Author: mantulin

Genetic study takes research on sex differences to new heights

Differences in male and female gene expression, including those contributing to height differences, found throughout the body in humans and other mammals.

Greta Friar | Whitehead Institute
July 19, 2019

Throughout the animal kingdom, males and females frequently exhibit sexual dimorphism: differences in characteristic traits that often make it easy to tell them apart. In mammals, one of the most common sex-biased traits is size, with males typically being larger than females. This is true in humans: Men are, on average, taller than women. However, biological differences among males and females aren’t limited to physical traits like height. They’re also common in disease. For example, women are much more likely to develop autoimmune diseases, while men are more likely to develop cardiovascular diseases.

In spite of the widespread nature of these sex biases, and their significant implications for medical research and treatment, little is known about the underlying biology that causes sex differences in characteristic traits or disease. In order to address this gap in understanding, Whitehead Institute Director David Page has transformed the focus of his lab in recent years from studying the X and Y sex chromosomes to working to understand the broader biology of sex differences throughout the body. In a paper published in Science, Page, a professor of biology at MIT and a Howard Hughes Medical Institute investigator; Sahin Naqvi, first author and former MIT graduate student (now a postdoc at Stanford University); and colleagues present the results of a wide-ranging investigation into sex biases in gene expression, revealing differences in the levels at which particular genes are expressed in males versus females.

The researchers’ findings span 12 tissue types in five species of mammals, including humans, and led to the discovery that a combination of sex-biased genes accounts for approximately 12 percent of the average height difference between men and women. This finding demonstrates a functional role for sex-biased gene expression in contributing to sex differences. The researchers also found that the majority of sex biases in gene expression are not shared between mammalian species, suggesting that — in some cases — sex-biased gene expression that can contribute to disease may differ between humans and the animals used as models in medical research.

Having the same gene expressed at different levels in each sex is one way to perpetuate sex differences in traits in spite of the genetic similarity of males and females within a species — since with the exception of the 46th chromosome (the Y in males or the second X in females), the sexes share the same pool of genes. For example, if a tall parent passes on a gene associated with an increase in height to both a son and a daughter, but the gene has male-biased expression, then that gene will be more highly expressed in the son, and so may contribute more height to the son than the daughter.

The researchers searched for sex-biased genes in tissues across the body in humans, macaques, mice, rats, and dogs, and they found hundreds of examples in every tissue. They used height for their first demonstration of the contribution of sex-biased gene expression to sex differences in traits because height is an easy-to-measure and heavily studied trait in quantitative genetics.

“Discovering contributions of sex-biased gene expression to height is exciting because identifying the determinants of height is a classic, century-old problem, and yet by looking at sex differences in this new way we were able to provide new insights,” Page says. “My hope is that we and other researchers can repeat this model to similarly gain new insights into diseases that show sex bias.”

Because height is so well studied, the researchers had access to public data on the identity of hundreds of genes that affect height. Naqvi decided to see how many of those height genes appeared in the researchers’ new dataset of sex-biased genes, and whether the genes’ sex biases corresponded to the expected effects on height. He found that sex-biased gene expression contributed approximately 1.6 centimeters to the average height difference between men and women, or 12 percent of the overall observed difference.

The scope of the researchers’ findings goes beyond height, however. Their database contains thousands of sex-biased genes. Slightly less than a quarter of the sex-biased genes that they catalogued appear to have evolved that sex bias in an early mammalian ancestor, and to have maintained that sex bias today in at least four of the five species studied. The majority of the genes appear to have evolved their sex biases more recently, and are specific to either one species or a certain lineage, such as rodents or primates.

Whether or not a sex-biased gene is shared across species is a particularly important consideration for medical and pharmaceutical research using animal models. For example, previous research identified certain genetic variants that increase the risk of Type 2 diabetes specifically in women; however, the same variants increase the risk of Type 2 diabetes indiscriminately in male and female mice. Therefore, mice would not be a good model to study the genetic basis of this sex difference in humans. Even when the animal appears to have the same sex difference in disease as humans, the specific sex-biased genes involved might be different. Based on their finding that most sex bias is not shared between species, Page and colleagues urge researchers to use caution when picking an animal model to study sex differences at the level of gene expression.

“We’re not saying to avoid animal models in sex-differences research, only not to take for granted that the sex-biased gene expression behind a trait or disease observed in an animal will be the same as that in humans. Now that researchers have species and tissue-specific data available to them, we hope they will use it to inform their interpretation of results from animal models,” Naqvi says.

The researchers have also begun to explore what exactly causes sex-biased expression of genes not found on the sex chromosomes. Naqvi discovered a mechanism by which sex-biased expression may be enabled: through sex-biased transcription factors, proteins that help to regulate gene expression. Transcription factors bind to specific DNA sequences called motifs, and he found that certain sex-biased genes had the motif for a sex-biased transcription factor in their promoter regions, the sections of DNA that turn on gene expression. This means that, for example, a male-biased transcription factor was selectively binding to the promoter region for, and so increasing the expression of, male-biased genes — and likewise for female-biased transcription factors and female-biased genes. The question of what regulates the transcription factors remains for further study — but all sex differences are ultimately controlled by either the sex chromosomes or sex hormones.

The researchers see the collective findings of this paper as a foundation for future sex-differences research.

“We’re beginning to build the infrastructure for a systematic understanding of sex biases throughout the body,” Page says. “We hope these datasets are used for further research, and we hope this work gives people a greater appreciation of the need for, and value of, research into the molecular differences in male and female biology.”

This work was supported by Biogen, Whitehead Institute, National Institutes of Health, Howard Hughes Medical Institute, and generous gifts from Brit and Alexander d’Arbeloff and Arthur W. and Carol Tobin Brill.

Unmasking mutant cancer cells

A new dosing regimen for an old cancer drug shows new promise as an immunotherapy.

Bendta Schroeder | Koch Institute
July 16, 2019

As cancer cells progress, they accumulate hundreds and even thousands of genetic and epigenetic changes, resulting in protein expression profiles that are radically different from that of healthy cells. But despite their heavily mutated proteome, cancer cells can evade recognition and attack by the immune system.

Immunotherapies, particularly checkpoint inhibitors that reinvigorate exhausted T cells, have revolutionized the treatment of certain forms of cancer. These breakthrough therapies have resulted in unprecedented response rates for some patients. Unfortunately, most cancers fail to respond to immunotherapies and new strategies are therefore needed to realize their full potential.

A team of cancer biologists including members of the laboratories of David H. Koch Professor of Biology Tyler Jacks, director of the Koch Institute for Integrative Cancer Research at MIT, and fellow Koch Institute member Forest White, the Ned C. and Janet Bemis Rice Professor and member of the MIT Center for Precision Cancer Medicine, took a complementary approach to boosting the immune system.

Although cancer cells are rife with mutant proteins, few of those proteins appear on a cell’s surface, where they can be recognized by immune cells. The researchers repurposed a well-studied class of anti-cancer drugs, heat shock protein 90 (HSP90) inhibitors, that make cancer cells easier to recognize by revealing their mutant proteomes.

Many HSP90 inhibitors have been studied extensively for the past several decades as potential cancer treatments. HSP90 protects the folded structure of a number of proteins when cells undergo stress, and in cancer cells plays an important role in stabilizing protein structure undermined by pervasive mutations. However, despite promising preclinical evidence, HSP90 inhibitors have produced discouraging outcomes in clinical trials, and none have achieved FDA approval.

In a study appearing in Clinical Cancer Research, the researchers identified a potential reason behind those disappointing results. HSP90 inhibitors have only been clinically tested at bolus doses — intermittent, large doses — that often result in unwanted side effects in patients.

RNA profiling of human clinical samples and cultured cancer cell lines revealed that this bolus-dosing schedule results in the profound suppression of immune activity as well as the activation of heat shock factor 1 protein (HSF1). Not only does HSF1 activate the cell’s heat shock response, which counteracts the effect of the HSP90 inhibitor, but it is known to be a powerful enabler of cancer cell malignancy.

In striking contrast, the researchers used cancer mouse models with intact immune systems to show that sustained, low-level dosing of HSP90 inhibitors avoids triggering both the heat shock response and the immunosuppression associated with high doses.

Using a method devised by the White lab that combines mass spectrometry-based proteomics and computational modeling, the researchers discovered that the new dosing regimen increased the number and diversity of peptides (protein fragments) on the cell surface. These peptides, which the team found to be released by HSP90 during sustained low-level inhibition, were then free to be taken up by the cell’s antigen-presenting machinery and used to flag patrolling immune cells.

“These results connect a fundamental aspect of cell biology — protein folding — to anti-tumor immune responses” says lead author Alex Jaeger, a postdoctoral fellow in the Jacks lab and a former member of the laboratory of the late MIT biologist and Professor Susan Lindquist, whose work inspired the study’s HSP90 dosing scheule. “Hopefully, our findings can reinvigorate interest in HSP90 inhibition as a complementary approach for immunotherapy.”

Using the new dosing regimen, the researchers were able to clear tumors in mouse models at drug concentrations that are 25-50 times lower than those used in clinical trials, significantly reducing the risk for toxic side effects in patients. Importantly, because several forms of HSP90 inhibitors have already undergone extensive clinical testing, the new dosing regimen can be tested in patients quickly.

This work was supported in part by the Damon Runyon Cancer Research Foundation, the Takeda Pharmaceuticals Immune Oncology Research Fund, and an MIT Training Grant in Environmental Science; foundational work on HSF1 was supported by the Koch Institute Frontier Research Program.

Meet the 2019 tenured professors in the School of Science

Eight faculty members are granted tenure in five science departments.

School of Science
July 10, 2019

MIT granted tenure to eight School of Science faculty members in the departments of Biology; Chemistry; Earth, Atmospheric and Planetary Sciences; Mathematics; and Physics.

William Detmold’s research within the area of theoretical particle and nuclear physics incorporates analytical methods, as well as the power of the world’s largest supercomputers, to understand the structure, dynamics, and interactions of particles like protons and to look for evidence of new physical laws at the sub-femtometer scale probed in experiments such as those at the Large Hadron Collider. He joined the Department of Physics in 2012 from the College of William and Mary, where he was an assistant professor. Prior to that, he was a research assistant professor at the University of Washington. He received his BS and PhD from the University of Adelaide in Australia in 1996 and 2002, respectively. Detmold is a researcher in the Center for Theoretical Physics in the Laboratory for Nuclear Science.

Semyon Dyatlov explores scattering theory, quantum chaos, and general relativity by employing microlocal analytical and dynamical system methods. He came to the Department of Mathematics as a research fellow in 2013 and became an assistant professor in 2015. He completed his doctorate in mathematics at the University of California at Berkeley in 2013 after receiving a BS in mathematics at Novosibirsk State University in Russia in 2008. Dyatlov spent time after finishing his PhD as a postdoc at the Mathematical Sciences Research Institute before moving to MIT.

Mary Gehring studies plant epigenetics. By using a combination of genetic, genomic, and molecular biology, she explores how plants inherit and interpret information that is not encoded in their DNA to better understand plant growth and development. Her lab focuses primarily on Arabidopsis thaliana, a small flowering plant that is a model species for plant research. Gehring joined the Department of Biology in 2010 after performing postdoctoral research at the Fred Hutchinson Cancer Research Center. She received her BA in biology from Williams College in 1998 and her doctorate from the University of California at Berkeley in 2005. She is also a member of the Whitehead Institute for Biomedical Research.

David McGee performs research in the field of paleoclimate, merging information from stalagmites, lake deposits, and marine sediments with insights from models and theory to understand how precipitation patterns and atmospheric circulation varied in the past. He came to MIT in 2012, joining the Department of Earth, Atmospheric and Planetary Sciences after completing a NOAA Climate and Global Change Postdoctoral Fellowship at the University of Minnesota. Before that, he attended Carleton College for his BA in geology in 1993-97, Chatham College for an MA in teaching from 1999 to 2003, Tulane University for his MS from 2004 to 2006, and Columbia University for his PhD from 2006 to 2009. McGee is the director of the MIT Terrascope First-Year Learning Community, a role he has held for the past four years.

Ankur Moitra works at the interface between theoretical computer science and machine learning by developing algorithms with provable guarantees and foundations for reasoning about their behavior. He joined the Department of Mathematics in 2013. Prior to that, he received his BS in electrical and computer engineering from Cornell University in 2007, and his MS and PhD in computer science from MIT in 2009 and 2011, respectively. He was a National Science Foundation postdoc at the Institute for Advanced Study until 2013. Moitra was a 2018 recipient of a School of Science Teaching Prize. He is also a principal investigator in the Computer Science and Artificial Intelligence Laboratory (CSAIL) and a core member of the Center for Statistics.

Matthew Shoulders focuses on integrating biology and chemistry to understand how proteins function in the cellular setting, including proteins’ shape, quantity, and location within the body. This research area has important implications for genetic disorders and neurodegenerative diseases such as Alzheimer’s, diabetes, cancer, and viral infections. Shoulders’ lab works to elucidate, at the molecular level, how cells solve the protein-folding problem, and then uses that information to identify how diseases can develop and to provide insight into new targets for drug development. Shoulders joined the Department of Chemistry in 2012 after earning a BS in chemistry and minor in biochemistry from Virginia Tech in 2004 and a PhD in chemistry from the University of Wisconsin at Madison in 2009. He is also an associate member of the Broad Institute of MIT and Harvard, and a member of the MIT Center for Environmental Health Sciences.

Tracy Slatyer researches fundamental aspects of theoretical physics, answering questions about both visible and dark matter by searching for potential indications of new physics in astrophysical and cosmological data. She has developed and adapted novel techniques for data analysis, modeling, and calculations in quantum field theory; her work has also inspired a range of experimental investigations. The Department of Physics welcomed Slatyer in 2013 after she completed a three-year postdoctoral fellowship at the Institute for Advanced Study. She majored in theoretical physics as an undergraduate at the Australian National University, receiving a BS in 2005, and completed her PhD in physics at Harvard University in 2010. In 2017, Slatyer received the School of Science Prize in Graduate Teaching and was also named the first recipient of the school’s Future of Science Award. She is a member of the Center for Theoretical Physics in the Laboratory for Nuclear Science.

Michael Williams uses novel experimental methods to improve our knowledge of fundamental particles, including searching for new particles and forces, such as dark matter. He also works on advancing the usage of machine learning within the domain of particle physics research. He joined the Department of Physics in 2012. He previously attended Saint Vincent College as an undergraduate, where he double majored in mathematics and physics. Graduating in 2001, Williams then pursued a doctorate at Carnegie Mellon University, which he completed in 2007. From 2008 to 2012 he was a postdoc at Imperial College London. He is a member of the Laboratory for Nuclear Science.

Cancer biologists identify new drug combo

Two drugs that block cell division synergize to kill tumor cells.

Anne Trafton | MIT News Office
July 10, 2019

When it comes to killing cancer cells, two drugs are often better than one. Some drug combinations offer a one-two punch that kills cells more effectively, requires lower doses of each drug, and can help to prevent drug resistance.

MIT biologists have now found that by combining two existing classes of drugs, both of which target cancer cells’ ability to divide, they can dramatically boost the drugs’ killing power. This drug combination also appears to largely spare normal cells, because cancer cells divide differently than healthy cells, the researchers say. They hope a clinical trial of this combination can be started within a year or two.

“This is a combination of one class of drugs that a lot of people are already using, with another type of drug that multiple companies have been developing,” says Michael Yaffe, a David H. Koch Professor of Science and the director of the MIT Center for Precision Cancer Medicine. “I think this opens up the possibility of rapid translation of these findings in patients.”

The discovery was enabled by a new software program the researchers developed, which revealed that one of the drugs had a previously unknown mechanism of action that strongly enhances the effect of the other drug.

Yaffe, who is also a member of the Koch Institute for Integrative Cancer Research, is the senior author of the study, which appears in the July 10 issue of Cell Systems. Koch Institute research scientists Jesse Patterson and Brian Joughin are the first authors of the paper.

Unexpected synergy

Yaffe’s lab has a longstanding interest in analyzing cellular pathways that are active in cancer cells, to find how these pathways work together in signaling networks to create disease-specific vulnerabilities that can be targeted with multiple drugs. When the researchers began this study, they were looking for a drug that would amplify the effects of a type of drug known as a PLK1 inhibitor. Several PLK1 inhibitors, which interfere with cell division, have been developed, and some are now in phase 2 clinical trials.

Based on their previous work, the researchers knew that PLK1 inhibitors also produce a type of DNA and protein damage known as oxidation. They hypothesized that pairing PLK1 inhibitors with a drug that prevents cells from repairing oxidative damage could make them work even better.

To explore that possibility, the researchers tested a PLK1 inhibitor along with a drug called TH588, which blocks MTH1, an enzyme that helps cells counteract oxidative damage. This combination worked extremely well against many types of human cancer cells. In some cases, the researchers could use one-tenth of the original doses of each drug, given together, and achieve the same rates of cell death of either drug given on its own.

“It’s really striking,” Joughin says. “It’s more synergy than you generally see from a rationally designed combination.”

However, they soon realized that this synergy had nothing to do with oxidative damage. When the researchers treated cancer cells missing the gene for MTH1, which they thought was TH588’s target, they found that the drug combination still killed cancer cells at the same high rates.

“Then we were really stuck, because we had a good combination, but we didn’t know why it worked,” Yaffe says.

To solve the mystery, they developed a new software program that allowed them to identify the cellular networks most affected by the drugs. The researchers tested the drug combination in 29 different types of human cancer cells, then fed the data into the software, which compared the results to gene expression data for those cell lines. This allowed them to discover patterns of gene expression that were linked with higher or lower levels of synergy between the two drugs.

This analysis suggested that both drugs were targeting the mitotic spindle, a structure that forms when chromosomes align in the center of a cell as it prepares to divide. Experiments in the lab confirmed that this was correct. The researchers had already known that PLK1 inhibitors target the mitotic spindle, but they were surprised to see that TH588 affected the same structure.

“This combination that we found was very nonobvious,” Yaffe says. “I would never have given two drugs that both targeted the same process and expected anything better than just additive effects.”

“This is an exciting paper for two reasons,” says David Pellman, associate director for basic science at Dana-Farber/Harvard Cancer Center, who was not involved in the study. “First, Yaffe and colleagues make an important advance for the rational design of drug therapy combinations. Second, if you like scientific mysteries, this is a riveting example of molecular sleuthing. A drug that was thought to act in one way is unmasked to work through an entirely different mechanism.”

Disrupting mitosis

The researchers found that while both of the drugs they tested disrupt mitosis, they appear to do so in different ways. TH588 binds to microtubules, which form the mitotic spindle, and slows their assembly. Many similar microtubule inhibitors are already used clinically to treat cancer. The researchers showed that some of those microtubule inhibitors also synergize with PLK1 inhibitors, and they believe those would likely be more readily available for rapid use in patients than TH588, the drug they originally tested.

While the PLK1 protein is involved in multiple aspects of cell division and spindle formation, it’s not known exactly how PLK1 inhibitors interfere with the mitotic spindle to produce this synergy. Yaffe said he suspects they may block a motor protein that is necessary for chromosomes to travel along the spindle.

One potential benefit of this drug combination is that the synergistic effects appear to specifically target cancer cell division and not normal cell division. The researchers believe this could be because cancer cells are forced to rely on alternative strategies for cell division because they often have too many or too few chromosomes, a state known as aneuploidy.

“Based on the work we have done, we propose that this drug combination targets something fundamentally different about the way cancer cells divide, such as altered cell division checkpoints, chromosome number and structure, or other structural differences in cancer cells,” Patterson says.

The researchers are now working on identifying biomarkers that could help them to predict which patients would respond best to this drug combination. They are also trying to determine the exact function of PLK1 that is responsible for this synergy, in hopes of finding additional drugs that would block that interaction.

The research was funded by the National Institutes of Health, the Charles and Marjorie Holloway Foundation, the Ovarian Cancer Research Fund, the MIT Center for Precision Cancer Medicine, the Koch Institute Dana Farber/Harvard Cancer Center Bridge Project, an American Cancer Society Postdoctoral Fellowship, the Koch Institute Support (core) Grant from the National Cancer Institute, and the Center for Environmental Health Support Grant.

Angelika Amon and Dina Katabi named Carnegie Corporation “Great Immigrants”

MIT biologist and electrical engineer are two of 38 naturalized U.S. citizens honored for contributions to American society.

MIT News Office
July 2, 2019

MIT professors Angelika Amon and Dina Katabi have been named to the Carnegie Corporation of New York’s 2019 list of Great Immigrants, Great Americans. These 38 naturalized U.S. citizens are noted as individuals who “strengthen America’s economy, enrich our culture and communities, and invigorate our democracy through their lives, their work, and their examples.”

Angelika Amon, who hails from Austria, is a molecular and cell biologist who studies cell growth and division and how errors in this process — specifically abnormal numbers of chromosomes — contribute to cancer, aging, and birth defects.

Amon arrived in Cambridge, Massachusetts, from Vienna in 1994 to complete a two-year postdoctoral fellowship at the Whitehead Institute for Biomedical Research; she was subsequently named a Whitehead Fellow for three years. Amon then joined the MIT Center for Cancer Research, now the Koch Institute for Integrative Cancer Research at MIT, and MIT’s Department of Biology in 1999. She became a full professor in 2007 and is currently the Kathleen and Curtis Marble Professor in Cancer Research, a Howard Hughes Medical Institute investigator, the co-associate director of the Glenn Center for Science of Aging Research at MIT, and the inaugural director of the Alana Down Syndrome Center at MIT. Her most recent awards include the 2019 Vilcek Prize in Biomedical Science and the 2019 Breakthrough Prize in Life Sciences.

Dina Katabi, who was born in Syria, is an engineer who works to improve the speed, reliability, and security of wireless networks. She is especially known for her work on a wireless system that can track human movement even through walls — a technology that has great potential for medical use.

Katabi joined the Department of Electrical Engineering and Computer Science faculty in 2003. She is a principal investigator in the Computer Science and Artificial Intelligence Laboratory (CSAIL), as well as director of the Networks at MIT research group and co-director of the MIT Center for Wireless Networks and Mobile Computing, both in CSAIL. Among other honors, Katabi has received a MacArthur Fellowship (sometimes called a “genius grant”), the Association for Computing Machinery (ACM) Prize in Computing, the ACM Grace Murray Hopper Award, a Test of Time Award from the ACM’s Special Interest Group on Data Communications, a National Science Foundation CAREER Award, and a Sloan Research Fellowship. She is an ACM Fellow and was elected to the National Academy of Engineering. She earned a bachelor’s degree from Damascus University and master’s and PhD degrees from MIT.

The Carnegie Corporation celebrates its Great Immigrants every Fourth of July as a way to honor exemplary naturalized U.S. citizens. The organization has named nearly 600 individuals to its list since 2006. Past MIT honorees include Professor Daron Acemoglu (Turkey), Professor Nergis Mavalvala (Pakistan), President L. Rafael Reif (Venezuela), Professor Emeritus Rainer Weiss (Germany), and Professor Feng Zhang (China).

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

Annual MITEI awards support research on methane conversion, efficient energy provision, plastics recycling, and more.

MIT Energy Initiative
July 2, 2019

The MIT Energy Initiative (MITEI) recently awarded seven grants totaling approximately $1 million through its Seed Fund Program, which supports early-stage innovative energy research at MIT through an annual competitive process.

“Supporting basic research has always been a core component of MITEI’s mission to transform and decarbonize global energy systems,” says MITEI Director Robert C. Armstrong, the Chevron Professor of Chemical Engineering. “This year’s funded projects highlight just a few examples of the many ways that people working across the energy field are researching vital topics to create a better world.”

The newly awarded projects will address topics such as developing efficient strategies for recycling plastics, improving the stability of high-energy metal-halogen flow batteries, and increasing the potential efficiency of silicon solar cells to accelerate the adoption of photovoltaics. Awardees include established energy faculty members and others who are new to the energy field, from disciplines including applied economics, chemical engineering, biology, and other areas.

Demand-response policies and incentives for energy efficiency adoption

Most of today’s energy growth is occurring in developing countries. Assistant Professor Namrata Kala and Professor Christopher Knittel, both of whom focus on applied economics at the MIT Sloan School of Management, will use their grant to examine key policy levers for meeting electricity demand and renewable energy growth without jeopardizing system reliability in the developing world.

Kala and Knittel plan to design and run a randomized control trial in New Delhi, India, in collaboration with a large Indian power company. “We will estimate the willingness of firms to enroll in services that reduce peak consumption, and also promote energy efficiency,” says Kala, the W. Maurice Young (1961) Career Development Professor of Management. “Estimating the costs and benefits of such services, and their allocation across customers and electricity providers, can inform policies that promote energy efficiency in a cost-effective manner.”

Efficient conversion of methane to methanol 

Methane, the primary component of natural gas, has become an increasingly important part of the global energy portfolio. However, the chemical inertness of methane and the lack of efficient methods to convert this gaseous carbon feedstock into liquid fuels has significantly limited its application. Yang Shao-Horn, the W.M. Keck Professor of Energy in the departments of Mechanical Engineering and Materials Science and Engineering, seeks to address this problem using her seed fund grant. Shao-Horn and Shuai Yuan, a postdoc in the Research Laboratory of Electronics, will focus on achieving efficient, cost-effective gas-to-liquid conversion using metal-organic frameworks (MOFs) as electrocatalysts.

Current methane activation and conversion processes are usually accomplished by costly and energy-intensive steam reforming at elevated temperature and high pressure. Shao-Horn and Yuan’s goal is to design efficient MOF-based electrocatalysts that will permit the methane-to-methanol conversion process to proceed at ambient temperature and pressure.

“If successful, this electrochemical gas-to-liquid concept could lead to a modular, efficient, and cost-effective solution that can be deployed in both large-scale industrial plants and remotely located oil fields to increase the utility of geographically isolated gas reserves,” says Shao-Horn.

Using machine learning to solve the “zeolite conundrum”

The energy field is replete with opportunities for machine learning to expedite progress toward a variety of innovative energy solutions. Rafael Gómez-Bombarelli, the Toyota Assistant Professor in Materials Processing in the Department of Materials Science and Engineering, received a grant for a project that will combine machine learning and simulation to accelerate the discovery cycle of zeolites.

Zeolites are materials with wide-ranging industrial applications as catalysts and molecular sieves because of their high stability and selective nanopores that can confine small molecules. Despite decades of abundant research, only 248 zeolite frameworks have been realized out of the millions of possible structures that have been proposed using computers — the so-called zeolite conundrum.

The problem, notes Gómez-Bombarelli, is that discovery of these new frameworks has relied mostly on trial-and-error in the lab — an approach that is both slow and labor-intensive.

In his seed grant work, Gómez-Bombarelli and his team will be using theory to speed up that process. “Using machine learning and first-principles simulations, we’ll design small molecules to dock on specific pores and direct the formation of targeted structures,” says Gómez-Bombarelli. “This computational approach will drive new synthetic outcomes in zeolites faster.”

Effective recycling of plastics

Professor Anthony Sinskey of the Department of Biology, Professor Gregory Stephanopoulos of the Department of Chemical Engineering, and graduate student Linda Zhong of biology have joined forces to address the environmental and economic problems posed by polyethylene terephthalate (PET). One of the most synthesized plastics, PET exhibits an extremely low degradation rate and its production is highly dependent on petroleum feedstocks.

“Due to the huge negative impacts of PET products, efficient recycling strategies need to be designed to decrease economic loss and adverse environmental impacts associated with single-use practices,” says Sinskey.

“PET is essentially an organic polymer of terephthalic acid and ethylene glycol, both of which can be metabolized by bacteria as energy and nutrients. These capacities exist in nature, though not together,” says Zhong. “Our goal is to engineer these metabolic pathways into E. coli to allow the bacterium to grow on PET. Using genetic engineering, we will introduce the PET-degrading enzymes into E. coli and ultimately transfer them into bioremediation organisms.”

The long-term goal of the project is to prototype a bioprocess for closed-loop PET recycling, which will decrease the volume of discarded PET products as well as the consumption of petroleum and energy for PET synthesis.

The researchers’ primary motivation in pursuing this project echoes MITEI’s overarching goal for the seed fund program: to push the boundaries of research and innovation to solve global energy and climate challenges. Zhong says, “We see a dire need for this research because our world is inundated in plastic trash. We’re only attempting to solve a tiny piece of the global problem, but we must try when much of what we hold dear depends on it.”

The MITEI Seed Fund Program has awarded new grants each year since it was established in 2008. Funding for the grants comes chiefly from MITEI’s founding and sustaining members, supplemented by gifts from generous donors. To date, MITEI has supported 177 projects with grants totaling approximately $23.6 million.

Recipients of MITEI Seed Fund grants for 2019 are:

  • “Development and prototyping of stable, safe, metal‐halogen flow batteries with high energy and power densities” — Martin Bazant of the departments of Chemical Engineering and Mathematics and T. Alan Hatton of the Department of Chemical Engineering;
  • “Silicon solar cells sensitized by exciton fission” — Marc Baldo of the Department of Electrical Engineering and Computer Science;
  • “Automatic design of structure‐directing agents for novel realizable zeolites” — Rafael Gómez‐Bombarelli of the Department of Materials Science and Engineering;
  • “Demand response, energy efficiency, and firm decisions” — Namrata Kala and Christopher Knittel of the Sloan School of Management;
  • “Direct conversion of methane to methanol by MOF‐based electrocatalysts” — Yang Shao‐Horn of the departments of Mechanical Engineering and Materials Science and Engineering;
  • “Biodegradation of plastics for efficient recycling and bioremediation” — Anthony Sinskey of the Department of Biology and Gregory Stephanopoulos of the Department of Chemical Engineering; and
  • “Asymmetric chemical doping for photocatalytic CO2 reduction” — Michael Strano of the Department of Chemical Engineering.
For Catherine Drennan, teaching and research are complementary passions

Professor of biology and chemistry is catalyzing new approaches in research and education to meet the climate challenge.

Leda Zimmerman | MIT Energy Initiative
June 26, 2019

Catherine Drennan says nothing in her job thrills her more than the process of discovery. But Drennan, a professor of biology and chemistry, is not referring to her landmark research on protein structures that could play a major role in reducing the world’s waste carbons.

“Really the most exciting thing for me is watching my students ask good questions, problem-solve, and then do something spectacular with what they’ve learned,” she says.

For Drennan, research and teaching are complementary passions, both flowing from a deep sense of “moral responsibility.” Everyone, she says, “should do something, based on their skill set, to make some kind of contribution.”

Drennan’s own research portfolio attests to this sense of mission. Since her arrival at MIT 20 years ago, she has focused on characterizing and harnessing metal-containing enzymes that catalyze complex chemical reactions, including those that break down carbon compounds.

She got her start in the field as a graduate student at the University of Michigan, where she became captivated by vitamin B12. This very large vitamin contains cobalt and is vital for amino acid metabolism, the proper formation of the spinal cord, and prevention of certain kinds of anemia. Bound to proteins in food, B12 is released during digestion.

“Back then, people were suggesting how B12-dependent enzymatic reactions worked, and I wondered how they could be right if they didn’t know what B12-dependent enzymes looked like,” she recalls. “I realized I needed to figure out how B12 is bound to protein to really understand what was going on.”

Drennan seized on X-ray crystallography as a way to visualize molecular structures. Using this technique, which involves bouncing X-ray beams off a crystallized sample of a protein of interest, she figured out how vitamin B12 is bound to a protein molecule.

“No one had previously been successful using this method to obtain a B12-bound protein structure, which turned out to be gorgeous, with a protein fold surrounding a novel configuration of the cofactor,” says Drennan.

Carbon-loving microbes show the way 

These studies of B12 led directly to Drennan’s one-carbon work. “Metallocofactors such as B12 are important not just medically, but in environmental processes,” she says. “Many microbes that live on carbon monoxide, carbon dioxide, or methane — eating carbon waste or transforming carbon — use metal-containing enzymes in their metabolic pathways, and it seemed like a natural extension to investigate them.”

Some of Drennan’s earliest work in this area, dating from the early 2000s, revealed a cluster of iron, nickel, and sulfur atoms at the center of the enzyme carbon monoxide dehydrogenase (CODH). This so-called C-cluster serves hungry microbes, allowing them to “eat” carbon monoxide and carbon dioxide.

Recent experiments by Drennan analyzing the structure of the C-cluster-containing enzyme CODH showed that in response to oxygen, it can change configurations, with sulfur, iron, and nickel atoms cartwheeling into different positions. Scientists looking for new avenues to reduce greenhouse gases took note of this discovery. CODH, suggested Drennan, might prove an effective tool for converting waste carbon dioxide into a less environmentally destructive compound, such as acetate, which might also be used for industrial purposes.

Drennan has also been investigating the biochemical pathways by which microbes break down hydrocarbon byproducts of crude oil production, such as toluene, an environmental pollutant.

“It’s really hard chemistry, but we’d like to put together a family of enzymes to work on all kinds of hydrocarbons, which would give us a lot of potential for cleaning up a range of oil spills,” she says.

The threat of climate change has increasingly galvanized Drennan’s research, propelling her toward new targets. A 2017 study she co-authored in Science detailed a previously unknown enzyme pathway in ocean microbes that leads to the production of methane, a formidable greenhouse gas: “I’m worried the ocean will make a lot more methane as the world warms,” she says.

Drennan hopes her work may soon help to reduce the planet’s greenhouse gas burden. Commercial firms have begun using the enzyme pathways that she studies, in one instance employing a proprietary microbe to capture carbon dioxide produced during steel production — before it is released into the atmosphere — and convert it into ethanol.

“Reengineering microbes so that enzymes take not just a little, but a lot of carbon dioxide out of the environment — this is an area I’m very excited about,” says Drennan.

Creating a meaningful life in the sciences 

At MIT, she has found an increasingly warm welcome for her efforts to address the climate challenge.

“There’s been a shift in the past decade or so, with more students focused on research that allows us to fuel the planet without destroying it,” she says.

In Drennan’s lab, a postdoc, Mary Andorfer, and a rising junior, Phoebe Li, are currently working to inhibit an enzyme present in an oil-consuming microbe whose unfortunate residence in refinery pipes leads to erosion and spills. “They are really excited about this research from the environmental perspective and even made a video about their microorganism,” says Drennan.

Drennan delights in this kind of enthusiasm for science. In high school, she thought chemistry was dry and dull, with no relevance to real-world problems. It wasn’t until college that she “saw chemistry as cool.”

The deeper she delved into the properties and processes of biological organisms, the more possibilities she found. X-ray crystallography offered a perfect platform for exploration. “Oh, what fun to tell the story about a three-dimensional structure — why it is interesting, what it does based on its form,” says Drennan.

The elements that excite Drennan about research in structural biology — capturing stunning images, discerning connections among biological systems, and telling stories — come into play in her teaching. In 2006, she received a $1 million grant from the Howard Hughes Medical Institute (HHMI) for her educational initiatives that use inventive visual tools to engage undergraduates in chemistry and biology. She is both an HHMI investigator and an HHMI professor, recognition of her parallel accomplishments in research and teaching, as well as a 2015 MacVicar Faculty Fellow for her sustained contribution to the education of undergraduates at MIT.

Drennan attempts to reach MIT students early. She taught introductory chemistry classes from 1999 to 2014, and in fall 2018 taught her first introductory biology class.

“I see a lot of undergraduates majoring in computer science, and I want to convince them of the value of these disciplines,” she says. “I tell them they will need chemistry and biology fundamentals to solve important problems someday.”

Drennan happily migrates among many disciplines, learning as she goes. It’s a lesson she hopes her students will absorb. “I want them to visualize the world of science and show what they can do,” she says. “Research takes you in different directions, and we need to bring the way we teach more in line with our research.”

She has high expectations for her students. “They’ll go out in the world as great teachers and researchers,” Drennan says. “But it’s most important that they be good human beings, taking care of other people, asking what they can do to make the world a better place.”

This article appears in the Spring 2019 issue of Energy Futures, the magazine of the MIT Energy Initiative. 

A chemical approach to imaging cells from the inside

Researchers develop a new microscopy system for creating maps of cells, using chemical reactions to encode spatial information.

Karen Zusi | Broad Institute
June 14, 2019

The following press release was issued today by the Broad Institute of MIT and Harvard.

A team of researchers at the McGovern Institute and Broad Institute of MIT and Harvard has developed a new technique for mapping cells. The approach, called DNA microscopy, shows how biomolecules such as DNA and RNA are organized in cells and tissues, revealing spatial and molecular information that is not easily accessible through other microscopy methods. DNA microscopy also does not require specialized equipment, enabling large numbers of samples to be processed simultaneously.

“DNA microscopy is an entirely new way of visualizing cells that captures both spatial and genetic information simultaneously from a single specimen,” says first author Joshua Weinstein, a postdoctoral associate at the Broad Institute. “It will allow us to see how genetically unique cells — those comprising the immune system, cancer, or the gut, for instance — interact with one another and give rise to complex multicellular life.”

The new technique is described in Cell. Aviv Regev, core institute member and director of the Klarman Cell Observatory at the Broad Institute and professor of biology at MIT, and Feng Zhang, core institute member of the Broad Institute, investigator at the McGovern Institute for Brain Research at MIT, and the James and Patricia Poitras Professor of Neuroscience at MIT, are co-authors. Regev and Zhang are also Howard Hughes Medical Institute Investigators.

The evolution of biological imaging

In recent decades, researchers have developed tools to collect molecular information from tissue samples, data that cannot be captured by either light or electron microscopes. However, attempts to couple this molecular information with spatial data — to see how it is naturally arranged in a sample — are often machinery-intensive, with limited scalability.

DNA microscopy takes a new approach to combining molecular information with spatial data, using DNA itself as a tool.

To visualize a tissue sample, researchers first add small synthetic DNA tags, which latch on to molecules of genetic material inside cells. The tags are then replicated, diffusing in “clouds” across cells and chemically reacting with each other, further combining and creating more unique DNA labels. The labeled biomolecules are collected, sequenced, and computationally decoded to reconstruct their relative positions and a physical image of the sample.

The interactions between these DNA tags enable researchers to calculate the locations of the different molecules — somewhat analogous to cell phone towers triangulating the locations of different cell phones in their vicinity. Because the process only requires standard lab tools, it is efficient and scalable.

In this study, the authors demonstrate the ability to molecularly map the locations of individual human cancer cells in a sample by tagging RNA molecules. DNA microscopy could be used to map any group of molecules that will interact with the synthetic DNA tags, including cellular genomes, RNA, or proteins with DNA-labeled antibodies, according to the team.

“DNA microscopy gives us microscopic information without a microscope-defined coordinate system,” says Weinstein. “We’ve used DNA in a way that’s mathematically similar to photons in light microscopy. This allows us to visualize biology as cells see it and not as the human eye does. We’re excited to use this tool in expanding our understanding of genetic and molecular complexity.”

Funding for this study was provided by the Simons Foundation, Klarman Cell Observatory, NIH (R01HG009276, 1R01- HG009761, 1R01- MH110049, and 1DP1-HL141201), New York Stem Cell Foundation, Simons Foundation, Paul G. Allen Family Foundation, Vallee Foundation, the Poitras Center for Affective Disorders Research at MIT, the Hock E. Tan and K. Lisa Yang Center for Autism Research at MIT, J. and P. Poitras, and R. Metcalfe. 

The authors have applied for a patent on this technology.

From one MSRP generation to the next

Squire Booker PhD ’94 met with former and current Summer Research Program students to explain how his summer experience at MIT shaped his research trajectory.

Raleigh McElvery | Department of Biology
June 11, 2019

On June 5, 20 students from the 2019 MIT Summer Research Program (MSRP) cohort and eight program alumni had the chance to meet Squire Booker PhD ’94. Booker was the keynote speaker at MIT’s Investiture of Doctoral Hoods and Degree Conferral Ceremony, which took place on June 6. He is also an MSRP alumnus from the very first cohort, and conducted his PhD work in the Department of Chemistry under the direction of JoAnne Stubbe.

He recounted how his MSRP experience changed his career path. “I discovered my passion for research that summer,” he said.

Today, Booker is the Evan Pugh Professor of chemistry, biochemistry, and molecular biology, and the Eberly Family Distinguished Chair in Science at Pennsylvania State University. He is also an investigator with the Howard Hughes Medical Institute, and was recently elected to the National Academy of Sciences.

The lunch was organized by Catherine Drennan, an MIT professor of biology and chemistry and a Howard Hughes Medical Institute Investigator.

“When I found out that Professor Booker was selected to speak at the MIT hooding ceremony, I knew that I wanted to arrange for him to meet with current and recent MSRP students,” she says. “It means a lot to meet someone successful who was once in your shoes.”

Stephanie Guerra, an undergraduate at the University of Puerto Rico at Humacao who will be working in the Laub lab this summer, says it was inspiring to meet someone whose career trajectory had been so impacted by the MSRP experience. “It resonated with me when he mentioned that we shouldn’t question the opportunities we get,” she says. “We should be grateful for them and make the best of them.”

These sentiments were echoed by Sofía Hernández Torres from the University of Puerto Rico at Mayagüez, who will be working in the Calo lab. “He is an accomplished man with very entertaining charisma,” she says. “I was motivated to continue to fight for a successful science career, where you are able to choose where you go next instead of having to follow a path defined by others.”

MSRP is a research-intensive summer training program for non-MIT sophomore and junior science majors who have an interest in a research career. Since 2003, it has been divided into two branches: MSRP General and MSRP-Bio. The latter offers a 10-week practical training in one of over 90 research laboratories affiliated with the departments of Biology, Brain and Cognitive Sciences, or Biological Engineering, and features weekly academic seminars, meetings with faculty, and many extracurricular activities.

At doctoral ceremony, a strong call to provide opportunity for all

Biochemist Squire Booker PhD ’94 says MIT’s new doctoral graduates will “grow as future leaders” by giving back.

Peter Dizikes | MIT News Office
June 7, 2019

Distinguished biochemist Squire Booker PhD ’94 emphasized the importance of opportunity for all, in his keynote speech at today’s 2019 Investiture of Doctoral Hoods and Degree Conferral, a ceremony for MIT’s new doctoral degree holders.

While congratulating MIT’s doctoral graduates, Booker also urged them to give back to society and to take responsibility for helping others accomplish their own goals — however daunting those goals, such as a PhD, may seem.

“Almost anyone can excel if given the chance,” Booker said. “Take advantage of opportunities, and make the most of them. But also, work to provide opportunities for others. That’s how you will grow as a future leader.”

Reflecting on his own trajectory, from a childhood when he knew no one working in the sciences to a career on the front lines of discovery, Booker called himself “just an average guy from southeast Texas, no different than anyone else.” But he said new opportunities had “made all the difference” in his career. One key moment of opportunity, Booker said, was his graduate training at the Institute.

“MIT gave me my first real opportunity to explore scientific research and realize my passion for discovery and working with people from all over the world to solve problems,” Booker said. He credited his mentors with “helping me to achieve goals that I didn’t even know existed when I undertook this journey, or that I didn’t even have for myself. I can honestly say my cup runneth over today.”

Booker is the Evan Pugh Professor of chemistry and of biochemistry and molecular biology and Eberly Family Distinguished Chair in Science at Penn State University. He is also an investigator with the Howard Hughes Medical Institute, and in April of this year was elected to the National Academy of Sciences.

During his career, Booker has conducted significant research uncovering the ways enzymes catalyze reactions within cells, a line of work with applications ranging from medicine to biofuels.

The ceremony honors graduate students who have earned their doctoral degrees within this academic year. It was held this year in MIT’s Killian Court, where a large audience of family members and friends filled the seats. Killian Court is also the site of Friday’s 2019 Commencement exercises.

Graduates from 26 departments, programs, and centers at the Institute, as well as MIT’s joint program with the Woods Hole Oceanographic Institution, received degrees on Thursday. MIT faculty — who wear the brightly colored formal garb of the universities where they received their own doctorates — placed doctoral hoods, a part of the formal academic clothing, over the shoulders of the new graduates.

In his remarks, Booker said he shared the experience this year’s doctoral graduates have gone through, and understood how hard they have worked at the Institute.

“I don’t just imagine the blood, the sweat, the tears, and the immense amount of time that you put into arriving at this point in your careers and your lives,” Booker said. “I actually experienced it firsthand as a graduate student here at MIT between 1987 and 1994.” He cited his graduate advisor, JoAnne Stubbe, as an important influence on his career.

Booker infused his remarks with self-deprecating humor, joking that he first thought MIT had ask him to speak by mistake. But he also spoke earnestly about the serious hurdles he had faced in his life.

Booker grew up in what he described as a segregated environment in Beaumont, Texas. He noted that it was not uncommon for him to hear teachers make disparaging remarks about the abilities of African-Americans, adding, “A career in science was about as likely as winning the lottery … largely because there were no role models.”

Raised by a grandmother with the help of three uncles, Booker earned his undergraduate degree in chemistry at Austin College in Sherman, Texas, and first came to MIT in 1986, as part of the Institute’s MIT Summer Research Program, which now supports 40 interns every year from underrepresented backgrounds.

That stint at MIT helped lead Booker to enter the graduate program, where he studied biochemistry. It also gave him a greater awareness of the travails of black scientists who had gone before him — partly through the work of MIT’s Kenneth Manning, the Thomas Maloy Professor in Rhetoric, whose 1983 book, “Black Apollo of Science: The Life of Ernest Everett Just,” chronicled the life of a pioneering black researcher excluded from American academia.

In his speech, Booker outlined the lives of both Just and Percy Lavon Julian, an innovative 20th-century African-American research chemist who also spent decades excluded from a conventional professorship in academia.

“We’re still trying to recover from the bigotry and misogyny of the past, some of which still exist,” Booker said. In that vein, he noted, in 2008, he became the first Afrcian-American professor in Penn State’s chemistry department.

‘That it took so long is completely tragic,” said Booker, observing that countless talented people had been excluded from promising careers and fulfilling lives as a result of prejudice.

“America’s strength is its people,” Booker said. “And there is so much untapped potential in people who have been traditionally disenfranchised, including people of color, women, the LGBTQ community, and the differently abled.”

At the same time, Booker added, “In fact, first-generation white students, or students from modest socioeconomic backgrounds, are the ones that I have impacted the greatest, directly, at Penn State. And you can’t imagine how appreciative they have been to have been given the chance, and some direction.”

Booker was introduced by MIT Chancellor Cynthia Barnhart SM ’86, PhD ’88, the Ford Foundation Professor of Engineering, who briefly delivered her own remarks to the graduates.

“Today is about honoring the accomplishment and success of all of you, our doctoral candidates,” Barnhart said. “Congratulations. Each and every one of you have succeeded. … You were curious and creative, determined to problem-solve, to collaborate, and to innovate.”

Barnhart also called the doctoral hooding ceremony a “delightfully hopeful moment where infinite possibilities stretch out in front of you,” and asked the graduates to rise in appreciation of their friends and families who have supported their efforts.

This is the fifth year in a row that MIT’s doctoral hooding ceremony has had a keynote speaker — who is annually drawn from the ranks of past MIT doctoral graduates. Booker was chosen with input from the MIT community.

The festive, bright regalia of the doctoral ceremony represents a mix of old traditions and recent changes. Formal academic wear, at least of the kind seen at commencement ceremonies, dates to the 1400s, if not earlier. However, American universities did not agree to standards for such gowns and hoods until 1893.

At MIT, the doctoral degree robes were redesigned as recently as 1995. MIT gowns feature a silver-gray robe with a cardinal red velvet front panel, and are embellished by cardinal red velvet bars on the sleeves. Additional color markings signify whether graduates have received the Doctor of Philosophy degree (PhD) or the Doctor of Science degree (ScD). Silver-gray academic caps complement the gowns. The doctoral hoods are an accessory to the main robe ensemble.

After Barnhart’s introductory remarks and Booker’s speech, all doctoral graduates had their names announced as they walked across the stage one by one. The newly minted degree holders then had the hoods draped over their shoulders by their department or program heads.

The names of all the new doctoral degree holders were read aloud, one after another, by two MIT staff members: Monica Lee, a senior communications officer in the Department of Facilities; and Steven M. Lanou, a project manager in the Office of Sustainability.