’s primary affiliation is with Whitehead Institute for Biomedical Research, where his laboratory is located and all his research is conducted. He is also a professor of biology at Massachusetts Institute of Technology and investigator with the Howard Hughes Medical Institute.

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Citation:

“The biochemical basis of microRNA targeting efficacy”

Science, online December 5, 2019, DOI: 10.1126/science.aav1741

Sean E. McGeary (1,2,3†), Kathy S. Lin (1,2,3,4†), Charlie Y. Shi (1,2,3), Thy Pham (1,2,3), Namita Bisaria (1,2,3), Gina M. Kelley (1,2,3), and David P. Bartel (1,2,3,4)

  1. Howard Hughes Medical Institute, Cambridge, MA, 02142, USA
  2. Whitehead Institute for Biomedical Research, Cambridge, MA, 02142, USA
  3. Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
  4. Computational and Systems Biology Program, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA

†These authors contributed equally to this work.