Author: MIT News

School of Science welcomes 10 professors

by School of Science |

The MIT School of Science recently welcomed 10 new professors in the departments of Biology Brain and Cognitive Sciences, Chemistry, Physics, Mathematics, and Earth, Atmospheric and Planetary Sciences.

Tristan Collins conducts research at the intersection of geometric analysis, partial differential equations, and algebraic geometry. In joint work with Valentino Tosatti, Collins described the singularity formation of the Ricci flow on Kahler manifolds in terms of algebraic data. In recent work with Gabor Szekelyhidi, he gave a necessary and sufficient algebraic condition for existence of Ricci-flat metrics, which play an important role in string theory and mathematical physics. This result lead to the discovery of infinitely many new Einstein metrics on the 5-dimensional sphere. With Shing-Tung Yau and Adam Jacob, Collins is currently studying the relationship between categorical stability conditions and existence of solutions to differential equations arising from mirror symmetry.

Collins earned his BS in mathematics at the University of British Columbia in 2009, after which he completed his PhD in mathematics at Columbia University in 2014 under the direction of Duong H. Phong. Following a four-year appointment as a Benjamin Peirce Assistant Professor at Harvard University, Collins joins MIT as an assistant professor in the Department of Mathematics.

Julien de Wit develops and applies new techniques to study exoplanets, their atmospheres, and their interactions with their stars. While a graduate student in the Sara Seager group at MIT, he developed innovative analysis techniques to map exoplanet atmospheres, studied the radiative and tidal planet-star interactions in eccentric planetary systems, and constrained the atmospheric properties and mass of exoplanets solely from transmission spectroscopy. He plays a critical role in the TRAPPIST/SPECULOOS project, headed by Université of Liège, leading the atmospheric characterization of the newly discovered TRAPPIST-1 planets, for which he has already obtained significant results with the Hubble Space Telescope. De Wit’s efforts are now also focused on expanding the SPECULOOS network of telescopes in the northern hemisphere to continue the search for new potentially habitable TRAPPIST-1-like systems.

De Wit earned a BEng in physics and mechanics from the Université de Liège in Belgium in 2008, an MS in aeronautic engineering and an MRes in astrophysics, planetology, and space sciences from the Institut Supérieur de l’Aéronautique et de l’Espace at the Université de Toulouse, France in 2010; he returned to the Université de Liège for an MS in aerospace engineering, completed in 2011. After finishing his PhD in planetary sciences in 2014 and a postdoc at MIT, both under the direction of Sara Seager, he joins the MIT faculty in the Department of Earth, Atmospheric and Planetary Sciences as an assistant professor.

Ila Fiete uses computational and theoretical tools to better understand the dynamical mechanisms and coding strategies that underlie computation in the brain, with a focus on elucidating how plasticity and development shape networks to perform computation and why information is encoded the way that it is. Her recent focus is on error control in neural codes, rules for synaptic plasticity that enable neural circuit organization, and questions at the nexus of information and dynamics in neural systems, such as understand how coding and statistics fundamentally constrain dynamics and vice-versa.

After earning a BS in mathematics and physics at the University of Michigan, Fiete obtained her PhD in 2004 at Harvard University in the Department of Physics. While holding an appointment at the Kavli Institute for Theoretical Physics at the University of California, Santa Barbara from 2004 to 2006, she was also a visiting member of the Center for Theoretical Biophysics at the University of California at San Diego. Fiete subsequently spent two years at Caltech as a Broad Fellow in brain circuitry, and in 2008 joined the faculty of the University of Texas at Austin. She joins the MIT faculty in the Department of Brain and Cognitive Sciences as an associate professor with tenure.

Ankur Jain explores the biology of RNA aggregation. Several genetic neuromuscular disorders, such as myotonic dystrophy and amyotrophic lateral sclerosis, are caused by expansions of nucleotide repeats in their cognate disease genes. Such repeats cause the transcribed RNA to form pathogenic clumps or aggregates. Jain uses a variety of biophysical approaches to understand how the RNA aggregates form, and how they can be disrupted to restore normal cell function. Jain will also study the role of RNA-DNA interactions in chromatin organization, investigating whether the RNA transcribed from telomeres (the protective repetitive sequences that cap the ends of chromosomes) undergoes the phase separation that characterizes repeat expansion diseases.

Jain completed a bachelor’s of technology degree in biotechnology and biochemical engineering at the Indian Institute of Technology Kharagpur, India in 2007, followed by a PhD in biophysics and computational biology at the University of Illinois at Urbana-Champaign under the direction of Taekjip Ha in 2013. After a postdoc at the University of California at San Francisco, he joins the MIT faculty in the Department of Biology as an assistant professor with an appointment as a member of the Whitehead Institute for Biomedical Research.

Kiyoshi Masui works to understand fundamental physics and the evolution of the universe through observations of the large-scale structure — the distribution of matter on scales much larger than galaxies. He works principally with radio-wavelength surveys to develop new observational methods such as hydrogen intensity mapping and fast radio bursts. Masui has shown that such observations will ultimately permit precise measurements of properties of the early and late universe and enable sensitive searches for primordial gravitational waves. To this end, he is working with a new generation of rapid-survey digital radio telescopes that have no moving parts and rely on signal processing software running on large computer clusters to focus and steer, including work on the Canadian Hydrogen Intensity Mapping Experiment (CHIME).

Masui obtained a BSCE in engineering physics at Queen’s University, Canada in 2008 and a PhD in physics at the University of Toronto in 2013 under the direction of Ue-Li Pen. After postdoctoral appointments at the University of British Columbia as the Canadian Institute for Advanced Research Global Scholar and the Canadian Institute for Theoretical Astrophysics National Fellow, Masui joins the MIT faculty in the Department of Physics as an assistant professor.

Phiala Shanahan studies theoretical nuclear and particle physics, in particular the structure and interactions of hadrons and nuclei from the fundamental (quark and gluon) degrees of freedom encoded in the Standard Model of particle physics. Shanahan’s recent work has focused on the role of gluons, the force carriers of the strong interactions described by quantum chromodynamics (QCD), in hadron and nuclear structure by using analytic tools and high-performance supercomputing. She recently achieved the first calculation of the gluon structure of light nuclei, making predictions that will be testable in new experiments proposed at Jefferson National Accelerator Facility and at the planned Electron-Ion Collider. She has also undertaken extensive studies of the role of strange quarks in the proton and light nuclei that sharpen theory predictions for dark matter cross-sections in direct detection experiments. To overcome computational limitations in QCD calculations for hadrons and in particular for nuclei, Shanahan is pursuing a program to integrate modern machine learning techniques in computational nuclear physics studies.

Shanahan obtained her BS in 2012 and her PhD in 2015, both in physics, from the University of Adelaide. She completed postdoctoral work at MIT in 2017, then held a joint position as an assistant professor at the College of William and Mary and senior staff scientist at the Thomas Jefferson National Accelerator Facility until 2018. She returns to MIT in the Department of Physics as an assistant professor.

Nike Sun works in probability theory at the interface of statistical physics and computation. Her research focuses in particular on phase transitions in average-case (randomized) formulations of classical computational problems. Her joint work with Jian Ding and Allan Sly establishes the satisfiability threshold of random k-SAT for large k, and relatedly the independence ratio of random regular graphs of large degree. Both are long-standing open problems where heuristic methods of statistical physics yield detailed conjectures, but few rigorous techniques exist. More recently she has been investigating phase transitions of dense graph models.

Sun completed BA mathematics and MA statistics degrees at Harvard in 2009, and an MASt in mathematics at Cambridge in 2010. She received her PhD in statistics from Stanford University in 2014 under the supervision of Amir Dembo. She held a Schramm fellowship at Microsoft New England and MIT Mathematics in 2014-2015 and a Simons postdoctoral fellowship at the University of California at Berkeley in 2016, and joined the Berkeley Department of Statistics as an assistant professor in 2016. She returns to the MIT Department of Mathematics as an associate professor with tenure.

Alison Wendlandt focuses on the development of selective, catalytic reactions using the tools of organic and organometallic synthesis and physical organic chemistry. Mechanistic study plays a central role in the development of these new transformations. Her projects involve the design of new catalysts and catalytic transformations, identification of important applications for selective catalytic processes, and elucidation of new mechanistic principles to expand powerful existing catalytic reaction manifolds.

Wendlandt received a BS in chemistry and biological chemistry from the University of Chicago in 2007, an MS in chemistry from Yale University in 2009, and a PhD in chemistry from the University of Wisconsin at Madison in 2015 under the direction of Shannon S. Stahl. Following an NIH Ruth L. Krichstein Postdoctoral Fellowship at Harvard University, Wendlandt joins the MIT faculty in the Department of Chemistry as an assistant professor.

Chengyang Xu specializes in higher-dimensional algebraic geometry, an area that involves classifying algebraic varieties, primarily through the minimal model program (MMP). MMP was introduced by Fields Medalist S. Mori in the early 1980s to make advances in higher dimensional birational geometry. The MMP was further developed by Hacon and McKernan in the mid-2000s, so that the MMP could be applied to other questions. Collaborating with Hacon, Xu expanded the MMP to varieties of certain conditions, such as those of characteristic p, and, with Hacon and McKernan, proved a fundamental conjecture on the MMP, generating a great deal of follow-up activity. In collaboration with Chi Li, Xu proved a conjecture of Gang Tian concerning higher-dimensional Fano varieties, a significant achievement. In a series of papers with different collaborators, he successfully applied MMP to singularities.

Xu received his BS in 2002 and MS in 2004 in mathematics from Peking University, and completed his PhD at Princeton University under János Kollár in 2008. He came to MIT as a CLE Moore Instructor in 2008-2011, and was subsequently appointed assistant professor at the University of Utah. He returned to Peking University as a research fellow at the Beijing International Center of Mathematical Research in 2012, and was promoted to professor in 2013. Xu joins the MIT faculty as a full professor in the Department of Mathematics.

Zhiwei Yun’s research is at the crossroads between algebraic geometry, number theory, and representation theory. He studies geometric structures aiming at solving problems in representation theory and number theory, especially those in the Langlands program. While he was a CLE Moore Instructor at MIT, he started to develop the theory of rigid automorphic forms, and used it to answer an open question of J-P Serre on motives, which also led to a major result on the inverse Galois problem in number theory. More recently, in his joint work with Wei Zhang, they give geometric interpretation of higher derivatives of automorphic L- functions in terms of intersection numbers, which sheds new light on the geometric analogue of the Birch and Swinnerton-Dyer conjecture.

Yun earned his BS at Peking University in 2004, after which he completed his PhD at Princeton University in 2009 under the direction of Robert MacPherson. After appointments at the Institute for Advanced Study and as a CLE Moore Instructor at MIT, he held faculty appointments at Stanford and Yale. He returned to the MIT Department of Mathematics as a full professor in the spring of 2018.

Study: Cellular changes lead to chronic allergic inflammation in the sinus

by Anne Trafton |

Chronic rhinosinusitis is distinct from your average case of seasonal allergies. It causes the sinuses to become inflamed and swollen for months to years at a time, leading to difficulty breathing and other symptoms that make patients feel miserable. In some people, this condition also produces tissue outgrowths known as nasal polyps, which, when severe enough, have to be removed surgically.

By performing a genome-wide analysis of thousands of single cells from human patients, MIT and Brigham and Women’s Hospital researchers have created the first global cellular map of a human barrier tissue during inflammation. Analysis of this data led them to propose a novel mechanism that may explain what sustains chronic rhinosinusitis.

Their findings also offer an explanation for why some rhinosinusitis patients develop nasal polyps, which arise from epithelial cells that line the respiratory tract. Furthermore, their study may have broader implications for how researchers think about and treat other chronic inflammatory diseases of barrier tissues, such as asthma, eczema, and inflammatory bowel disease.

“We saw major gene-expression differences in subsets of epithelial cells which had been previously obscured in bulk tissue analyses,” says Alex K. Shalek, the Pfizer-Laubach Career Development Assistant Professor of Chemistry, a core member of MIT’s Institute for Medical Engineering and Science (IMES), and an extramural member of the Koch Institute for Integrative Cancer Research, as well as an associate member of the Ragon and Broad Institutes.

“When you look across the entire transcriptome, comparing cells from patients with different disease statuses over thousands of genes, you can start to understand the relationships between them and discover which transcriptional programs have supplanted the usual ones,” Shalek says.

The lead authors of the paper, which appears in the Aug. 22 issue of Nature, are Jose Ordovas-Montanes, an IMES postdoc fellow supported by the Damon Runyon Cancer Research Foundation, and Daniel Dwyer, a research fellow at Brigham and Women’s Hospital. Shalek and Nora Barrett, an assistant professor of medicine at Brigham and Women’s, are the paper’s senior authors.

Clinical single-cell RNA sequencing

Last year, Shalek and his colleagues developed a new portable technology that enables rapid sequencing of the RNA contents of several thousand single cells in parallel from tiny clinical samples. This technology, known as Seq-Well, allows researchers to see what transcriptional programs are turned on inside individual cells, giving them insight into the identities and functions of those cells.

In their latest study, the MIT and Brigham and Women’s researchers applied this technology to cells from the upper respiratory tract of patients suffering from chronic rhinosinusitis, with the hypothesis that distinct gene-expression patterns within epithelial cells might reveal why some patients develop nasal polyps while others do not.

This analysis revealed striking differences in the genes expressed in basal epithelial cells (a type of tissue stem cell) from patients with and without nasal polyps. In nonpolyp patients and in healthy people, these cells normally form a flat base layer of tissue that coats the inside of the nasal passages. In patients with polyps, these cells begin to pile up and form thicker layers instead of differentiating into epithelial cell subsets needed for host defense.

This type of gross tissue abnormality has been observed through histology for decades, but the new study revealed that basal cells from patients with polyps had turned on a specific program of gene expression that explains their blunted differentiation trajectory. This program appears to be sustained directly by IL-4 and IL-13, immune response cytokines known to drive allergic inflammation when overproduced at pathologic levels.

The researchers found that these basal cells also retain a “memory” of their exposure to IL-4 and IL-13: When they removed basal cells from nonpolyps and polyps, grew them in equivalent conditions for a month, and then exposed them to IL-4 and IL-13, they found that unstimulated cells from patients with polyps already expressed many of the genes that were induced in those without polyps. Among the IL-4 and IL-13 responsive memory signatures were genes from a cell signaling pathway known as Wnt, which controls cell differentiation.

Immunologists have long known that B cells and T cells can store memory of an allergen that they have been exposed to, which partly explains why the immune system may overreact the next time the same allergen is encountered. However, the new finding suggests that basal cells also contribute a great deal to this memory.

Since basal cells are stem cells that generate the other cells found in the respiratory epithelium, this memory may influence their subsequent patterns of gene expression and ability to generate mature specialized epithelial cells. The team noted a substantial impact on the balance of cell types within the epithelium in patients with severe disease, leading to a population of cells with diminished diversity.

“Once you know that IL-4 and IL-13 act on stem cells, it changes the way in which you have to think about intervening, versus if they acted on differentiated cells, because you have to erase that memory in order to bring the system back to homeostasis,” Shalek says. “Otherwise you’re not actually dealing with a root cause of the problem.”

The findings show the importance of looking beyond immune cells for factors that influence chronic allergies, says Shruti Naik, an assistant professor of pathology, medicine, and dermatology at New York University School of Medicine.

“They examined the tissue as a whole rather than biasing the study toward one cell type or another, and what they found is that other components of the tissue are irreversibly impacted by inflammation,” says Naik, who was not involved in the research.

Blocking cytokines in humans

The findings suggested that ongoing efforts to block the effects of IL-4 and IL-13 might be a good way to try to treat chronic rhinosinusitis, a hypothesis that the researchers validated using an antibody that blocks a common receptor for these two cytokines. This antibody has been approved to treat eczema and is undergoing further testing for other uses. The researchers analyzed the gene expression of basal cells taken from one of the patients with polyps before and after he had been treated with this antibody. They found that most, but not all, of the genes that had been stimulated by IL-4 and IL-13 had returned to normal expression levels.

“It suggests that blockade of IL-4 and IL-13 can help to restore basal cells and secretory cells towards a healthier state,” Ordovas-Montanes says. “However, there’s still some residual genetic signature left. So now the question will be, how do you intelligently target that remainder?”

The researchers now plan to further detail the molecular mechanisms of how basal cells store inflammatory memory, which could help them to discover additional drug targets. They are also studying inflammatory diseases that affect other parts of the body, such as inflammatory bowel disease, where inflammation often leads to polyps that can become cancerous. Investigating whether stem cells in the gut might also remember immunological events, sustain disease, and play a role in tumor formation, will be key to designing early interventions for inflammation-induced cancers.

The research was funded by the Searle Scholars Program, the Beckman Young Investigator Program, the Pew-Stewart Scholars Program, Sloan Fellowship Program, the Steven and Judy Kaye Young Innovators program, the Damon Runyon Cancer Research Foundation, the Bill and Melinda Gates Foundation, and the National Institutes of Health.

Professor Richard Schrock announces emeritus status

by Danielle Randall |

Nobel laureate, Killian lecturer, and F.G. Keyes Professor Richard Royce Schrock recently announced his retirement from teaching and will officially transition to emeritus status within the Department of Chemistry on Sept. 1.

“I look forward to a period in my life with fewer deadlines, which is the point of retirement,” said Schrock. “However, it is difficult to imagine the next few years without the challenges and joys of fundamental research, which I have enjoyed throughout my career.”

Schrock intends to remain research-active at MIT and will continue to maintain his laboratory and mentor a research group in Cambridge, while simultaneously taking advantage of the spare time that retiring from teaching allows.

“I have had the good fortune to have been part of the discovery and development of an area of research that has spanned 50 years; that growth continues, even at a fundamental level,” he says. “Recently, my group made some potentially important discoveries so I hope to support a few postdoctoral students to complete these studies.”

Schrock also intends to use his retirement to contribute to chemistry as a whole. Part of that plan involves spending winters at the University of California at Riverside, his undergraduate alma mater. His appointment to the inaugural George K. Helmkamp Founder’s Chair in Chemistry will afford him the opportunity to meet with Riverside faculty and students while enjoying warm winters near his family in Long Beach. Schrock will continue to call Winchester, Massachusetts, where he and his wife Nancy live, home surrounded by their friends and hobbies. “Our home includes a bookbinding studio for Nancy, a woodworking shop for me, and a garden and kitchen for both of us,” Schrock says.

As for his retirement “to-do list,” Schrock remains open. “I do not have a so-called ‘bucket list’ of travel goals, but I intend to enjoy traveling to see family — including my youngest son and his family in Atlanta — and friends, as opportunities arise,” he says. “Much of the future is part of the experiment of life, and involves making choices that I cannot predict.”

Light-controlled polymers can switch between sturdy and soft

by Anne Trafton | MIT News Office |

MIT researchers have designed a polymer material that can change its structure in response to light, converting from a rigid substance to a softer one that can heal itself when damaged.

“You can switch the material states back and forth, and in each of those states, the material acts as though it were a completely different material, even though it’s made of all the same components,” says Jeremiah Johnson, an associate professor of chemistry at MIT, a member of MIT’s Koch Institute for Integrative Cancer Research and the Program in Polymers and Soft Matter, and the leader of the research team.

The material consists of polymers attached to a light-sensitive molecule that can be used to alter the bonds formed within the material. Such materials could be used to coat objects such as cars or satellites, giving them the ability to heal after being damaged, though such applications are still far in the future, Johnson says.

The lead author of the paper, which appears in the July 18 issue of Nature, is MIT graduate student Yuwei Gu. Other authors are MIT graduate student Eric Alt, MIT assistant professor of chemistry Adam Willard, and Heng Wang and Xiaopeng Li of the University of South Florida.

Controlled structure

Many of the properties of polymers, such as their stiffness and their ability to expand, are controlled by their topology — how the components of the material are arranged. Usually, once a material is formed, its topology cannot be changed reversibly. For example, a rubber ball remains elastic and cannot be made brittle without changing its chemical composition.

In this paper, the researchers wanted to create a material that could reversibly switch between two different topological states, which has not been done before.

Johnson and his colleagues realized that a type of material they designed a few years ago, known as polymer metal-organic cages, or polyMOCs, was a promising candidate for this approach. PolyMOCs consist of metal-containing, cage-like structures joined together by flexible polymer linkers. The researchers created these materials by mixing polymers attached to groups called ligands, which can bind to a metal atom.

Each metal atom — in this case, palladium — can form bonds with four ligand molecules, creating rigid cage-like clusters with varying ratios of palladium to ligand molecules. Those ratios determine the size of the cages.

In the new study, the researchers set out to design a material that could reversibly switch between two different-sized cages: one with 24 atoms of palladium and 48 ligands, and one with three palladium atoms and six ligand molecules.

To achieve that, they incorporated a light-sensitive molecule called DTE into the ligand. The size of the cages is determined by the angle of bonds that a nitrogen molecule on the ligand forms with palladium. When DTE is exposed to ultraviolet light, it forms a ring in the ligand, which increases the size of the angle at which nitrogen can bond to palladium. This makes the clusters break apart and form larger clusters.

When the researchers shine green light on the material, the ring is broken, the bond angle becomes smaller, and the smaller clusters re-form. The process takes about five hours to complete, and the researchers found they could perform the reversal up to seven times; with each reversal, a small percentage of the polymers fails to switch back, which eventually causes the material to fall apart.

When the material is in the small-cluster state, it becomes up to 10 times softer and more dynamic. “They can flow when heated up, which means you could cut them and upon mild heating that damage will heal,” Johnson says.

This approach overcomes the tradeoff that usually occurs with self-healing materials, which is that structurally they tend to be relatively weak. In this case, the material can switch between the softer, self-healing state and a more rigid state.

“Reversibly switching topology of polymer networks has never been reported before and represents a significant advancement in the field,” says Sergei Sheiko, a professor of chemistry at the University of North Carolina, who was not involved in the research. “Without changing network composition, photoswitchable ligands enable remotely activated transition between two topological states possessing distinct static and dynamic properties.”

Self-healing materials

In this paper, the researchers used the polymer polyethylene glycol (PEG) to make their material, but they say this approach could be used with any kind of polymer. Potential applications include self-healing materials, although for this approach to be widely used, palladium, a rare and expensive metal, would likely have to be replaced by a cheaper alternative.

“Anything made from plastic or rubber, if it could be healed when it was damaged, then it wouldn’t have to be thrown away. Maybe this approach would provide materials with longer life cycles,” Johnson says.

Another possible application for these materials is drug delivery. Johnson believes it could be possible to encapsulate drugs inside the larger cages, then expose them to green light to make them open up and release their contents. Applying green light could enable recapture of the drugs, providing a novel approach to reversible drug delivery.

The researchers are also working on creating materials that can reversibly switch from a solid state to a liquid state, and on using light to create patterns of soft and rigid sections within the same material.

The research was funded by the National Science Foundation.

Advancing knowledge in medical and genetic sciences

by Danielle Randall |

Research proposals from Laurie Boyer, associate professor of biology; Matt Shoulders, the Whitehead Career Development Associate Professor of Chemistry; and Feng Zhang, associate professor in the departments of Brain and Cognitive Sciences and Biological Engineering, Patricia and James Poitras ’63 Professor in Neuroscience, investigator at the McGovern Institute for Brain Research, and core member of the Broad Institute, have recently been selected for funding by the G. Harold and Leila Y. Mathers Foundation. These three grants from the Mathers Foundation will enable, over the next three years, key projects in the researchers’ respective labs.

Regenerative medicine holds great promise for treating heart failure, but that promise is unrealized, in part, due to a lack of sufficient understanding of heart development at the mechanistic level. Boyer’s research aims to achieve a deep, mechanistic understanding of the gene control switches that coordinate normal heart development. She then aims to leverage this knowledge and design effective strategies for rewiring faulty circuits in aging and disease.

“We are very grateful to receive support and recognition of our work from the Mathers Foundation,” said Boyer. “This award will allow us to build upon our prior work and to embark upon high risk projects that could ultimately change how we think about treating diseases resulting from faulty wiring of gene expression programs.”

Shoulders’ goal, with this support from the Mathers Foundation, is to elucidate underlying causes of osteoarthritis. There is currently no cure for osteoarthritis, which is perhaps the most common aging-related disease and is characterized by a progressive deterioration of joint cartilage culminating in inflammation, debilitating pain, and joint dysfunction. The Shoulders Group aims to test a new model for osteoarthritis — specifically, the concept that a collapse of proteostasis in aging cartilage cells creates an unrecoverable cartilage repair defect, thus initiating a self-amplifying, destructive feedback loop leading to pathology. Proteostasis collapse in aging cells is a well-known, disease-causing phenomenon that has previously been considered primarily in the context of neurodegenerative disorders. If correct, the proteostasis collapse model for osteoarthritis could one day lead to a novel class of therapeutic options for the disease.

“We are delighted to receive this generous support from the Mathers Foundation, which makes it possible for us to pursue an outside-the-box, high-risk/high-impact idea regarding the origins of osteoarthritis,” said Shoulders. “The research we are now able to pursue will not only provide fundamental, molecular-level insights into joint function, but also could change how we think about this widespread disease.”

Many genetic diseases are caused by the change of just a single base of DNA. Zhang is a leader in the field of genome editing, and he and his team have developed an array of tools based on the microbial immune CRISPR-Cas systems that can manipulate DNA and RNA in human cells. Together, these tools are changing the way molecular biology research is conducted, and they hold immense potential as therapeutic agents to correct thousands of genetic diseases. Now, with the support of the Mathers Foundation, Zhang is working to realize this potential by developing a CRISPR-based therapeutic that works at the level of RNA and offers a safe, effective route to treating a range of diseases, including diseases of the brain and central nervous system, which are difficult to treat with existing gene therapies.

“The generous support from the Mathers Foundation allows us the freedom to explore this exciting new direction for CRISPR-based technologies,” Zhang stated.

Known for their generosity and philanthropy, G. Harold and Leila Y. Mathers created their foundation with the goal of distributing their wealth among sustainable, charitable causes, with a particular interest in basic scientific research. The Mathers Foundation, whose ongoing mission is to advance knowledge in the life sciences by sponsoring scientific research and applying learnings and discoveries to benefit mankind, has issued grants since 1982.

Charting a path to better cell models of the intestine

by Institute for Medical Engineering and Science |

For many years, drug development has relied on simplified and scalable cell culture models to find and test new drugs for a wide variety of diseases. However, cells grown in a dish are often a feint representation of healthy and diseased cell types in vivo. This limitation has serious consequences: Many potential medicines that originally appear promising in cell cultures often fail to work when tested in patients, and targets may be completely missed if they do not appear in a dish.

A highly collaborative team of researchers from the Harvard-MIT Program in Health Sciences and Technology (HST) and Institute for Medical Engineering and Science (IMES) at MIT recently set out to tackle this issue as it relates to a type of cell found in the intestine that is implicated in inflammatory bowel disease (IBD). In new work, the team was able to generate an intestinal cell that is a substantially better mimic of the real cell and can therefore be used in studies of diseases such as IBD. They reported their findings in a recent issue of BMC Biology.

The team was led by Ben Mead, a doctoral student in the HST Medical Engineering and Medical Physics Program; Jeffrey Karp, a professor at Brigham and Women’s Hospital, working closely with Jose Ordovas-Montanes, a postdoc in the lab of Pfizer-Laubach Career Development Assistant Professor Alex K. Shalek in the MIT Department of Chemistry; and the labs of MIT professor of biological engineering Jim Collins, Institute Professor Robert Langer, and scientists from the Broad Institute of Harvard and MIT and Koch Institute for Integrative Cancer Research.

Understanding genetic risk at the level of single cells

This study was catalyzed by the new technology of high-throughput single-cell RNA-sequencing, which enables transcriptome-wide profiling of tissues at the level of individual cells. Through the lens of single-cell RNA-sequencing, scientists are now able to ‘map’ our single cells and potentially the changes which give rise to disease. The team of researchers turned this method towards determining how well an existing cell culture model mimics a particular type of cell within the body, comparing two single cell ‘maps’: one of a mouse’s small intestine, and another of an adult stem cell-derived model of the small intestine, known as an organoid.

They used these maps to isolate a single cell type and ask how well the organoid-derived cell matched its natural counterpart. “Based on the differences between model and actual cell, we utilized a computationally driven bioengineering approach to improve the fidelity of the model.” said Karp. “We believe this approach may be key to unlocking the next generation of therapeutic development from cellular models, including those made from patient-derived stem cells.”

Individual genes can alter one’s risk of developing diseases such as Crohn’s disease, a type of IBD. One active area of research is understanding where these genes act in a tissue in order to further our understanding of disease mechanisms and propose novel therapeutic interventions. To address this, techniques are needed to reliably map “risk” genes not only within an affected tissue, but to individual cells, to properly surmise if a drug screen can correct a faulty gene or potentially improve a patient’s condition.

Single-cell RNA-sequencing at scale, a revolutionary technique pioneered for low-input clinical biopsies at MIT between Alex K. Shalek’s and Chris Love’s group, now allows researchers to deconstruct a tissue into its elemental components — cells — and identify the key patterns of gene expression which specify each cell type. The ability to efficiently profile tens of thousands of cells economically has unlocked the possibility to identify critical cell types in tissues whose genetic makeup had previously been difficult to discern.

Using single-cell “maps” to re-orient the development of a key cell type

Mapping tissues, such as the small intestine, is highly important in understanding where specific “risk” genes are acting. However, the key advances required to translate findings to the clinic will inevitably be through representative models for the cell types identified as interpreting genes and displaying a disease phenotype. One key IBD-relevant cell type already implicated through genetic studies is known as the Paneth cell, responsible for a key anti-microbial role in the small intestine and defending the stem cell niche.

When adult intestinal stem cells are grown in a dish, they self-organize into remarkable structures known as intestinal organoids: 3-D cellular structures that contain many of the cell types found in a real intestine. Nevertheless, how these intestinal organoids correspond to the bona fide cell types found in the intestine has proven challenging for researchers to tackle. To directly address this question, Shalek suggested a “quick” experiment to Mead, which then gave rise to the fruitful collaboration between the labs.

Mead and Ordovas-Montanes developed a single-cell map of the true characteristics of small intestinal cell types as found within the mouse and, when comparing them to what a map of the intestinal-derived organoid looks like, identified several differences, particularly within the key IBD-relevant cell type known as the Paneth cell. Since the field’s map of an organoid didn’t quite correspond to the real tissue, it may have led them astray in the hunt for drug targets.

Fortunately, through their single-cell data, the team was able to learn how the maps were mis-aligned, and “correct” the developmental pathways which were missing in the dish. As a result, they were able to generate a Paneth cell that is a substantially better mimic of the real cell and can now function to kill bacteria and support the neighboring stem cells which give rise to them.

Translational opportunities afforded by improved representations of tissues

“With this improved cell in-hand, we are now developing a screening platform that will allow us to target relevant Paneth cell biology,” says Mead, who plans to continue the work he started as a postdoc in Shalek’s group.

Their approach for generating physiologically faithful intestinal cell types is a major technological advance that will provide other researchers a powerful tool to further their understanding of the specialized cell states of the epithelial barrier. “As we begin to understand which cell types specifically express genes that alter risk for IBD, it will be critical to ensure the disease models provide an accurate representation of that cell type,” says Ordovas-Montanes.

“We want to make better cell models to not only understand basic disease biology, but also to fast-track development of therapeutics” says Mead. “This research will have impact beyond the intestinal organoid community as organoids are increasingly employed for liver, kidney, lung, and even brain research, and our approach can be generalized for relating and aligning the cell types found in vivo with the models generated from these tissues.”

QS ranks MIT the world’s No. 1 university for 2018-19

by MIT News |

For the seventh year in a row MIT has topped the QS World University Rankings, which were announced today.

The full 2018-19 rankings — published by Quacquarelli Symonds, an organization specializing in education and study abroad — can be found at topuniversities.com. The QS rankings were based on academic reputation, employer reputation, citations per faculty, student-to-faculty ratio, proportion of international faculty, and proportion of international students. MIT earned a perfect overall score of 100.

MIT was also ranked the world’s top university in 12 of 48 disciplines ranked by QS, as announced in February of this year.

MIT received a No. 1 ranking in the following QS subject areas: Architecture/Built Environment; Linguistics; Chemical Engineering; Civil and Structural Engineering; Computer Science and Information Systems; Electrical and Electronic Engineering; Mechanical, Aeronautical and Manufacturing Engineering; Chemistry; Materials Science; Mathematics; Physics and Astronomy; and Statistics and Operational Research.

Additional high-ranking MIT subjects include: Art and Design (No. 4), Biological Sciences (No. 2), Earth and Marine Sciences (No. 3), Environmental Sciences (No. 3), Accounting and Finance (No. 2), Business and Management Studies (No. 4), and Economics and Econometrics (No. 2).

MIT Energy Initiative awards nine Seed Fund grants for early-stage energy research

by Francesca McCaffrey, MIT Energy Initiative |

In spring 2018, the MIT Energy Initiative (MITEI) awarded nine grants totaling $1,350,000 through its Seed Fund Program, an annual competition that supports early-stage innovative research across the energy spectrum. The awardees will be using the $150,000 grants to explore highly creative and promising energy research projects.

“This is an extremely competitive process,” said MITEI Director Robert C. Armstrong, the Chevron Professor of Chemical Engineering. “Every year the submissions we receive are incredibly impressive, and this year was no exception. Our grantees are remarkable in their creative, interdisciplinary approaches to addressing key global energy and climate challenges.”

To date, MITEI has supported 170 projects with grants totaling approximately $22.75 million. These projects have covered a variety of energy research areas, from fundamental physics and chemistry to engineering to policy and economics, and have drawn from all five MIT schools and 28 departments, labs, and centers.

Seed grant awardees run the gamut from established professors to new faculty members. This year, six of the nine grant recipients are first-time awardees — including four researchers early in their careers at MIT.

The chemistry of energy

While research in the lab can be critical to advancing energy technologies, computer simulations are also valuable, serving as an efficient testing ground where new ideas can be explored rapidly and at low risk. Simulations at the atomic level can be especially valuable in discovering new energy materials and in investigating chemical change in energy generation and storage. But the computational cost associated with such “atomistic” simulations can be extremely high — a problem that Professor Rafael Gomez-Bombarelli and his team will be addressing in their project. Gomez-Bombarelli, the Toyota Assistant Professor in Materials Processing, plans to use machine learning to create software that, by leveraging already existing computational results, can accelerate high-accuracy quantum-chemical calculations, reducing the cost incurred.

“We will use existing computer simulations that took many years of computer time to automatically learn consistent patterns about the behavior of matter in energy processes,” says Gomez-Bombarelli. “This newly gained information will make chemically accurate simulations thousands of times faster and accelerate the predictive design of more efficient and sustainable fuels, photovoltaic materials, solid-state lighting, battery chemicals, and industrial catalysts.”

Karthish Manthiram, an assistant professor of chemical engineering, is approaching energy generation and storage from a different angle. His team is investigating lithium-based materials as electrocatalysts for nitrogen reduction, a key step in the production of ammonia, which is a potential route for storing electrical energy from intermittent renewable sources in a liquid fuel. The intrinsic reactivity of lithium makes it a prime candidate for use in catalysis, potentially beginning a new chapter in liquid fuel creation and energy storage.

Making a better grid: Batteries and economics

Betar Gallant, an assistant professor of mechanical engineering, won a seed grant for her team’s research into calcium as a promising anode for low-cost, high-energy-density batteries. Such batteries, if successfully developed, can play critical roles in ensuring stability on a renewables-heavy power grid and also in achieving the electrification of our transportation system. Today, the most common electric-vehicle battery pack on the market is the lithium-ion battery, but improvements in gravimetric and volumetric energy density are needed to achieve longer driving ranges. While widespread efforts have focused on developing the lithium anode to replace the graphite electrode in today’s lithium-ion batteries, lithium metal cycles poorly, is expensive, and raises significant safety concerns. Gallant and others believe there is substantial room for improvement to be made by pursuing alternative metal anodes. Calcium-based batteries possess particularly attractive volumetric energy densities and potentials compared to lithium-based cells and are also safer, less expensive, and potentially more versatile if key challenges can be overcome.

“This field is very much in its infancy; while the lithium anode has been subject to study for decades, researchers have just begun studying the fundamental behavior of calcium-based electrodes,” Gallant says. “Among the most significant challenges facing calcium electrodes are limited round-trip efficiency and poor cycleability. If these challenges can be overcome, the calcium electrode will be unlocked for use in a wide range of advanced battery chemistries and will open new and exciting avenues for research and development.”

Jing Li, an incoming MIT Sloan School of Management faculty member, and her team plan to produce a more accurate cost-reduction curve for batteries by developing models based on fundamental materials and underlying science and then estimating them using data on the design, structure, cost, and quantities of batteries used in commercial products on the market. Results should help clarify why battery costs have decreased dramatically in recent years and whether that trend will continue in the future.

Li’s team will also examine what changes in the regulatory structure of electricity markets are needed in light of expanding energy storage capacity. The goal is to understand who should own and operate energy storage units on the grid and the social welfare implications of different options for energy storage ownership. The researchers will model the decision-making strategies of potential owners, including private firms and system operators, to determine possible impacts on market outcomes, including prices, quantities, and costs.

Deep expertise, new ideas

Joining those four early-career researchers were several faculty members with long, deep experience in their areas of expertise. First-time seed grant winner Ignacio Pérez-Arriaga, a visiting professor at the MIT Sloan School of Management, is leading a study that combines electricity and economic modeling with policy analysis of renewable portfolio standards and other incentives meant to encourage renewable energy growth in the United States. The goal is to determine the mix of renewable energy generation types that will ensure high reliability in a given state as well as the most cost-effective capacity expansion strategy for renewables, given differing natural resources and energy and environmental regulations across the country.

Chemistry Professor Tim Swager is also a first-time seed grantee. His team’s research focuses on a new approach to generating polymer membranes with three-dimensional porosity. Such membranes are used in chemical separations to transport ions in fuel cells as well as in processes related to chemical production and water purification. Separations often account for the majority of energy consumed during such processes, so improving their effectiveness is critical. Swager’s group is also focusing on related materials that have great potential for gas separations and on applying new ion-conducting materials to enable chemical and electrochemical transformations.

Growing long-term innovation

Seed grants may target early-stage energy research, but MITEI’s hope is that this research will continue and lead to practical solutions to real-world problems. Several past seed fund projects have made progress in that direction since their initial grants.

For example, 2016 grantee Marta Gonzalez, a visiting associate professor in the Department of Civil and Environmental Engineering, and her team developed an electric-vehicle planning app called Human Mobility, Energy and Autonomy, or HUMEA. As described in a paper published in Nature Energy in April, the app aims to make owning and operating an electric vehicle (EV) in the city easier and less disruptive to the power grid by connecting a network of electric vehicles and optimizing the schedule for when and where they should charge. “Most people begin charging their EV when they get to work and then unplug around 6 p.m. when they leave,” says Gonzalez. “Power operators can’t handle that kind of steep peak. We want to incentivize individuals to bring the trend to an overall flatter demand.” People using the app can create personalized energy profiles that will point out openings in their schedules when they can charge outside of peak times.

Funding for the new grants comes chiefly from MITEI’s founding and sustaining members, supplemented by gifts from generous donors.

Recipients of MITEI Seed Fund grants for spring 2018 are:

  • “3D porosity: Approaches to new generations of polymer membranes” — Tim Swager of the Department of Chemistry;
  • “Carbon capture from chemical processes in the intermediate temperature range” — T. Alan Hatton of the Department of Chemical Engineering and Alexie Kolpak of the Department of Mechanical Engineering;
  • “Deep learning of contracted basis sets for rapid quantum calculation of thermochemistry and other energy processes” — Rafael Gomez-Bombarelli of the Department of Materials Science and Engineering;
  • “Economics of energy storage” — Jing Li of the MIT Energy Initiative;
  • “Effective capacity expansion of renewable electricity with mosaic design of state energy and environmental regulations in the United States” — Ignacio Pérez-Arriaga of the MIT Sloan School of Management;
  • “Electrochemical ammonia synthesis for modular electrical energy storage” — Karthish Manthiram of the Department of Chemical Engineering;
  • “Oxidative coupling of methane using ion-conducting ceramic membranes” — Ahmed Ghoniem of the Department of Mechanical Engineering and Bilge Yildiz of the Department of Nuclear Science and Engineering;
  • “Scalable nanoporous membranes for energy-efficient chemical separations” — Jeffrey Grossman of the Department of Materials Science and Engineering; and
  • “Unlocking the rechargeability of calcium for high-energy-density batteries” — Betar Gallant of the Department of Mechanical Engineering.

Solutions to great chemical science challenges

by Danielle Randall, Department of Chemistry |

Professors Elizabeth M. Nolan and Jeremiah Johnson shared their efforts to address some of the greatest challenges currently faced by the chemical sciences at a recent Alumni and Friends reception hosted by the Department of Chemistry and the School of Science. Invited guests gathered in the Samberg Conference Center on May 16 for an evening of food, drink, and stimulating talks.

Employing metal withholding to inhibit microbial colonization

Nolan’s research addresses the chemistry and biology of human innate immunity and microbial pathogenesis. The lab employs toolkits of biological chemistry, inorganic chemistry, and microbiology to decipher the interplay between human host-defense molecules and microbes, and to evaluate new strategies for treating and preventing microbial infections. A significant portion of the research program is focused on metals and immunity.

Because transition metal ions are essential nutrients for all organisms, metal withholding is one strategy that the mammalian host employs to inhibit microbial colonization. At sites of infection, the host innate immune system deploys metal-sequestering proteins to capture inorganic nutrients (magnesium, iron, and zinc, for example) in the extracellular space and starve invading pathogens. This immune mechanism presents a fascinating problem in biological coordination chemistry and metal homeostasis with central importance to infectious disease. Nolan shared her findings on the effectiveness of human calprotectin (CP) in the metal-withholding innate immune response.

CP is produced by neutrophils and can constitute more than 40 percent of total cytoplasmic protein in these cells. Neutrophils are white blood cells that are recruited to sites of infection and contribute to innate immunity, and they release CP and many other antimicrobial biomolecules into the extracellular space. Following release from the neutrophil, CP chelates transition metal ions in the extracellular milieu, thereby starving bacteria of these nutrients. In addition to this accepted role in the host/pathogen interaction, CP is implicated in a variety of pathophysiological conditions that range from cardiovascular disease to cancer, and it is a U.S. Food and Drug Administration-approved biomarker for inflammatory conditions of the bowel. Thus, molecular and functional insights about CP also provide a foundation for conceptualizing and evaluating how CP participates in these facets of human disease.

Research conducted in Nolan’s lab has revealed many new aspects about how CP functions in metal homeostasis and host defense. She presented vignettes from her group’s fundamental research that highlighted advances towards elucidating the biological coordination chemistry of CP, deciphering how CP affects metal homeostasis in two microbial pathogens, and understanding the lifetime and fate of CP in the biological milieu.

“We discovered that CP uses Ca(II) ions to modulate its coordination chemistry, antimicrobial activity, and proteolytic stability,” Nolan explained. The group also deciphered how CP sequesters first-row transition metals, which included the evaluation of an unprecedented biological coordination motif.

“Contrary to the accepted dogma, we discovered that CP is an iron-sequestering protein that blocks microbial acquisition of this essential nutrient,” Nolan said.

This paradigm-changing result adds another layer of complexity to the interplay between CP and transition metals in biological systems and affords a new model in which CP contributes to iron homeostasis. Subsequently, Nolan’s group has uncovered that CP also sequesters nickel, a metal nutrient important for the virulence of human pathogens that infect the gastrointestinal and urinary tracts. In total, this research program affords paradigms for discovering and elucidating new bioinorganic chemistry, advancing fundamental understanding of human innate immunity and microbial pathogenesis, and achieving new approaches to combating infectious disease. It highlights how fundamental chemistry can be used to open up new doors for exploring and understanding complex biological systems.

“I am fascinated by chemistry and biology and the natural world,” Nolan said. “I am inspired to use the chemistry toolkit to learn more, at the molecular level, about living systems, health, and disease. Studying the bioinorganic chemistry of the host/microbe interaction and infectious disease interfaces concepts and toolkits from many different disciplines and provides opportunities to contribute out-of-the-box ideas both for fundamental research and non-traditional ways to approach the prevention and treatment of infectious disease.”

New synthetic strategies for macromolecules

Just as natural-products chemists must often invent new reaction methodologies to access complex structures and their corresponding derivatives, Professor Jeremiah Johnson’s group seeks to develop new methodologies for the construction and modification of complex material libraries. Iterative library synthesis, function-based screening, and design optimization will ultimately yield basic knowledge, such as structure-function relationships for materials in specific applications, and new materials-based technologies that outperform current alternatives. Some examples of target material platforms and their associated applications are: novel, nanoscopic branched-arm star polymer architectures for in vivo drug delivery and supported catalysis; hybrid synthetic-natural hydrogels for correlation of the effects of network microstructure on cell response; and new types of semiconducting organometallic polymers and polymer films for sensing, supported catalysis, and energy conversion.

“I am inspired by thinking creatively in the context of macromolecular synthesis, and then by seeing initial creations become reality via working with the awesome members of my group,” Johnson said. “Seeing our chemistry translate into commercial uses, such as helping patients, is the dream.”

Johnson presented his group’s efforts to develop a drug-agnostic materials platform that can enable the rapid improvement of therapeutic index for drugs with known targets and established efficacy but poor safety profiles.

“Accomplishing this goal would allow us to rescue drugs that are stalled in early clinical trials due to unmanageable side effects, or to utilize already approved drugs in new ways,” he explained.

One of the major challenges in chemical science is the development of methods and strategies for the controlled and scalable synthesis of large molecules, which are also known as macromolecules. Johnson’s research is driven by the desire to address this challenge and overcome it.

“We synthesize large abiotic molecules with improved structural control at the molecular level, which ultimately translates into new function at the macroscopic level,” he said.  “In addition, we focus a lot of our efforts on making these synthetic approaches scalable.”

Johnson’s presentation demonstrated a new synthetic strategy that can enable the kilo-scale synthesis of macromolecular prodrug scaffolds with tunable size and drug release kinetics. These materials can be employed to treat diseases ranging from cancer to liver fibrosis.

Celebrating basic science

Department head Timothy F. Jamison said the Department of Chemistry was pleased to co-host its third annual Alumni and Friends reception with the School of Science. As in years past, this event proved to be an excellent opportunity to showcase a sampling of the revolutionary work being conducted within the halls of the Department of Chemistry and, further still, the MIT campus as a whole.

“I cherish any opportunity I get to hear my colleagues present their research,” Jamison said in his closing remarks. “I am especially delighted that you were able to join us this evening to meet professors Nolan and Johnson and to learn about their spectacular scientific advances. Nolan and Johnson are representative of the extremely high caliber of research in the Department of Chemistry.”

Chemists synthesize millions of proteins not found in nature

by Anne Trafton |

MIT chemists have devised a way to rapidly synthesize and screen millions of novel proteins that could be used as drugs against Ebola and other viruses.

All proteins produced by living cells are made from the 20 amino acids that are programmed by the genetic code. The MIT team came up with a way to assemble proteins from amino acids not used in nature, including many that are mirror images of natural amino acids.

These proteins, which the researchers call “xenoproteins,” offer many advantages over naturally occurring proteins. They are more stable, meaning that unlike most protein drugs, they don’t require refrigeration, and may not provoke an immune response.

“There is no other technological platform that can be used to create these xenoproteins because people haven’t worked through the ability to use completely nonnatural sets of amino acids throughout the entire shape of the molecule,” says Brad Pentelute, an MIT associate professor of chemistry and the senior author of the paper, which appears in the Proceedings of the National Academy of Sciences the week of May 21.

Zachary Gates, an MIT postdoc, is the lead author of the paper. Timothy Jamison, head of MIT’s Department of Chemistry, and members of his lab also contributed to the paper.

Nonnatural proteins

Pentelute and Jamison launched this project four years ago, working with the Defense Advanced Research Projects Agency (DARPA), which asked them to come up with a way to create molecules that mimic naturally occurring proteins but are made from nonnatural amino acids.

“The mission was to generate discovery platforms that allow you to chemically manufacture large libraries of molecules that don’t exist in nature, and then sift through those libraries for the particular function that you desired,” Pentelute says.

For this project, the research team built on technology that Pentelute’s lab had previously developed for rapidly synthesizing protein chains. His tabletop machine can perform all of the chemical reactions needed to string together amino acids, synthesizing the desired proteins within minutes.

As building blocks for their xenoproteins, the researchers used 16 “mirror-image” amino acids. Amino acids can exist in two different configurations, known as L and D. The L and D versions of a particular amino acid have the same chemical composition but are mirror images of each other. Cells use only L amino acids.

The researchers then used synthetic chemistry to assemble tens of millions of proteins, each about 30 amino acids in length, all of the D configuration. These proteins all had a similar folded structure that is based on the shape of a naturally occurring protein known as a trypsin inhibitor.

Before this study, no research group had been able to create so many proteins made purely of nonnatural amino acids.

“Significant effort has been devoted to development of methods for the incorporation of nonnatural amino acids into protein molecules, but these are generally limited with regard to the number of nonnatural amino acids that can simultaneously be incorporated into a protein molecule,” Gates says.

After synthesizing the xenoproteins, the researchers screened them to identify proteins that would bind to an IgG antibody against an influenza virus surface protein. The antibodies were tagged with a fluorescent molecule and then mixed with the xenoproteins. Using a system called fluorescence-activated cell sorting, the researchers were able to isolate xenoproteins that bind to the fluorescent IgG molecule.

This screen, which can be done in only a few hours, revealed several xenoproteins that bind to the target. In other experiments, not published in the PNAS paper, the researchers have also identified xenoproteins that bind to anthrax toxin and to a glycoprotein produced by the Ebola virus. This work is in collaboration with John Dye, Spencer Stonier, and Christopher Cote at the U.S. Army Medical Research Institute of Infectious Diseases.

“This is an extremely important first step in finding a good way of rapidly screening complex mirror image proteins,” says Stephen Kent, a professor of chemistry at the University of Chicago, who was not involved in the research. “Being able to use chemistry to make a library of mirror image proteins, with their high stability and specificity for a given target, is obviously of potential therapeutic interest.”

Built on demand

The researchers are now working on synthesizing proteins modeled on different scaffold shapes, and they are searching for xenoproteins that bind to other potential drug targets. Their long-term goal is to use this system to rapidly synthesize and identify proteins that could be used to neutralize any type of emerging infectious disease.

“The hope is that we can discover molecules in a rapid manner using this platform, and we can chemically manufacture them on demand. And after we make them, they can be shipped all over the place without refrigeration, for use in the field,” Pentelute says.

In addition to potential drugs, the researchers also hope to develop “xenozymes” — xenoproteins that can act as enzymes to catalyze novel types of chemical reactions.

The research was funded by DARPA and a STAR Postdoctoral Fellowship from Novo Nordisk.