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Researchers discover a new toxin that impedes bacterial growth
Raleigh McElvery
November 6, 2019

An international research collaboration has discovered a new toxin, which bacteria inject into their neighboring cells to hinder growth and compete for limited resources. Their findings were published on November 6 in Nature.

At McMaster University in Ontario, Canada, co-senior author John Whitney and his team were studying a secretion system that allows bacteria to deliver these deleterious molecules, when they came across a new toxin. This toxin was an enzyme, and one they had never seen before. Based on their structural analyses, it looked a lot like the enzymes that synthesize guanosine tetra- and penta-phosphate, collectively known as “(p)ppGpp.” (p)ppGpp is a signaling molecule that helps bacteria safely dial down their growth rate in response to starvation. Suspecting the toxin might produce (p)ppGpp in recipient cells and ultimately impact their growth, the McMaster team shared their findings with Michael Laub, a professor of biology at MIT and a Howard Hughes Medical Institute investigator.

Researchers identified Tas1 in Pseudomonas aeruginosa bacteria. Credit: U.S. Centers for Disease Control and Prevention – Medical Illustrator.

Boyuan Wang, a postdoc in the Laub lab who specializes in (p)ppGpp synthesis, examined the unknown enzyme’s activity to determine its product. He soon realized that, rather than making (p)ppGpp, this enzyme was instead producing related molecules, adenosine tetraphosphate and adenosine pentaphosphate, collectively referred to as (p)ppApp. Somehow, (p)ppApp production was hindering growth.

“Scientists have known about (p)ppApp for decades, but it hadn’t been shown to have a physiological role in organisms until now,” says Wang, a co-first author. Researchers had previously speculated that (p)ppApp was merely a non-specific product generated during (p)ppGpp synthesis, so it was surprising to find an enzyme that made it specifically.

The researchers named their enzyme Tas1, and determined that it uses the cell’s main energy currency, ATP, and its precursor, ADP, to produce (p)ppApp. In fact, one molecule of Tas1 was enough to consume 180,000 molecules of ATP per minute — two orders of magnitude faster than the fastest known (p)ppGpp synthetases work to make (p)ppGpp. Using metabolomic analyses, the MIT group showed that this exceptional rate of (p)ppApp production requires so much energy that there’s not enough left to carry out essential cellular processes, effectively killing the bacterium.

“Bacteria can inject only one Tas1 molecule at a time, and yet the toxin has such a powerful impact on its target, depleting the ATP supply in a matter of minutes,” Wang says. “The secretion system is kind of like a miniaturized intercontinental ballistic missile in terms of its structure and impact, except it functions ‘intercompartmentally’ between two bacteria.”

“It’s amazing that the first (p)ppApp synthase ever discovered actually serves as a novel, and quite clever, means of killing another cell,” says Laub, a co-senior author. “Findings like these really highlight the diversity of mechanisms that bacteria use to inhibit each other’s growth.”

Tas1, the researchers believe, may augment other known toxins that bacteria inject into one another to hinder cell growth, including those that work in the cytoplasm or target the cell envelope.

As a biochemist, Wang is excited by the prospect of using Tas1 as a tool in future experiments to deplete ATP, and probe the networks of metabolic regulation within bacteria and higher organisms.

“It’s fascinating to uncover the strategies nature uses to repurpose proteins,” Wang says. “Before this study, we wouldn’t have considered the possibility that a member of this protein family could be used as a deadly toxin.”

Image: Tas1, a newly discovered enzyme, has a similar structure to the widespread bacterial Rel proteins that produce (p)ppGpp to promote survival during starvation. Tas1 alters its specificity to quickly produce large amounts of (p)ppApp, serving as a toxin in Pseudomonas aeruginosa and killing competing bacteria. Credit: Boyuan Wang.

Citation:
“An interbacterial toxin inhibits target cell growth by synthesizing (p)ppApp”
Nature, online November, 6, DOI: 10.1038/s41586-019-1735-9
Shehryar Ahmad, Boyuan Wang, Matthew D. Walker, Hiu-Ki R. Tran, Peter J. Stogios, Alexei Savchenko, Robert A. Grant, Andrew G. McArthur, Michael T.  Laub, and John C. Whitney.

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.

Golden Anniversary for Luria’s Gold Medal
Koch Institute
October 22, 2019

Fifty years ago, on the heels of an extraordinary summer—the Cuyahoga River Fire, Stonewall Riots, Apollo 11, Manson and Woodstock—a microbiologist in Cambridge, Massachusetts received one more heady piece news. Originally from Torino, Italy, Salvador E. Luria had joined the faculty of MIT ten years earlier. It was here in the US, where he immigrated in 1940, that he conducted the research that had just won him the Nobel Prize.

Luria, with collaborators Max Delbrück and Alfred Hershey, won the Nobel in Medicine for discoveries about the replication mechanism and genetic structure of viruses called bacteriophages. Luria also showed that bacterial resistance to these viruses is genetically inherited, uncovering mutations that permit them to overcome immunological barriers.The scientists’ work illuminated key unanswered questions in virology and genetics, pioneered biological materials and techniques, and is regarded as being primarily responsible for modern advances in the control of viral diseases and for advances in molecular biology.

By time of his award, however, Luria was looking for new challenges, and shortly after the passage of the National Cancer Act of 1971 he successfully applied for funds to build a cancer research facility at MIT.  As founder and first director of the fledgling MIT Center for Cancer Research (CCR), he oversaw the conversion of a former chocolate factory abutting campus into a research laboratory and National Cancer Institute-designated basic cancer research center; he also sought out and recruited scientists with expertise in genetics, immunology, and cell biology. Luria and his founding faculty opened the CCR in 1974, setting in motion an unprecedented era of progress in cancer research.  Under his leadership, the Center set the standard for investigating the fundamental nature of cancer.  Among their accomplishments, faculty members isolated the first human oncogene, discovered RNA splicing, and made numerous other seminal contributions to cancer biology and genetics.  Beyond their importance in understanding the disease, these advances laid the groundwork for new methods to treat and diagnose cancer.  At institutions around the world, generations of CCR-trained scientists have shaped the evolution of cancer research in their own labs.  Here at MIT, the legacy of Luria and the CCR continues to flourish through the work of the Koch Institute for Integrative Cancer Research, where cancer scientists and engineers collaborate to create the next generation of cancer solutions.

As a tribute to the individual who spearheaded the formation of MIT’s first dedicated cancer research effort the Koch Institute is working, with friends and the MIT administration, to name the Koch Institute’s main meeting space the Salvador E. Luria Auditorium.  A hub of daily life in the Koch Institute, the Luria Auditorium will host scientific and community meetings and programs, visiting presenters, K-12 educational workshops, and special and public events. The Luria Auditorium will also include an installation describing the history of the CCR and its many contributions to cancer science.

Contributions to the campaign to name the Salvador E. Luria Auditorium can be made online or by mail to Lisa Marks Schwarz, Managing Director of Development, Koch Institute at MIT, 77 Massachusetts Avenue (76-158), Cambridge, MA 02139. Your support will help to ensure that the pioneering work of Luria and the CCR remain a living legacy within the heart of the Koch 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.

Researchers discover new source of drug resistance in pancreatic cancer
Lucy Jackub
October 17, 2019

The best available treatments for pancreatic cancer are highly toxic, and, as chemotherapies go, not very effective. The drug gemcitabine has been used for decades to extend the life of patients, but very high doses are required to combat the tumor, which grows in the pancreas surrounded by stiff, fibrous, noncancerous tissue called stroma. This hallmark of pancreatic cancer makes it unusually difficult to treat: the more stromal tissue accumulates, the less the drug works, while patients still endure brutal side effects. Only 8.5 percent of pancreatic cancer patients survive five years beyond their diagnosis, so there’s an urgent need to figure out why existing treatments are failing.

Scientists have known for a long time that gemcitabine fights cancer by killing cells during replication, though why it works for pancreatic cancer in particular is a bit of a mystery. The drug is a small molecule that masquerades as the nucleoside deoxycytidine, one unit in the nucleic acids that make up DNA. Once gemcitabine is integrated into a replicating strand of DNA, additional nucleosides can’t be joined to it. The new DNA strand can’t be completed, and the cell dies. Now, researchers from MIT have discovered that non-cancer cells in the pancreatic stromal tissue secrete astonishing quantities of deoxycytidine. They found that competition with deoxycytidine makes its imposter, gemcitabine, less effective, explaining why higher doses of the drug are needed as more stromal tissue grows around the tumor.

“That was an answer we were looking for — what is making pancreatic tumors resistant to gemcitabine?” says Michael Hemann, associate professor of biology, a member of MIT’s Koch Institute for Integrative Cancer Research, and co-senior author of the study. “Understanding the basic mechanisms of these drugs allows us to return to the clinic with improved strategies to treat patients with cancer.”

Douglas Lauffenburger, a professor of biological engineering, is also a co-senior author of the study, which represents a collaboration between the Hemann lab, the Lauffenburger lab, and the Vander Heiden lab, and appeared online in Cancer Research on September 4. Hemann lab graduate student Simona Dalin is the lead author.

The mystery ingredient

For years, researchers at MIT have been investigating different sources of chemotherapy resistance in stromal tissue. When Dalin took up the study two years ago, she was building on the findings of a former postdoc in the Hemann lab, Emanuel Kreidl. Kreidl had found that stellate cells, one type of cell in the pancreatic stromal tissue surrounding the tumor, were releasing something into the microenvironment of the pancreas that disrupted the function of gemcitabine.

Cells secrete all sorts of things — micro RNAs, fatty acids, proteins — that may be taken up and used by neighboring cells. Biologists call these ambient materials around the cell its “media.”  Kreidl had tried boiling, digesting, and filtering the stellate cell media, but nothing he did made gemcitabine any more effective against the cancer cells. The usual suspects commonly implicated in drug resistance caused by neighboring cells, like proteins, would break down under such tests. “That’s when we knew there was something new here,” says Dalin. Her challenge was to figure out what that mystery ingredient was.

Mark Sullivan PhD ‘19, then a graduate student and biochemist in Vander Heiden lab, was enlisted to help separate the stellate cell media into its molecular components and identify them. After doing so, Dalin says, “it was fairly obvious that deoxycytidine was the thing that we were looking for.” Because gemcitabine works by taking deoxycytidine’s place in DNA replication, it made sense that the presence of a lot of deoxycytidine could make it difficult for gemcitabine to fulfill its function.

Molecules pass in and out of cells through gates in the cell membrane, called transporters. Using a drug that blocks certain transporters, Dalin was able to shut the gate in the stellate cells through which deoxycytidine is released. With less deoxycytidine around, the gemcitabine was effective at lower doses, confirming her hypothesis. Now, the researchers just needed to figure out how and where deoxycytidine was getting in the way of the drug.

Once inside the cell, a nucleoside must have one or more phosphate groups added to it by several enzymes in order to become a nucleotide that can be used to build DNA. Gemcitabine goes through the same process. The researchers determined that gemcitabine was competing with deoxycytidine for the first of those enzymes, deoxycytidine kinase. When they flooded the cell with that enzyme, gemcitabine didn’t have to wait in line for its phosphate groups — and could get into the DNA to work its fatal subterfuge.

Upending Assumptions

Going forward, the Hemann lab aims to identify drugs that could inhibit the production of deoxycytidine and restore the tumor’s sensitivity to gemcitabine. Senthil Muthuswamy, an associate professor of medicine at Beth Israel Deaconess Medical Center who was not involved in the research, says this study provides “new and important insights” into how and why tumors develop resistance to gemcitabine. The findings, he adds, are “likely to have important implications for developing ways to overcome gemcitabine resistance in pancreatic cancer.”

The study’s findings may shed light on other cancer treatments that work similarly to gemcitabine. For every nucleoside, there are look-alike molecules, or analogs, that are used in cancer therapies. For example, the purine analog fludarabine is used to treat acute myeloid leukemia, another tenacious carcinoma. These generic drugs have been adopted through trial and error in the clinic, but scientists don’t fully understand why they are effective at the molecular level.

In theory, nucleoside analog drugs should work interchangeably; every nucleoside is necessary in either the replication of DNA or RNA. In practice, though, these drugs are only effective for certain cancers. The MIT researchers speculate that the sheer amount of deoxycytidine being produced in the pancreas could suggest that pancreatic cells have a particular need for deoxycytidine that also makes them more responsive to its analogs — perhaps explaining why gemcitabine targets pancreatic cancer cells effectively.

“Understanding more about nucleoside biology, and more about which organs have high levels of which nucleosides, might help us understand when to use which chemotherapies,” Dalin says.

This study leaves the researchers with many questions about how and why nucleosides are produced in the body, a realm of basic biology that is still poorly understood. It’s generally assumed that cells only make nucleosides for their own internal use in DNA replication. But pancreatic stellate cells produce a lot of deoxycytidine, far more than they need for themselves, suggesting the excess nucleosides may serve some unknown purpose in neighboring cells. Although more experiments are needed to determine this mysterious purpose, the MIT researchers have some ideas.

“These extra nucleosides introduce a possibility that perhaps making deoxycytidine is a normal function of stellate cells in the pancreas, in order to provide building blocks for the cells around them,” says Hemann. “And that’s a real surprise.”

This work was funded in part by a David H. Koch Fellowship and the MIT Center for Precision Cancer Medicine.

Image: Deoxycytidine and gemcitabine, its look-alike molecule, enter a cancer cell through the same gate in the cell membrane and are altered by the same enzyme (dCK) before they are integrated into DNA. Credit: Courtesy of the researchers.

Citation:
“Deoxycytidine Release from Pancreatic Stellate Cells Promotes Gemcitabine Resistance.”
Cancer Research, online Sept. 4, 2019, DOI: 10.1158/0008-5472.CAN-19-0960.
Dalin, S., Sullivan, M.R., Lau, A.N., Grauman-Boss, B., Mueller, H.S., Kreidl, E., Fenoglio, S., Luengo, A., Lees, J.A., Vander Heiden, M.G. and Lauffenburger, D.A.

“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.

Ankur Jain named 2019 Packard Fellow
Packard Foundation
October 15, 2019

October 15, 2019 (Los Altos, CA) – Today, the David and Lucile Packard Foundation announced the 2019 class of Packard Fellows for Science and Engineering. This year’s class features 22 early-career scientists and engineers, who will each receive $875,000 over five years to pursue their research.

The Packard Fellowships in Science and Engineering are among the nation’s largest nongovernmental fellowships, designed to allow maximum flexibility in how the funding is used. Since 1988, this program has supported the blue-sky thinking of scientists and engineers with the belief that their research over time will lead to new discoveries that improve people’s lives and enhance our understanding of the universe.

Fellows have gone on to receive a range of accolades, including Nobel Prizes in Chemistry and Physics, the Fields Medal, the Alan T. Waterman Award, MacArthur Fellowships, and elections to the National Academies. The Fellows also gather at annual meetings to discuss their research, where conversations have led to unexpected collaborations across disciplines.

“This new class of Fellows is about to embark on a journey to pursue their curiosity down unknown paths in ways that could lead to big discoveries,” said Frances Arnold, Chair of the Packard Fellowships Advisory Panel, 2018 Nobel Laureate in Chemistry, and 1989 Packard Fellow. “I can’t wait to see what direction the work of these brilliant scientists and engineers will take. Their efforts will add to this beautiful web of science that connects us all to a better understanding of the world around us.”

Through the interactive online experience Pursuing the Unknown, the inspiring work, ideas, and careers of over 30 years of Fellows comes to life, including 2014 Fellow Trisha Andrew’s work developing smart clothing, 2016 Fellow Meg Crofoot’s use of GPS technology to track how primates socialize in groups, and the efforts of 2014 Fellows Vedran Lekic and Brice Ménard, who met as Packard Fellows and are collaborating to improve our understanding of earthquakes.

The Fellowships program was inspired by David Packard’s commitment to strengthen university-based science and engineering programs in the United States. He recognized that the success of the Hewlett-Packard Company, which he cofounded, was derived in large measure from research and development in university laboratories. Since 1988, the Foundation has awarded $429 million to support 617 scientists and engineers from 54 national universities. This year’s Fellowships are also supported in part by the Ross M. Brown Family Foundation.

The recipients of the 2019 Packard Fellowships in Science and Engineering are:

Ludmil Alexandrov
Department of Cellular and Molecular Medicine, University of California, San Diego
Discipline: Biological Sciences

The Alexandrov Lab is focused on mapping and understanding the mutagenic processes that cause cancer. By developing novel computational approaches and applying them to large datasets from cancer patients, our lab aims to provide a detailed roadmap for preventing human cancer.

Jacob Allgeier
Department of Ecology and Evolutionary Biology, University of Michigan
Discipline: Ecology, Evolutionary Biology

Rebuilding marine fisheries requires solutions that sustainably increase the productivity of ecosystems. The Allgeier Lab uses artificial reefs, modeling, and community-based conservation programs to understand how an unlikely but renewable source of fertilizer, fish excretion, can be used to stimulate fish production and improve food security in tropical coastal ecosystems.

Peter Behroozi
Department of Astronomy, University of Arizona
Discipline: Astronomy, Astrophysics, Cosmology

Behroozi’s lab will generate a complete, transformative picture of how supermassive black holes (like those imaged by the Event Horizon Telescope) form in galaxies. This will resolve key questions about black holes’ radiative efficiencies and spins, as well as constrain the rates of black hole mergers and detectable gravitational waves.

Yi-Wei Chang
Department of Biochemistry and Biophysics, University of Pennsylvania
Discipline: Biological Sciences

In biology, function arises from structure. The Chang lab uses cutting-edge electron and optical imaging methods combining with innovative analytical tools to look into cells in unprecedented details, aiming to decipher the principle and mechanism of cellular processes through direct molecular structural investigations.

Lauren Ilsedore Cleeves
Department of Astronomy, University of Virginia
Discipline: Astronomy, Astrophysics, Cosmology

Planet formation is complex, both physically and chemically. Cleeves studies the dusty disks around young stars where planet formation happens. Using both computer models and observations, her group aims to figure out how the properties of disks lead to robust planet formation, especially with respect to potentially habitable planets.

Courtney Dressing
Department of Astronomy, University of California, Berkeley
Discipline: Astronomy, Astrophysics, Cosmology

Currently, the Earth is the only planet known to harbor life. The Dressing group is advancing the search for life on planets orbiting nearby stars by using a variety of ground-based and space-based telescopes to discover new planets, determine their characteristics, and assess their suitability for life.

Ankur Jain
Department of Biology, Massachusetts Institute of Technology
Discipline: Biological Sciences

A single human cell contains several billion macromolecular building blocks. We investigate the design principles that cells use to organize their contents, and how defects in the cellular organization can contribute to human disease.

Shimon Kolkowitz
Department of Physics, University of Wisconsin, Madison
Discipline: Physics

Optical atomic clocks are the most precise devices ever constructed by humankind. The Kolkowitz group is researching ways to harness this precision to shed light on some of the big open questions in physics, such as the nature of dark matter, and the connections between quantum mechanics and gravity.

Bronwen Konecky
Department of Earth and Planetary Sciences, Washington University
Discipline: Geosciences

The relationship between tropical rainfall and global climate depends on complex interactions between the oceans, atmosphere, and land surfaces. The Konecky group integrates field, lab, and climate model experiments in order to disentangle these hydroclimatic processes on scales from molecular to global, from the geologic past to today.

Wesley Legant
Department of Biomedical Engineering, University of North Carolina, Chapel Hill
Discipline: Engineering – Chemical or Biological

Microscopy has enabled fields ranging from chemistry and materials science to biology. Work in the Legant Lab spans the development of cutting-edge fluorescent microscopes, machine learning algorithms for intelligent instrument control and image analysis, and applications to fundamental biological phenomena including cell division, cell migration, and cell differentiation.

Jingchun Li
Department of Ecology and Evolutionary Biology, University of Colorado, Boulder
Discipline: Ecology, Evolutionary Biology

The natural world is not always red in tooth and claw – species collaborate. The Li lab studies how animals and algae closely work together to efficiently convert solar power to organic nutrients. She explores the genetic and biochemical mechanisms behind this collaboration and applications to agriculture.

Aleksandr Logunov
Department of Mathematics, Princeton University
Discipline: Mathematics

In the 19th century Napoleon set a prize for the best mathematical explanation of Chladni’s resonance experiments. Nodal geometry studies the zeroes of solutions of elliptic differential equations such as the visible curves that appear in these physical experiments. Logunov’s research focuses on problems in nodal geometry, harmonic analysis, partial differential equations and geometrical analysis.

Kyle Loh
Department of Developmental Biology and Institute for Stem Cell Biology & Regenerative Medicine, Stanford University
Discipline: Biological Sciences

An enduring mystery is how all the amazingly different types of cells within the human body emerge from a single cell. By understanding the biological principles underlying how cells become different, Loh’s laboratory seeks to artificially build various types of human cells in a Petri dish from pluripotent stem cells.

Kirstin Petersen
Department of Electrical and Computer Engineering, Cornell University
Discipline: Engineering – Electrical or Computer

Petersen’s research involves design and coordination of large robot collectives able to achieve complex behaviors beyond the reach of single robot systems, and corresponding studies on how social insects do so in nature. The goal is to achieve robust autonomous systems for applications in construction, agriculture, exploration, and more.

Jose Rodriguez
Department of Chemistry and Biochemistry, University of California, Los Angeles
Discipline: Chemistry

Molecules can’t be seen with the naked eye. Instead, we rely on their interaction with quanta to interrogate their structures. The development of new technologies and methods makes that possible, particularly our use of electron microscopy. These tools and techniques can reveal undiscovered structures important to both chemistry and biology.

Alvaro Sanchez
Department of Ecology and Evolutionary Biology, Yale University
Discipline: Ecology, Evolutionary Biology; Biotechnology

Microbes are most often found forming complex ecological communities that carry out essential functions throughout the biosphere.By tightly integrating genomic information, dynamic metabolic models, and high-throughput experimentation, the Sanchez lab seeks to quantitatively predict how microbial communities will assemble, and how they will evolve in a given environment.

Daniel Scolnic
Physics Department, Duke University
Discipline: Astronomy, Astrophysics, Cosmology

We don’t understand 95% of the universe, which is made up of the mysterious dark energy and dark matter. Scolnic’s research group is using a `cosmic distance ladder’ to measuring the current expansion rate of the universe and the components of the universe driving the expansion. Scolnic’s group is doing this by measuring thousands of exploding stars to map out the history of the universe.

Sichen Shao
Department of Cell Biology, Harvard University
Discipline: Biological Sciences

Maintaining protein homeostasis is essential for cell viability, fate, and function. Shao’s lab aims to understand the molecular mechanisms that detect and handle problems at different steps of protein biosynthesis by biochemically rebuilding cellular pathways for mechanistic and structural dissection.

Ashleigh Theberge
Department of Chemistry, University of Washington
Discipline: Engineering – Chemical or Biological

Communication across cell types – within the human body and across microbial communities – is central to life. Theberge’s group develops new approaches to decipher chemical dialog across cells using open microfluidic culture systems and particle-based extraction methods to selectively isolate chemical signals from complex biological systems.

Matt Thomson
Department of Biology and Biological Engineering, California Institute of Technology
Discipline: Biological Sciences; Biotechnology

We seek to understand and program collective behavior in biological systems across different scales of organization ranging from the molecular to cellular scale. We construct and apply mathematical models to control processes ranging from the self-organization of active matter to the development of neural circuits in the brain.

Da Yang
Department of Land, Air and Water Resources, University of California, Davis
Discipline: Geosciences

The Yang group uses a combination of satellite observations, computer models and theory to study the Earth’s weather and climate. We focus on understanding the physics of rainstorms to address what sets their temporal and spatial scales, and how the collective effect of individual rainstorms shapes the Earth’s climate.

Lauren Zarzar
Department of Chemistry, Pennsylvania State University
Discipline: Chemistry

Understanding how to program life-like dynamic characteristics into what otherwise would be a static system is an important aspect of designing functional materials. Zarzar’s lab investigates how chemical and mechanical pathways couple in soft materials, such as droplets and gels, to yield such adaptive behaviors and also explores laser writing to synthesize and integrate diverse microscale materials.

For more detailed information on each of the Fellows, please visit the Fellowship Directory.

About the Packard Fellowships for Science and Engineering Selection Process

Each year, the Foundation invites 50 universities to nominate two faculty members for consideration. The Packard Fellowships Advisory Panel, a group of 12 internationally-recognized scientists and engineers, evaluates the nominations and recommends Fellows for approval by the Packard Foundation Board of Trustees. Packard Fellows must be faculty members who are eligible to serve as principal investigators on research in the natural and physical sciences or engineering and must be within the first three years of their faculty careers. Disciplines that are considered include physics, chemistry, mathematics, biology, astronomy, computer science, earth science, ocean science and all branches of engineering. The Packard Fellowship is among the nation’s largest nongovernmental fellowships, designed with minimal constraints on how the funding is used to give the Fellows freedom to think big and look at complex issues with a fresh perspective. Visit the Packard Fellowships for Science and Engineering webpage to learn more about the program.

About the David and Lucile Packard Foundation

The David and Lucile Packard Foundation is a private family foundation created in 1964 by David Packard (1912–1996), cofounder of the Hewlett-Packard Company, and Lucile Salter Packard (1914–1987). The Foundation provides grants to nonprofit organizations in the following program areas: Conservation and Science; Population and Reproductive Health; Children, Families, and Communities; and Local Grantmaking. The Foundation makes national and international grants and has a special focus on the Northern California counties of San Benito, San Mateo, Santa Clara, Santa Cruz and Monterey. Foundation grantmaking includes support for a wide variety of activities including direct services, research and policy development, and public information and education. Learn more at www.packard.org.