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Friends of biology gather to recognize achievements
December 10, 2018

Members of the MIT biology community came together on Nov. 7, 2018, to celebrate the department’s myriad accomplishments at the inaugural Friends of Biology Reception at the Hyatt Regency Hotel along the Charles River. Current students, alumni, faculty, staff, parents, supporters, and industry representatives gathered to recognize the remarkable achievements of the Department of Biology, and to honor the many generous supporters who make it all possible. Guests had the opportunity to mingle with faculty and students, who discussed topics including the importance of basic science and research, and applications of this work in cancer, genetics, immunology, and microbiology.

Alan Grossman, Praecis Professor of Biology, and head of the Department of Biology, opened the program portion of the evening by thanking attendees for their crucial role in enabling innovative biology research at MIT. He highlighted recent progress and accomplishments by biology alumni, students, and faculty.

“It was wonderful to bring many of our friends and alumni together for this event and to be able to share with them some of the exciting work going on in our department,” Grossman said, reflecting on the Friends of Biology gathering. “I’m delighted that we were able to showcase talks by some of our graduate students. I think our core mission of excellence in research, teaching, and service resonated with everyone, and we are tremendously grateful to all those who support our mission.”

Five biology graduate students then spoke about their career paths and described the research taking place in each of their diverse laboratories.

Rebecca Silberman described the work of the Amon lab, which examines basic biological processes such as cell growth and division, and how errors in these processes lead to disease.

Conor McClune shared that in the Laub lab studies are revealing how cells process information and regulate their own behavior.

Steve Sando of the Horvitz lab noted their progress in using nematodes to learn more about fundamental human biology and the development of disease.

Jose Orozco discussed research from the Sabatini lab at the Whitehead Institute, which focuses on growth and metabolism regulation in mammals.

Frances Diehl, a student researcher in the Vander Heiden lab, concluded the evening by detailing her team’s efforts to better understand cell metabolism and its role in diseases like cancer.

Daniel E. Griffin, the development officer for the department and organizer of the event, said the reception had registrants from five countries and 13 states and received such a positive response that it will be held annually as a signature event.

Faculty members in attendance included Robert Horvitz, David H. Koch Professor of Biology; Robert Sauer, Salvador E. Luria Professor of Biology; Amy Keating, professor of biology and biological engineering; Rebecca Lamason, Robert A. Swanson Career Development Assistant Professor; and Gene-Wei Li, assistant professor of biology, as well as Michael Sipser, dean of the School of Science.

Professor of Biology Dennis Kim bids farewell to the department

Since his arrival in 2005, Kim has contributed to the MIT community through his exceptional research and commitment to undergraduate education and advising.

Raleigh McElvery
December 6, 2018

Dennis Kim, the Ivan R. Cottrell Professor of Immunology, is leaving the MIT Department of Biology at the end of this semester to serve as the Chief of the Division of Infectious Diseases at Boston Children’s Hospital.

Kim has been a member of the department for 13 years, serving as the Biology Undergraduate Officer for the past four years and Chair of the Committee on Prehealth Advising for the past six.

“Dennis has made remarkable contributions to our community, including outstanding research and as our Undergraduate Officer,” says Department Head Alan Grossman. “His teaching is exceptional, and his service to the department and MIT has been invaluable. He will be greatly missed.”

Kim became enthralled by basic science as an undergraduate at the University of California, Berkeley. There — in the cold and in the dark — he performed light- and temperature-sensitive experiments under Ken Sauer to understand the mechanism of water oxidation and oxygen evolution in plant photosynthesis. He traces his commitment to undergraduate education back to these formative experiences in the lab. Although he was already planning to attend graduate school, a run-in with a car on his motor scooter and a broken femur ignited an additional passion: human health.

As an MD-PhD student at Harvard Medical School, Kim had the opportunity to explore both avenues. There, under the mentorship of Chris Walsh, he studied enzymatic reaction mechanisms in bacterial cell wall synthesis, cultivating an interest in infectious disease that he pursued during his clinical training.

Later, as a postdoctoral fellow at Massachusetts General Hospital, Kim and his advisor Fred Ausubel, with help from Gary Ruvkun, worked to understand host-microbe interactions with a focus on innate immunity in a simple animal host, the roundworm Caenorhabditis elegans. Together, Kim and colleagues carried out a forward genetic analysis of host defense against pathogen infection in C. elegans, which eventually laid the foundation for his work as an independent investigator.

Kim arrived at the MIT Department of Biology in 2005, and since then has felt continually inspired and supported by the community. For all thirteen years, his lab has been located next door to Nobel Laureate H. Robert Horvitz, who also works in C. elegans.

“Dennis has been my nearest neighbor and closest colleague at MIT for many years,” Horvitz says. “He is a spectacular scientist whose curiosity and demand for rigor have led him to make striking discoveries repeatedly. Our labs have interacted daily, and Dennis has been a wonderful mentor to and role model for the members of my research group. Dennis has been a great friend. I will miss his wisdom and his cheer.”

“It has been an incredible opportunity and privilege to work in the Department of Biology,” Kim says. “MIT Biology promotes freedom to pursue curiosity-driven research, with phenomenal students and fantastic colleagues. And I got to set up my ‘worm’ lab next door to Bob Horvitz’s lab. It’s hard to imagine how anyone could be more fortunate!”

Over the years — and “thanks to some really terrific graduate students” — Kim has discovered molecular pathways governing how C. elegans recognizes and responds to its microbial environment, with a more recent emphasis on understanding how bacterial metabolites can influence host animal behavior. Questions like these are particularly well-suited to C. elegans, given its simplicity, defined nervous system structure, and well-established genetics.

“A picture has started to emerge that reveals how immunity, stress, and physiology are integrated to promote survival of the host organism,” Kim says. “Our findings have implications for understanding how interactions with microbes can affect the physiology of more complex hosts as well.”

In addition to his achievements in the lab, Kim has been a passionate advocate for undergraduate education. He’s been the Department of Biology’s Undergraduate Officer for four years, working at the departmental and institutional levels to develop and implement initiatives related to campus life, educational programs, and the curriculum. He has also chaired the Committee on Prehealth Advising for the past six years and worked to help MIT undergraduates gain admission to competitive medical schools.

“I really enjoyed working in Professor Kim’s lab because he was accessible and always willing to answer questions,” says Sonika Reddy, a former undergraduate researcher in Kim’s lab and currently a student at New York Medical College. “His mentorship was an invaluable part of my education at MIT. He helped me navigate the biology major and decide which courses to take. He also helped me decide what I wanted to do in the future and was an amazing resource as I applied to medical school.”

“The students are really remarkable here at MIT,” Kim says. “Being the Undergraduate Officer and prehealth advisor has allowed me to engage with them on a regular basis and work to improve educational and advising programs based on their feedback. These roles have meant a lot to me over the years.”

During his time at MIT, Kim developed a new subject, 7.26/7.66 (Molecular Basis of Infectious Disease), which provides an overview of viruses, bacterial pathogenesis, and parasites to advanced undergraduates and graduate students, respectively.

Former student Eta Atolia, now an MD-PhD candidate at UCLA-Caltech, says this was one of her favorite classes as an undergraduate. “I already enjoyed the topic, but the elegant way Professor Kim told the story of bacteria, toxins, antibiotics, and drug resistance really made me appreciate the field,” she says. “He also mentored me during the MD-PhD application process. He was very approachable and always available to meet and provide feedback. He introduced me to microbiology, and is a major reason why I am pursuing an MD-PhD now.”

Kim also recently worked with the Biology Undergraduate Committee and colleagues in the Department of Chemistry to develop the new 5-7 (Chemistry and Biology) major.

“I am delighted that there are a number of students who are very enthusiastic about the major and are well-prepared to work at the exciting interface of these traditional disciplines,” he says.

Kim has served at the Institutional level, chairing the Committee on Curricula and serving on the Committee on Nominations, and maintained a part-time clinical instructor appointment at Harvard Medical School.

“When we interviewed Dennis, we were amazed by the versatility and breadth of his research interests,” says Chris Kaiser, the department head who initially hired Kim. “He moves effortlessly from genome wide approaches to incisive pointed tests of mechanism, with interests ranging from innate immunity to neurological sensing and avoidance of bad environments. While running a highly successful basic research lab at MIT, he maintained an enormously important clinical footing in infectious disease at Massachusetts General Hospital. He also developed or redesigned at least five undergraduate classes and energetically ran the Biology Undergraduate program. I will miss having him as an immediate colleague.”

Of his numerous pursuits, Kim has found working with the undergraduates and graduate students to be the most rewarding.

“I’ve really enjoyed watching the scientists and physicians of tomorrow grow and mature,” he says. “To me, being an undergraduate advisor and faculty member requires having an open door for students, and these mentor-mentee relationships have been incredibly gratifying.”

As Kim transitions to his new position as Chief of the Division of Infectious Diseases at Boston Children’s Hospital, it will take three people to fill his shoes as Undergraduate Officer and Prehealth Advisor. Adam Martin and Catherine Drennan have agreed to share the role of Undergraduate Officer, and Matthew Vander Heiden will co-chair the Committee on Prehealth Advising.

“Dennis has left a significant legacy at MIT as the Undergraduate Officer,” Martin says. “He worked with the Department of Chemistry to get the 5-7 major approved, and revised our lab curriculum to increase the flexibility in Course 7. Dennis is really committed to his trainees; I often see him talking with students and postdocs in his lab and he has trained some wonderful and creative students.”

What will Kim miss the most about MIT? That goes without saying: his students.

Decoding patterns and meaning in biological data

Senior Anna Sappington found her perfect balance of “innovative computer science and innovative biology” as a member of the team mapping every cell in the human body.

Raleigh McElvery
December 5, 2018

When Anna Sappington was six years old, her parents gave her a black and white composition notebook. Together, they began jotting down observations to identify the patterns in their wooded backyard near the Chesapeake Bay. How would the harsh winters or the early springs affect the blooming trees? How many bluebirds nested each season and how many eggs would they lay? When would the cicada population cycle peak? Her father, the environmental scientist, taught her to sift through data to uncover the trends. Her mother, the journalist, gave her the words to describe her findings.

But it wasn’t until Sappington competed in the Intel International Science and Engineering Fair her junior year of high school that she probed one tiny niche of the natural world more keenly than she ever had before: the physiology of the water flea. Specifically, she investigated the developmental changes that these minute creatures experienced after being exposed to the antimicrobial compound triclosan, present in many soaps and toothpastes. She was surprised to learn that it required only a low concentration of triclosan (0.5 ppm) to cause developmental defects.

She’d been familiar with the concept of DNA since middle school, but her fellow science fair finalists were delving beyond their observations and into the letters of the genetic code. This gave her a new impetus: to understand how triclosan worked at the level of the genome and epigenome to engender the physical deformities she observed under the microscope. She just needed the proper tools, so she made some calls.

Environmental geneticist and water flea aficionado John Colbourne took an interest, and invited her to his lab at University of Birmingham in the U.K. the following summer so she could learn basic lab techniques. Although her friends and classmates didn’t quite get why she needed to travel to an entirely different country to study an organism they’d never heard of, as she puts it, she had burning scientific questions that needed answers.

“That was the experience that really turned me on to genomics,” says Sappington, now a senior and 6-7 (Computer Science and Molecular Biology) major. “I was finally getting the tools to dig through large amounts of data, using code to find patterns and meaning. I wanted to keep asking ‘why?’ and ‘how?’ all the way down to the molecular level.”

The summer before her freshman year of college, Sappington asked these questions in humans for the time as an intern at the National Human Genome Research Institute (NHGRI). There, she helped create a computational pipeline to identify the genomic changes associated with heightened risk of cardiovascular disease.

She enrolled at MIT the following fall, because she wanted to be around people from every scientific subfield imaginable. When she arrived, the joint major in computer science and biology was still relatively new.

“While a few of the required classes did meld the two, many of them offered training in each separately,” she says. “That approach really appealed to me because I was hoping to develop both skill sets independently. I wanted to learn code and write algorithms that could be applied to any field, and I also loved understanding the biological mechanisms behind different diseases and viruses.”

Before she’d even officially declared her major, Sappington was already running experiments in Sangeeta Bhatia’s lab. There, at the Koch Institute, she studied the effects of HPV infection on gene expression in liver cells. Sappington’s main role was data analysis, striving to determine which genes were amplified in response to disease.Despite their obvious differences, Sappington found the two areas to be more similar than she had initially anticipated. In her Introduction to Algorithms class, she leveraged an arsenal of algorithms with certain outputs, conditions, and run times to decode her problem sets. In Organic Chemistry, she deployed a list of foundational reactions to solve synthesis questions on her exams. “In each case, you have to combine your understanding of these fundamental rules and come up with a creative solution to decipher an unknown,” she says.

One year later, Sappington moved to Aviv Regev’s lab at the Broad Institute. There, she learned computational techniques for decoding protein interaction networks. After a year, she began working on an international project called the Human Cell Atlas as a member of the Regev and the Sanes lab collaboration.

“The overarching mission is to create a reference map of all human cells,” Sappington explains. “We want to add a layer of functional understanding on top of what we know about the genome, to understand how different cell types differ and how they interact to impact disease. This kind of endeavor has never been undertaken on such a large scale before, so it’s incredibly exciting.”

Even within a single cell type — say, retinal cells — there are about six main cell categories, each of which splinter into as many as 40 subtypes with distinct molecular profiles and roles.

Beyond the biological challenges that go along with trying to distinguish all these cell types, there are numerous computational hurdles as well. Sappington enjoys these the most — grappling with how best to analyze the gene expression of a single cell separated from its tissue of origin.

“Since you’re only working with single cells rather than entire groups of cells from a tissue, the data that you get are much more sparse,” she says. “You have to sequence a lot of individual cells and build up lots of statistical power before you can be confident that a given cell is expressing specific genes. Coming up with models to determine what constitutes a cell type — and map cell types between time points or between species — are broad problems in computer science that we’re now applying to this very specific type of data.”

Although she’s been at the Broad since her sophomore year, Sappington has supplemented her MIT research experiences with summer studies elsewhere: another stint at the NHGRI and an Amgen Scholars fellowship in Japan. She’s especially excited because her first co-authored paper will soon be published. As she puts it, she’s finally found her ideal balance of “innovative computer science and innovative biology.”

But Sappington’s time at MIT has been defined by more than just lab work. She is the co-president of the Biology Undergraduate Student Association, which serves as a liaison between the Department of Biology and the wider community. She’s also a member of MedLinks, a volunteer at the Massachusetts General Hospital Department of Radiology, former managing director of TechX, and a performer for several campus dance troupes. In 2018, Sappington earned the prestigious Barry Goldwater Scholarship Award, alongside fellow 6-7 major Meena Chakraborty.

She was recently awarded the Marshall Scholarship, which will fund her master’s degrees in machine learning at University College London and oncology at the University of Cambridge beginning in the fall of 2019. After two years, she plans to start her MD-PhD. That way, she can become a practicing physician without having to give up her computer science research.

Her advice to prospective students: “When you get to MIT, just explore. Try different academic disciplines, different extracurriculars, and talk to as many people as you can. The campus is full of passionate individuals in every field imaginable, whether that’s computer science or political science.”

Posted 12.5.18
Five MIT students named 2019 Marshall Scholars

Radha Mastandrea, Katie O’Nell, Anna Sappington, Kyle Swanson, and Crystal Winston will begin graduate studies in the UK next fall.

Julia Mongo | Office of Distinguished Fellowships
December 3, 2018

Five MIT students — Radha Mastandrea, Kathryn O’Nell, Anna Sappington, Kyle Swanson ’18, and Crystal Winston — have been awarded Marshall Scholarships to pursue graduate studies in the United Kingdom. This class represents the largest number of Marshall Scholars from the Institute in a single year, and continues MIT students’ exceptional record of achievement in this elite fellowship program.

Funded by the British government, the Marshall Scholarship provides outstanding young Americans with the opportunity to earn advanced degrees in any academic subject at any university in the United Kingdom. Scholars are chosen through a rigorous national competition that assesses academic merit, leadership, and ambassadorial potential. Up to 40 Marshall Scholarships are granted each year.

The MIT students were guided by Kimberly Benard, assistant dean of distinguished fellowships within MIT Career Advising and Professional Development, and by the Presidential Committee on Distinguished Fellowships co-chaired by professors Rebecca Saxe and Will Broadhead. “Working with students like our Marshall Scholars is one of the great pleasures and privileges of teaching at MIT,” says Saxe. “Every year I’m impressed by how hard all of the finalists work to develop and communicate their distinctive vision for the future and their place in it.”

“MIT’s five Marshall Scholars, Radha, Katie, Anna, Kyle, and Crystal, are extraordinary; they are intelligent, creative, and dedicated to making a better world,” says MIT Chancellor Cynthia Barnhart. “Together, they make up an eighth of the entire class of 2019 Marshall Scholars, a remarkable accomplishment that would not have been possible without the hard work and passion of these students; the incredible efforts of professors Broadhead and Saxe and the entire Presidential Committee for Distinguished Fellowships; and the staff who work around the clock to support all applicants through this demanding process. We are fortunate that our 2019 Marshall Scholars have such exciting opportunities to look forward to, and that they will be representing the MIT community to the world.”

Radha Mastandrea

Hailing from Westwood, Massachusetts, Mastandrea is an MIT senior double-majoring in physics and mathematics. She is headed to Cambridge, where she will study theoretical and experimental physics before returning to the U.S. to undertake a PhD in high-energy particle physics. She aims for a career in academia as a researcher and an advocate for open data.

As an undergraduate researcher with Professor Jesse Thaler at the MIT Center for Theoretical Physics, Mastandrea has been using machine learning to analyze a trove of open data from the CERN Large Hadron Collider to gain insight on quarks and gluons. Mastandrea has also conducted research on galaxy spectral emission data with Professor Michael McDonald at the MIT Kavli Institute for Astrophysics and Space Research, and neutrinoless double beta decays with Professor Lindley Winslow at the MIT Laboratory for Nuclear Science. During a summer internship at Caltech, she researched black holes with the Laser Interferometer Gravitational-wave Observatory (LIGO) Scientific Collaboration.

Mastandrea is committed to championing women in physics. As president of MIT’s Undergraduate Women in Physics, she has established connections between undergraduates and older role models to showcase women’s accomplishments in the physics field. She has mentored local high school girls by leading physics exploration days on the MIT campus, and she helped write the MIT physics department’s first community values statement to foster a culture of respect and support. Mastandrea is also co-captain of MIT Bhangra and has taught bhangra dance classes to members of the local community.

Kathryn “Katie” O’Nell

O’Nell, from San Diego, California, is an MIT senior majoring in brain and cognitive sciences. At Oxford University, she will pursue an MS in the Department of Experimental Psychology. She will then return to the U.S. to embark on doctoral studies in computational neuroscience with the goal of becoming a professor and researcher.

O’Nell is currently conducting studies on facial perception in the laboratories of Professor Rebecca Saxe in MIT’s Department of Brain and Cognitive Sciences and Professor Stefano Anzellotti of Boston College. O’Nell has also been examining the connection between gestures and speech with the MIT Speech Communication Group, and she has created calcium imaging processing pipelines in the laboratory of Professor Ann Graybiel at the McGovern Institute for Brain Research at MIT. O’Nell spent two summers interning at the J. Craig Venter Institute, which conducts genomic and bioinformatics research.

On campus, O’Nell is an associate advisor to first-year students and a member of the associate advisor steering committee. She is active with the MIT Model UN Conference for high school students and serves as special political and decolonization committee chair. She also mentors high school students as a Splash instructor for the MIT Educational Studies Program and as president of the MIT Academic Teaching Initiative. As campus engagement chair for the MIT Addir Interfaith Program, O’Nell plans and promotes campus-wide events, including an upcoming interfaith hackathon. O’Nell originated and oversees the popular murder mystery-themed puzzle hunt for her residence hall, MacGregor House.

Anna Sappington

A native of Riva, Maryland, Sappington will graduate this spring with a BS in computer science and molecular biology. She will earn master’s degrees in machine learning at University College London and medical sciences in oncology at the Cambridge University. She will then pursue an interdisciplinary career as a physician-scientist using computer science to improve precision medicine.

As an undergraduate researcher at the laboratory of Professor Aviv Regev in MIT’s Department of Biology and the Broad Institute of MIT and Harvard, Sappington has been developing machine-learning techniques to improve cell type classification for the Human Cell Atlas Initiative. She has also conducted research on hepatitis B virus infection in the laboratory of Professor Sangeeta Bhatia in the Department of Electrical Engineering and Computer Science and the Koch Institute for Integrative Cancer Research. Sappington has held summer research internships at the National Institutes of Health in Bethesda, Maryland, and as an Amgen Scholar at Kyoto University, Japan. In 2018, she was named a national Barry M. Goldwater Scholar and an MIT Burchard Scholar.

Sappington served as the Director of TechX, which hosts world-renowned events such as HackMIT. She is co-president of the MIT Biology Undergraduate Student Association, a teaching assistant for the biology department, and a peer health counselor and former residential director for MIT MedLinks. A talented dancer, Sappington has performed with MIT DanceTroupe and the MIT Asian Dance Team. For the past two years, she has volunteered for the Massachusetts General Hospital department of radiation oncology.

Kyle Swanson

Hailing from Bronxville, New York, Swanson graduated from MIT in 2018 with a BS in computer science and engineering, a BS in mathematics, and a minor in music. He will receive his MEng in computer science and engineering this spring. As a Marshall Scholar, Swanson will study mathematics and computer science at Cambridge. He intends to pursue a PhD in computer science to research applications of machine learning to the diagnosis and treatment of cancer.

As an undergraduate, Swanson worked with Professor Regina Barzilay in MIT’s Computer Science and Artificial Intelligence Laboratory (CSAIL) and Constance Lehman in the Breast Imaging Division of Massachusetts General Hospital on machine learning to improve breast cancer detection in mammography, and recently co-authored a paper published in Radiology.

Swanson’s master’s research with Barzilay focuses on machine learning for chemistry. He is currently developing machine-learning algorithms to predict molecular properties such as toxicity or solubility, with the hope of developing a property-prediction tool that can accelerate drug discovery. Swanson previously conducted research on cybersecurity at CSAIL. He has interned at Microsoft and other companies and taught machine learning to university students in Kazakhstan.

An accomplished musician, Swanson plays flute and piccolo with the MIT Symphony Orchestra where he has served as president. He is active with the music service club Ribotones, which performs concerts at nursing homes, and he has played with MIT’s Chamber Music Society and Wind Ensemble. Swanson has received multiple MIT awards recognizing his musical talent and scholarship.

Crystal Winston

Winston, from Charlotte, North Carolina, is an MIT senior majoring in mechanical engineering. At Imperial College, Winston will embark on a PhD in aerospace materials and structures to further develop her skills in redesigning transportation systems. Her goal is to start a company that transforms transportation technology.

As a sophomore, Winston co-invented a remote-controlled four-wheeled robot that converts into a flying drone, which won first place in a campus project exhibition. She has continued to refine this project and hopes it can eventually be used to reduce traffic congestion by transporting people on ground or through the air.

Winston has conducted research on a robot for detecting and repairing pipe leaks, at the MIT Mechatronics Research Laboratory. As a mechanical engineering intern at Google, she designed and programmed systems for the cameras on Google Maps Streetview cars, and at the NASA Jet Propulsion Laboratory she designed and prototyped an animal-inspired foot for the Europa Lander. She has been a mechanical team member for the MIT Solar Electric Vehicle Team, and helped design and manufacture an electric solar car for the 2017 Formula Sun Grand Prix.

Winston is dedicated to her work with the National Society of Black Engineers (NSBE) where she has held several executive positions. As an engineering immersion program mentor with NSBE, she helps local underrepresented minority high school students prepare for STEM careers. Winston is a member of the Tau Beta Pi and Pi Tau Sigma engineering honors societies.

The long and short of CDK12

A new study linking RNA processing to DNA repair may open new avenues to cancer therapy.

Bendta Schroeder | Koch Institute
December 3, 2018

Mutations in the BRCA1 and BRCA2 genes pose a serious risk for breast and ovarian cancer because they endanger the genomic stability of a cell by interfering with homologous recombination repair (HR), a key mechanism for accurately repairing harmful double-stranded breaks in DNA. Without the ability to use HR to fix double-stranded breaks, the cell is forced to resort to more error-prone — and thus more cancer-prone — forms of DNA repair.

The BRCA1 and BRCA2 genes are not the only genes whose mutations foster tumorigenesis by causing an inability to repair DNA double strand breaks by HR. Mutations in twenty-two genes are known to disrupt HR, giving rise to tumors with what researchers call “BRCAness” characteristics. All but one of these BRCAness genes are known to be directly involved in the HR pathway.

The one exception, CDK12, is thought to facilitate a set of different processes altogether, involving how RNA transcripts are elongated, spliced and cleaved into their mature forms. While the connection between this RNA-modulating gene to DNA repair remained poorly understood, the identification of CDK12 as a BRCAness gene piqued significant clinical interest.

The researchers who pinpointed this connection, Sara Dubbury and Paul Boutz, both work in the laboratory of Phillip Sharp, Institute Professor, professor of biology, and member of the Koch Institute for Integrative Cancer Research. In a study appearing online in Nature on Nov. 28, they describe how they discovered a previously unknown mechanism by which CDK12 enables the production of full-length RNA transcripts and that this mechanism was especially critical to maintain functional expression of the other BRCAness genes.

When the researchers knocked out expression of CDK12, mouse stem cells showed many signs of accumulating DNA damage that prevented DNA replication from going forward, classic indications of a BRCAness phenotype. To identify what roles CDK12 may play in regulating gene expression, the researchers turned to RNA sequencing to determine which genes had increased or decreased their overall expression.

To their surprise, only genes activated by p53 and early differentiation (side effects of accumulating unrepaired DNA damage and BRCAness in mouse stem cells) accounted for the lion’s share of changes to RNA transcription. However, when the researchers instead focused on the types of RNAs transcribed, they found that many genes produced unusually short transcripts when CDK12 was absent.

Not every stretch of DNA in a gene makes it into the final RNA transcript. The initial RNA from a gene often includes sections, which researchers call “introns,” that are cut out of transcript, the discovery that earned Sharp the 1993 Nobel Prize in Physiology or Medicine and the remaining sections. “Exons,” are spliced together to form a mature transcript (mRNA). Alternately, an intronic polyadenylation (IPA) site may be activated to cleave away the RNA sequence that follows it preventing intron removal and generating a prematurely shortened transcript. These processes allow the same gene to produce alternate forms of messenger RNA (mRNA), and thus be translated into different protein sequences.

Surprisingly CDK12 knockout cells produced significantly more IPA-truncated transcripts genome-wide, while full-length transcripts for the same genes were reduced. These shortened mRNAs can vary greatly in their stability, their ability to be translated into protein, and their protein function. Thus, even while a gene may be actively transcribed, its translation into functional proteins can be radically altered or depleted by IPA activation.

While this observation began to illuminate CDK12’s role in regulating mRNA processing, what remained puzzling was why CDK12 loss affected the HR pathway so disproportionately. In investigating this question, Dubbury and Boutz found that BRCAness genes were overrepresented as a group among those genes that have increased IPA activity upon CDK12 loss.

Additionally, while CDK12 suppresses IPA activity genome-wide, 13 of the other 21 BRCAness genes were found to be particularly vulnerable to CDK12 loss, in part, because they possess multiple high-sensitivity IPA sites, which have a compound effect in decreasing the total amount of full-length transcripts. Moreover, because multiple CDK12-senstive BRCAness genes operate in the same HR pathway, the researchers believe that the disruption to HR repair of double-stranded DNA breaks is amplified.

CDK12 mutations are found recurrently in prostate and ovarian cancer patients, making them an attractive diagnostic and therapeutic target for cancer. However, not enough is known about CDK12 to distinguish between true loss-of-function mutations and so-called “passenger mutations” with no functional consequence.

“The ability to identify patients with true loss-of-function mutations in CDK12 would enable clinicians to label a new cohort of patients with bona fide BRCAness tumors that could benefit from certain highly effective and targeted chemotherapeutics against BRCAness, such as PARP1 inhibitors,” says Dubbury, a former David H. Koch Fellow.

Dubbury and Boutz were able to confirm that IPA sites in key BRCAness genes were also used more frequently upon CDK12 loss in human tumor cells using RNA sequencing data from prostate and ovarian tumor patients with CDK12 mutations and by treating human prostate adenocarcinoma and ovarian carcinoma cells with a CDK12 inhibitor. This result suggests that the CDK12 mechanism observed in mouse cell lines is conserved in humans and that CDK12 mutations in human ovarian and prostate tumors may promote tumorigenesis by increasing IPA activity and thus functionally attenuating HR repair.

“These results not only give us a better understanding how CDK12 contributes to BRCAness, they also may have exciting potential impact in the clinic,” Dubbury says. “Currently available diagnostic techniques could be used to probe the usage of IPA sites found in this study to rapidly screen for patients with true loss-of-function CDK12 mutations, who would respond to BRCAness-targeted treatments.”

Paul Boutz, a research scientist in the Sharp Lab, is co-first author of the study, and has plans to follow-up many of these implications for ovarian and prostate cancer his lab at the University of Rochester School of Medicine and Dentistry.

“CDK12 provides a remarkable example of how factors that control the processing of RNA molecules can function as master regulators of gene networks, and thereby profoundly affect the physiology of both normal and cancerous cells,” he says.

Phil Sharp, the senior author on the work, says “Sara’s and Paul’s surprising discovery that CDK12 suppresses intronic polyadenylation has implications for fundamental new insights into gene structure as well as for control of cancer.”

Uncovering the “must-haves” of tissue regeneration
Nicole Davis | Whitehead Institute
November 27, 2018

Cambridge, MA.  – The ability to regrow missing or damaged body parts is one of the great marvels of modern biology. In an effort to lay bare the biological underpinnings of this phenomenon, scientists at Whitehead Institute have begun to define the core features that are required for regeneration in flatworms. Their research, which appears online November 27 in Cell Reports, reveals that a set of cellular and molecular responses — previously thought to be essential for regeneration following amputations and other major injuries — is in fact dispensable.

“This is a real surprise,” said senior author Peter Reddien, a Member of Whitehead Institute, professor of biology at Massachusetts Institute of Technology, and investigator with the Howard Hughes Medical Institute. “These responses are broad, prominent attributes of tissue regeneration and repair and, a reasonable bet was that they function to bring about regeneration.”

About eight years ago, Reddien and his team described a set of biological activities that are triggered by injuries that remove tissue. Whereas a cut or a scrape removes little if any tissue, more damaging injuries, like amputations, cause significant tissue loss. That missing tissue must be regenerated to ensure the organism retains its proper anatomical proportions.

A series of cellular and molecular activities — known collectively as the missing tissue response — were believed to enable this regeneration to occur. They include the sustained action of genes that respond to injury, a period of intense cell division in areas surrounding the wound, and a general increase in cell death throughout the body. “This happens prominently, not only in planarians but also in other organisms capable of regeneration, so we suspected that the missing tissue response must play a very fundamental role in regeneration,” recalled Reddien.

What types of injuries require the missing tissue response for repair, and what is the function of the missing tissue response in regeneration? Graduate student and first author Aneesha Tewari, Reddien and colleagues, including Sarah Stern and Isaac Oderberg, set out to uncover the answers. This work forms the basis of their latest Cell Reports study.

The researchers harnessed an earlier discovery that a gene known as follistatin is required for the missing tissue response in flatworms (known as planarians). By using molecular tools to inhibit this gene, they could block the missing tissue response and observe what happens under various wound conditions, ranging from minimal (the removal of an eye, for example) to moderate (the removal of the pharynx or part of the head) to significant tissue loss (the removal of a complete side of the body). Remarkably, in every case, the missing tissue was regenerated, albeit much more slowly than it would be otherwise.

“These results tell us that what the missing tissue response is really doing is simply pushing the foot down on the gas pedal — basically accelerating the process of regeneration,” explained Reddien. “If you can’t accelerate, you’ll still get there, it just takes longer.”

Tewari, Reddien, and their colleagues also cracked a thorny mystery surrounding the missing tissue response. Although their results show that it is not required across a wide range of injuries, there is one lingering instance in which regeneration failed to occur when they blocked the missing tissue response: head amputation.

“This was a big puzzle,” said Tewari. “It left us wondering whether or not we could generalize our findings to all types of wounds — is there something special about the head that makes it uniquely dependent on the missing tissue response?”

The answer, it turns out, is no. When follistatin is blocked, a key signaling protein, called Wnt1, kicks into overdrive. And when that happens, the tissue destined to form the head does not receive the positional cues it needs to properly regrow, which means regeneration fails to proceed. But, when both the missing tissue response and Wnt1 are blocked, the head does indeed regenerate, the team uncovered.

Taken together, the researchers’ findings begin to clarify what is essential for regeneration to take place and what is not. “Our study greatly simplifies the picture of what it takes to regenerate,” said Reddien. “And that’s an important step along the path towards dissecting the central elements of regeneration in animals that do regenerate well, like flatworms, and then applying that knowledge to understand what the limits might be in those animals that don’t regenerate as well, like humans.”

This research was supported by the NIH (R01GM080639), the National Science Foundation, the Eleanor Schwartz Charitable Foundation, and the Howard Hughes Medical Institute.

***
Peter Reddien’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 Howard Hughes Medical Institute Investigator and a professor of biology at Massachusetts Institute of Technology.
***
Full citation:
Cell Reports,  Vol. 25, Is. 9, P2577-2590.E3, November 27, 2018, DOI:https://doi.org/10.1016/j.celrep.2018.11.004
“Cellular and molecular responses unique to major injury are dispensable for planarian regeneration”
Aneesha G. Tewari (1,2), Sarah R. Stern (1,2), Isaac M. Oderberg (1,2,4), and Peter W. Reddien (1,2,3)
 1.Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA
2. Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
3. Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA
4. Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
Computer model offers more control over protein design

New approach generates a wider variety of protein sequences optimized to bind to drug targets.

Anne Trafton | MIT News Office
October 15, 2018

Designing synthetic proteins that can act as drugs for cancer or other diseases can be a tedious process: It generally involves creating a library of millions of proteins, then screening the library to find proteins that bind the correct target.

MIT biologists have now come up with a more refined approach in which they use computer modeling to predict how different protein sequences will interact with the target. This strategy generates a larger number of candidates and also offers greater control over a variety of protein traits, says Amy Keating, a professor of biology, a member of the Koch Institute, and the leader of the research team.

“Our method gives you a much bigger playing field where you can select solutions that are very different from one another and are going to have different strengths and liabilities,” she says. “Our hope is that we can provide a broader range of possible solutions to increase the throughput of those initial hits into useful, functional molecules.”

In a paper appearing in the Proceedings of the National Academy of Sciences the week of Oct. 15, Keating and her colleagues used this approach to generate several peptides that can target different members of a protein family called Bcl-2, which help to drive cancer growth.

Recent PhD recipients Justin Jenson and Vincent Xue are the lead authors of the paper. Other authors are postdoc Tirtha Mandal, former lab technician Lindsey Stretz, and former postdoc Lothar Reich.

Modeling interactions

Protein drugs, also called biopharmaceuticals, are a rapidly growing class of drugs that hold promise for treating a wide range of diseases. The usual method for identifying such drugs is to screen millions of proteins, either randomly chosen or selected by creating variants of protein sequences already shown to be promising candidates. This involves engineering viruses or yeast to produce each of the proteins, then exposing them to the target to see which ones bind the best.

“That is the standard approach: Either completely randomly, or with some prior knowledge, design a library of proteins, and then go fishing in the library to pull out the most promising members,” Keating says.

While that method works well, it usually produces proteins that are optimized for only a single trait: how well it binds to the target. It does not allow for any control over other features that could be useful, such as traits that contribute to a protein’s ability to get into cells or its tendency to provoke an immune response.

“There’s no obvious way to do that kind of thing — specify a positively charged peptide, for example — using the brute force library screening,” Keating says.

Another desirable feature is the ability to identify proteins that bind tightly to their target but not to similar targets, which helps to ensure that drugs do not have unintended side effects. The standard approach does allow researchers to do this, but the experiments become more cumbersome, Keating says.

The new strategy involves first creating a computer model that can relate peptide sequences to their binding affinity for the target protein. To create this model, the researchers first chose about 10,000 peptides, each 23 amino acids in length and helical in structure, and tested their binding to three different members of the Bcl-2 family. They intentionally chose some sequences they already knew would bind well, plus others they knew would not, so the model could incorporate data about a range of binding abilities.

From this set of data, the model can produce a “landscape” of how each peptide sequence interacts with each target. The researchers can then use the model to predict how other sequences will interact with the targets, and generate peptides that meet the desired criteria.

Using this model, the researchers produced 36 peptides that were predicted to tightly bind one family member but not the other two. All of the candidates performed extremely well when the researchers tested them experimentally, so they tried a more difficult problem: identifying proteins that bind to two of the members but not the third. Many of these proteins were also successful.

“This approach represents a shift from posing a very specific problem and then designing an experiment to solve it, to investing some work up front to generate this landscape of how sequence is related to function, capturing the landscape in a model, and then being able to explore it at will for multiple properties,” Keating says.

Sagar Khare, an associate professor of chemistry and chemical biology at Rutgers University, says the new approach is impressive in its ability to discriminate between closely related protein targets.

“Selectivity of drugs is critical for minimizing off-target effects, and often selectivity is very difficult to encode because there are so many similar-looking molecular competitors that will also bind the drug apart from the intended target. This work shows how to encode this selectivity in the design itself,” says Khare, who was not involved in the research. “Applications in the development of therapeutic peptides will almost certainly ensue.”

Selective drugs

Members of the Bcl-2 protein family play an important role in regulating programmed cell death. Dysregulation of these proteins can inhibit cell death, helping tumors to grow unchecked, so many drug companies have been working on developing drugs that target this protein family. For such drugs to be effective, it may be important for them to target just one of the proteins, because disrupting all of them could cause harmful side effects in healthy cells.

“In many cases, cancer cells seem to be using just one or two members of the family to promote cell survival,” Keating says. “In general, it is acknowledged that having a panel of selective agents would be much better than a crude tool that just knocked them all out.”

The researchers have filed for patents on the peptides they identified in this study, and they hope that they will be further tested as possible drugs. Keating’s lab is now working on applying this new modeling approach to other protein targets. This kind of modeling could be useful for not only developing potential drugs, but also generating proteins for use in agricultural or energy applications, she says.

The research was funded by the National Institute of General Medical Sciences, National Science Foundation Graduate Fellowships, and the National Institutes of Health.

Plant characteristics shaped by parental conflict
Greta Friar | Whitehead Institute
November 19, 2018

CAMBRIDGE, Mass. – Different subpopulations of a plant species can have distinct traits, varying in size, seed count, coloration, and so on. The primary source of this variation is genes: different versions of a gene can lead to different traits. However, genes are not the only determinant of such traits, and researchers are learning more about another contributor: epigenetics. Epigenetic factors are things that regulate genes, altering their expression, and like genes they can be inherited from generation to generation, even though they are independent of the actual DNA sequences of the genes.

One epigenetic mechanism is DNA methylation, in which the addition of chemical tags called methyl groups can turn genes on or off. Genes that share the identical DNA sequence but have different patterns of methylation are called epialleles. Several studies have shown that epialleles, like different versions of genes, can cause differences in traits between plant subpopulations, or strains, but whether genetic factors are also at play can be difficult to determine.

The lab of Whitehead Member Mary Gehring, who is also an associate professor at Massachusetts Institute of Technology, has described evidence that epialleles alone can lead to different heritable traits in plants. In research published online November 5 in the journal PLoS Genetics, Gehring, along with co-first authors and former lab members Daniela Pignatta and Katherine Novitzky, showed that altering the methylation state of the gene HDG3 in different strains of the plant Arabidopsis thaliana was enough to cause changes in seed weight and in the timing of certain aspects of seed development.

In plants, methylation states of genes change most frequently during seed development, when genes are switched on or off to progress development of the organism. This period is also when a conflict of interest arises in the genome of each seed between the parts inherited from its mother and father. The mother plants produce seeds fertilized by different fathers at the same time. It’s in the mother’s interest to give an equal share of nutrients to each seed—to have many smaller seeds. But it’s in the father’s interest for its seed to get the most nutrients and grow larger. This conflict plays out through an epigenetic mechanism called imprinting, in which, through differential methylation between the father’s and mother’s copies of a gene, one parent’s copy is silenced in the offspring so that only the other parent’s version of the gene is expressed.

The gene HDG3 is imprinted in one strain of Arabidopsis so that only the father’s copy is expressed. Gehring and her team found that when the strain loses its paternal imprinting, the timing of seed development is affected and the plant ends up with smaller seeds. This is consistent with the theory of imprinting: When the father’s genes have the advantage, the seeds are larger than when both parents’ genes are equally expressed.

Other experiments tested the effect of either activating or silencing HDG3 by methylation in a variety of scenarios, both in a separate strain of Arabidopsis in which the gene starts off silenced, as well as in crosses between the two strains. The researchers found that altering the methylation state of the gene was sufficient to affect seed size and the timing of seed development. In the crosses, these traits depended on whether the paternal copy of the gene came from the strain in which HDG3 was normally silenced or the strain in which it was normally activated.

Altogether these experiments demonstrate a link between changes in methylation state and differences in seed development and size. This suggests that epialleles in natural populations function much like variations in genes, creating heritable traits that differ within the larger population.

This work was funded by the National Science Foundation (NSF grant 1453459).

***

Mary Gehring’s primary affiliation is with Whitehead Institute for Biomedical Research, where her laboratory is located and all her research is conducted. She is also an associate professor of biology at Massachusetts Institute of Technology.
***
Full citation:
“A variably imprinted epiallele impacts seed development”
PLoS Genetics, online November 5 2018, https://doi.org/10.1371/journal.pgen.1007469
Daniela Pignatta (1,3), Katherine Novitzky (1,3), P. R. V. Satyaki (1), Mary Gehring (1,2)
1. Whitehead Institute for Biomedical Research, Cambridge, MA, United States of America
2. Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, United States of America
3. These authors contributed equally to this work.
Heart-healthy plant chemistry
Greta Friar | Whitehead Institute
October 29, 2018

Plants have been a rich source of medicines for thousands of years. Compounds such as artemisinin, for example, used to treat malaria, and morphine, a pain reliever, are mainstay therapeutics derived from plants. However, several roadblocks in plant chemistry research have prevented scientists from tapping into the full potential of plant-based medicinal compounds, thwarting drug discovery and development. Researchers typically screen for molecules of interest by breaking the plant into very small pieces, using biochemistry to test the activity of the pieces, and isolating the molecules responsible for the activity. It is often difficult, however, to pick the right compound responsible for a medicinal effect out of the plant mixture, or to identify the genes responsible for producing it.

The Chinese wolfberry plant (Lycium barbarum), also known as goji berry, has been used in traditional Chinese herbal medicine for millennia to treat symptoms such as high blood pressure. Researchers had identified small protein-like molecules called lyciumins, produced by the goji berry, as the source of its antihypertensive properties but little else was known about the molecules.

In research published online October 29 in the journal Proceedings of the National Academy of Sciences, Whitehead Institute Member Jing-Ke Weng and postdoctoral researcher Roland Kersten describe an approach to speed up the process of identifying plant chemistry that they used to investigate lyciumins. The approach capitalizes on the growing number of plants that have had their genomes sequenced. The wealth of genomic data available enabled Kersten to identify the gene that is associated with lyciumin production in goji berries by searching for a DNA sequence that matched the sequences of the lyciumins. Once Kersten found the matching precursor gene in goji berries he inserted it into a tobacco plant, which began producing lyciumins, confirming that he had found the right gene.

Kersten then hunted for lyciumin-producing genes in other plant genomes using a common feature of the genes that he had identified as a search query. He discovered more than one hundred unknown lyciumins in everything from potatoes to beets to soybeans.

Having sped up the gene discovery stage, Kersten used gene expression techniques to likewise speed up the molecule production stage. Being able to quickly produce large quantities of a drug candidate is necessary for testing and manufacturing the drug. Kersten edited the lyciumin precursor genes to make more copies of the molecule and then inserted the edited genes into the tobacco plant to mass produce lyciumins up to 40 times faster than the original plants. Kersten was also able to edit the lyciumins’ DNA sequences to alter the molecules’ structure, creating new varieties of lyciumins not found in nature. Together, these results allow for the future creation of a lyciumin library, a valuable repository for drug discovery research. Millions of different lyciumins can be grown in tobacco and tested for their efficacy as antihypertensive drugs or in other potential agrochemical and pharmaceutical applications.

Weng and Kersten’s approach leverages the recent explosion in plant genomics to uncover important medicinal compounds in plants and reveal the secrets of plants used in traditional global medicine for generations. For Kersten, the research was also an exciting demonstration of just how much undiscovered chemistry lies waiting to be tapped in even the best-studied crop plants.

This work was supported by grants from the Thome Foundation, the Pew Scholars Program in the Biomedical Sciences, the Searle Scholars Program, and the Family Larsson Rosenquist Foundation.

***
Jing-Ke Weng’s primary affiliation is with Whitehead Institute for Biomedical Research, where his laboratory is located and all his research is conducted. He is also an assistant professor of biology at Massachusetts Institute of Technology.
***
Full citation:
“Gene-guided discovery and engineering of branched cyclic peptides in plants”
PNAS, online on October 29.
Roland D. Kersten (1), Jing-Ke Weng (1,2)
1. Whitehead Institute for Biomedical Research, 455 Main Street, Cambridge, MA, United States
2. Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, United States
Activating a new understanding of gene regulation
Greta Friar | Whitehead Institute
November 15, 2018

CAMBRIDGE, Mass. – Regulation of gene expression — turning genes on or off, increasing or decreasing their expression — is critical for defining cell identity during development and coordinating cellular activity throughout the cell’s lifetime. The common model of gene regulation imagines the nucleus of the cell as a large space in which molecules involved in DNA transcription float around seemingly at random until they stumble across a DNA sequence or other transcriptional machinery to which they can bind — a haphazard approach. However, this paradigm is being upended as over the last few years researchers have discovered that rather than being amorphous spaces dependent upon fortuitous collisions, cells actually compartmentalize their processes into discrete membraneless structures in order to congregate relevant molecules, thereby better coordinating their interactions. Research from the lab of Whitehead Member Richard Young and others earlier this year reported that such compartmentalization is a crucial, previously unobserved aspect of gene regulation.[1]

The latest research from Young’s lab, published online November 15 in the journal Cell, delves further into how such compartmentalization helps orchestrate transcriptional regulation by revealing the role of the activation domain, a part of transcription factors previously shrouded in mystery. One side of transcription factors, containing the DNA binding domain, binds to a region of DNA near a gene. The other end, called the activation domain, then captures molecules that impact gene expression, anchoring that transcriptional machinery near the gene.

This most recent work reveals that activation domains do their job by meshing with other transcription proteins to form liquid droplets near the genes they regulate. The process by which the molecules form a distinct liquid compartment within the environment of the cell — like oil refusing to mix with vinegar in a salad dressing — is called phase separation.

Such an evolved understanding of gene regulation has enormous implications for medicine and drug discovery, as errors in gene regulation are key components of many diseases, including cancers. The new model could help illuminate how diseases coopt regulatory mechanisms and how therapeutic interventions might remedy such dysregulation. Transcription factors have traditionally been hard to target therapeutically, and the incomplete understanding of their structure and function may have been part of the reason.

“Transcriptional regulation is important for every human function, from cell differentiation to development to cell maintenance,” says Ann Boija, co-first author and postdoctoral researcher in Young’s lab. “Despite that fact the structure and function of the activation domain on the transcription factors have been poorly understood.”

Most proteins settle into defined three-dimensional structures and can only bind with other molecules that fit them perfectly, in a specific orientation, like a key in a lock. The activation domains of transcription factor proteins, however, contain what are known as intrinsically disordered regions, which behave more like strands of cooked spaghetti, tangling at random into flexible shapes. This disorder allows the molecules to bind at many points, creating a dynamic network of loose connections that appears to precipitate phase separation.

“I have taught regulatory biology for decades using inspiration from lock and key structures. They are elegant, and easy to visualize and model, but they don’t tell the whole story. Phase separation was the missing piece,” says Young, who is also a professor of biology at MIT.

In experiments with a variety of transcription factors, Boija and co-first author Isaac Klein, a postdoctoral researcher in Young’s lab and medical oncology fellow at the Dana-Farber Cancer Institute, found that the transcription factors meshed with Mediator, a molecule that helps activate genes, and phase separated into droplets, and that this process was associated with gene activation. The transcription factors they investigated included OCT4, which is important for maintaining the state of embryonic stem cells; the estrogen receptor (ER), which plays a role in breast cancer; and GCN4, a well-studied model transcription factor in yeast.

The discovery has implications for many diseases, such as cancer, in which cancer genes may use phase separated droplets to help ramp up their expression. New therapeutic approaches could focus on dissolving the droplets, and drug discovery can incorporate testing of how the drug — or target molecule — behaves inside versus outside of the droplets. This new model of how transcription factors function is not only rewriting the understanding of transcriptional regulation, it is opening up new paths for drug discovery and therapeutic approaches.“We found a link between gene activation and phase separation across a broad spectrum of contexts,” Klein says, suggesting that this mechanism is a common feature of transcriptional regulation.

The work was supported by the National Institutes of Health (NIH grants GM123511, GM117370, T32CA009172, T32GM08759), the National Science Foundation (NSF grant PHY1743900), Swedish Research Council (VR 2017-00372), Damon Runyon Cancer Research Foundation (2309-17), Hope Funds for Cancer Research, Cancer Research Institute, and Netherlands Organisation for Scientific Research (NWO).

***
Richard Young’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.
***
Full citation:
“Transcription factors activate genes through the phase separation capacity of their activation domains”
Cell, online November 15, DOI: 10.1016/j.cell.2018.10.042
Ann Boija (1,7), Isaac A. Klein (1,2,7), Benjamin R. Sabari (1), Alessandra Dall’Agnese (1), Eliot L. Coffey (1,3), Alicia V. Zamudio (1,3), Charles H. Li (1), Krishna Shrinivas (4,5), John C. Manteiga (1,3), Nancy M. Hannett (1), Brian J. Abraham (1), Lena K. Afeyan (1,3), Yang E. Guo (1), Jenna K. Rimel (6), Charli B. Fant (6), Jurian Schuijers (1), Tong Ihn Lee (1), Dylan J. Taatjes (6), and Richard A. Young (1,3)
  1. Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA
  2. Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA
  3. Department of Biology
  4. Department of Chemical Engineering
  5. Institute of Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA
  6. Department of Biochemistry, University of Colorado, Boulder, CO 80303, USA
  7. These authors contributed equally
[1] Sabari et al., “Coactivator condensation at super-enhancers links phase separation and gene control,”
Science, June 21, 2018; Cho et al., “Mediator and RNA polymerase II clusters associate in transcription-dependent condensates,” Science, June 21 2018.