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Junk DNA makes a comeback

Third-year graduate student Emma Kowal is searching DNA for sequences that regulate gene expression.

Saima Sidik
July 8, 2019

“I went into science because of a certain obsession with the romance of it,” says Emma Kowal, a third-year graduate student in Chris Burge’s lab in the MIT Department of Biology. “I loved the idea of the scientist as an adventurer exploring the frontiers of knowledge and the universe. And I haven’t let go of that yet.”

Kowal has always been an avid science fiction reader, and now she’s living out a real-life scientific odyssey. The quest she’s taken on for her PhD research involves an understudied type of DNA sequence called an intron, and the roles that introns might play in regulating gene expression.

Introns lie between the DNA sequences that cells use for protein production, and are initially incorporated into the messenger RNA, or mRNA, that cells produce as an intermediate step in synthesizing proteins from DNA. But before they complete protein synthesis, cells remove introns from mRNA through a process called splicing, which has led many people to view introns as junk DNA with splicing acting like a garbage disposal.

“Introns appeal to me as the underdog genomic region,” Kowal says. Although they’re often seen as unimportant, introns are ubiquitous and plentiful, collectively making up 24% of the human genome. All eukaryotes have them, and, on average, each human gene encodes eight. Many researchers, including Kowal, think that introns have been underestimated, and that they may play an important role in regulating gene expression.

Introns are only the latest chapter in Kowal’s RNA story. She began her research career as a Harvard University undergraduate student working in the Szostak Lab at Massachusetts General Hospital, where she studied how RNA catalyzed the evolution of cells on the early earth. Although studying primordial life was intellectually stimulating, Kowal wanted to work on something more applied, and so she joined the Church Lab in the Harvard Department of Genetics. There she developed methods for purifying and imaging enigmatic RNA-containing lipid compartments called extracellular vesicles, which cells release into their surrounding environments possibly to communicate with one another.

For the sequel to her bachelor’s degree, Kowal chose to attend MIT Biology because she’d heard that, “at MIT, everyone is one standard deviation nerdier, on average, than they are at other schools.” In this sense, she has not been disappointed. Kowal calls the energy at MIT “unparalleled,” and she says, “people are jazzed about what they’re doing, and the whole campus reflects that.”

In some ways, these reflections are physical. Much of the artwork around MIT pays homage to major scientific discoveries, and Kowal says this reverence for science is one factor that attracted her to MIT. From the mural of DNA in the Biology Department to the golden neurons that descend alongside the staircase in the McGovern Institute for Brain Research, it’s as if the community is saying, “look at how awesome the universe is!” as Kowal puts it.

In other ways, this energy is reflected in the people she converses with daily. “I really like the students here,” Kowal says. “Everyone is enthusiastic, but also down to earth.” When she’s not exploring the realms of science, Kowal sometimes has more fanciful adventures with the Dungeons and Dragons group that she’s formed with some of her classmates.

Kowal didn’t necessarily intend to continue working on RNA at MIT Biology, but when she heard about Chris Burge’s lab, which focuses on RNA and the proteins that mediate its production and stability, she felt a call to action.

The Burge Lab combines high throughput experimental techniques with bioinformatics, and Kowal wants to develop expertise in both these fields. “If you’re skilled in generating and analyzing big data sets, you can ask questions that other people can’t,” she says. The Burge lab seemed like the perfect setting for her PhD.

Over and over, scientists have noticed that cells produce more protein from genes that contain introns than when those same introns are removed. Intron mediated enhancement (IME), as this effect is called, is a “stunningly broad phenomenon,” Kowal says, and scientists have observed it in a wide range of organisms, from yeast to plants to humans.Burge asks his students to begin their degrees with a month-long reading period during which they sift through the literature to find a topic that they want to study. “You’re not allowed to pick up a pipette or do any analysis during your reading period,” Kowal says. “You just read and discuss your ideas and let things percolate.” As she read, Kowal came across a number of studies that discussed the influence that introns have on gene expression levels.

Splicing machinery, which removes introns from mRNA, likely plays a role in IME. This machinery binds mRNA as it’s being produced from DNA, then interacts with, and influences, the RNA production machinery. However, researchers have created mutant introns that can’t be recognized by splicing machinery, and sometimes these introns still enhance gene expression, so splicing isn’t the only factor that drives IME. Moreover, replacing one intron with another of the same size containing a different DNA sequence can change its effect, implying that the exact DNA sequences within introns may dictate their effects on gene expression. Kowal is intrigued by this last point, and wants to find these intronic sequences and figure out which have the largest effects on gene expression and why.

“This is an old mystery that’s ripe for new tools,” Kowal says. Over the last decade, researchers have begun using a technique called RNAseq to count the copies of mRNA that are made from each gene in a population of cells. Instead of replacing an intron with a single alternative DNA sequence, Kowal plans to replace an intron with a myriad of random DNA sequences, then use RNAseq to count how many copies of mRNA cells make when they encode each of these random introns.

Preparing to test these random sequences has been an odyssey in and of itself, and Kowal has spent the last year building the system that she’ll use. First, she needed to decide which intron to replace. She chose one from a gene called UbC. Removing this intron reduces expression of UbC by ten-fold.

Besides contributing strongly to IME, the UbC intron is a great candidate for Kowal’s experiment because it lies in a regulatory region of the UbC mRNA that precedes the portion that’s translated into protein. This let her replace the UbC protein coding region with a fluorescent protein that she’ll use to visualize how much protein cells make when they encode each random intron sequence.

Kowal has spent the last year meticulously incorporating a library of random introns into this synthetic version of the UbC gene. She anticipates being able to introduce them into cells soon, to see which random introns result in the highest levels of mRNA and protein production. Thanks to RNAseq, she’ll be able to monitor how much each random intron contributes to mRNA expression. Because she can measure how brightly the fluorescent protein glows, she can correlate these mRNA levels with protein levels. From this, she’ll learn which intron sequences enhance gene expression most strongly, and she’ll also know whether these introns lead to higher levels of mRNA production, or if the same amount of mRNA is made into more protein. This distinction will offer her clues about the mechanism that introns use to enhance gene expression.

Once Kowal knows which intron sequences promote gene expression most effectively, she’ll take advantage of the Burge lab’s bioinformatics expertise to analyze the distribution of these sequences throughout genomes and predict how they affect global gene expression. Kowal suspects certain intron sequences are bound by proteins that mediate mRNA production and stability, and she thinks her work will identify these protein-intron pairs.

Kowal balances her scientific adventures with outdoor adventures. Specifically, she’s recently fallen in love with rock climbing. “Climbing is a great counterpart to science because it’s something you can chip away at, and then there’s this huge satisfaction when you finally achieve a climb,” she says. “And also, between climbing and pipetting, I have really strong fingers.”

As for her love of science fiction, Kowal hopes to one day pen a science-based adventure of her own, but not before she’s made her mark as a scientist, either as a professor or in industry. ”It makes sense for me to focus most of my energy on science right now,” she says. “But after I’ve led a spectacular, adventurous life in science, maybe I’ll use my reflections to write a novel.”

Posted 7.8.19
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.
Bruce Walker

Education

  • PhD, 1993, University of Vienna
  • BS, 1989, Biology, University of Vienna

Research Summary

The overarching goal of my laboratory is to define the interplay of immunologic, virologic and host genetic factors that determine control of human viral infections, to guide vaccine development and immunotherapeutic interventions. To address this goal, we focus on HIV infection.

Awards

  • ​Bernard Fields Lectureship, 2015
  • NIH Merit Award, 2011, 2004
  • American Academy of Arts and Sciences, 2010
  • National Academy of Medicine, 2009
  • American Association of Physicians, 2000
  • Doris Duke Charitable Foundation Distinguished Clinical Scientist Award, 1999
  • American Society for Clinical Investigation, 1993
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. 

JoAnne Stubbe named 2020 Priestley Medalist

MIT biochemist is being honored for her work in understanding enzyme mechanisms

Celia Arnaud | Chemical & Engineering News
June 24, 2019

JoAnne Stubbe, the Novartis Professor of Chemistry and Biology, emerita, at the Massachusetts Institute of Technology, will receive the 2020 Priestley Medal, the American Chemical Society’s highest honor.

“JoAnne is the top mechanistic biochemist of her generation,” says Stephen J. Lippard, one of Stubbe’s colleagues in the MIT chemistry department. “Among her major achievements is understanding the controlled generation of radicals in biology.”

“Throughout her career, JoAnne has taken on some of the experimentally most challenging problems, and time and time again, she provided insights that, while sometimes controversial when she first introduced them, have stood the test of time,” says Wilfred van der Donk, a chemistry professor at the University of Illinois at Urbana-Champaign who was a postdoc in Stubbe’s lab in the 1990s.

Stubbe is best known for figuring out the mechanism of ribonucleotide reductase, an enzyme that catalyzes the conversion of ribonucleotides used in RNA to deoxyribonucleotides used in DNA. That reaction is the only route in nature for making deoxyribonucleotides.

Stubbe showed that the reduction at the 2′ position on the ribose sugar ring involves hydrogen removal at the 3′ position, which was unexpected because a 3′ hydrogen still exists in the final structure. The reaction is particularly unusual because later crystal structures showed a metal cofactor initiates the electron transfer required to power the reduction from more than 35 Å from the reactive site. Such a long distance between the two sites was unexpected because it was too far for conventional electron transfer. Stubbe proposed and demonstrated that the transfer happens in multiple steps.

“The remarkable part of this now widely accepted mechanism is that no crystallographic information was available when JoAnne proposed it,” van der Donk says. “When the structure of the enzyme was reported years later, her predictions proved to be correct, and she herself later provided experimental evidence of many of the radical intermediates.” Donald Hilvert, a chemistry professor at the Swiss Federal Institute of Technology Zurich, says, “Her groundbreaking studies of ribonucleotide reductases revolutionized the field of enzymology.”

Stubbe also uncovered details of the mechanism of action of bleomycin, a cancer drug that works by cleaving double-stranded DNA. “Her group determined the mechanism of this unusual process and solved the NMR structure of cobalt-substituted bleomycin bound to double-stranded DNA, a true tour de force,” van der Donk says.

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.

Pulin Li

Education

  • PhD, 2012, Chemical Biology, Harvard University
  • BS, 2006, Life Sciences, Peking University

Research Summary

We are fascinated by how and why cells organize into spatial patterns within tissues, aiming to uncover the fundamental design principles that govern tissue form and function. To explore this, we adopt a bottom-up approach to reconstitute multicellular patterns in vitro using synthetic biology tools, guided by mathematical modeling. In parallel, we study how patterns emerge in natural tissues and investigate their functional roles, using a combination of quantitative imaging, mouse genetics, machine learning, and stem cell engineering. Our current focus is on the patterning of the embryonic and adult lung. Through these complementary efforts, we strive to achieve a quantitative, multi-scale understanding of tissue development and to create new strategies for tissue engineering.

Awards

  • Teaching Prize for Undergraduate Education, MIT School of Science, 2023
  • Allen Distinguished Investigator, The Paul Alen Frontiers Group, 2021
  • New Innovator Award, National Institutes of Health Common Fund’s High-Risk, High-Reward Research Program, 2021
  • R.R. Bensley Award in Cell Biology, American Association for Anatomy, 2021
  • Santa Cruz Developmental Biology Young Investigator Award, 2016
  • NIH Pathway to Independence Award K99/R00 (NICHD), 2016
  • American Cancer Society Postdoctoral Fellowship, 2015
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.