Author: mantulin

New pathway for lung cancer treatment

MIT researchers identify pyrimidine biosynthesis as a target for the treatment of small cell lung cancer.

Bendta Schroeder | Koch Institute
November 11, 2019

MIT cancer biologists have identified a new therapeutic target for small cell lung cancer, an especially aggressive form of lung cancer with limited options for treatment.

Lung cancer is the leading cause of cancer-associated mortality in the United States and worldwide, with a five-year survival rate of less than 20 percent. But of the two major sub-types of lung cancer, small cell and non-small cell, small cell is more aggressive and has a much poorer prognosis. Small cell lung cancer tumors grow quickly and metastasize early, resulting in a five-year survival rate of about 6 percent.

“Unfortunately, we haven’t seen the same kinds of new treatments for small cell lung cancer as we have for other lung tumors,” says Tyler Jacks, director of the Koch Institute for Integrative Cancer Research at MIT. “In fact, patients are treated today more or less the same way they were treated 40 or 50 years ago, so clearly there is a great need for the development of new treatments.”

A study appearing in the Nov. 6 issue of Science Translational Medicine shows that small cell lung cancer cells are especially reliant on the pyrimidine biosynthesis pathway and that an enzyme inhibitor called brequinar is effective against the disease in cell lines and mouse models.

Jacks is the senior author of this study. Other MIT researchers include Associate Professor of Biology and Koch Institute member Matthew Vander Heiden, and co-lead authors postdoc researcher Leanne Li and graduate student Sheng Rong Ng.

Roadblock for cell replication

Researchers in the Jacks lab used CRISPR to screen small cell lung cancer cell lines for genes that already have drugs targeting them, or that are likely to be druggable, in order to find therapeutic targets that can be tested more quickly and easily in a clinical setting.

The group found that small cell lung cancer tumors are particularly sensitive to the loss of a gene encoding dihydroorotate dehydrogenase (DHODH), a key enzyme in the de novo pyrimidine biosynthesis pathway. Upon discovering that the sensitivity involved a metabolic pathway, the researchers sought the collaboration of the Vander Heiden lab, experts in normal and cancer cell metabolism who were already conducting studies on the role of pyrimidine metabolism and DHODH inhibitors in other cancers.

Pyrimidine is one of the major building blocks of DNA and RNA. Unlike healthy cells, cancer cells are constantly dividing and need to synthesize new DNA and RNA to support the production of new cells. The investigators found that small cell lung cancer cells have an unexpected vulnerability: Despite their dependence on the availability of pyrimidine, this synthesis pathway is much less active in small cell lung cancer cells than in other types of cancer cells examined in the study. Through inhibiting DHODH, they found that small cell lung cancer cells were not able to produce enough pyrimidine to keep up with demand.

When researchers treated a genetically engineered mouse model of small cell lung cancer tumors with the DHODH inhibitor brequinar, tumor progression slowed down and the mice survived longer than untreated mice. Similar results were observed for small cell lung cancer tumors in the liver, a frequent site of metastasis in patients.

In addition to mouse model studies, the researchers tested four patient-derived small cell lung cancer tumor models and found that brequinar worked well for two of these models — one of which does not respond to the standard platinum-etoposide regimen for this disease.

“These findings are noteworthy because second-line treatment options are very limited for patients whose cancers no longer respond to the initial treatment, and we think that this could potentially represent a new option for these patients,” says Ng.

Shorter pathway to the clinic

Brequinar has already been approved for use in patients as an immunosuppressant, and there has been some preclinical research showing that brequinar and other DHODH inhibitors may be effective for other types of cancers.

“We’re excited because our findings could provide a new way to help small cell lung cancer patients in the future,” says Li. “While we still have a lot of work to do before brequinar can be tested in the clinic as a therapy for small cell lung cancer, we’re hopeful that this might happen more quickly now that we’re starting with a drug that is known to be safe in humans.”

Next steps for the researchers include optimizing the therapeutic efficacy of DHODH inhibitors and combining them with other currently available treatment options for small cell lung cancer, such as chemotherapy and immunotherapy. To help clinicians tailor treatments to individual patients, researchers will also work to identify biomarkers for tumors that are susceptible to this therapy, and investigate resistance mechanisms in tumors that do not respond to this treatment.

The research was funded, in part, by the MIT Center for Precision Cancer Medicine and the Ludwig Center for Molecular Oncology at MIT.

School of Science appoints 14 faculty members to named professorships

Those selected for these positions receive additional support to pursue their research and develop their careers.

School of Science
November 4, 2019

The School of Science has announced that 14 of its faculty members have been appointed to named professorships. The faculty members selected for these positions receive additional support to pursue their research and develop their careers.

Riccardo Comin is an assistant professor in the Department of Physics. He has been named a Class of 1947 Career Development Professor. This three-year professorship is granted in recognition of the recipient’s outstanding work in both research and teaching. Comin is interested in condensed matter physics. He uses experimental methods to synthesize new materials, as well as analysis through spectroscopy and scattering to investigate solid state physics. Specifically, the Comin lab attempts to discover and characterize electronic phases of quantum materials. Recently, his lab, in collaboration with colleagues, discovered that weaving a conductive material into a particular pattern known as the “kagome” pattern can result in quantum behavior when electricity is passed through.

Joseph Davis, assistant professor in the Department of Biology, has been named a Whitehead Career Development Professor. He looks at how cells build and deconstruct complex molecular machinery. The work of his lab group relies on biochemistry, biophysics, and structural approaches that include spectrometry and microscopy. A current project investigates the formation of the ribosome, an essential component in all cells. His work has implications for metabolic engineering, drug delivery, and materials science.

Lawrence Guth is now the Claude E. Shannon (1940) Professor of Mathematics. Guth explores harmonic analysis and combinatorics, and he is also interested in metric geometry and identifying connections between geometric inequalities and topology. The subject of metric geometry revolves around being able to estimate measurements, including length, area, volume and distance, and combinatorial geometry is essentially the estimation of the intersection of patters in simple shapes, including lines and circles.

Michael Halassa, an assistant professor in the Department of Brain and Cognitive Sciences, will hold the three-year Class of 1958 Career Development Professorship. His area of interest is brain circuitry. By investigating the networks and connections in the brain, he hopes to understand how they operate — and identify any ways in which they might deviate from normal operations, causing neurological and psychiatric disorders. Several publications from his lab discuss improvements in the treatment of the deleterious symptoms of autism spectrum disorder and schizophrenia, and his latest news provides insights on how the brain filters out distractions, particularly noise. Halassa is an associate investigator at the McGovern Institute for Brain Research and an affiliate member of the Picower Institute for Learning and Memory.

Sebastian Lourido, an assistant professor and the new Latham Family Career Development Professor in the Department of Biology for the next three years, works on treatments for infectious disease by learning about parasitic vulnerabilities. Focusing on human pathogens, Lourido and his lab are interested in what allows parasites to be so widespread and deadly, looking on a molecular level. This includes exploring how calcium regulates eukaryotic cells, which, in turn, affect processes such as muscle contraction and membrane repair, in addition to kinase responses.

Brent Minchew is named a Cecil and Ida Green Career Development Professor for a three-year term. Minchew, a faculty member in the Department of Earth, Atmospheric and Planetary Sciences, studies glaciers using remote sensing methods, such as interferometric synthetic aperture radar. His research into glaciers, including their mechanics, rheology, and interactions with their surrounding environment, extends as far as observing their responses to climate change. His group recently determined that Antarctica, in a worst-case scenario climate projection, would not contribute as much as predicted to rising sea level.

Elly Nedivi, a professor in the departments of Brain and Cognitive Sciences and Biology, has been named the inaugural William R. (1964) And Linda R. Young Professor. She works on brain plasticity, defined as the brain’s ability to adapt with experience, by identifying genes that play a role in plasticity and their neuronal and synaptic functions. In one of her lab’s recent publications, they suggest that variants of a particular gene may undermine expression or production of a protein, increasing the risk of bipolar disorder. In addition, she collaborates with others at MIT to develop new microscopy tools that allow better analysis of brain connectivity. Nedivi is also a member of the Picower Institute for Learning and Memory.

Andrei Negut has been named a Class of 1947 Career Development Professor for a three-year term. Negut, a member of the Department of Mathematics, fixates on problems in geometric representation theory. This topic requires investigation within algebraic geometry and representation theory simultaneously, with implications for mathematical physics, symplectic geometry, combinatorics and probability theory.

Matĕj Peč, the Victor P. Starr Career Development Professor in the Department of Earth, Atmospheric and Planetary Science until 2021, studies how the movement of the Earth’s tectonic plates affects rocks, mechanically and microstructurally. To investigate such a large-scale topic, he utilizes high-pressure, high-temperature experiments in a lab to simulate the driving forces associated with plate motion, and compares results with natural observations and theoretical modeling. His lab has identified a particular boundary beneath the Earth’s crust where rock properties shift from brittle, like peanut brittle, to viscous, like honey, and determined how that layer accommodates building strain between the two. In his investigations, he also considers the effect on melt generation miles underground.

Kerstin Perez has been named the three-year Class of 1948 Career Development Professor in the Department of Physics. Her research interest is dark matter. She uses novel analytical tools, such as those affixed on a balloon-borne instrument that can carry out processes similar to that of a particle collider (like the Large Hadron Collider) to detect new particle interactions in space with the help of cosmic rays. In another research project, Perez uses a satellite telescope array on Earth to search for X-ray signatures of mysterious particles. Her work requires heavy involvement with collaborative observatories, instruments, and telescopes. Perez is affiliated with the Kavli Institute for Astrophysics and Space Research.

Bjorn Poonen, named a Distinguished Professor of Science in the Department of Mathematics, studies number theory and algebraic geometry. He, his colleagues, and his lab members generate algorithms that can solve polynomial equations with the particular requirement that the solutions be rational numbers. These types of problems can be useful in encoding data. He also helps to determine what is undeterminable, that is exploring the limits of computing.

Daniel Suess, named a Class of 1948 Career Development Professor in the Department of Chemistry, uses molecular chemistry to explain global biogeochemical cycles. In the fields of inorganic and biological chemistry, Suess and his lab look into understanding complex and challenging reactions and clustering of particular chemical elements and their catalysts. Most notably, these reactions include those that are essential to solar fuels. Suess’s efforts to investigate both biological and synthetic systems have broad aims of both improving human health and decreasing environmental impacts.

Alison Wendlandt is the new holder of the five-year Cecil and Ida Green Career Development Professorship. In the Department of Chemistry, the Wendlandt research group focuses on physical organic chemistry and organic and organometallic synthesis to develop reaction catalysts. Her team fixates on designing new catalysts, identifying processes to which these catalysts can be applied, and determining principles that can expand preexisting reactions. Her team’s efforts delve into the fields of synthetic organic chemistry, reaction kinetics, and mechanics.

Julien de Wit, a Department of Earth, Atmospheric and Planetary Sciences assistant professor, has been named a Class of 1954 Career Development Professor. He combines math and science to answer questions about big-picture planetary questions. Using data science, de Wit develops new analytical techniques for mapping exoplanetary atmospheres, studies planet-star interactions of planetary systems, and determines atmospheric and planetary properties of exoplanets from spectroscopic information. He is a member of the scientific team involved in the Search for habitable Planets EClipsing ULtra-cOOl Stars (SPECULOOS) TRANsiting Planets and Planetesimals Small Telescope (TRAPPIST), made up of an international collection of observatories. He is affiliated with the Kavli Institute.

Biologists build proteins that avoid crosstalk with existing molecules

Engineered signaling pathways could offer a new way to build synthetic biology circuits.

Anne Trafton | MIT News Office
October 23, 2019

Inside a living cell, many important messages are communicated via interactions between proteins. For these signals to be accurately relayed, each protein must interact only with its specific partner, avoiding unwanted crosstalk with any similar proteins.

A new MIT study sheds light on how cells are able to prevent crosstalk between these proteins, and also shows that there remains a huge number of possible protein interactions that cells have not used for signaling. This means that synthetic biologists could generate new pairs of proteins that can act as artificial circuits for applications such as diagnosing disease, without interfering with cells’ existing signaling pathways.

“Using our high-throughput approach, you can generate many orthogonal versions of a particular interaction, allowing you to see how many different insulated versions of that protein complex can be built,” says Conor McClune, an MIT graduate student and the lead author of the study.

In the new paper, which appears today in Nature, the researchers produced novel pairs of signaling proteins and demonstrated how they can be used to link new signals to new outputs by engineering E. coli cells that produce yellow fluorescence after encountering a specific plant hormone.

Michael Laub, an MIT professor of biology, is the senior author of the study. Other authors are recent MIT graduate Aurora Alvarez-Buylla and Christopher Voigt, the Daniel I.C. Wang Professor of Advanced Biotechnology.

New combinations

In this study, the researchers focused on a type of signaling pathway called two-component signaling, which is found in bacteria and some other organisms. A wide variety of two-component pathways has evolved through a process in which cells duplicate genes for signaling proteins they already have, and then mutate them, creating families of similar proteins.

“It’s intrinsically advantageous for organisms to be able to expand this small number of signaling families quite dramatically, but it runs the risk that you’re going to have crosstalk between these systems that are all very similar,” Laub says. “It then becomes an interesting challenge for cells: How do you maintain the fidelity of information flow, and how do you couple specific inputs to specific outputs?”

Most of these signaling pairs consist of an enzyme called a kinase and its substrate, which is activated by the kinase. Bacteria can have dozens or even hundreds of these protein pairs relaying different signals.

About 10 years ago, Laub showed that the specificity between bacterial kinases and their substrates is determined by only five amino acids in each of the partner proteins. This raised the question of whether cells have already used up, or are coming close to using up, all of the possible unique combinations that won’t interfere with existing pathways.

Some previous studies from other labs had suggested that the possible number of interactions that would not interfere with each other might be running out, but the evidence was not definitive. The MIT researchers decided to take a systematic approach in which they began with one pair of existing E. coli signaling proteins, known as PhoQ and PhoP, and then introduced mutations in the regions that determine their specificity.

This yielded more than 10,000 pairs of proteins. The researchers tested each kinase to see if they would activate any of the substrates, and identified about 200 pairs that interact with each other but not the parent proteins, the other novel pairs, or any other type of kinase-substrate family found in E. coli.

“What we found is that it’s pretty easy to find combinations that will work, where two proteins interact to transduce a signal and they don’t talk to anything else inside the cell,” Laub says.

He now plans to try to reconstruct the evolutionary history that has led to certain protein pairs being used by cells while many other possible combinations have not naturally evolved.

Synthetic circuits

This study also offers a new strategy for creating new synthetic biology circuits based on protein pairs that don’t crosstalk with other cellular proteins, the researchers say. To demonstrate that possibility, they took one of their new protein pairs and modified the kinase so that it would be activated by a plant hormone called trans-zeatin, and engineered the substrate so that it would glow yellow when the kinase activated it.

“This shows that we can overcome one of the challenges of putting a synthetic circuit in a cell, which is that the cell is already filled with signaling proteins,” Voigt says. “When we try to move a sensor or circuit between species, one of the biggest problems is that it interferes with the pathways already there.”

One possible application for this new approach is designing circuits that detect the presence of other microbes. Such circuits could be useful for creating probiotic bacteria that could help diagnose infectious diseases.

“Bacteria can be engineered to sense and respond to their environment, with widespread applications such as ‘smart’ gut bacteria that could diagnose and treat inflammation, diabetes, or cancer, or soil microbes that maintain proper nitrogen levels and eliminate the need for fertilizer. To build such bacteria, synthetic biologists require genetically encoded ‘sensors,’” says Jeffrey Tabor, an associate professor of bioengineering and biosciences at Rice University.

“One of the major limitations of synthetic biology has been our genetic parts failing in new organisms for reasons that we don’t understand (like cross-talk). What this paper shows is that there is a lot of space available to re-engineer circuits so that this doesn’t happen,” says Tabor, who was not involved in the research.

If adapted for use in human cells, this approach could also help researchers design new ways to program human T cells to destroy cancer cells. This type of therapy, known as CAR-T cell therapy, has been approved to treat some blood cancers and is being developed for other cancers as well.

Although the signaling proteins involved would be different from those in this study, “the same principle applies in that the therapeutic relies on our ability to take sets of engineered proteins and put them into a novel genomic context, and hope that they don’t interfere with pathways already in the cells,” McClune says.

The research was funded by the Howard Hughes Medical Institute, the Office of Naval Research, and the National Institutes of Health Pre-Doctoral Training Grant.

Ankur Jain awarded Packard Foundation Fellowship

Whitehead Institute member and assistant professor of biology receives one of the most prestigious non-governmental awards for early-career scientists.

Merrill Meadow | Whitehead Institute
October 23, 2019

The David and Lucile Packard Foundation has announced that Ankur Jain, Whitehead Institute member and assistant professor of biology at MIT, has been named a Packard Fellow for Science and Engineering. The Packard Foundation Fellowships are one of the most prestigious and well-funded non-governmental awards for early-career scientists.

Each year, the foundation invites 50 university presidents to nominate two early-career professors each from their institutions; from those 100 nominees, an advisory panel of distinguished scientists and engineers select the fellows, who receive individual grants of $875,000 over five years. The 2019 class comprises 22 fellows.

“We are extraordinarily pleased that Ankur has received such clear and substantive affirmation of his pioneering research on the role that RNAs play in devastating neurological diseases,” says Whitehead Institute Director David C. Page. “This exciting work is at the forefront of soft-matter physics and cell biology, and could well open new chapters in RNA regulation specifically and in cell biology more broadly.”

“I am very grateful for the Packard Foundation’s support of our continued investigations of how RNA aggregation contributes to disease,” says Jain.

Jain has discovered that certain RNAs can form aggregates, clumping together into membrane-less gels. This process, known as phase separation, has been widely studied in proteins, but not in RNA. He has found that RNA gels occur in, and could contribute to, a set of neurological conditions such as amyotrophic lateral sclerosis and Huntington’s disease. These conditions, known as repeat expansion diseases, are marked by abnormal repetition of short sequences of nucleotides, the building blocks of DNA and RNA. The RNAs containing these sequences are more likely to clump together.

The fellowship will enable Jain to advance his research program around this phenomenon. “Although it is well-appreciated that RNA can form aggregates in test tubes, the biological implications of this process are not yet known,” he explains. “The award will allow us to examine how RNA aggregates affect cell function and ultimately contribute to neurological disease.”

Jain joined Whitehead Institute and MIT in 2018, after conducting postdoctoral research in the lab of Ronald Vale at the University of California at San Francisco. He earned a doctorate in biophysics and computational biology at University of Illinois at Urbana-Champaign in 2013, and received his bachelor’s degree (with honors) in biotechnology and biochemical engineering from Indian Institute of Technology Kharagpur in 2007.

Past Packard Fellows have gone on to receive a range of accolades, including the Nobel Prize in chemistry and physics, the Fields Medal, the Alan T. Waterman Award, MacArthur Fellowships, and elections to the National Academies. They include Frances Arnold, recipient of the 2018 Nobel Prize in Chemistry, who chairs the Packard Fellowships Advisory Panel, and Sangeeta Bhatia, the John and Dorthy Wilson Professor of Health Sciences and Technology at MIT, who is a member of all three National Academies (science, engineering, and medicine).

Two from MIT elected to the National Academy of Medicine for 2019

Sangeeta Bhatia and Richard Young recognized for their contributions to “advancement of the medical sciences, health care, and public health.”

Anne Trafton | MIT News Office
October 21, 2019

Sangeeta Bhatia, an MIT professor of electrical engineering and computer science and of health sciences and technology, and Richard Young, an MIT professor of biology, are among the 100 new members elected to the National Academy of Medicine today.

Bhatia is already a member of the National Academies of Science and of Engineering, making her just the 25th person to be elected to all three national academies. Earlier this year, Paula Hammond, head of MIT’s Department of Chemical Engineering, also joined that exclusive group; MIT faculty members Emery Brown, Arup Chakraborty, James Collins, and Robert Langer have also achieved that distinction.

Bhatia, who is a member of MIT’s Koch Institute for Integrative Cancer Research and Institute for Medical Engineering and Science, develops micro- and nanoscale technologies to improve human health. She has designed nanoparticles and other materials to diagnose and treat disease, including cancer, and she has also engineered human microlivers that can be used to model liver disease and test new drugs. She and her students have founded several biotechnology companies to further develop these technologies.

Young, who is a member of MIT’s Whitehead Institute for Biomedical Research, studies the regulatory circuitry that controls cell state and differentiation. His lab uses experimental and computational techniques to determine how signaling pathways, transcription factors, chromatin regulators, and small RNAs control gene expression. Since defects in gene expression can cause diabetes, cancer, hypertension, immune deficiencies, neurological disorders, and other health issues, improved understanding of this circuitry should lead to new insights into disease mechanisms and the development of new diagnostics and therapeutics.

“I am humbled to have been elected to the National Academy of Medicine,” Young says. “More than just a personal honor, it is an affirmation of the importance of basic biomedical research to understanding, preventing, and treating disease.”

Young was also elected to the National Academy of Science in 2012.

Bhatia and Hammond, both of whom have spent most of their careers at MIT, are now the only two women of color to belong to all three of the National Academies.

“I’m incredibly honored to be part of this group of thinkers and doers that I have long admired,” says Bhatia, the John and Dorothy Wilson Professor of Electrical Engineering and Computer Science. “I’m grateful to have been supported by MIT for decades and to have benefited from the gender equity movement that Nancy Hopkins and colleagues initiated in the 90s. My position, salary, promotion trajectory, space, leadership opportunities, and sense of community with amazing people like Paula are all the products of deliberate, hard work to overcome systemic unconscious bias. I hope we can serve as examples of what is possible for the next generation of researchers and the institutions that support them.”

“I am delighted to share this honor with my wonderful colleague, Sangeeta,” Hammond says. “We have truly benefited from the hard work of so many of our colleagues here at MIT who have stood up and voiced the importance of equity among scholars across race, culture, and gender. MIT has been an incredible place for me to further my career and to find outstanding male and female colleagues who continuously uplift and support each other. It is through the constant efforts we make together as a community to become a better place that we create opportunities for current and future scholars to shine.”

The National Academy of Medicine, established in 1970 as the Institute of Medicine, is an independent organization of eminent professionals from fields including health and medicine, as well as the natural, social, and behavioral sciences. Election to the National Academy of Medicine is considered one of the highest honors in the fields of health and medicine and recognizes individuals who have demonstrated outstanding professional achievement and commitment to service.

“Biogenesis” podcast highlights MIT students behind cutting-edge biology research

The MIT Department of Biology and Whitehead Institute are producing a podcast featuring young scientists and why they chose to study biology.

Department of Biology | Whitehead Institute
October 16, 2019

The MIT Department of Biology and Whitehead Institute have launched “BioGenesis,” a new podcast highlighting affiliated graduate students and their stories about where they came from, and how their experiences have shaped their research.

In each episode, co-hosts Raleigh McElvery, communications coordinator at the Department of Biology, and Conor Gearin, digital and social media specialist at Whitehead Institute, introduce a different student and — as the title of the podcast suggests — explore the guest’s origin story.

This first season centers on the theme of surprises. The inaugural episode features Kwadwo Owusu-Boaitey, a soccer player-turned MD/PhD student studying tissue regeneration in planarians, a type of flatworm. Owusu-Boaitey was struggling to find an effective means to map the stem cells in these remarkable animals when he happened upon a new tool that would allow him to do just that, and probe how the flatworm can regrow its entire body.

The second episode features Alicia Zamudio, who grew up in Mexico City, Mexico, intent on attending college in the United States and studying human behavior. Although she initially intended to pursue writing or psychology, one class persuaded her to consider molecular biology instead — with a focus on how cells control the expression of genes that dictate the identity of every cell in our bodies.

The third episode features Summer Morrill, who was determined to use her background in biology to become a genetic counselor before arriving at MIT and becoming captivated by fundamental cellular biology. Now, she investigates cancer and other diseases from a molecular perspective, asking what happens when chromosomes mis-segregate and cells end up with an improper number of genes.

BioGenesis is part of a larger effort to share the personal stories behind scientific discoveries, clarifying the experimental process and demonstrating the importance of fundamental biology research in the MIT community and beyond. From studying tissue regeneration in worms to probing the molecular basis for disease, fundamental research has ramifications far beyond the lab bench.

“The enthusiasm for basic biology that these graduate students have, and their excitement for sharing their science with the world, really impressed us,” Gearin says.

“Hearing them revisit the moments and people that initially inspired them to pursue research underscored the importance of good mentorship — and the many ways that fundamental biological discoveries can impact society,” McElvery adds.

BioGenesis is available on iTunes, SoundCloud, Spotify, and Google Play, as well as the podcast pages for the MIT Department of Biology and Whitehead Institute.

Ruth Lehmann elected as director of Whitehead Institute

Lehmann, a world-renowned developmental and cell biology researcher, is the institute’s fifth director.

Lisa Girard | Whitehead Institute
September 19, 2019

The Whitehead Institute board of directors today announced the selection of Ruth Lehmann, a world-renowned developmental and cell biology researcher, as the institute’s fifth director. Lehmann will succeed current Director David Page on July 1, 2020.

Lehmann is now the Laura and Isaac Perlmutter Professor of Cell Biology and chair of the Department of Cell Biology at New York University (NYU), where she also directs the Skirball Institute of Biomolecular Medicine and The Helen L. and Martin S. Kimmel Center for Stem Cell Biology. She is currently an investigator of the Howard Hughes Medical Institute. The Whitehead Institute appointment represents a homecoming: Lehmann was a Whitehead Institute member and a faculty member of MIT from 1988 to 1996, before beginning a distinguished 23-year career at NYU.

“Ruth Lehmann will continue a line of prestigious and highly accomplished scientist-leaders who have served as Whitehead Institute directors,” says Charles D. Ellis, chair of the Whitehead Institute board of directors. “She perfectly fits our vision for the next director: an eminent scientist and experienced leader, who is passionately committed to Whitehead Institute’s mission, and possesses a compelling vision for basic biomedical research in the coming decade.”

“I am delighted to return to Whitehead Institute and look forward to joining the illustrious faculty to recruit and mentor the next generation of Whitehead Institute faculty and fellows,” Lehmann says. “When I was recruited to Whitehead Institute in the late 1980s, David Baltimore took a huge risk in giving an inexperienced young scientist from Germany the chance to follow her passion for science with unending encouragement and minimal restraints. Now I am thrilled to have the opportunity to help shape the future of this wonderful institute that has been at the forefront of biomedical research for decades. I am pleased to become part of the succession of Whitehead Institute’s forward-thinking directors, David Baltimore, Gerald Fink, Susan Lindquist, and David Page. I look forward to working with faculty, fellows, trainees, and staff to build a future with ambitious goals that will allow us to reveal the unknown and connect the unexpected in a collaborative, diverse, and flexible environment.”

“Ruth Lehmann is an inspired choice to lead the institute into the future and I look forward to working with her in that capacity,” Page says. “Ruth is an internationally renowned and influential leader in the field of germ cell biology, and her outstanding contributions to the field are the product of her sustained brilliance, insatiable curiosity, uncompromising rigor and scholarship, and clarity of thought and expression. Across the course of the past three decades, no scientist anywhere in the world has made greater contributions to our understanding of germ cells and their remarkable biology. I’m especially pleased to gain a colleague with such an impressive track record of discovery and institutional leadership.”

The new director will have an impressive line of predecessors: Whitehead Institute’s founding director was Nobel laureate and former Caltech president David Baltimore; he was succeeded by internationally honored geneticist and science enterprise leader Gerald Fink, and then by National Medal of Science recipient Susan Lindquist, followed by the current director, leading human geneticist David Page, who became director in 2004.

“Ruth Lehmann is a brilliant choice as the next director of Whitehead Institute,” Baltimore says. “She is a world-class scientist and a seasoned leader. Most importantly, she understands the unique nature of Whitehead Institute and will maintain it as a key element of the biomedical complex that has grown up in Cambridge, Massachusetts.”

“Ruth Lehmann is an extraordinary scientist, who began her distinguished career here at Whitehead,” Fink says. “Her innovative work on germ cells, which give rise to eggs and sperm, has paved the path for the entire field. She is an inspiring leader who is an outspoken advocate for fundamental research. We are all delighted to welcome her back as our new director and scientific colleague.”

Lehmann has made seminal discoveries in the field of developmental and cell biology. Germ cells, the cells that give rise to the sperm and egg, carry a precious cargo of genetic information from the parent that they ultimately contribute to the embryo, transmitting the currency of heredity to a new generation. Work in Lehmann’s lab using Drosophila (fruit flies) has shed light on how these important cells “know” to become germ cells, and how they are able to make their way from where they originate to the gonad during early embryonic development. Her discoveries uncovering the mechanisms needed for proper specification and migration of germ cells have not only informed our understanding of processes essential for the perpetuation of life itself, but have also made important contributions to related fields including stem cell biology, lipid biology, and DNA repair.

“I’m so pleased to be welcoming Ruth back to the community,” MIT Provost Martin A. Schmidt says. “Her dedication to, and expertise in, basic research will underscore Whitehead Institute’s reputation as a leader in this arena.”

Susan Hockfield, MIT president emerita and professor of neuroscience, chaired the committee that recommended Lehmann to the Whitehead Institute board. “Our committee considered eminent candidates from across the globe,” Hockfield says, “and found in Ruth Lehmann a person uniquely qualified to guide this pioneering research institution forward.”

Lehmann earned an undergraduate degree and a PhD in biology from the University of Tubingen in Germany, in the laboratory of future Nobel laureate Christiane Nüsslein-Volhard. Between those programs, she conducted research at the University of Washington and earned a diploma degree — equivalent to a master’s degree — in biology from the University of Freiburg in Germany. She then conducted postdoctoral research at the Medical Research Council Laboratory of Molecular Biology in Cambridge, England. Then, Lehmann moved to Cambridge, Massachusetts, to become a Whitehead Institute member and MIT faculty member. In 1996, she accepted a professorship at NYU Langone School of Medicine and was subsequently named director of the Skirball Institute of Biomolecular Medicine and The Helen L. and Martin S. Kimmel Center for Stem Cell Biology, NYU Stem Cell Biology Graduate Program director, and chair of the NYU Department of Cell Biology in 2014 (all roles that she continues to hold).

She has served as president of the Society for Developmental Biology, the Drosophila Board, and the Harvey Society; is currently editor-in-chief of the Annual Review of Cell and Developmental Biology; and will serve as president of the American Society for Cell Biology starting in 2021. Additionally, she has been a council member of the National Institute of Child Health and Human Development.

Among her many awards, Lehmann has received the Society for Developmental Biology’s Conklin Medal, the Porter Award from the American Society for Cell Biology, and the Lifetime Achievement Award from the German Society for Developmental Biology. She is an elected member of the National Academy of Sciences, a fellow of the American Academy of Arts and Sciences, and a member of the European Molecular Biology Organization.

Lehmann has also been a committed mentor, having fostered the education and professional development of scores of undergraduate and graduate students and postdoctoral researchers. Many of her mentees have gone on to become leaders in the biomedical industry or at academic institutions in the United States and around the world, including Johns Hopkins University, Princeton University, MIT, the University of Cambridge (UK), European Molecular Biology Laboratory (Heidelberg, Germany), and University of Toronto (Canada).

Study finds hub linking movement and motivation in the brain

Detailed observations in the lateral septum indicate region processes movement and reward information to help direct behavior.

David Orenstein | Picower Institute for Learning and Memory
September 19, 2019

Our everyday lives rely on planned movement through the environment to achieve goals. A new study by MIT neuroscientists at the Picower Institute for Learning and Memory at MIT identifies a well-connected brain region as a crucial link between circuits guiding goal-directed movement and motivated behavior.

Published Sept. 19 in Current Biology, the research shows that the lateral septum (LS), a region considered integral to modulating behavior and implicated in many psychiatric disorders, directly encodes information about the speed and acceleration of an animal as it navigates and learns how to obtain a reward in an environment.

“Completing a simple task, such as acquiring food for dinner, requires the participation and coordination of a large number of regions of the brain, and the weighing of a number of factors: for example, how much effort is it to get food from the fridge versus a restaurant,” says Hannah Wirtshafter PhD ’19, the study’s lead author. “We have discovered that the LS may be aiding you in making some of those decisions. That the LS represents place, movement, and motivational information may enable the LS to help you integrate or optimize performance across considerations of place, speed, and other environmental signals.”

Previous research has attributed important behavioral functions to the LS, such as modulating anxiety, aggression, and affect. It is also believed to be involved in addiction, psychosis, depression, and anxiety. Neuroscientists have traced its connections to the hippocampus, a crucial center for encoding spatial memories and associating them with context, and to the ventral tegmental area (VTA), a region that mediates goal-directed behaviors via the neurotransmitter dopamine. But until now, no one had shown that the LS directly tracks movement or communicated with the hippocampus, for instance by synchronizing to certain neural rhythms, about movement and the spatial context of reward.

“The hippocampus is one of the most studied regions of the brain due to its involvement in memory, spatial navigation, and a large number of illnesses such as Alzheimer’s disease,” says Wirtshafter, who recently earned her PhD working on the research as a graduate student in the lab of senior author Matthew Wilson, Sherman Fairchild Professor of Neurobiology. “Comparatively little is known about the lateral septum, even though it receives a large amount of information from the hippocampus and is connected to multiple areas involved in motivation and movement.”

Wilson says the study helps to illuminate the importance of the LS as a crossroads of movement and motivation information between regions such as the hippocampus and the VTA.

“The discovery that activity in the LS is controlled by movement points to a link between movement and dopaminergic control through the LS that that could be relevant to memory, cognition, and disease,” he says.

Tracking thoughts

Wirtshafter was able to directly observe the interactions between the LS and the hippocampus by simultaneously recording the electrical spiking activity of hundreds of neurons in each region in rats both as they sought a reward in a T-shaped maze, and as they became conditioned to associate light and sound cues with a reward in an open box environment.

In that data, she and Wilson observed a speed and acceleration spiking code in the dorsal area of the LS, and saw clear signs that an overlapping population of neurons were processing information based on signals from the hippocampus, including spiking activity locked to hippocampal brain rhythms, location-dependent firing in the T-maze, and cue and reward responses during the conditioning task. Those observations suggested to the researchers that the septum may serve as a point of convergence of information about movement and spatial context.

Wirtshafter’s measurements also showed that coordination of LS spiking with the hippocampal theta rhythm is selectively enhanced during choice behavior that relies on spatial working memory, suggesting that the LS may be a key relay of information about choice outcome during navigation.

Putting movement in context

Overall, the findings suggest that movement-related signaling in the LS, combined with the input that it receives from the hippocampus, may allow the LS to contribute to an animal’s awareness of its own position in space, as well as its ability to evaluate task-relevant changes in context arising from the animal’s movement, such as when it has reached a choice point, Wilson and Wirtshafter said.

This also suggests that the reported ability of the LS to modulate affect and behavior may result from its ability to evaluate how internal states change during movement, and the consequences and outcomes of these changes. For instance, the LS may contribute to directing movement toward or away from the location of a positive or negative stimulus.

The new study therefore offers new perspectives on the role of the lateral septum in directed behavior, the researchers added, and given the known associations of the LS with some disorders, it may also offer new implications for broader understanding of the mechanisms relating mood, motivation, and movement, and the neuropsychiatric basis of mental illnesses.

“Understanding how the LS functions in movement and motivation will aid us in understanding how the brain makes basic decisions, and how disruption in these processed might lead to different disorders,” Wirtshafter says.

A National Defense Science and Engineering Graduate Fellowship and the JPB Foundation funded the research.

Jazayeri and Sive awarded 2019 School of Science teaching prizes

Nominated by peers and students, professors in brain and cognitive sciences and biology are recognized for excellence in graduate and undergraduate education.

School of Science
September 18, 2019

The School of Science has announced that the recipients of the school’s 2019 Teaching Prizes for Graduate and Undergraduate Education are Mehrdad Jazayeri and Hazel Sive. Nominated by peers and students, the faculty members chosen to receive these prizes are selected to acknowledge their exemplary efforts in teaching graduate and undergraduate students.

Mehrdad Jazayeri, an associate professor in the Department of Brain and Cognitive Sciences and investigator at the McGovern Institute for Brain Research, is awarded the prize for graduate education for 9.014 (Quantitative Methods and Computational Models in Neuroscience). Earlier this year, he was recognized for excellence in graduate teaching by the Department of Brain and Cognitive Sciences and won a Graduate Student Council teaching award in 2016. In their nomination letters, peers and students alike remarked that he displays not only great knowledge, but extraordinary skill in teaching, most notably by ensuring everyone learns the material. Jazayeri does so by considering students’ diverse backgrounds and contextualizing subject material to relatable applications in various fields of science according to students’ interests. He also improves and adjusts the course content, pace, and intensity in response to student input via surveys administered throughout the semester.

Hazel Sive, a professor in the Department of Biology, member of the Whitehead Institute for Biomedical Research, and associate member of the Broad Institute of MIT and Harvard, is awarded the prize for undergraduate education. A MacVicar Faculty Fellow, she has been recognized with MIT’s highest undergraduate teaching award in the past, as well as the 2003 School of Science Teaching Prize for Graduate Education. Exemplified by her nominations, Sive’s laudable teaching career at MIT continues to receive praise from undergraduate students who take her classes. In recent post-course evaluations, students commended her exemplary and dedicated efforts to her field and to their education.

The School of Science welcomes nominations for the teaching prize in the spring semester of each academic year. Nominations can be submitted at the school’s website.

Understanding genetic circuits and genome organization

Assistant professors Pulin Li and Seychelle Vos are investigating how cells become tissues and the proteins that organize DNA.

Raleigh McElvery | Department of Biology
September 12, 2019

MIT’s Department of Biology welcomed two new assistant professors in recent months: Pulin Li began at the Whitehead Institute in May, and Seychelle Vos arrived at Building 68 in September. Their respective expertise in genetic circuits and genome organization will augment the department’s efforts to explore cell biology at all levels — from intricate molecular structures to the basis for human disease.

“Pulin and Seychelle bring new perspectives and exciting ideas to our research community,” says Alan Grossman, department head. “I’m excited to see them start their independent research programs and look forward to the impact that they will have.”

From cells to tissues

Growing up in Yingkou, China, Li was exposed to science at a young age. Her dad worked for a pharmaceutical company researching traditional Chinese medicine, and Li would spend hours playing with his lab tools and beakers. “I can still vividly remember the smell of his Chinese herbs,” she says. “Maybe that’s part of the reason why I’ve always been interested in biology as it relates to medical sciences.”

She earned her BS in life sciences from Peking University, and went on to pursue a PhD in chemical biology at Harvard University studying hematopoietic stem cells. Li performed chemical screens to find drugs that would make stem cell transplantation in animal models more efficient, and eventually help patients with leukemia. In doing so, she became captivated by the molecular mechanisms that control cell-to-cell communication.

“I would like to eventually go back to developing new therapies and medicines,” she says, “but that translational research requires a basic understanding of how things work at a molecular level.”

As a result, her postdoc at Caltech was firmly rooted in basic biology. She investigated the genetic circuits that underlie cell-cell communication in developing and regenerating tissues, and now aims to develop new methods to study these same processes here at MIT.

Traditional genetic approaches involve breaking components of a system one at a time to investigate the role they play. However, Li’s lab will adopt a “bottom-up” approach that involves building these systems from the ground up, adding the components back into the cell one by one to pinpoint which genetic circuits are sufficient for programming tissue function. “Building up a system, rather than tearing it down, allows you to test different circuit designs, tune important parameters, and understand why a circuit has evolved to perform a specific function,” she explains.

She is most interested in determining which aspects of cellular communication are critical for tissue formation, in hopes of understanding the diversity of life forms in nature, as well as inspiring new methods to engineer or regenerate different tissues.

“My dream would be to put a bunch of genetic circuits into cells in such a way that they could enable the cells to self-organize into certain patterns and shapes, and replace damaged tissues in a patient,” she says.

Proteins that organize DNA

Although Vos was born in South Africa, her family moved so frequently for her father’s job that she doesn’t call any one place home. “If I had to pick, I’d say it would be the middle of the Atlantic Ocean,” she says.

Both of her grandparents on her mother’s side were researchers, and encouraged various scientific escapades, like bringing wolf spiders to kindergarten for show-and-tell. Her grandmother on her father’s side found her early passions “mildly disturbing,” but dutifully fulfilled her requests for high-resolution insect microscopy books nonetheless.

“I really wanted to know how plants and animals worked starting from a young age, thanks to my grandparents,” Vos says.

In high school she was already conducting research on the side at Clemson University, South Carolina, and went on to earn her BS in genetics from the University of Georgia. She began her PhD in molecular cell biology at the University of California at Berkeley intending to study immunology, but surprised herself by becoming taken with structural biology instead.

Purifying proteins and solving structures required a much different skill set than performing screens and manipulating genomes, but she very much enjoyed her work on topoisomerase, the enzyme that modifies DNA so it doesn’t become too coiled.

She continued conducting biochemical and structural research during her postdoc at the Max Planck Institute for Biophysical Chemistry in Germany. There, she used cryogenic electron microscopy to probe how different RNA polymerase II complexes are regulated during transcription in eukaryotes.

Today, she’s a molecular biologist at her core, but she’s prepared to use “whatever technique gets the answer.” As she explains: “You need biochemistry to solve structures and genetics to understand how they’re working within the whole organism, so it’s all related.”

In her new lab in Building 68, she will continue investigating gene expression, but this time in the context of genome organization. DNA must be compacted in order to fit into a cell, and Vos will study the proteins that organize DNA so it can be compressed without interfering with gene expression. She also wants to know how those same proteins are affected by gene expression.

“How gene regulation impacts compaction is a really critical question to address because different cell types are organized in different ways, and that impacts which genes are ultimately expressed,” she says. “We still don’t really understand how these processes work at an atomic level, so that’s where my expertise in biochemistry and structural biology can be useful.”

When asked what they are most excited about as the school year begins, both Li and Vos say the same thing: the diverse skills and expertise of the students and faculty.

“It’s not just about solving one structure, people here want to understand the entire process,” Vos says. “Biology is a conglomeration of many different fields, and if we can have engineers, mathematicians, physicists, chemists, biologists, and others work together, we can begin to tackle pressing questions.”