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Gerald Fink wins faculty’s Killian Award

Biologist honored for his work developing yeast as a model organism for genetic studies.

Anne Trafton | MIT News Office
May 16, 2018

Gerald Fink, an MIT biologist and former director of the Whitehead Institute, has been named the recipient of the 2018-2019 James R. Killian Jr. Faculty Achievement Award.

Fink, the Margaret and Herman Sokol Professor in Biomedical Research and American Cancer Society Professor of Genetics, was honored for his work in the development of baker’s yeast, Saccharomyces cerevisiae. Fink’s work transformed yeast into the leading model for studying the genetics of eukaryotes, organisms whose cells contain nuclei.

“Professor Fink is among the very few scientists who can be singularly credited with fundamentally changing the way we approach biological problems. He has made numerous seminal contributions to understanding the fundamentals of all nucleated life on the planet, significantly advancing our knowledge of many cellular processes critical to life systems and human diseases,” according to the award citation, which was read at the May 16 faculty meeting by Michael Strano, the chair of the Killian Award selection committee and the Carbon P. Dubbs Professor of Chemical Engineering at MIT.

Established in 1971 to honor MIT’s 10th president, James Killian, the Killian Award recognizes extraordinary professional achievements by an MIT faculty member. “From understanding how cells are formed and function, to understanding cancer and developing insights into aging, his research has proved critical to modern day science,” the award committee wrote of Fink.

Fink, who was inspired to go into science partly by the Soviet Union’s launch of the Sputnik satellite in 1957, began studying yeast while working toward his PhD at Yale University in the 1960s.

“I studied yeast as a graduate student, when it was an extremely unpopular organism,” Fink recalls. “In fact, I was cautioned by my thesis advisor not to tackle it because it was an intractable system.”

Despite that warning, Fink dove into studies of yeast metabolism — in particular, the mechanism that yeast uses to regulate amino acid biosynthesis. At the time, yeast engineering was impeded because there was no way to insert a gene into yeast cells. Then, in 1976, Fink developed a way to insert any DNA into yeast cells, thus allowing researchers to study gene functions in eukaryotic cells in a way that was previously impossible.

“That technology dramatically changed everything, because it made it possible to insert a gene from any organism into yeast,” Fink says.

Fink’s advance allowed scientists to manipulate the yeast genome at will, turning the organism into a cell factory. This technology enabled the current large-scale production of vaccines, drugs (including insulin), and biofuels in yeast.

Fink, who joined the MIT faculty in 1982, currently studies the fungus Candida albicans — which can cause thrush, yeast infections, and severe blood infections — in hopes of developing new antifungal drugs. His lab recently discovered how this human pathogen switches back and forth from its usual yeast form to an invasive filamentous form.

Fink taught genetics to MIT undergraduates and graduate students for many years, and as director of the Whitehead Institute from 1990 to 2001 oversaw the Whitehead’s contribution to the Human Genome Project.

“The Human Genome Project would not have happened here at MIT if it had not been for the unique structure of the Whitehead Institute, which was able to move quickly,” Fink says. “We committed resources and space from the Whitehead to propel the project forward.”

In 2003, the Whitehead/MIT Center for Genome Research became the cornerstone of the newly launched Broad Institute. “MIT’s premier place in the world of biological research is due in no small part to Professor Fink’s selfless, tireless, and generally unheralded work in creating and nurturing these institutions,” reads the award citation.

In 2003, Fink chaired the National Academy of Sciences Committee on Research Standards and Practices to Prevent the Destructive Application of Biotechnology, which provided the nation with guidance on how to deal with the threat of bioterrorism without jeopardizing scientific progress.

Fink has received many other honors, including the National Academy of Sciences Award in Molecular Biology, the George W. Beadle Award from the Genetics Society of America, and the Gruber International Prize in Genetics. He has served as president of both the American Association for the Advancement of Science and the Genetics Society of America, and he is an elected member or fellow of the National Academy of Sciences, the American Academy of Arts and Sciences, the Institute of Medicine, and the American Philosophical Society.

Alumni Blog
Linc Sonenshein and Rich Losick
May 15, 2018

When the two of us, who were classmates and dorm mates at Princeton, came to MIT in 1965, we were joined by two other Princeton classmates, Mike Newlon (also a dorm mate) and Charlie Emerson. As a result, our Princeton class produced four of the 20 students who formed the entering class of 1965 of the MIT Biology Graduate Program. (The class was originally meant to include 21 students, but one of the accepted students, the recent Nobel Prize recipient Michael Rosbash, decided to spend a year at the Pasteur Institute before joining the MIT program.) Initially, we roomed together with Mike in Porter Square with a fourth member of our class, Ray White. As PhD students, we worked in the labs of Phillip Robbins (Rich), Salvador Luria (Linc and Mike), and Maury Fox (Ray); Charlie moved to UCSD to finish his degree. Back then the Luria and Robbins labs were located in Buildings 56 and 16. (Why does MIT use numbers rather than names for their buildings?) The department consisted of semi-independent sub-departments of Biochemistry, Microbiology, and Biophysics. All of us eventually became faculty members at various universities: Rich at Harvard, Linc at Tufts Medical School, Mike at Rutgers, Ray at UMass, Utah, and UCSF, and Charlie at UMass Medical School.

At Princeton, Rich had done thesis research in the lab of Charles Gilvarg, studying the synthesis of lysine oligopeptides in E. coli; Mike and Linc worked in the lab of Donald Helinski on the genetics of colicin synthesis. Our backgrounds in microbiology research served as inducements to continue studying microbes at MIT and throughout our careers. Indeed, Linc’s PhD thesis research with Luria on the bacterium Bacillus subtilis and its ability to produce spores sparked a collaboration with Rich that greatly influenced both their subsequent careers. Yet another lifelong collaboration emerged when Linc married another member of our class, Gail Entner, who worked with Ned Holt and went on to become a professor at Boston University Medical School and Tufts Medical School. Mike Newlon also married a classmate, Carol Shaw, who was also in the Holt lab and has been a professor at the University of Iowa and Rutgers Medical School.

Linc and Rich are proud to have trained many students (six of whom went on to be postdocs at MIT) and multiple postdocs who have continued productive careers in their own labs based on our beloved B. subtilis bacterium. Indeed one such individual went on to become the chairman of the very department for which we have written these recollections.

Memories fade with time, but we have recreated at least a partial list of the entering class of 1965 and their mentors.

Entering Class of 1965: Name (Lab) Academic/Industry Employment

Roberta Berrien  (B. Magasanik) MD, VA Health Center
Lynne Brown (V. Ingram) Penn State University
Gail Bruns (V. Ingram) Children’s Hospital, Harvard Medical School
Judith Ebel Tsipis  (M. Fox) Brandeis University
Charles Emerson (moved to UCSD) UMass Medical School
Gail Entner Sonenshein (C. Holt) Boston University Medical School, Tufts Medical School
Stephen Fahnestock (A. Rich) Penn State University, DuPont
Costa Georgopoulos (S. Luria) University of Utah, University of Geneva
John Lisman (J. Brown) Brandeis University
Richard Losick (P. Robbins) Harvard University
Susan Neiman Offner (B. Magasanik) Plymouth, Milton, and Lexington High Schools
Michael Newlon (S. Luria) University of Iowa, Rutgers
Steven Raymond (J. Lettvin) MIT, Harvard Medical School, Personal Health Technologies, Inc.
Carol Shaw Newlon (C. Holt) University of Iowa, Rutgers Med School
Abraham L. Sonenshein (S. Luria) Tufts Medical School
Joel Sussman (A. Rich) Weizmann Institute
Walter Vinson (E. Bell)
Raymond White (M. Fox) UMass Med School, University of Utah, UC San Francisco

3Q: Hazel Sive on MIT-Africa

Faculty director discusses the future of the initiative and Africa’s position as a global priority for the Institute.

Sarah McDonnell | MIT News Office
May 8, 2018

In 2017, MIT released a report entitled “A Global Strategy for MIT,” which offered a framework for the Institute’s ever-growing international activities in education, research, and innovation. The report, written by Richard Lester, associate provost for MIT overseeing international activities, offered recommendations organized around three broad themes: bringing MIT to the world, bringing the world to MIT, and strengthening governance and operations. 

Specifically, Lester identified China, Latin America, and Africa as global priorities and regions where the Institute should expand engagement.  

Reflecting that increased focus, the MIT-Africa initiative, led by Faculty Director Hazel Sive, a professor in the Department of Biology and member of the Whitehead Institute for Biomedical Research, has launched a new website, africa.mit.edu, to further formalize MIT’s commitment to expanding its already robust presence in Africa. Sive spoke with MIT News about the initiative’s future and Africa’s position as a global priority for MIT.

Q: Can you start by explaining what the MIT-Africa initiative is?

A: MIT-Africa began in 2014 as a mechanism to promote and communicate connections between MIT students, faculty, and staff, and African counterparts in the spheres of research, education, and innovation.

Together with the enthusiastic participation of many faculty, senior staff, and students, I originated the MIT-Africa initiative because a number of us who are either from Africa (I am from South Africa) or interested in the continent were doing important work together with African colleagues. We thought that the strong connections MIT was making in Africa should be understood more broadly, and that tremendous synergies would develop from sharing our work and promoting joint projects.

The initiative provided the first public face of MIT engagement with Africa, comprising a portal to disseminate information, and a means to invite potential collaborators to connect with MIT. We developed community through the MIT-Africa Interest Group; through supporting student groups such as the African Students Association and through a growing network of MIT students who have interned or worked in Africa.

MIT-Africa both consolidates Africa-relevant opportunities and directly promotes new programs. Multiple MIT initiatives and units include an Africa focus: the MIT International Science and Technology Initiatives (MISTI), D-Lab, the Abdul Latif Jameel Poverty Action Lab (J-PAL), the Abdul Latif Jameel World Water and Food Security Lab (J-WAFS), the Abdul Latif Jameel World Education Lab (J-WEL), the Environmental Solutions Initiative (ESI), MITx, the Legatum Center, and others.

The tagline for MIT-Africa is “Collaborating for impact,” and through the pillars of research, education, and innovation, our goal is to develop even more substantial collaborations between the MIT community and in Africa.

Q: What are your thoughts on Africa’s inclusion as a priority in MIT’s recent global strategy report?

A: We are very pleased that MIT has recognized the importance of Africa in the world and as a focus for the Institute.

At the outset of the MIT-Africa initiative, we brought together an Africa Advisory Committee for strategic discussions. Last year, at the request of Richard Lester, we put together a strategic plan for MIT engagement in Africa, and the findings in this document interfaced with his decision to define Africa as a global priority for MIT.

In our plan, we made it clear that MIT priorities overlap with issues of vital importance to Africa — in tackling critical challenges relating to the environment, climate change, energy, population growth, food, health, education, industry, and urbanization. We are confident that this emphasis will facilitate expanded connections between MIT and our African collaborators and supporters.

A useful outcome of formalizing MIT’s priority of Africa engagement is recognition of our already extensive engagement with Africa. MIT has projects in half the countries of Africa! There are hundreds of examples in progress, from water utilization in Mozambique to entrepreneurship in South Africa and education in Nigeria. We are well-represented, and this engagement is growing rapidly.

The new website is both a way to acknowledge the outstanding scholarship and work already progressing on the continent, as well as a call to expand collaborations in a high impact way.

Q: What’s next for MIT-Africa?  

A:  Our strategic discussions identified key priorities over the next five years. These include: higher visibility of MIT in Africa through “MIT-Africa” branding, coordination in purpose and scope of MIT engagement in Africa, increased student internship and travel opportunities, increased research funding, new collaborations in education, expanded innovation presence, revised Africa-relevant education at MIT, and increased numbers of African trainees at MIT.

We are well on our way to meeting these goals, aided by a team with broad experience. For example, in 2014, we sent two students to Africa through MISTI, and last year we sent 92, so this has been a hugely fast-growing program. The MISTI Global Seed Fund Program newly includes Africa, and units such as J-WAFS, J-WEL, and ESI offer research funding that can be focused on Africa. A key aspect encompasses our alumni who envision a significant and influential African and African diaspora alumni group.

The distinguished MIT-Africa Working Group advises on policy, strategy, and implementation. Many members are leaders of other MIT initiatives, facilitating development of intersecting and productive joint programs with MIT-Africa.

All of this takes effort and collaborators, and we look forward to an expanded set of connections. We extend an invitation to potential collaborators: Come and speak with us. The expertise at MIT is enormous, and our focus on Africa-relevant engagement will have outcomes that advance intellectual, societal, and economic trajectories.

Biologists discover function of gene linked to familial ALS

Study in worms reveals gene loss can lead to accumulation of waste products in cells.

Anne Trafton | MIT News Office
May 4, 2018

MIT biologists have discovered a function of a gene that is believed to account for up to 40 percent of all familial cases of amyotrophic lateral sclerosis (ALS). Studies of ALS patients have shown that an abnormally expanded region of DNA in a specific region of this gene can cause the disease.

In a study of the microscopic worm Caenorhabditis elegans, the researchers found that the gene has a key role in helping cells to remove waste products via structures known as lysosomes. When the gene is mutated, these unwanted substances build up inside cells. The researchers believe that if this also happens in neurons of human ALS patients, it could account for some of those patients’ symptoms.

“Our studies indicate what happens when the activities of such a gene are inhibited — defects in lysosomal function. Certain features of ALS are consistent with their being caused by defects in lysosomal function, such as inflammation,” says H. Robert Horvitz, the David H. Koch Professor of Biology at MIT, a member of the McGovern Institute for Brain Research and the Koch Institute for Integrative Cancer Research, and the senior author of the study.

Mutations in this gene, known as C9orf72, have also been linked to another neurodegenerative brain disorder known as frontotemporal dementia (FTD), which is estimated to affect about 60,000 people in the United States.

“ALS and FTD are now thought to be aspects of the same disease, with different presentations. There are genes that when mutated cause only ALS, and others that cause only FTD, but there are a number of other genes in which mutations can cause either ALS or FTD or a mixture of the two,” says Anna Corrionero, an MIT postdoc and the lead author of the paper, which appears in the May 3 issue of the journal Current Biology.

Genetic link

Scientists have identified dozens of genes linked to familial ALS, which occurs when two or more family members suffer from the disease. Doctors believe that genetics may also be a factor in nonfamilial cases of the disease, which are much more common, accounting for 90 percent of cases.

Of all ALS-linked mutations identified so far, the C9orf72 mutation is the most prevalent, and it is also found in about 25 percent of frontotemporal dementia patients. The MIT team set out to study the gene’s function in C. elegans, which has an equivalent gene known as alfa-1.

In studies of worms that lack alfa-1, the researchers discovered that defects became apparent early in embryonic development. C. elegans embryos have a yolk that helps to sustain them before they hatch, and in embryos missing alfa-1, the researchers found “blobs” of yolk floating in the fluid surrounding the embryos.

This led the researchers to discover that the gene mutation was affecting the lysosomal degradation of yolk once it is absorbed into the cells. Lysosomes, which also remove cellular waste products, are cell structures which carry enzymes that can break down many kinds of molecules.

When lysosomes degrade their contents — such as yolk — they are reformed into tubular structures that split, after which they are able to degrade other materials. The MIT team found that in cells with the alfa-1 mutation and impaired lysosomal degradation, lysosomes were unable to reform and could not be used again, disrupting the cell’s waste removal process.

“It seems that lysosomes do not reform as they should, and material accumulates in the cells,” Corrionero says.

For C. elegans embryos, that meant that they could not properly absorb the nutrients found in yolk, which made it harder for them to survive under starvation conditions. The embryos that did survive appeared to be normal, the researchers say.

Neuronal effects

The researchers were able to partially reverse the effects of alfa-1 loss in the C. elegans embryos by expressing the human protein encoded by the c9orf72 gene. “This suggests that the worm and human proteins are performing the same molecular function,” Corrionero says.

If loss of C9orf72 affects lysosome function in human neurons, it could lead to a slow, gradual buildup of waste products in those cells. ALS usually affects cells of the motor cortex, which controls movement, and motor neurons in the spinal cord, while frontotemporal dementia affects the frontal areas of the brain’s cortex.

“If you cannot degrade things properly in cells that live for very long periods of time, like neurons, that might well affect the survival of the cells and lead to disease,” Corrionero says.

Many pharmaceutical companies are now researching drugs that would block the expression of the mutant C9orf72. The new study suggests certain possible side effects to watch for in studies of such drugs.

“If you generate drugs that decrease c9orf72 expression, you might cause problems in lysosomal homeostasis,” Corrionero says. “In developing any drug, you have to be careful to watch for possible side effects. Our observations suggest some things to look for in studying drugs that inhibit C9orf72 in ALS/FTD patients.”

The research was funded by an EMBO postdoctoral fellowship, an ALS Therapy Alliance grant, a gift from Rose and Douglas Barnard ’79 to the McGovern Institute, and a gift from the Halis Family Foundation to the MIT Aging Brain Initiative.

Fasting boosts stem cells’ regenerative capacity

A drug treatment that mimics fasting can also provide the same benefit, study finds.

Anne Trafton | MIT News Office
May 1, 2018

As people age, their intestinal stem cells begin to lose their ability to regenerate. These stem cells are the source for all new intestinal cells, so this decline can make it more difficult to recover from gastrointestinal infections or other conditions that affect the intestine.

This age-related loss of stem cell function can be reversed by a 24-hour fast, according to a new study from MIT biologists. The researchers found that fasting dramatically improves stem cells’ ability to regenerate, in both aged and young mice.

In fasting mice, cells begin breaking down fatty acids instead of glucose, a change that stimulates the stem cells to become more regenerative. The researchers found that they could also boost regeneration with a molecule that activates the same metabolic switch. Such an intervention could potentially help older people recovering from GI infections or cancer patients undergoing chemotherapy, the researchers say.

“Fasting has many effects in the intestine, which include boosting regeneration as well as potential uses in any type of ailment that impinges on the intestine, such as infections or cancers,” says Omer Yilmaz, an MIT assistant professor of biology, a member of the Koch Institute for Integrative Cancer Research, and one of the senior authors of the study. “Understanding how fasting improves overall health, including the role of adult stem cells in intestinal regeneration, in repair, and in aging, is a fundamental interest of my laboratory.”

David Sabatini, an MIT professor of biology and member of the Whitehead Institute for Biomedical Research and the Koch Institute, is also a senior author of the paper, which appears in the May 3 issue of Cell Stem Cell.

“This study provided evidence that fasting induces a metabolic switch in the intestinal stem cells, from utilizing carbohydrates to burning fat,” Sabatini says. “Interestingly, switching these cells to fatty acid oxidation enhanced their function significantly. Pharmacological targeting of this pathway may provide a therapeutic opportunity to improve tissue homeostasis in age-associated pathologies.”

The paper’s lead authors are Whitehead Institute postdoc Maria Mihaylova and Koch Institute postdoc Chia-Wei Cheng.

Boosting regeneration

For many decades, scientists have known that low caloric intake is linked with enhanced longevity in humans and other organisms. Yilmaz and his colleagues were interested in exploring how fasting exerts its effects at the molecular level, specifically in the intestine.

Intestinal stem cells are responsible for maintaining the lining of the intestine, which typically renews itself every five days. When an injury or infection occurs, stem cells are key to repairing any damage. As people age, the regenerative abilities of these intestinal stem cells decline, so it takes longer for the intestine to recover.

“Intestinal stem cells are the workhorses of the intestine that give rise to more stem cells and to all of the various differentiated cell types of the intestine. Notably, during aging, intestinal stem function declines, which impairs the ability of the intestine to repair itself after damage,” Yilmaz says. “In this line of investigation, we focused on understanding how a 24-hour fast enhances the function of young and old intestinal stem cells.”

After mice fasted for 24 hours, the researchers removed intestinal stem cells and grew them in a culture dish, allowing them to determine whether the cells can give rise to “mini-intestines” known as organoids.

The researchers found that stem cells from the fasting mice doubled their regenerative capacity.

“It was very obvious that fasting had this really immense effect on the ability of intestinal crypts to form more organoids, which is stem-cell-driven,” Mihaylova says. “This was something that we saw in both the young mice and the aged mice, and we really wanted to understand the molecular mechanisms driving this.”

Metabolic switch

Further studies, including sequencing the messenger RNA of stem cells from the mice that fasted, revealed that fasting induces cells to switch from their usual metabolism, which burns carbohydrates such as sugars, to metabolizing fatty acids. This switch occurs through the activation of transcription factors called PPARs, which turn on many genes that are involved in metabolizing fatty acids.

The researchers found that if they turned off this pathway, fasting could no longer boost regeneration. They now plan to study how this metabolic switch provokes stem cells to enhance their regenerative abilities.

They also found that they could reproduce the beneficial effects of fasting by treating mice with a molecule that mimics the effects of PPARs. “That was also very surprising,” Cheng says. “Just activating one metabolic pathway is sufficient to reverse certain age phenotypes.”

Jared Rutter, a professor of biochemistry at the University of Utah School of Medicine, described the findings as “interesting and important.”

“This paper shows that fasting causes a metabolic change in the stem cells that reside in this organ and thereby changes their behavior to promote more cell division. In a beautiful set of experiments, the authors subvert the system by causing those metabolic changes without fasting and see similar effects,” says Rutter, who was not involved in the research. “This work fits into a rapidly growing field that is demonstrating that nutrition and metabolism has profound effects on the behavior of cells and this can predispose for human disease.”

The findings suggest that drug treatment could stimulate regeneration without requiring patients to fast, which is difficult for most people. One group that could benefit from such treatment is cancer patients who are receiving chemotherapy, which often harms intestinal cells. It could also benefit older people who experience intestinal infections or other gastrointestinal disorders that can damage the lining of the intestine.

The researchers plan to explore the potential effectiveness of such treatments, and they also hope to study whether fasting affects regenerative abilities in stem cells in other types of tissue.

The research was funded by the National Institutes of Health, the V Foundation, a Sidney Kimmel Scholar Award, a Pew-Stewart Trust Scholar Award, the Kathy and Curt Marble Cancer Research Fund, the MIT Stem Cell Initiative through Fondation MIT, the Koch Institute Frontier Research Program through the Kathy and Curt Marble Cancer Research Fund, the American Federation of Aging Research, the Damon Runyon Cancer Research Foundation, the Robert Black Charitable Foundation, a Koch Institute Ludwig Postdoctoral Fellowship, a Glenn/AFAR Breakthroughs in Gerontology Award, and the Howard Hughes Medical Institute.

Computing changes in cell fate

Meena Chakraborty ’19 has spent two years in the lab of Nobel Prize winner Philip Sharp, combining computer science and wet lab techniques to study the impact of microRNAs on gene expression.

Raleigh McElvery
May 2, 2018

When Meena Chakraborty was eleven years old, her parents took her to South Africa to show her what life was like outside her hometown of Lexington, Massachusetts. The trip was first and foremost a family vacation, but what struck Chakraborty, now a junior at MIT, was neither the sights nor safaris, but their visit to a children’s hospital. Looking back, she identifies that experience as the catalyst that spurred her current career path, centered on three years of biology research with implications for human health.

“I remember being astounded that the patients there were my age,” she says. “I had all these things in my life to look forward to, while they were fighting HIV and might not survive. That’s when I started thinking that I could do something to counter disease, and studying biology seemed like the best way to do that.”

Up until that point, she’d intended to be a writer. So when it came time to choose a college, she initially shied away from MIT, fearing it would be too “tech-focused.”

“Even though I was primarily interested in biology, I still wanted diversity in terms of the academic subjects and the people around me,” she says. “But it became clear that MIT really encourages you to step outside your major. Every undergrad has to complete a Humanities, Arts, or Social Sciences concentration, and I chose philosophy. Those classes have become a staple of my undergrad experience, and allowed me to keep in touch with my love for writing while still focusing on my science.”

Given her propensity for math, she declared Course 6-7 (Computer Science and Molecular Biology), as a means to develop analytical tools to decipher large data sets and better understand biological systems. The summer after her freshman year, she had her first chance to marry these two skills in a real-world setting: she began working in the lab of Nobel Prize winner Philip Sharp, located in the Koch Institute for Integrative Cancer Research.

This was her first foray into computational biology, but it wasn’t her first time at the Koch — she’d shadowed two graduates students in the Irvine lab for a summer as a junior in high school. This time, though, as an undergraduate, she was assigned her own project, under the guidance of postdoctoral fellow Salil Garg. Together, they’ve studied a type of RNA known as microRNA (miRNA) for the past two years.

Messenger RNA (mRNA) — perhaps the most well-known of the RNAs — constitutes the intermediate step between DNA and the final product of gene expression: the protein. In contrast, miRNAs are never translated into proteins. Instead, they bind to complementary sequences in target mRNAs, preventing those mRNAs from being turned into proteins, and blocking gene expression.

This miRNA-directed silencing is widespread and complex. In some cases, miRNAs silence single genes. In others, multiple miRNAs coordinate to turn groups of genes on and off in concert, thereby controlling entire sets of genes that interact with one another.  For example, two years ago, Chakraborty’s mentor used computational methods to pinpoint a group of poorly expressed, understudied “nonclassical” miRNAs that appear to coordinate the expression of pluripotency genes. Pluripotency gene levels dictate the behavior and fate of embryonic stem cells — non-specialized cells awaiting instructions to “differentiate” and assume a particular cell type (skin cell, blood cell, neuron, and so on).

Chakraborty then used a technique known as fluorescence-activated cell sorting (FACS) to determine how nonclassical miRNAs affect gene expression in embryonic stem cells. She used a FACS assay to detect miRNA activity, engineering special DNA and inserting it into mouse embryonic stem cells. The DNA contained two genes: one encoding a red fluorescent protein with a place for miRNAs to bind, and another that makes a blue fluorescent protein and lacks this miRNA attachment site. When the miRNA binds to the gene expressing the red fluorescing protein, it is silenced, and the cell makes fewer red proteins compared to blue ones, whose production remains unhindered.

“We know when miRNAs are active, they will reduce the expression of the red florescent protein, but not the blue one,” she says. “And that’s precisely what we’ve seen with these nonclassical miRNAs, suggesting that they are active in the cell.”

Chakraborty is excited about what this finding could mean for cancer research. A growing number of studies have shown that some cancers arise when miRNAs fail to help embryonic stem cells interconvert between cell states.

Although she spends anywhere from four to 20 hours a week in lab, Chakraborty hasn’t lost sight of her extracurriculars. As co-president of the Biology Undergraduate Student Association, she serves as a liaison between biology students and faculty, coordinating events to connect the two. As the discussion chair for the Effective Altruism Club, she promotes dialogue between student club members regarding charities — how these organizations can maximize their donations, and how the public should decide which ones to support. As a volunteer for the non-profit Help at Your Door, she inputs grocery lists from senior citizens and disabled individuals into a computer program, and then coordinates with community members to deliver the specified order.

Last summer, she was accepted into the Johnson & Johnson UROP Scholars Program, joining approximately 20 fellow undergraduate women in STEM research at MIT during the summer term. Her cohort attended faculty presentations, workshops, and networking events geared towards post-graduate careers in the sciences.

“I really appreciated that program, because I think a lot of women are afraid of science due to societal norms,” she says. “I remember originally thinking I wouldn’t be good at computer science or math, and now here I am combining both skills with wet lab techniques in my research.”

Most recently, Chakraborty was a recipient of the 2017-2018 Barry Goldwater Scholarship Award, selected from a nationwide field of candidates nominated by university faculty. She will also remain on campus this coming summer to conduct faculty-mentored research as part of the MIT Amgen Scholars Program.

After she graduates in 2019, Chakraborty intends to pursue a PhD in a biology-related discipline, perhaps computational biology. After that, the options are endless — professor, consultant, research scientist. She’s still weighing the possibilities, and doesn’t seem too concerned about selecting one just yet.

“I know I’m going in the right direction, because it hits me every time I finish a challenging assignment or whenever I figure out a new approach in the lab,” she says. “When I complete a task like that with the help of friends and mentors, there’s this sense of pride and a feeling that I can’t believe how much I’ve learned in just once semester. The way my brain considers problems and finds solutions is just so different from the way it was three years ago when I first started out as a freshman.”

Photo credit: Raleigh McElvery
Single-cell database to propel biological studies

Whitehead team analyzes transcriptomes for roughly 70,000 cells in planarians, creates publicly available database to drive further research.

Nicole Davis | Whitehead Institute
April 20, 2018

A team at Whitehead Institute and MIT has harnessed single-cell technologies to analyze over 65,000 cells from the regenerative planarian flatworm, Schmidtea mediterranea, revealing the complete suite of actives genes (or “transcriptome”) for practically every type of cell in a complete organism. This transcriptome atlas represents a treasure trove of biological information on planarians, which is the subject of intense study in part because of its unique ability to regrow lost or damaged body parts. As described in the April 19 advance online issue of the journal Science, this new, publicly available resource has already fueled important discoveries, including the identification of novel planarian cell types, the characterization of key transition states as cells mature from one type to another, and the identity of new genes that could impart positional cues from muscles cells — a critical component of tissue regeneration.

“We’re really at the beginning of an amazing era,” says senior author Peter Reddien, a member of Whitehead Institute, professor of biology at MIT, and investigator with the Howard Hughes Medical Institute. “Just as genome sequences became indispensable resources for studying the biology of countless organisms, analyzing the transcriptomes of every cell type will become another fundamental tool — not just for planarians, but for many different organisms.”

The ability to systematically reveal which genes in the genome are active within an individual cell flows from a critical technology known as single-cell RNA sequencing. Recent advances in the technique have dramatically reduced the per-cell cost, making it feasible for a single laboratory to analyze a suitably large number of cells to capture the cell type diversity present in complex, multi-cellular organisms.

Reddien has maintained a careful eye on the technology from its earliest days because he believed it offered an ideal way to unravel planarian biology. “Planarians are relatively simple, so it would be theoretically possible for us to capture every cell type. Yet they still have a sufficiently large number of cells — including types we know little or even nothing about,” he explains. “And because of the unusual aspects of planarian biology — essentially, adults maintain developmental information and progenitor cells that in other organisms might be present transiently only in embryos — we could capture information about mature cells, progenitor cells, and information guiding cell decisions by sampling just one stage, the adult.”

Two and a half years ago, Reddien and his colleagues — led by first author Christopher Fincher, a graduate student in Reddien’s laboratory — set out to apply single-cell RNA sequencing systematically to planarians. The group isolated individual cells from five regions of the animal and gathered data from a total of 66,783 cells. The results include transcriptomes for rare cell types, such as those that comprise on the order of 10 cells out of an adult animal that consists of roughly 500,000 to 1 million cells.

In addition, the researchers uncovered some cell types that have yet to be described in planarians, as well cell types common to many organisms, making the atlas a valuable tool across the scientific community. “We identified many cells that were present widely throughout the animal, but had not been previously identified. This surprising finding highlights the great value of this approach in identifying new cells, a method that could be applied widely to many understudied organisms,” Fincher says.

“One main important aspect of our transcriptome atlas is its utility for the scientific community,” Reddien says. “Because many of the cell types present in planarians emerged long ago in evolution, similar cells still exist today in various organisms across the planet. That means these cell types and the genes active within them can be studied using this resource.”

The Whitehead team also conducted some preliminary analyses of their atlas, which they’ve dubbed “Planarian Digiworm.” For example, they were able to discern in the transcriptome data a variety of transition states that reflect the progression of stem cells into more specialized, differentiated cell types. Some of these cellular transition states have been previously analyzed in painstaking detail, thereby providing an important validation of the team’s approach.

In addition, Reddien and his colleagues knew from their own prior, extensive research that there is positional information encoded in adult planarian muscle — information that is required not only for the general maintenance of adult tissues but also for the regeneration of lost or damaged tissue. Based on the activity pattern of known genes, they could determine roughly which positions the cells had occupied in the intact animal, and then sort through those cells’ transcriptomes to identify new genes that are candidates for transmitting positional information.

“There are an unlimited number of directions that can now be taken with these data,” Reddien says. “We plan to extend our initial work, using further single-cell analyses, and also to mine the transcriptome atlas for addressing important questions in regenerative biology. We hope many other investigators find this to be a very valuable resource, too.”

This work was supported by the National Institutes of Health, the Howard Hughes Medical Institute, and the Eleanor Schwartz Charitable Foundation.

Study suggests perioperative NSAIDs may prevent early metastatic relapse in post-surgical breast cancer patients
Nicole Giese Rura | Whitehead Institute
April 11, 2018

Cambridge, MA – According to research conducted in mice by Whitehead Institute scientists, surgery in breast cancer patients, which while often curative, may trigger a systemic immunosuppressive response, allowing the outgrowth of dormant cancer cells at distant sites whose ability to generate tumors had previously been kept in check by the immune system. Taking a non-steroidal anti-inflammatory drug (NSAID) around the time of surgery may thwart such early metastatic relapse without impeding post-surgical wound healing.

The team’s work was published in the April 11 issue of the journal Science Translational Medicine.

“This represents the first causative evidence of surgery having this kind of systemic response,” says Jordan Krall, the first author of the paper and a former postdoctoral researcher in the lab of Whitehead Founding Member Robert Weinberg. “Surgery is essential for treating a lot of tumors, especially breast cancer. But there are some side effects of surgery, just as there are side effects to any treatment.  We’re starting to understand what appears to be one of those potential side effects, and this could lead to supportive treatment alongside of surgery that could mitigate some of those effects.”

Although the association between surgery and metastatic relapse has been documented, a causal line between the two has never been established, leading many to consider early metastatic relapse to be the natural disease progression in some patients. Previous studies of breast cancer patients have shown a marked peak in metastatic relapse 12-18 months following surgery. Although the underlying mechanism for such a spike has not been understood, a 2010 retrospective clinical trial conducted in Belgium provides a clue: Breast cancer patients taking a non-steroidal anti-inflammatory (NSAID) for pain following tumor resection had lower rates of this early type of metastatic relapse than patients taking opioids for post-surgical pain. Anti-inflammatory drugs also have previously been shown to directly inhibit tumor growth, but Krall and Weinberg thought that the NSAIDs’ effects in these studies may be independent of the mechanism responsible for the effects noted in the retrospective clinical trial.

To investigate the causes of early metastatic relapse after surgery, the team created a mouse model that seems to mirror the immunological detente keeping in check dormant, disseminated tumor cells in breast cancer patients. In this experimental model, the mice’s T cells stall the growth of tumors that are seeded by injected cancer cells. When mice harboring dormant cancer cells underwent simulated surgeries at sites distant from the tumor cells, tumor incidence and size dramatically increased. Analysis of the blood and tumors from wounded mice showed that wound healing increases levels of cells called inflammatory monocytes, which differentiate into tumor-associated macrophages.  Such macrophages, in turn, can act at distant sites to suppress the actions of T lymphocytes that previously succeeded in keeping the implanted tumors under control. Krall and Weinberg then tested the effects of the NSAID meloxicam (Mobic®), thinking that this anti-inflammatory drug might block the effects of immuno-suppressive effects of wound healing.  In fact, when mice received the NSAID after or at the time of surgery, the drug prevented a systemic inflammatory response created by the wound healing and the meloxicam-treated mice developed significantly smaller tumors than wounded, untreated mice; often these tumors completely disappeared. Notably, meloxicam did not impede the mice’s wound healing

Still, Weinberg cautions that scientists are just beginning to understand the connections between post-surgical wound healing, inflammation, and metastasis.

“This is an important first step in exploring the potential importance of this mechanism in oncology,” says Weinberg, who is also a professor of biology at Massachusetts Institute of Technology (MIT) and director of the MIT/Ludwig Center for Molecular Oncology.

This work was supported by the Advanced Medical Research Foundation, the Transcend Program (a partnership between the Koch Institute and Janssen Pharmaceuticals Inc.), the Breast Cancer Research Foundation, the Ludwig Center for Molecular Oncology at MIT, and the Samuel Waxman Cancer Research Foundation, the American Cancer Society, Hope Funds for Cancer Research, the Charles A. King Trust, the National Health and Medical Research Council of Australia (NHMRC APP1071853), the National Institutes of Health (NIH/NCI 1K99CA201574-01A1), the American Cancer Society Ellison Foundation (PF-15-131-01-CSM), and the U.S. Department of Defense (W81XWH-10-1-0647).

* * *
Robert Weinberg’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 director of the MIT/Ludwig Center for Molecular Oncology.
* * *
Full Citation:
“The systemic response to surgery triggers the outgrowth of distant immune-controlled tumors in mouse models of dormancy”
Science Translational Medicine, April 11, 2018.
 Jordan A. Krall (1), Ferenc Reinhardt (1), Oblaise A. Mercury (1), Diwakar R. Pattabiraman (1), Mary W. Brooks (1), Michael Dougan (1,2), Arthur W. Lambert (1), Brian Bierie (1), Hidde L. Ploegh (1,3 *) Stephanie K. Dougan (1,4), Robert A. Weinberg (1,3,5).
1. Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
2. Division of Gastroenterology, Massachusetts General Hospital, Boston, MA 02114, USA.
3. Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
4. Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
5. Ludwig Center for Molecular Oncology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
*Present address: Program in Cellular and Molecular Medicine, Boston Children’s Hospital, Boston, MA 02115, USA.
AACR Announces Special Recognition Awards
American Association for Cancer Research
April 2, 2018

PHILADELPHIA — The American Association for Cancer Research (AACR) will present Special Recognition Awards to four individuals whose work has made extraordinary contributions to the AACR’s mission to accelerate the prevention and cure of all cancers through research, education, communication, and collaboration.

Anna D. Barker, PhD; C. Kent Osborne, MD; Phillip A. Sharp, PhD; and Col. James E. Williams will receive the awards at the AACR Annual Meeting 2018, which is being held from Saturday, April 14, through Wednesday, April 18, at McCormick Place in Chicago.

These AACR Awards recognize groundbreaking, innovative work across the entire cancer community, and they reflect a wide range of contributions to cancer science and medicine. This year’s award recipients represent meritorious work in research, patient care, policymaking, and advocacy.

“It is our great personal honor to present these Special Recognition Awards,” said AACR Chief Executive Officer Margaret Foti, PhD, MD (hc). “This year’s award recipients have made such tremendous contributions to the cancer field. Their extraordinary accomplishments, whether in the lab, the clinic, the halls of Congress, or in their very own community, have truly changed the lives of cancer patients and their loved ones. We are so grateful for their enduring commitments to the cause.”

This year’s winners:

Anna D. Barker, PhD, will receive the 2018 AACR Distinguished Award for Exceptional Leadership in Cancer Science Policy and Advocacy.

Barker is the director of the National Biomarker Development Alliance; the director of Transformative Healthcare Knowledge Networks; co-director, Complex Adaptive Systems; and a professor in the School of Life Sciences at Arizona State University.

Barker has been chairperson of the AACR Scientist↔Survivor Program since she conceptualized the program more than two decades ago. She also provided outstanding leadership in cancer science policy and advocacy for the AACR through her work as Chair of the AACR’s Public Education Committee (now the Science Policy and Government Affairs Committee) from 1993-2002. She continues to serve on this committee, lending her considerable expertise to its initiatives. In addition, she served on the AACR Board of Directors from 1995-1996 and 1998-2001. She was Deputy Director of the National Cancer Institute from 2002-2010.

“Dr. Barker’s innovative leadership in cancer advocacy has driven the success of her brainchild, the AACR Scientist↔Survivor Program, for it brings together cancer scientists and physicians along with cancer advocates at our scientifically vibrant Annual Meeting and at the Science of Cancer Health Disparities Meeting,” Foti said. “This unique program has had an indelible, positive effect on the professional and personal lives of both cancer researchers and advocates, and it has been hailed around the world as the most important initiative of its type.”

C. Kent Osborne, MD, will receive the 2018 AACR Distinguished Award for Extraordinary Scientific Achievement and Leadership in Breast Cancer Research.

Osborne is the director of the Dan L Duncan Comprehensive Cancer Center at Baylor College of Medicine, where he is also a professor and the Dudley and Tina Sharp Chair for Cancer Research. Since 1992, he has been a codirector of the San Antonio Breast Cancer Symposium (SABCS), the world’s largest and most prestigious conference devoted to breast cancer.
Osborne’s own research has focused on improving the effectiveness of endocrine and HER-2 targeted therapies in patients with breast cancer.

“Dr. Osborne has made extraordinary contributions to breast cancer research during his spectacular career as a physician-scientist, producing significant new insights and providing important data that have improved the clinical outcomes of breast cancer patients,” Foti said. “In addition, this award recognizes his exceptional, selfless stewardship of SABCS, which has grown and thrived under his capable leadership. The AACR is proud to be a partner in SABCS, along with UT Health and Baylor College of Medicine, and we look forward to a long and fruitful relationship with Dr. Osborne.”

Phillip A. Sharp, PhD, FAACR, will receive the 2018 AACR Distinguished Award for Extraordinary Scientific Innovation and Exceptional Leadership in Cancer Research and Biomedical Science.

Sharp is an Institute professor and faculty member at Massachusetts Institute of Technology’s David H. Koch Institute for Integrative Cancer Research. A world leader in molecular biology and biochemistry, he won the 1993 Nobel Prize in Physiology or Medicine for his co-discovery of RNA splicing. He was elected as an inaugural Fellow of the AACR Academy in 2013.

Dr. Sharp has been Chair of the Stand Up To Cancer (SU2C) Scientific Advisory Committee over the past decade, leading the selection of 23 “Dream Teams” of top researchers and other SU2C research groups. He served as program chair of the AACR’s Inaugural Special Conference in 1988. That conference, “Gene Regulation and Oncogenes,” has been characterized as a watershed meeting in stimulating novel, transformative thinking about the molecular biology of cancer. In October 2018, he will lead the 30th Anniversary Special Conference on “Convergence: Artificial Intelligence, Big Data, and Prediction in Cancer.”

“During his illustrious career, Dr. Sharp has consistently manifested extraordinary dedication to the AACR and its mission,” Foti said. “He has provided sage advice and counsel to the AACR on numerous important issues, and his loyalty to our organization continues to this day.

“As the Scientific Partner of Stand Up To Cancer, the AACR has had a spectacular vantage point to witness how Dr. Sharp embraces the urgent need for collaboration in cancer research. He has translated his considerable scientific expertise into a dynamic leadership role in cancer science that stimulates innovation and encourages other scientists to bring their best original work to the goal of defeating cancer in all its forms,” Foti said.

Col. James E. Williams will receive the AACR 2018 Distinguished Public Service Award for Exceptional Leadership in Cancer Advocacy.

Williams, a retired Army colonel who served in the Vietnam War, was diagnosed with prostate cancer in 1991. After he beat the disease, he embarked on a passionate effort to educate men about the disease. His advocacy efforts include serving as a member of the Editorial Advisory Board of the AACR’s Cancer Today magazine; serving as Chairman of the Board of The Intercultural Cancer Council (ICC); serving as Chairman of the Pennsylvania Prostate Cancer Coalition; participating on the Patient Advocacy Committee of the Alliance for Clinical Trials in Oncology; and serving as a Board member of the Alliance for Prostate Cancer Prevention.

“Jim Williams is an inspiration and a role model not only to other cancer survivors, but also to the scientific community at large,” Foti said.  “We are indebted to him for his steadfast passion to advocate for increased funding and research dedicated to men’s health issues, with an emphasis on prostate cancer. His selfless efforts are also instrumental in improving outcomes for racial and ethnic minorities and the medically underserved.”

Scientists find different cell types contain the same enzyme ratios

New discovery suggests that all life may share a common design principle.

Justin Chen | Department of Biology
March 29, 2018

By studying bacteria and yeast, researchers at MIT have discovered that vastly different types of cells still share fundamental similarities, conserved across species and refined over time. More specifically, these cells contain the same proportion of specialized proteins, known as enzymes, which coordinate chemical reactions within the cell.

To grow and divide, cells rely on a unique mixture of enzymes that perform millions of chemical reactions per second. Many enzymes, working in relay, perform a linked series of chemical reactions called a “pathway,” where the products of one chemical reaction are the starting materials for the next. By making many incremental changes to molecules, enzymes in a pathway perform vital functions such as turning nutrients into energy or duplicating DNA.

For decades, scientists wondered whether the relative amounts of enzymes in a pathway were tightly controlled in order to better coordinate their chemical reactions. Now, researchers have demonstrated that cells not only produce precise amounts of enzymes, but that evolutionary pressure selects for a preferred ratio of enzymes. In this way, enzymes behave like ingredients of a cake that must be combined in the correct proportions and all life may share the same enzyme recipe.

“We still don’t know why this combination of enzymes is ideal,” says Gene-Wei Li, assistant professor of biology at MIT, “but this question opens up an entirely new field of biology that we’re calling systems level optimization of pathways. In this discipline, researchers would study how different enzymes and pathways behave within the complex environment of the cell.”

Li is the senior author of the study, which appears online in the journal Cell on March 29, and in print on April 19. The paper’s lead author, Jean-Benoît Lalanne, is a graduate student in the MIT Department of Physics.

An unexpected observation

For more than 100 years, biologists have studied enzymes by watching them catalyze chemical reactions in test tubes, and — more recently — using X-rays to observe their molecular structure.

And yet, despite years of work describing individual proteins in great detail, scientists still don’t understand many of the basic properties of enzymes within the cell. For example, it is not yet possible to predict the optimal amount of enzyme a cell should make to maximize its chance of survival.

The calculation is tricky because the answer depends not only on the specific function of the enzyme, but also how its actions may have a ripple effect on other chemical reactions and enzymes within the cell.

“Even if we know exactly what an enzyme does,” Li says, “we still don’t have a sense for how much of that protein the cell will make. Thinking about biochemical pathways is even more complicated. If we gave biochemists three enzymes in a pathway that, for example, break down sugar into energy, they would probably not know how to mix the proteins at the proper ratios to optimize the reaction.”

The study of the relative amounts of substances — including proteins — is known as “stoichiometry.” To investigate the stoichiometry of enzymes in different types of cells, Li and his colleagues analyzed three different species of bacteria — Escherichia coli, Bacillus subtilis, and Vibrio natriegens — as well as the budding yeast Saccharomyces cerevisiae. Among these cells, scientists compared the amount of enzymes in 21 pathways responsible for a variety of tasks including repairing DNA, constructing fatty acids, and converting sugar to energy. Because these species of yeast and bacteria have evolved to live in different environments and have different cellular structures, such as the presence or lack of a nucleus, researchers were surprised to find that all four cells types had nearly identical enzyme stoichiometry in all pathways examined.

Li’s team followed up their unexpected results by detailing how bacteria achieve a consistent enzyme stoichiometry. Cells control enzyme production by regulating two processes. The first, transcription, converts the information contained in a strand of DNA into many copies of messenger RNA (mRNA). The second, translation, occurs as ribosomes decode the mRNAs to construct proteins. By analyzing transcription across all three bacterial species, Li’s team discovered that the different bacteria produced varying amounts of mRNA encoding for enzymes in a pathway.

Different amounts of mRNA theoretically lead to differences in protein production, but the researchers found instead that the cells adjusted their rates of translation to compensate for changes in transcription. Cells that produced more mRNA slowed their rates of protein synthesis, while cells that produced less mRNA increased the speed of protein synthesis. Thanks to this compensation, the stoichiometry of enzymes remained constant across the different bacteria.

“It is remarkable that E. coli and B. subtilis need the same relative amount of the corresponding proteins, as seen by the compensatory variations in transcription and translation efficiencies,” says Johan Elf, professor of physical biology at Uppsala University in Sweden. “These results raise interesting questions about how enzyme production in different cells have evolved.”

“Examining bacterial gene clusters was really striking,” lead author Lalanne says. “Over a long evolutionary history, these genes have shifted positions, mutated into different sequences, and been bombarded by mobile pieces of DNA that randomly insert themselves into the genome. Despite all this, the bacteria have compensated for these changes by adjusting translation to maintain the stoichiometry of their enzymes. This suggests that evolutionary forces, which we don’t yet understand, have shaped cells to have the same enzyme stoichiometry.”

Searching for the stoichiometry regulating human health

In the future, Li and his colleagues will test whether their findings in bacteria and yeast extend to humans. Because unicellular and multicellular organisms manage energy and nutrients differently, and experience different selection pressures, researchers are not sure what they will discover.

“Perhaps there will be enzymes whose stoichiometry varies, and a smaller subset of enzymes whose levels are more conserved,” Li says. “This would indicate that the human body is sensitive to changes in specific enzymes that could make good drug targets. But we won’t know until we look.”

Beyond the human body, Li and his team believe that it is possible to find simplicity underlying the complex bustle of molecules within all cells. Like other mathematical patterns in nature, such as the the spiral of seashells or the branching pattern of trees, the stoichiometry of enzymes may be a widespread design principle of life.

The research was funded by the National Institutes of Health, Pew Biomedical Scholars Program, Sloan Research Fellowship, Searle Scholars Program, National Sciences and Engineering Research Council of Canada, Howard Hughes Medical Institute, National Science Foundation, Helen Hay Whitney Foundation, Jane Coffin Childs Memorial Fund, and the Smith Family Foundation.