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Mary Gehring: Using flowering plants to explore epigenetic inheritance

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

Anne Trafton | MIT News Office
December 16, 2019

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

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

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

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

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

Seeds of discovery

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

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

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

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

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

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

Patterns of inheritance

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

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

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

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

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

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

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

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

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

A new way to regulate gene expression

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

Raleigh McElvery | Department of Biology
December 9, 2019

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

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

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

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

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

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

Promoting gene expression

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

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

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

A more flexible genome

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Written by Greta Friar

***

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

***

Citation:

“The biochemical basis of microRNA targeting efficacy”

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

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

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

†These authors contributed equally to this work.

Three MIT seniors to join 2021 class of Schwarzman Scholars

Two alumni have also been selected; the scholars will study global affairs at Beijing’s Tsinghua University.

Julia Mongo | Distinguished Fellowships
December 4, 2019

Three MIT seniors, Mariam Dogar, Adedoyin Olateru-Olagbegi, and Jessica Quaye, and alumna Jessica Wang ’16, MEng ’17 are recipients of this year’s Schwarzman Scholarship distinguished fellowship. Another alumna was also awarded a scholarship but is waiting to make a public announcement until she has shared the news with her employer.

The five winners were selected from an applicant of pool over 4,700 candidates and will join fellow Schwarzman Scholars from around the world in China next August. Scholars complete a one-year master’s degree in global affairs at Beijing’s Tsinghua University. Their education is complemented by internships, career development mentors, high-profile speakers, and opportunities to travel throughout China.

Inspired by the Rhodes Scholarship, the Schwarzman Scholarship program began in 2015 to bring together talented young leaders and prepare them for the geopolitical and economic challenges of the 21st century by deepening their understanding of China. Since its inception, 18 MIT students and alumni have been named Schwarzman Scholars.

Kim Benard, assistant dean of distinguished fellowships in Career Advising and Professional Development prepares MIT’s applicants, with assistance from the Presidential Committee on Distinguished Fellowships’ faculty members. MIT students and recent alumni interested in learning more about the Schwarzman Scholarship program should contact fellowships@mit.edu.

Hailing from Northborough, Massachusetts, Mariam Dogar is majoring in biology and minoring in urban studies and planning. She aims to make health care more accessible and equitable through reworking outdated policies and utilizing technology. Dogar has worked at the World Bank developing telemedicine policy recommendations for lower middle-income countries. She has two years of experience on the teaching team of MIT’s negotiation and leadership classes, where she shaped pedagogy and co-taught a workshop for MBA students in Malaysia. She has taught humanitarian design in Greece with MIT D-Lab, worked in digital health care investing in the Middle East, and volunteered in refugee programs in Jordan. She is a co-president of MIT Mock Trial and GlobeMed@MIT. She is also an executive member of PaksMIT and counselor for Camp Kesem.

Jessica Quaye, an electrical engineering and computer science major, has conducted research with MIT.nano and the HCIE group in CSAIL. She has also sharpened her technical and business management skills through internships at Google, Microsoft, and Bain and Company. Quaye, a Tau Beta Pi Scholar, is president of the MIT African Students’ Association. She serves on MIT’s Undergraduate Association committees and the EECS Undergraduate Student Advisory Group. She founded the International Students of Color Working Group to support the needs of first-year international students, and she established the first MIT Global Teaching Lab initiative in Ghana. Quaye is from Accra, Ghana. As a Schwarzman Scholar, she hopes to deepen her understanding of public policy and dreams of one day driving policy change in Ghana.

Adedoyin Olateru-Olagbegi, from Hanover, Maryland, is majoring in computer science, economics, and data science. She envisions a world where quality health care is accessible to all, and plans to focus on health in developing countries with an emphasis on innovative digital tools. She has explored her interests in development and public health through classes that have taken her to South Africa and Colombia. As director of Camp Kesem at MIT, Olateru-Olagbegi organizes an annual summer camp for children affected by a parent’s cancer and oversees the MIT students who work with them. She has also held leadership roles with MIT Emergency Medical Services, the MIT Black Students’ Union, and Sigma Kappa Sorority, and has served on several MIT Institute Committees, including as a student advisor to President L. Rafael Reif.

Jessica Wang graduated from MIT in 2016 with a Bachelor of Science in computer science and engineering and received a Master of Engineering in 2017. She is passionate about utilizing technology for good and bringing her joint engineering and design background to shape technology policy. She currently lives in San Francisco, where she builds collaborative design software at Figma. She works on diversity and inclusion initiatives in the workplace and volunteers with Larkin Street, a nonprofit serving homeless youth, as a YCore Fellow. In the past, she’s worked at a machine learning startup, Facebook, and Uber. At MIT, Wang researched online sociopolitical discourse and misinformation, writing her thesis on digital systems to bridge ideological divides. She served as president of MIT Chinese Students’ Club and held leadership positions in MIT TechX and HackMIT.

Whitehead Institute team develops new method to study human brain cells
Nicole Davis | Whitehead
November 25, 2019

A groundswell of evidence connects defects in the function of microglia, the brain’s resident immune cells, to neurodegenerative diseases, yet the tools for studying these cells in the laboratory have been limited. Now, a team of Whitehead Institute scientists has developed a new experimental platform for generating microglia from human stem cells that includes transplantation into newborn mice. As described online November 26 in the Proceedings of the National Academy of Sciences (PNAS), this new method yields microglial cells that resemble those in the human brain more closely than previous approaches, which could help enable future studies aimed at unravelling the role of microglia in neurodegeneration and other brain disorders.

“The dysfunction of microglia is implicated in a wide variety of brain conditions, and yet our knowledge of them, especially in humans, is really quite limited,” says senior author Rudolph Jaenisch, a Founding Member of the Whitehead Institute and professor of biology at the Massachusetts Institute of Technology. “This new approach will help us lift the hood on these important yet enigmatic brain cells.”

Microglia are increasingly recognized as key players in brain health and disease, but the majority of what is known about them comes from studies of mice, not humans. Yet human and mouse microglia are quite distinct — in humans, the cells are much larger, and have a more branched appearance, suggesting significant differences in their biology.

To address this gap in knowledge, multiple research teams have recently devised methods to generate microglia using human stem cells and grow them under laboratory conditions that mimic their natural environment. However, this approach has a fundamental drawback: the cultured cells do not look like microglia nor do they behave much like them, even though they display the appropriate molecular hallmarks.

“That really suggests to us that this is not the optimal approach to study how microglia are behaving in healthy and diseased brains,” says first author Devon Svoboda, a postdoctoral fellow in the Jaenisch lab. “We set out to create a new method in which the stem-cell derived microglial cells can reside in the brains of mice — one of the best models of the human brain that we have.”

Transplanting human cells into mice — creating “chimeras” — is a well-established technique. However, Svoboda and her colleagues discovered they needed to use special strains of mice that carry human genes for certain growth factors, called cytokines, which are required for microglial development and survival. The researchers utilized mice that carry human genes for four crucial cytokines: CSF1, IL3, SCF, and GM-CSF.

“What is special about these chimeras is really the mice we are using,” says Svoboda. “They express the human alleles of these cytokines which is key because the mouse versions are not able to communicate with receptors on human microglia, so the cells die.”

After transplanting the stem-cell derived microglia into these mice, the research team examined the cells’ morphology and their molecular characteristics. They found that the transplanted cells closely resembled those found in the human brain.

Further analyses revealed some striking differences between the team’s “chimera-grown” microglia and those grown in the laboratory using conventional cell culture methods. Surprisingly, Svoboda and her colleagues found that the cultured microglia showed strong similarities to the diseased microglia from patients with multiple sclerosis, another brain condition in which the cells are implicated.

“If you want to learn more about the role of microglia in disease, then studying them in culture is probably not the best way,” says Svoboda. “The chimeras and the in vitro methods really complement each other, and we think there is a place for both systems in microglia research going forward.”

The Whitehead-led team plans to extend their initial studies in several ways. One is to identify which cytokines and other growth factors are most crucial to microglial development. That knowledge could help improve existing cell culture methods and enable them to more closely mirror the cells’ natural environment. Another key direction is to use the new chimera-based system to create models of neurodegenerative diseases, including Alzheimer’s and Parkinson’s disease, to understand how microglia respond to diseased neurons and, in turn, how diseased microglia can impair neuron function.

“Our chimera-based method will give us a good handle to begin to stringently test the role of microglia in brain health and disease,” says Jaenisch. “This is an important step forward for the field.”

Support for this work was provided by the Cure Alzheimer’s Foundation, MassCATS, and NIH Grants R01 AG058002-01, R01 MH104610, R37 CA084198, and U19 AI131135 (to R.J.). L.D.S. is supported by NIH Grants R24 OD26440, AI32963, and CA034196. J.S. is supported by the National Institute of Child Health and Human Development (K99HD096049).

Written by Nicole Davis

***

Rudolf Jaenisch’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.

***

Paper cited:

Human iPSC-derived microglia assumer a primary microglia-like state after transplantation into the neonatal mouse brain.

PNAS, online November 26, 2019. DOI: 10.1073/pnas.1913541116

Devon S. Svoboda (1), M. Inmaculada Barrasa (1), Jian Shu (1,3), Rosalie Rietjens (1), Shupei Zhang (1), Maya Mitalipova (1), Peter Berube (3), Dongdong Fu (1), Leonard D. Shultz (4), George W. Bell (1), and Rudolf Jaenisch (1,2)

 

1. Whitehead Institute, Cambridge, MA 02142, USA

2. Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA

3. Broad Institute of MIT and Harvard, Cambridge, MA 02142

4. The Jackson Laboratory Cancer Center, The Jackson Laboratory, Bar Harbor, ME 04609

Six MIT faculty elected 2019 AAAS Fellows

Baggereroer, Flynn, Harris, Klopfer, Lauffenburger, and Leonard are recognized for their efforts to advance science.

MIT News Office
November 26, 2019

Six MIT faculty members have been elected as fellows of the American Association for the Advancement of Science (AAAS).

The new fellows are among a group of 443 AAAS members elected by their peers in recognition of their scientifically or socially distinguished efforts to advance science. This year’s fellows will be honored at a ceremony on Feb. 15, at the AAAS Annual Meeting in Seattle.

Arthur B. Baggeroer is a professor of mechanical, ocean and electrical engineering, the Ford Professor of Engineering, Emeritus, and an international authority on underwater acoustics. Throughout his career he made significant advances to geophysical signal processing and sonar technology, in addition to serving as a long-time intellectual resource to the U.S. Navy.

Suzanne Flynn is a professor of linguistics and language acquisition, and a leading researcher on the acquisition of various aspects of syntax by children and adults in bilingual, second- and third-language contexts. She also works on the neural representation of the multilingual brain and issues related to language impairment, autism, and aging. Flynn is currently editor-in-chief and a co-founding editor of Syntax: A Journal of Theoretical, Experimental and Interdisciplinary Research.

Wesley L. Harris is the Charles Stark Draper Professor of Aeronautics and Astronautics and has served as MIT associate provost and head of the Department of Aeronautics and Astronautics. His academic research program includes unsteady aerodynamics, aeroacoustics, rarefied gas dynamics, sustainment of capital assets, and chaos in sickle cell disease. Prior to coming to MIT, he was a NASA associate administrator, responsible for all programs, facilities, and personnel in aeronautics.

Eric Klopfer is a professor and head of the Comparative Media Studies/Writing program and the director of the Scheller Teacher Education Program and The Education Arcade at MIT. His interests range from the design and development of new technologies for learning to professional development and implementation in schools. Much of Klopfer’s research has focused on computer games and simulations for building understanding of science, technology, engineering, and mathematics.

Douglas Lauffenburger, is the Ford Professor of Biological Engineering, Chemical Engineering, and Biology, and head of the Department of Biological Engineering. He and his research group investigate the interface of bioengineering, quantitative cell biology, and systems biology. The lab’s main focus has been on fundamental aspects of cell dysregulation, complemented by translational efforts in identifying and testing new therapeutic ideas.

John J. Leonard is the Samuel C. Collins Professor of Mechanical and Ocean Engineering and a leading expert in navigation and mapping for autonomous mobile robots. His research focuses on long-term visual simultaneous localization and mapping in dynamic environments. In addition to underwater vehicles, Leonard has applied his pursuit of persistent autonomy to the development of self-driving cars.

This year’s fellows will be formally announced in the AAAS News and Notes section of Science on Nov. 28.

Building a roadmap for salicylic acid
Nicole Giese Rura | Whitehead Institute
November 25, 2019

Salicylic acid, which may be best known as a treatment for skin conditions such as acne and warts and in its modified form as aspirin, is a critical plant hormone involved in growth and development as well as regulating plants’ immune defenses. Unable to move and evade physical damage or attacks by bacteria and other pathogens, plants respond to these assaults through the biosynthesis of salicylic acid, which in turn controls cascades of other defense responses. Consequently, control of salicylic acid production in agricultural plants could boost crops’ resilience to pathogens and insects, thereby reducing the overuse of potentially toxic pesticides that can lead to pathogen resistance. Yet scientists have been missing a key tool necessary for manipulating salicylic acid levels in plants: a full description of the pathway necessary to synthesize the hormone. Now Whitehead Institute Member Jing-Ke Weng, along with Weng lab postdoc Michael Torrens-Spence, have uncovered the last missing steps in the Arabidopsis plant’s salicylic acid pathway and solved a puzzle that has dogged Weng and his field for decades.

The quest to define the salicylic acid biosynthesis pathway started about 50 years ago when researchers determined that salicylic acid is principally formed downstream from a ubiquitous compound called chorismate. In 2001 another step was resolved: Chorismate is converted to isochorismate before eventually becoming salicylic acid. Encouraged by this progress, many in the fields of plant biology and biochemistry thought that the rest of the biosynthesis pathway in plants would be quickly defined by looking for enzymes similar to those that comprise the bacterial version of the pathway, rather an almost two decade-long drought in discoveries followed instead.

Weng and Torrens-Spence tried a different tack using genetic and biochemical methods to break the dry spell in the identification of the pathway’s missing links. Their work is described online this week in the journal Molecular Plant. From previous research, Torrens-Spence knew that the enzymes encoded by two genes – PBS3 and EPS1 – play roles in salicylic acid accumulation after pathogen attacks. In order to determine the role of these enzymes in salicylic acid biosynthesis pathway, Torrens-Spence generated plants lacking in S3H and DMR6, two genes known to breakdown salicylic acid and keep its production in check. With those genes disrupted, plants overproduce salicylic acid to an extreme extent, resulting in a severely stunted growth and other physical traits associated with surplus salicylic acid. Using these transgenic plants, Torrens-Spence had a model in which he could see if a particular gene affects salicylic acid production: If Torrens-Spence mutates genes responsible for salicylic acid biosynthesis, salicylic acid production should be abolished along with the associated visible plant characteristics. Mutations in PBS3 and EPS1 did just that – they rescued the stunted phenotypes associated with salicylic acid overproduction, and the plants accumulated less salicylic acid in their leaves than plants without the PBS3 or EPS1 mutations.

Next Torrens-Spence analyzed and compared the metabolites – the compounds created by cellular processes – in the leaves of plants without mutations and plants with PBS3 or EPS1 mutations. The results identified the probable products of the PBS3 protein’s enzymatic activity and also determined that the EPS1 protein likely acts downstream of PBS3. In order to confirm PBS3 and EPS1’s roles in salicylic acid biosynthesis, Torrens-Spence recreated the pathway in the test tube and in a relative of the tobacco plant. In both models, the reconstructed pathway efficiently converts isochorismate into salicylic acid. Interestingly, Torrens-Spence found that the intermediate produced by PBS3 could be spontaneously converted to salicylic acid in plants, but EPS1 greatly increased this step’s efficiency.

A recent evolutionary study indicates that PBS3 and variations of this gene are found throughout flowering plants, and Torrens-Spence’s work uncovered that PBS3 is an essential enzyme in the production of salicylic acid likely across all flowering plants as well. EPS1 is found only within the mustard family, which includes broccoli, Brussel sprouts, and turnips. According to Torrens-Spence and Weng, other enzymes may fulfill a role similar in plants that lack EPS1. Though the EPS1 aspect of the biosynthesis pathway described by Torrens-Spence and Weng are specific to Arabidopsis, their work provides a roadmap that researchers could follow to explore salicylic acid production in other organisms.

Weng, who has been trying to solve salicylic acid’s biosynthesis pathway in plants since he was in graduate school, says that he’s proud to have finally identified the remaining steps in Arabidopsis. With the complete salicylic acid biosynthesis pathway in Arabidopsis now known, agricultural scientists can use it to try to precisely manipulate salicylic acid’s immunological benefits in crop plants without the stunted growth associated with its excessive production.

 

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

 

Written by Nicole Giese Rura

 

***

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 associate professor of biology at Massachusetts Institute of Technology.

***

Citation:

“PBS3 and EPS1 complete salicylic acid biosynthesis from isochorismate in Arabidopsis”

Molecular Plant, online November 21, 2019 [online] DOI:10.1016/j.molp.2019.11.005

1. Whitehead Institute, Cambridge, MA 02142, USA

2. Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA

Committed to reproduction
Greta Friar | Whitehead Institute
November 21, 2019

Cambridge, MA – Early in mammalian embryonic development, long before the organism’s ultimate form has taken shape, a precious subset of its cells are set aside for future use in creating offspring. This task bestows on that subset of cells a special kind of immortality. While the majority of the embryo’s cells go on to construct the growing body, and their journey begins and ends in that body, the cells that are set aside, called primordial germ cells (PGCs), will eventually produce sperm and eggs, which will in turn produce a new body—and so the circle of life continues.

An embryo’s earliest cells are pluripotent, meaning they have the potential to develop into many different cell types—for example, heart, brain, blood—but the descendants of these cells eventually become committed to a specific identity, after which each can only produce one type of cell. Scientists have long believed that when PGCs are set aside, they are immediately committed to the path of producing egg and sperm cells. However, new research from Whitehead Institute Director David Page, also a professor of biology at the Massachusetts Institute of Technology (MIT) and a Howard Hughes Medical Institute investigator, and postdoctoral researcher Peter Nicholls, suggests that instead, the primordial germ cells’ fate remains flexible for much longer: until much closer to the end of embryonic development. In most species, PGCs are set aside long before the gonads—the testes or ovaries—form, and then later travel to these developing gonads where they will ultimately produce sex cells. Page and Nicholls have found evidence that the fate of these PGCs remains flexible until shortly after they reach the gonads. Their findings, which appear in the journal PNAS on November 21, deepen our understanding of the process of reproduction.

“A fundamental question in biology is how we get from one generation to the next,” Page says. “And the cells that are tasked with producing the next generation are an important part of that story.”

Establishing a new timeline for when PGCs become committed could also shed light on the origins of some reproductive tract cancers, including testicular cancer, the incidence of which is on the rise, and which is already the most commonly diagnosed cancer in young men.

Although PGCs are precursors of sperm and eggs, they also share many features with pluripotent cells, like embryonic stem cells. If migrating PGCs are isolated and cultured like embryonic stem cells, the PGCs show indicators of pluripotency, and are able to spontaneously form tumors containing multiple cell types—a trademark of pluripotent cells. Page and Nicholls found evidence confirming that shortly after the PGCs reach the gonads, they lose this capacity to produce pluripotent cell lines, and their ability for tumor formation. From that point on, the PGCs can only develop into eggs and sperm, no matter their environment.

The researchers then set out to identify the gene that prompts PGCs to become committed to produce only eggs or sperm. First, Nicholls identified a set of genes that are activated around the time that PGCs enter the gonads in mice and humans, and of those, focused on the genes that appeared to have equivalents involved in sex cell commitment across a variety of animals, not just in mammals. He then narrowed in on one of these genes, Dazl, as the single gene necessary for PGCs to become irrevocably committed to their path as sex cells. Nicholls found that when the Dazl gene is deleted from mice, PGCs travel to the gonads but don’t develop into committed precursors of egg and sperm, suggesting that Dazl is the key ingredient in the recipe for sex cell commitment.

In the absence of Dazl, PGCs remain uncommitted, and in some cases, will form gonadal tumors. The researchers argue, based on their findings, that testicular cancer and other gonadal cancers may develop from PGCs that have travelled to the gonads, but have not properly committed to becoming sex cells and so are prone to forming tumors. In Dazl-deficient mice, which had large amounts of uncommitted PGCs, more than one out of four males developed testicular tumors at a young age. The early onset of the tumors is consistent with that seen in children and men with testicular cancer, most of whom are under 45 years old.

The researchers also found that female Dazl-deficient mice developed gonadal tumors, though at a lower rate than males. Further research demonstrated that the testis environment is particularly favorable for tumor formation from uncommitted PGCs.

“Testicular cancer is on the rise for reasons not yet known, and our findings suggest that the cancer has embryonic origins,” Page says. “Understanding the nature of primordial germ cells will be important for investigating and addressing this disease.”

The researchers hope that, along with providing insights into gonadal cancers, their work could help improve the derivation of eggs and sperm from stem cells in the lab. Figuring out the specifics of the process for sex cell commitment should allow researchers recreate it in a dish. Nicholls is also excited about the evolutionary implications of the work: he found evidence that a similar process of sex cell commitment occurs across a wide variety of species. In particular, research with DAZL-deficient pigs—whose last common ancestor with mice and humans lived 95 million years ago—provides strong evidence that this DAZL-dependent process has been in play since the early days of modern mammals.

“This work completely shifts the timing for when sex cells become committed in mammals,” Nicholls says. “Furthermore, our data suggest that a common set of factors might operate in sex cell commitment not only in mammals, but perhaps across all vertebrates, regardless of how the primordial germ cells are first established.”

This work was supported by the Howard Hughes Medical Institute; a Hope Funds for Cancer Research Fellowship; an Early Career Fellowship; a DFG grant; a research grant from Biogen, Inc.; the National Natural Science Foundation of China; and a National Institutes of Health SBIR award.

Written by Greta Friar

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David Page’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 the Massachusetts Institute of Technology.

***

Citation:

“Mammalian germ cells are determined after PGC colonization of the nascent gonad”

PNAS, online, Nov 21, 2019, DOI: 10.1073/pnas.1910733116

Peter K. Nicholls (1), Hubert Schorle (1,2),  Sahin Naqvi (1,3), Yueh-Chiang Hu (1,4), Fan Yuting (1,5), Michelle A. Carmell (1), Ina Dobrinski (6), Adrienne L. Watson (7), Daniel F. Carlson (7), Scott C. Fahrenkrug (7) and David C. Page (1,3,8)

1. Whitehead Institute, Cambridge, MA 02142, USA

2. Department of Developmental Pathology, Institute of Pathology, University of Bonn Medical

School, Bonn 53127, Germany

3. Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA

4. Divisions of Developmental Biology and Reproductive Sciences, Cincinnati Children’s

Hospital Medical Center, Cincinnati, OH 45229, USA

5. Reproductive Medicine Center, Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou,

510655, China

6. Department of Comparative Biology & Experimental Medicine, Faculty of Veterinary

Medicine, University of Calgary, Alberta, T2N 4N1, Canada

7. Recombinetics, Inc., Saint Paul, MN 55104, USA

8. Howard Hughes Medical Institute, Whitehead Institute, Cambridge, MA 02142, USA

Creating my niche in grad school

How diversity and outreach initiatives helped me find my place in MIT

YamilexA.-S.
November 15, 2019

Imagine being in a roller coaster that’s on fire, adrift, going full speed. That was my first year at MIT. Coming straight from an undergraduate institution in Puerto Rico, it was difficult for me to get used to the fast pace in which topics were taught in a different language and to the amount of work we had to constantly do. Recognizing these struggles, I convinced myself that I had to work even harder. However, towards the end of my first year, I couldn’t help but feel like something was missing. While struggling with that inner voice, I stumbled one day upon my personal statement for graduate school applications. I remember thinking, “who wrote this?”. One sentence in particular felt completely foreign to me: “I wish to provide a voice and an example that encourages minority students to pursue a career in science.” How was it that one year into my PhD program, I had completely lost the drive to start paving the path for people that looked and felt like me?

Being in STEM, it is quite easy to feel that if science isn’t the most important thing in your life, you are probably doing something wrong. For me, however, although science is definitely an important part of my life, it surely isn’t my entire life. I realize this isn’t a popular view among my peers, especially at a place like MIT, and it took some time for me to even embrace this mentality. I knew I appreciated my science more when I started doing things that fulfilled me outside the lab. This was clear in my mind, but I didn’t know where to start. How could I begin creating my niche in grad school?

While talking to a friend of mine about my interest in getting involved in diversity initiatives, I learn about a graduate student group called the Biology Diversity Community (BDC). The main mission of this group was to help foster networking amongst underrepresented graduate students in the biology community and connect students to resources that may be helpful. As it turned out, they were looking for volunteers to help plan out activities for the upcoming academic year. I reached out to the organizers, who listened to my ideas on how to create a healthy environment for students with a diverse array of backgrounds. They must have liked those ideas, since they then allowed me to carry out some activities for the semester including one for the MIT Summer Research Program (MSRP).

The MSRP is a summer program that enables undergraduate students from all over the country to conduct cutting-edge research at MIT, especially those from disadvantaged or underrepresented groups. My idea was to host a BDC-MSRP mixer to encourage summer students to interact with the greater MIT Biology community. A few days into the planning of the event, I started having doubts and worrying that very few people would actually show up. In between sending emails, ordering food, and publicizing the event, this thought kept haunting me. I wanted the mixer to be a success, not only because this was my first time planning an event of this magnitude, but also because this was part of fulfilling my major goal at MIT. I wanted to give back to the community that allowed me to be where I am today.

When the day of the event came, I was happy and reassured to see roughly 50 people show up, including post-docs, graduate students, and faculty! Many interns thanked me for the event, saying it made them feel like they were part of the community. I had a chance to speak with people from my program that I didn’t even know, and learned more about their lives and their experience in the department. Overall, I was genuinely excited my event was helpful for both the interns and the department.  

Enabling the bonding between upper year grad students and prospective students led me to become an organizer for BioPals. BioPals’ main goal is to increase communication amongst biology graduate students from all levels. First-year graduate students get paired with upper-year students (aka, “Pals”) to meet on a monthly basis and interact with other pairs during social events. I was part of the kickoff year as a BioPals mentee, which made my first semester here more bearable. My biopal was a fifth-year student that gave me all the pointers I needed to survive my first year. She went the extra mile to ensure I was ok, from giving me a gift after I passed my first round of exams, to staying with me for over an hour when I was having an anxiety attack. She really inspired me to become a resource for incoming first-years. I currently work on organizing BioPals along with 4 other students from my year. BioPals is now starting its second year, with more social events and roughly an 80% participation rate from first-year students.

With all these activities, I feel a sense of purpose by doing something that matters to me. That sentence in my personal statement doesn’t feel that foreign to me anymore. I can safely say that I have “provided a voice and an example that encourages minority students” to pursue a career in science. I feel happy I am able to do the two things I love during my graduate school trajectory: helping others and doing science!

I could continue talking about my niche forever, but I want to take some time to address yours! I have found that diversity and outreach are some of the things that keep me sane and happy in graduate school. If your niche is mentoring, policy, or startups, (or anything), make some time for that! Graduate school is long. You can run your experiment the next day or troubleshoot that equipment piece later. Make your graduate experience one that is worth looking back on. And I hope in no time, you’ll create your own niche in grad school!

Scholarships Open Up Learning Opportunities at MIT
MIT Better World
November 18, 2019

When Muskaan Aggarwal ’20 was considering colleges, she was looking for undergraduate research opportunities and a strong humanities program. “Choosing MIT was a convergence of factors,” she says. “I knew that there’s no better place for biological research than Cambridge, but I did not know that MIT students are required to take eight humanities classes over their four years. It was so surprising to learn that it’s built into the degree!”

And there was another important draw to the Institute: “Scholarship support was a big factor in me coming to MIT because I probably would not have been able to afford it otherwise,” says Aggarwal, who is a recipient of the Malcolm E. and Donna M. Wheeler Scholarship. As one of five universities in the country with need-blind admissions for both US and international students, MIT is committed to meeting the full financial need of every accepted undergraduate through scholarships. “My scholarship has made it possible for me to pursue extracurriculars based on my passions,” she continues. “It would be much more difficult to participate in those experiences if I had to support myself by working multiple jobs.”

In addition to majoring in biology, Aggarwal minors in ancient and medieval studies and participates in the Burchard Scholars Program, which facilitates monthly faculty-led humanities seminars. “To be a good scientist, you need to be able to communicate your work very effectively, and you cannot do that without a humanities background,” she says, noting that her minor and major intersect in interesting ways. “With ancient and medieval studies, we have very little evidence with which to reconstruct the past, so imagination is key. It’s similar with biology—we’ve learned so much but there’s still so much we don’t know; we have to combine existing knowledge with imagination to construct the future.”

Since her first year at MIT, Aggarwal has been working in the lab of Angelika Amon, who is the Kathleen and Curtis Marble Professor in Cancer Research, through the Undergraduate Research Opportunities Program. “In Professor Amon’s lab, I’ve been fortunate to be able to work with Marianna Trakala [postdoc researcher], an incredible mentor, since the infancy of the project. Our project explores how deviation from the normal chromosome number can lead to tumorigenesis,” Aggarwal says.

Aggarwal is planning to become a physician-scientist to pursue both patient care and research—her “true love”—but she is also looking for ways to integrate her other passions into her future profession. She sees MIT as the ideal place to explore a wide range of interests—and the scholarship support she receives is a vital component of her education. “MIT is an extraordinary place. In high school, I never imagined that I would be minoring in ancient and medieval studies, or dancing with middle school girls on Monday afternoons as a SHINE mentor, or writing a review of a Dutch film about a famous Swedish author for The Tech,” she says. “I could have done research at other schools, but would I be working in the lab of someone like Professor Amon, who won nearly every single big prize in science in the past year? I’m immensely grateful that the scholarship has given me the opportunity to explore all of my interests during college.”