Author: MIT News

Third annual Science Slam becomes first virtual Research Slam

by Raleigh McElvery | Department of Biology |

When MIT announced its pandemic polices back in March, all in-person events were canceled, including the Department of Biology’s third annual Science Slam. Instead, the department devised a new plan in tandem with MIT’s Alumni Association: a virtual slam featuring biology alumni. On April 30, roughly 300 attendees gathered via Zoom to hear nine graduates from Course 7 (Biology) and 5-7 (Chemistry and Biology) share their research.

A science slam features a series of short presentations where researchers explain their work in a compelling manner, and — as the name suggests — make an impact. These presentations aren’t just talks; they’re performances geared toward a science-literate but non-specialized public audience. In this case, competitors were each given one slide and three minutes to tell their scientific tales and earn votes from audience members and judges. Viewers could type questions into the Zoom Q&A function in real-time, and after the prizes were awarded the audience split into breakout rooms to connect with the top three finishers.

The judges included Holden Thorp, editor-in-chief of the Science family of journals; Bob Prior, executive editor of the MIT Press; Vivian Siegel, director of communications for the Department of Biology; and Ari Daniel PhD ’08, an independent science reporter who crafts digital videos for PBS NOVA and co-produces the Boston branch of Story Collider.

The nine competitors included alumnae currently working as graduate students, postdocs, and research scientists — as well as the associate director for research at the U.S. Food and Drug Administration (FDA). In order of appearance, they were:

  • Hanna Starobinets ’09, a research scientist at Genocea, who spoke about devising personalized vaccines that train the immune system to fight cancer;
  • Suzanne Epstein PhD ’79, the FDA’s associate director for research, who spoke about targeting conserved viral proteins to formulate universal vaccines that combat all influenza strains;
  • Amy Norovich ’08, a postdoc at Columbia University, who spoke about the ways male and female fish see the world, and how those differences impact behavior;
  • Helen Hou ’10, also a postdoc at Columbia University, who spoke about how our brains distinguish the sounds we generate from the sounds others make, and what happens when disease interferes with this ability;
  • Maya Jay, ’18, a graduate student at Harvard Medical School, who spoke about how the chemical dopamine helps the brain encode actions and learn behaviors;
  • Lori Huberman ’07, a project scientist at the University of California at Berkeley, who spoke about developing a high-throughput functional genomics platform to study filamentous fungi;
  • Juhyun Oh ’09, a postdoc at Massachusetts General Hospital, who spoke about designing antibody-based imaging techniques, which allow deep profiling of immune cells in a scalable fashion to treat cancer;
  • Alissandra Hillis ’18, a graduate student at Harvard University, who spoke about using genetic tools to identify combinatorial breast cancer treatments that require lower doses and prevent drug resistance; and
  • Allegra Hawkins ’14, a postdoc at Weill Cornell Medicine, who spoke about mapping tumors in order to understand the location and function of each individual cancer cell.

The event was moderated and co-organized by Joe McGonegal, director of alumni education. Like the Department of Biology, the Alumni Association has been hosting research slams for three years running. “It was a natural collaboration,” McGonegal says. “There were lots of moving parts, and given our lean staffing and remote production, I’m surprised the entire thing didn’t sink for one reason or another. There was plenty of room for improvement for sure, but for a pilot virtual slam I couldn’t have asked for more.”

McGonegal collaborated with Siegel, a judge and co-organizer, to plan the event. “It’s always a great treat to hear members of our biology community share their research in the slam format,” she says. “When Joe approached me about collaborating to hold a virtual slam, I immediately agreed. Hearing from our alumni was inspiring, and I hope we can do it again.”

There were four prizes: three awarded by the judges and another determined by the audience. Jay earned first place from the judges, as well as the honor of crowd favorite, while Hawkins and Oh received second and third places, respectively. The Alumni Association donated a total of $2,000 to MIT’s Covid-19 research funds in their names.

First-place winner Jay says that many scientists make a habit of describing their work in inaccessible terms — but conveying research to a wider audience is a critical skill. “The slam provided a perfect opportunity to share my graduate work with the MIT and alumni communities, while practicing explaining our science and its applications for anyone to understand,” she says. “Condensing complex science into a three-minute spiel is hard, but I appreciated the challenge and am glad the work paid off!”

Ramachandra Dasari, associate director of the GR Harrison Spectroscopy Lab, dies at 87

by Danielle Doughty | Department of Chemistry |

Ramachandra Rao Dasari, associate director of the GR Harrison Spectroscopy Laboratory, which houses the MIT-Laser Biomedical Research Center, passed away peacefully of natural causes, surrounded by family, on April 12. He was 87.

Dasari was a member of the MIT community for over 50 years, and was inducted into the Institute’s Half-Century Club in 2017.

“Ramachandra’s numerous contributions range from laser science to non-invasive biomedical diagnosis, publishing nearly 400 scientific papers,” says Peter T.C. So, professor of mechanical engineering and biological engineering. “He mentored several generations of MIT students and postdocs who are now leaders in academia and industry. Dr. Dasari was a good friend and will be greatly missed.”

Educated in his native India, Dasari earned a bachelor’s degree from Andhra University in 1954, a master’s degree from Benares Hindu University in 1956, and a doctoral degree from Aligarh Muslim University in 1960. Dasari joined the faculty of the Indian Institute of Technology (IIT), Kanpur, where he went on to build one of the largest laser laboratories for university research in India, in 1962. During his tenure at IIT, Dasari spent two years (1966-68) as a visiting scientist at MIT, studying the fabrication of lasers and conducting research in laser physics. He left IIT Kanpur in 1978, and spent a year as a visiting senior research officer at the National Research Council of Canada, Ottawa (1978-79), and another year as a visiting scientist at the Department of Physics, University of British Columbia, Vancouver (1979-80) before coming to MIT permanently in 1980 — first as a visiting professor of physics, and then, in 1981, as a principal research scientist in the GR Harrison Spectroscopy Laboratory. He was appointed assistant director of the spectroscopy laboratory in 1984, and was promoted to associate director in 1992. In 2008, Dasari moved to northwest Indiana to be close his family and grandchildren. His work continued, with frequent visits to MIT, until 2017.

Over his many decades overseeing the spectroscopy laboratory, Dasari touched the lives of many, and his countless attributes — not the least being his kind demeanor as a patient mentor, his genuine concern for those around him, and his masterful negotiating tactics — will be forever remembered by those who knew him.

Adam Wax, now a professor of biomedical engineering at Duke University, worked with Dasari from 1999 to 2002 while conducting postdoctoral research at the spectroscopy laboratory. “Ramachandra was a kind and thoughtful soul who touched the lives of everyone who came through spec lab,” says Wax. “He was also a tough negotiator and kept a watchful eye on everything and everyone in the lab. He lived a long and rich life, and I am very sad that it has come to an end during this difficult time, when we cannot all join together and share his memory.”

“Ramachandra was the most considerate person in my life who cared every aspect of people around from research to personal life,” says Wonshik Choi, professor of physics at Korea University and a former visiting student and postdoc. Choi described Dasari’s mentorship as “unforgettable.” “With deep and broad knowledge, he used to identify and support whatever was necessary to break through the gridlock,” remembers Choi.  “His warm spiritual support enabled us to go through all-or-nothing type of tough projects, such as proving the nonclassicality of the single-atom laser radiation, and his enthusiastic inspiration led us to develop exciting label-free cell tomography.”

Charles H. Holbrow, emeritus professor of physics at Colgate University and current visiting professor of physics at MIT, met and became friends with Dasari in 1983, when Holbrow arrived at MIT for the first of several visiting professorships. Holbrow credits Dasari with fostering the creativity and productivity of the spectroscopy laboratory, and supporting the lab’s director. The two men extended their friendship to include their families, a connection that Holbrow considers “a memorial to a fine man.”

“Ramachandra provided skillful management, expertise in Raman spectroscopy, and important mentoring of graduate students and postdocs — many experiencing America for the first time,” says Holbrow. “He was deeply concerned about their welfare and was a source of personal warmth and helpful guidance. He cared about them, and they knew it. He was also an exceptional negotiator; his work with equipment vendors was an art form. It was a pleasure to watch him persuade salesmen and company managers to reduce prices, provide special services, and give early access to technical innovations and improvements.”

Rebecca Richards-Kortum SM ’87, PhD ’90, currently the Malcolm Gillis University Professor of Bioengineering at Rice University, worked with Dasari from 1985 to 1990 and credits him with inspiring his mentees to be better mentors through his actions. “[Dasari] was a great scientist, but he was an especially generous mentor to all the students and staff who worked in the spectroscopy lab,” she says. “Many people relied on him for great career advice. I remember when I was graduating, he sat down with me to think through many options and helped me come to the right choice. As I reached back out over the years, he was always willing to listen and offer wisdom and great advice.”

Dasari is survived by Suhasini, his wife of 69 years; his son Satish Dasari and daughter-in-law Veda Praveena; daughter Lakshmi Dasari; and grandchildren, Sidarth and Vivek. In addition to his family, his pride and joy were his students, both at IITK and at MIT, and their success will remain his lasting legacy. Due to Centers for Disease Control and Prevention guidelines during the Covid-19 crisis, a private service was held on April 14. The family will hold a celebration of his life at a later date, when it is safe to do so.

Alex Shalek wins Edgerton Faculty Award

by MIT News |

Alex K. Shalek, the Pfizer-Laubach Career Development Associate Professor of Chemistry, core member of the Institute for Medical Engineering and Science (IMES), and extramural member of the Koch Institute for Integrative Cancer Research, has been named the recipient of the 2019-20 Harold E. Edgerton Faculty Achievement Award. The award’s selection committee chose to recognize Shalek for “his leadership and pioneering spirit; his vision, inventiveness, and enthusiasm for mentorship and collaboration; and his tremendous contributions to a critical area at the intersection of science and medicine.”

Shalek’s research is directed toward the creation and implementation of new technologies to understand how cells collectively perform systems-level functions in healthy and diseased states. A leader in creating and implementing new methods, both experimental and computational, Shalek studies how cells collectively drive health and disease. He and his team work to make technology available to people, simplifying and economizing approaches to facilitate global and clinical utilization, and to deepen our understanding of human malignant, infectious, and inflammatory diseases. The insights developed through his profiling methods are helping to both transform our understanding of the cellular basis of disease and inform therapeutic intervention strategies.

“When Professor Shalek first came to MIT, he helped to develop a method called Drop-Seq that revolutionized single‐cell analysis by allowing researchers to reproducibly recover the transcriptomes — the set of all the RNA transcripts (information copied from a strand of DNA) — of thousands of single cells at minimal cost,” Professor Antoinette Schoar, chair of the selection committee, said in a statement on the committee’s behalf. “Such unbiased single‐cell profiling promised transformative opportunities to understand human health and disease — for example, to identify malignant clones in cancer biopsies or the cellular targets of acute HIV infection in blood. To realize this potential, Professor Shalek and his team, in collaboration with Professor Chris Love’s lab, subsequently reengineered this method, developing Seq-Well, an ultra‐portable, low‐cost single‐cell RNA‐sequencing technology that can profile the transcriptomes of thousands of cells from multiple clinical samples at once. This technology redefines what scientists around the world can learn from precious samples, enabling both basic and clinical research on a global scale.”

In addition to his positions in the chemistry department and IMES, Shalek is an extramural member of the Koch Institute, an institute member of the Broad Institute of MIT and Harvard, an associate member of the Ragon Institute, an assistant in immunology at Massachusetts General Hospital, an instructor of health sciences and technology at Harvard Medical School, and an affiliate faculty member of the Harvard Stem Cell Institute. He received three degrees in chemical physics: a BA from Columbia University, and MA and PhD degrees from Harvard University. After receiving his doctorate, he was a postdoc at Harvard, MIT, and the Broad Institute. Shalek joined the MIT faculty in 2014 as an assistant professor in the Department of Chemistry and a core member of IMES. He was promoted to associate professor without tenure in 2019.

Shalek has obtained 18 patents since joining the MIT faculty, with another 15 pending. Over the same period, he has coauthored 66 papers, reviews, perspectives, and commentaries. Among his numerous accolades are an NIH New Innovator Award, a Sloan Research Fellowship in Chemistry, a Pew-Stewart Scholarship, a Beckman Young Investigator Award, and a Searle Scholarship. In 2019, he was selected as a voice who will guide the next 15 years of methods development by the journal Nature Methods, and as one of the 25 voices who will guide the next 25 years of immunology by the journal Immunity.

The selection committee commended Shalek’s “critically important” dedication to educating and empowering the next generation of scientists, at MIT and beyond. “At MIT, he has designed a highly successful graduate subject that covers the biophysics behind genomic measurement techniques, as well as their applications in medicine,” stated the selection committee in their report. “At the undergraduate level, he has added to the established curriculum by including examples inspired by modern research to illustrate the relevance of his lecture material and promote student engagement. He has been involved in significant curriculum development and education planning projects within Chemistry and IMES. His lab has participated in local events such as the Cambridge Science Festival, HubWeek, and Science on Saturday, as well as doing outreach to middle and high schoolers.”

Shalek’s internal and external service to his community is also to be admired. Shalek serves as an advisor to first-year MIT undergraduates, as well as students in chemistry, in the Harvard-MIT Program in Health Sciences and Technology’s Medical Engineering and Medical Physics (MEMP) PhD program, and in the Harvard/MIT MD-PhD program. He has served on the graduate admissions committees not only for chemistry, but also for MEMP, computational and systems biology, and the Harvard Medical School Immunology Program, and the faculty search committees in not only chemistry and IMES, but also the Ragon Institute of MGH, MIT, and Harvard. In addition, he served a term on the Institute Committee on Prehealth Advising when he joined MIT as assistant professor. Shalek frequently serves as a reviewer for NIH grant panels and is a member of the Bill and Melinda Gates Foundation Collaborations for AIDS Vaccine Discovery and TB Vaccine Discovery. He is also involved in the Human Cell Atlas Project, serving as co-leader of its Equity Working Group.

The annual Edgerton Faculty Award was established in 1982 as a tribute to Institute Professor Emeritus Harold E. Edgerton in recognition of his active support of junior faculty members. Each year, a committee presents the award to one or more non-tenured faculty members to recognize exceptional contributions in research, teaching, and service.

The 2019-20 Edgerton Award Selection Committee was chaired by Professor Antoinette Schoar, the Stewart C. Myers-Horn Family Professor of Finance and Entrepreneurship at the MIT Sloan School of Management. Committee members included biological engineering Professor Bevin Engelward; Camille Dreyfus Professor of Chemistry Stephen L. Buchwald; literature Professor Shankar Raman; and art, culture, and technology Professor Gediminas Urbonas.

Researchers identify cells likely targeted by Covid-19 virus

by Anne Trafton | MIT News Office |

Researchers at MIT; the Ragon Institute of MGH, MIT, and Harvard; and the Broad Institute of MIT and Harvard; along with colleagues from around the world have identified specific types of cells that appear to be targets of the coronavirus that is causing the Covid-19 pandemic.

Using existing data on the RNA found in different types of cells, the researchers were able to search for cells that express the two proteins that help the SARS-CoV-19 virus enter human cells. They found subsets of cells in the lung, the nasal passages, and the intestine that express RNA for both of these proteins much more than other cells.

The researchers hope that their findings will help guide scientists who are working on developing new drug treatments or testing existing drugs that could be repurposed for treating Covid-19.

“Our goal is to get information out to the community and to share data as soon as is humanly possible, so that we can help accelerate ongoing efforts in the scientific and medical communities,” says Alex K. Shalek, the Pfizer-Laubach Career Development Associate Professor of Chemistry, a core member of MIT’s Institute for Medical Engineering and Science (IMES), an extramural member of the Koch Institute for Integrative Cancer Research, an associate member of the Ragon Institute, and an institute member at the Broad Institute.

Shalek and Jose Ordovas-Montanes, a former MIT postdoc who now runs his own lab at Boston Children’s Hospital, are the senior authors of the study, which appears today in Cell. The paper’s lead authors are MIT graduate students Carly Ziegler, Samuel Allon, and Sarah Nyquist; and Ian Mbano, a researcher at the Africa Health Research Institute in Durban, South Africa.

Digging into data

Not long after the SARS-CoV-2 outbreak began, scientists discovered that the viral “spike” protein binds to a receptor on human cells known as angiotensin-converting enzyme 2 (ACE2). Another human protein, an enzyme called TMPRSS2, helps to activate the coronavirus spike protein, to allow for cell entry. The combined binding and activation allows the virus to get into host cells.

“As soon as we realized that the role of these proteins had been biochemically confirmed, we started looking to see where those genes were in our existing datasets,” Ordovas-Montanes says. “We were really in a good position to start to investigate which are the cells that this virus might actually target.”

Shalek’s lab, and many other labs around the world, have performed large-scale studies of tens of thousands of human, nonhuman primate, and mouse cells, in which they use single-cell RNA sequencing technology to determine which genes are turned on in a given cell type. Since last year, Nyquist has been building a database with partners at the Broad Institute to store a huge collection of these datasets in one place, allowing researchers to study potential roles for particular cells in a variety of infectious diseases.

Much of the data came from labs that belong to the Human Cell Atlas project, whose goal is to catalog the distinctive patterns of gene activity for every cell type in the human body. The datasets that the MIT team used for this study included hundreds of cell types from the lungs, nasal passages, and intestine. The researchers chose those organs for the Covid-19 study because previous evidence had indicated that the virus can infect each of them. They then compared their results to cell types from unaffected organs.

“Because we have this incredible repository of information, we were able to begin to look at what would be likely target cells for infection,” Shalek says. “Even though these datasets weren’t designed specifically to study Covid, it’s hopefully given us a jump start on identifying some of the things that might be relevant there.”

In the nasal passages, the researchers found that goblet secretory cells, which produce mucus, express RNAs for both of the proteins that SARS-CoV-2 uses to infect cells. In the lungs, they found the RNAs for these proteins mainly in cells called type II pneumocytes. These cells line the alveoli (air sacs) of the lungs and are responsible for keeping them open.

In the intestine, they found that cells called absorptive enterocytes, which are responsible for the absorption of some nutrients, express the RNAs for these two proteins more than any other intestinal cell type.

“This may not be the full story, but it definitely paints a much more precise picture than where the field stood before,” Ordovas-Montanes says. “Now we can say with some level of confidence that these receptors are expressed on these specific cells in these tissues.”

Fighting infection

In their data, the researchers also saw a surprising phenomenon — expression of the ACE2 gene appeared to be correlated with activation of genes that are known to be turned on by interferon, a protein that the body produces in response to viral infection. To explore this further, the researchers performed new experiments in which they treated cells that line the airway with interferon, and they discovered that the treatment did indeed turn on the ACE2 gene.

Interferon helps to fight off infection by interfering with viral replication and helping to activate immune cells. It also turns on a distinctive set of genes that help cells fight off infection. Previous studies have suggested that ACE2 plays a role in helping lung cells to tolerate damage, but this is the first time that ACE2 has been connected with the interferon response.

The finding suggests that coronaviruses may have evolved to take advantage of host cells’ natural defenses, hijacking some proteins for their own use.

“This isn’t the only example of that,” Ordovas-Montanes says. “There are other examples of coronaviruses and other viruses that actually target interferon-stimulated genes as ways of getting into cells. In a way, it’s the most reliable response of the host.”

Because interferon has so many beneficial effects against viral infection, it is sometimes used to treat infections such as hepatitis B and hepatitis C. The findings of the MIT team suggest that interferon’s potential role in fighting Covid-19 may be complex. On one hand, it can stimulate genes that fight off infection or help cells survive damage, but on the other hand, it may provide extra targets that help the virus infect more cells.

“It’s hard to make any broad conclusions about the role of interferon against this virus. The only way we’ll begin to understand that is through carefully controlled clinical trials,” Shalek says. “What we are trying to do is put information out there, because there are so many rapid clinical responses that people are making. We’re trying to make them aware of things that might be relevant.”

Shalek now hopes to work with collaborators to profile tissue models that incorporate the cells identified in this study. Such models could be used to test existing antiviral drugs and predict how they might affect SARS-CoV-2 infection.

The MIT team and their collaborators have made all the data they used in this study available to other labs who want to use it. Much of the data used in this study was generated in collaboration with researchers around the world, who were very willing to share it, Shalek says.

“There’s been an incredible outpouring of information from the scientific community with a number of different parties interested in contributing to the battle against Covid in any way possible,” he says. “It’s been incredible to see a large number of labs from around the world come together to try and collaboratively tackle this.”

The research was funded by the Searle Scholars Program, the Beckman Young Investigator Program, the Pew-Stewart Scholars Program for Cancer Research, a Sloan Fellowship in Chemistry, the National Institutes of Health, the Aeras Foundation, the Bill and Melinda Gates Foundation, the Richard and Susan Smith Family Foundation, the National Institute of General Medical Sciences, the UMass Center for Clinical and Translational Science Project Pilot Program, and the Office of the Assistant Secretary of Defense for Health Affairs.

Pyae Phyo: From Myanmar to NMR

by Paul Rivenberg | Plasma Science and Fusion Center |

It began with a bowl of soup. When Pyae Phyo was a young girl in Myanmar, her older sister pointed out the circles of oil floating in the steaming broth and asked her why she supposed the water and oil did not mix. The ensuing explanation of the differing polarities of water and oil sparked in 5-year-old Pyae a lifelong interest in uncovering what she calls “the basic properties of everyday materials.”

Now a graduate student in the Magnetic Resonance Division of the MIT Plasma Science and Fusion Center, under the supervision of Professor of Chemistry Mei Hong, Phyo continues to ask questions about everyday phenomena. Most recently her questions revolve around plant cell walls: how they are created, and how understanding their molecular structure could aid in developing sustainable biofuels. She’s finding the answers with the help of solid-state nuclear magnetic resonance spectroscopy.

Phyo first learned about NMR as part of a university summer research program. She had arrived in the United States for the first time in 2011 to pursue a fully funded undergraduate degree at Berea College in Kentucky. Having grown up mainly under a military government with an educational system that promoted rote memorization over practical, hands-on scientific experience, Phyo was eager to study in the United States, where laboratory work is part of the curriculum. After her first year in college, her academic advisor, Professor Jay Baltisberger, invited her to join a summer research program at the Ohio State University (OSU) in the Grandinetti Lab, where he was taking his sabbatical year.

The summer study of silicate glass introduced her to a tool for seeing and analyzing the hidden structures that make up the materials of everyday life. NMR measures nuclear magnetic interactions in a material to gain understanding of its molecular structure, information that could be important in producing new medicines, predicting drug interactions, or developing  new materials and substances, like biofuels.

“I got a lot of experience at OSU seeing how my colleagues would troubleshoot and fix NMR probes and solve issues with the experiments, how they designed experiments to answer specific questions, and how they analyzed and interpreted the results.”

After a week in the program she had learned enough to oversee the project alone while her advisor and colleagues attended a conference. The program became her summer home for the next three years.

Phyo chose to continue her studies at MIT, drawn by what she felt would be the most challenging and motivating academic environment. The larger city environment was also a challenge, inhibiting her at first from venturing out after dark. Eventually familiarity with MIT and her Hong group colleagues, as well as enjoyment of the Charles River, the magnolias on Commonwealth Avenue and plentiful Asian cuisine, reversed her original fears.

Phyo’s research focuses on understanding the fundamental plant cell wall structure in order to give critical insight into how to convert plant waste to biofuel. She employs and develops sophisticated two- and three-dimensional solid-state NMR techniques to examine the plant cell wall structures at the molecular level.

“Back in Myanmar,’ she notes, “our main staple is rice, and we burn the majority of rice straw to get rid of it, polluting the air in the process. Creating a carbon-neutral method of turning this refuse into liquid fuel that could be used for combustion engines would be revolutionary for the environment and the economy.”

To that end, she studies the molecular structure of the plant cell wall to better understand how plants grow. Unlike animal cells, plant cells have walls that provide their main structural support. But plant cells must expand these walls for growth to occur.

“We wouldn’t have either the giant redwood tree or the massive Aspen colony without this extraordinary ability,” she explains.

The major components of the plant cell wall are well known. Cellulose, composed of a long chain of glucose molecules, forms the main scaffold of plant cell wall structure by forming microfibrils that provide strength and rigidity. But exactly how is cellulose synthesized and bundled together in microfibrils to strengthen the wall, while still allowing plant growth through complex interactions with other polysaccharides?

Studying this process and developing a universal 3D molecular cell wall model is the focus of Phyo’s research. She says that having a 3D model would aid future work on genetically engineered plants for biotech, agricultural, and energy applications.

“We see a two-dimensional structure in a textbook,” she notes, “but we don’t know if it is true or not. It is an approximation of what we think is happening. There are so many different types of polysaccharides such as pectin, cellulose, hemicellulose. But how are they spatially arranged? Where is the cellulose? What is attached to it and where?”

Understanding the 3D structure of a cell wall would make it easier to manipulate specific molecular bonds to create novel materials for agriculture and biofuel applications. Phyo likens it to removing a door from its frame.

“If you want to get rid of a wooden door, you could burn it, or chop it, again and again. You would eventually succeed in breaking it down. But if you know the structure of the door, how it is assembled, and where the hinge is, you can quickly take it apart. With cell walls, if you have a 3D reference system for its formation and structure, you know exactly where to attack.”

Phyo is not alone in her quest. While working in the Hong group at MIT to conduct cutting-edge solid-state NMR experiments, she is part of a dynamic Energy Frontier Research Center, funded by the Department of Energy. The Center for Lignocellulose Structure and Formation includes collaborators from Penn State, Oak Ridge National Laboratory, the University of Cambridge, and other institutions, all working to increase understanding of cell wall formation and structure in order to lay a foundation for future developments in genetically engineered plants for biotech, agricultural, and energy applications.

Phyo is also not alone in the United States. Although her parents remain in Myanmar, her three siblings have all come to the United States to study science. Her older sister, who excited her about the chemistry in a bowl of soup, received her own PhD in solid-state nuclear magnetic resonance spectroscopy; her younger sister studies biochemistry and molecular biology as an undergraduate student in Ohio; and her brother is a third-year PhD candidate at MIT, part of the Willard group in the Department of Chemistry.

As Phyo prepares to defend her dissertation and move on to a position as senior scientist at Merck in New Jersey, she remembers fondly the walks along the Charles, past the rhododendrons or under the magnolias, elements of her everyday life that have become familiar.

“You have something around you all the time, like a plant or a leaf or a flower, and you ask, ‘What is inside this?’”

Her research, which has revealed some molecular details of the cell walls inside these plants, is helping to answer that question.

Newly discovered enzyme “square dance” helps generate DNA building blocks

by Raleigh McElvery | Department of Biology |

How do you capture a cellular process that transpires in the blink of an eye? Biochemists at MIT have devised a way to trap and visualize a vital enzyme at the moment it becomes active — informing drug development and revealing how biological systems store and transfer energy.

The enzyme, ribonucleotide reductase (RNR), is responsible for converting RNA building blocks into DNA building blocks, in order to build new DNA strands and repair old ones. RNR is a target for anti-cancer therapies, as well as drugs that treat viral diseases like HIV/AIDS. But for decades, scientists struggled to determine how the enzyme is activated because it happens so quickly. Now, for the first time, researchers have trapped the enzyme in its active state and observed how the enzyme changes shape, bringing its two subunits closer together and transferring the energy needed to produce the building blocks for DNA assembly.

Before this study, many believed RNR’s two subunits came together and fit with perfect symmetry, like a key into a lock. “For 30 years, that’s what we thought,” says Catherine Drennan, an MIT professor of chemistry and biology and a Howard Hughes Medical Institute investigator. “But now, we can see the movement is much more elegant. The enzyme is actually performing a ‘molecular square dance,’ where different parts of the protein hook onto and swing around other parts. It’s really quite beautiful.”

Drennan and JoAnne Stubbe, professor emerita of chemistry and biology at MIT, are the senior authors on the study, which appeared in the journal Science on March 26. Former graduate student Gyunghoon “Kenny” Kang PhD ’19 is the lead author.

All proteins, including RNR, are composed of fundamental units known as amino acids. For over a decade, Stubbe’s lab has been experimenting with substituting RNR’s natural amino acids for synthetic ones. In doing so, the lab realized they could trap the enzyme in its active state and slow down its return to normal. However, it wasn’t until the Drennan lab gained access to a key technological advancement — cryo-electron microscopy — that they could snap high-resolution images of these “trapped” enzymes from the Stubbe lab and get a closer look.

“We really hadn’t done any cryo-electron microscopy at the point that we actively started trying to do the impossible: get the structure of RNR in its active state,” Drennan says. “I can’t believe it worked; I’m still pinching myself.”

The combination of these techniques allowed the team to visualize the complex molecular dance that allows the enzyme to transport the catalytic “firepower” from one subunit to the next, in order to generate DNA building blocks. This firepower is derived from a highly reactive unpaired electron (a radical), which must be carefully controlled to prevent damage to the enzyme.

According to Drennan, the team “wanted to see how RNR does the equivalent of playing with fire without getting burned.”

First author Kang says slowing down the radical transfer allowed them to observe parts of the enzyme no one had been able to see before in full. “Before this study, we knew this molecular dance was happening, but we’d never seen the dance in action,” he says. “But now that we have a structure for RNR in its active state, we have a much better idea about how the different components of the enzyme are moving and interacting in order to transfer the radical across long distances.”

Although this molecular dance brings the subunits together, there is still considerable distance between them: The radical must travel 35-40 angstroms from the first subunit to the second. This journey is roughly 10 times farther than the average radical transfer, according to Drennan. The radical must then travel back to its starting place and be stored safely, all within a fraction of a second before the enzyme returns to its normal conformation.

Because RNR is a target for drugs treating cancer and certain viruses, knowing its active-state structure could help researchers devise more effective treatments. Understanding the enzyme’s active state could also provide insight into biological electron transport for applications like biofuels. Drennan and Kang hope their study will encourage others to capture fleeting cellular events that have been difficult to observe in the past.

“We may need to reassess decades of past results,” Drennan says. “This study could open more questions than it answers; it’s more of a beginning than an end.”

This research was funded by the National Institutes of Health, a David H. Koch Graduate Fellowship, and the Howard Hughes Medical Institute.

An experimental peptide could block Covid-19

by Anne Trafton | MIT News Office |

The research described in this article has been published on a preprint server but has not yet been peer-reviewed by scientific or medical experts.

In hopes of developing a possible treatment for Covid-19, a team of MIT chemists has designed a drug candidate that they believe may block coronaviruses’ ability to enter human cells. The potential drug is a short protein fragment, or peptide, that mimics a protein found on the surface of human cells.

The researchers have shown that their new peptide can bind to the viral protein that coronaviruses use to enter human cells, potentially disarming it.

“We have a lead compound that we really want to explore, because it does, in fact, interact with a viral protein in the way that we predicted it to interact, so it has a chance of inhibiting viral entry into a host cell,” says Brad Pentelute, an MIT associate professor of chemistry, who is leading the research team.

The MIT team reported its initial findings in a preprint posted on bioRxiv, an online preprint server, on March 20. They have sent samples of the peptide to collaborators who plan to carry out tests in human cells.

Molecular targeting

Pentelute’s lab began working on this project in early March, after the Cryo-EM structure of the coronavirus spike protein, along with the human cell receptor that it binds to, was published by a research group in China. Coronaviruses, including SARS-CoV-2, which is causing the current Covid-19 outbreak, have many protein spikes protruding from their viral envelope.

Studies of SARS-CoV-2 have also shown that a specific region of the spike protein, known as the receptor binding domain, binds to a receptor called angiotensin-converting enzyme 2 (ACE2). This receptor is found on the surface of many human cells, including those in the lungs. The ACE2 receptor is also the entry point used by the coronavirus that caused the 2002-03 SARS outbreak.

In hopes of developing drugs that could block viral entry, Genwei Zhang, a postdoc in Pentelute’s lab, performed computational simulations of the interactions between the ACE2 receptor and the receptor binding domain of the coronavirus spike protein. These simulations revealed the location where the receptor binding domain attaches to the ACE2 receptor — a stretch of the ACE2 protein that forms a structure called an alpha helix.

“This kind of simulation can give us views of how atoms and biomolecules interact with each other, and which parts are essential for this interaction,” Zhang says. “Molecular dynamics helps us narrow down particular regions that we want to focus on to develop therapeutics.”

The MIT team then used peptide synthesis technology that Pentelute’s lab has previously developed, to rapidly generate a 23-amino acid peptide with the same sequence as the alpha helix of the ACE2 receptor. Their benchtop flow-based peptide synthesis machine can form linkages between amino acids, the buildings blocks of proteins, in about 37 seconds, and it takes less than an hour to generate complete peptide molecules containing up to 50 amino acids.

“We’ve built these platforms for really rapid turnaround, so I think that’s why we’re at this point right now,” Pentelute says. “It’s because we have these tools we’ve built up at MIT over the years.”

They also synthesized a shorter sequence of only 12 amino acids found in the alpha helix, and then tested both of the peptides using equipment at MIT’s Biophysical Instrumentation Facility that can measure how strongly two molecules bind together. They found that the longer peptide showed strong binding to the receptor binding domain of the Covid-19 spike protein, while the shorter one showed negligible binding.

Many variants

Although MIT has been scaling back on-campus research since mid-March, Pentelute’s lab was granted special permission allowing a small group of researchers to continue to work on this project. They are now developing about 100 different variants of the peptide in hopes of increasing its binding strength and making it more stable in the body.

“We have confidence that we know exactly where this molecule is interacting, and we can use that information to further guide refinement, so that we can hopefully get a higher affinity and more potency to block viral entry in cells,” Pentelute says.

In the meantime, the researchers have already sent their original 23-amino acid peptide to a research lab at the Icahn School of Medicine at Mount Sinai for testing in human cells and potentially in animal models of Covid-19 infection.

While dozens of research groups around the world are using a variety of approaches to seek new treatments for Covid-19, Pentelute believes his lab is one of a few currently working on peptide drugs for this purpose. One advantage of such drugs is that they are relatively easy to manufacture in large quantities. They also have a larger surface area than small-molecule drugs.

“Peptides are larger molecules, so they can really grip onto the coronavirus and inhibit entry into cells, whereas if you used a small molecule, it’s difficult to block that entire area that the virus is using,” Pentelute says. “Antibodies also have a large surface area, so those might also prove useful. Those just take longer to manufacture and discover.”

One drawback of peptide drugs is that they typically can’t be taken orally, so they would have to be either administered intravenously or injected under the skin. They would also need to be modified so that they can stay in the bloodstream long enough to be effective, which Pentelute’s lab is also working on.

“It’s hard to project how long it will take to have something we can test in patients, but my aim is to have something within a matter of weeks. If it turns out to be more challenging, it may take months,” he says.

In addition to Pentelute and Zhang, other researchers listed as authors on the preprint are postdoc Sebastian Pomplun, grad student Alexander Loftis, and research scientist Andrei Loas.

New sensor could help prevent food waste

by Anne Trafton | MIT News Office |

As flowers bloom and fruits ripen, they emit a colorless, sweet-smelling gas called ethylene. MIT chemists have now created a tiny sensor that can detect this gas in concentrations as low as 15 parts per billion, which they believe could be useful in preventing food spoilage.

The sensor, which is made from semiconducting cylinders called carbon nanotubes, could be used to monitor fruit and vegetables as they are shipped and stored, helping to reduce food waste, says Timothy Swager, the John D. MacArthur Professor of Chemistry at MIT.

“There is a persistent need for better food management and reduction of food waste,” says Swager. “People who transport fruit around would like to know how it’s doing during transit, and whether they need to take measures to keep ethylene down while they’re transporting it.”

In addition to its natural role as a plant hormone, ethylene is also the world’s most widely manufactured organic compound and is used to manufacture products such as plastics and clothing. A detector for ethylene could also be useful for monitoring this kind of industrial ethylene manufacturing, the researchers say.

Swager is the senior author of the study, which appears today in the journal ACS Central. MIT postdoc Darryl Fong is the lead author of the paper, and MIT graduate student Shao-Xiong (Lennon) Luo and visiting scholar Rafaela Da Silveira Andre are also authors.

Ripe or not

Ethylene is produced by most plants, which use it as a hormone to stimulate growth, ripening, and other key stages of their life cycle. Bananas, for instance, produce increasing amounts of ethylene as they ripen and turn brown, and flowers produce it as they get ready to bloom. Produce and flowers under stress can overproduce ethylene, leading them to ripen or wilt prematurely. It is estimated that every year U.S. supermarkets lose about 12 percent of their fruits and vegetables to spoilage, according to the U.S. Department of Agriculture.

In 2012, Swager’s lab developed an ethylene sensor containing arrays of tens of thousands of carbon nanotubes. These carbon cylinders allow electrons to flow along them, but the researchers added copper atoms that slow down the electron flow. When ethylene is present, it binds to the copper atoms and slows down electrons even more. Measuring this slowdown can reveal how much ethylene is present. However, this sensor can only detect ethylene levels down to 500 parts per billion, and because the sensors contain copper, they are likely to eventually become corroded by oxygen and stop working.

“There still is not a good commercial sensor for ethylene,” Swager says. “To manage any kind of produce that’s stored long-term, like apples or potatoes, people would like to be able to measure its ethylene to determine if it’s in a stasis mode or if it’s ripening.”

Swager and Fong created a new kind of ethylene sensor that is also based on carbon nanotubes but works by an entirely different mechanism, known as Wacker oxidation. Instead of incorporating a metal such as copper that binds directly to ethylene, they used a metal catalyst called palladium that adds oxygen to ethylene during a process called oxidation.

As the palladium catalyst performs this oxidation, the catalyst temporarily gains electrons. Palladium then passes these extra electrons to carbon nanotubes, making them more conductive. By measuring the resulting change in current flow, the researchers can detect the presence of ethylene.

The sensor responds to ethylene within a few seconds of exposure, and once the gas is gone, the sensor returns to its baseline conductivity within a few minutes.

“You’re toggling between two different states of the metal, and once ethylene is no longer there, it goes from that transient, electron-rich state back to its original state,” Fong says.

“The repurposing of the Wacker oxidation catalytic system for ethylene detection was an exceptionally clever and fundamentally interdisciplinary idea,” says Zachary Wickens, an assistant professor of chemistry at the University of Wisconsin, who was not involved in the study. “The research team drew upon recent modifications to the Wacker oxidation to provide a robust catalytic system and incorporated it into a carbon nanotube-based device to provide a remarkably selective and simple ethylene sensor.”

In bloom

To test the sensor’s capabilities, the researchers deposited the carbon nanotubes and other sensor components onto a glass slide. They then used it to monitor ethylene production in two types of flowers — carnations and purple lisianthus. They measured ethylene production over five days, allowing them to track the relationship between ethylene levels and the plants’ flowering.

In their studies of carnations, the researchers found that there was a rapid spike in ethylene concentration on the first day of the experiment, and the flowers bloomed shortly after that, all within a day or two.

Purple lisianthus flowers showed a more gradual increase in ethylene that started during the first day and lasted until the fourth day, when it started to decline. Correspondingly, the flowers’ blooming was spread out over several days, and some still hadn’t bloomed by the end of the experiment.

The researchers also studied whether the plant food packets that came with the flowers had any effect on ethylene production. They found that plants given the food showed slight delays in ethylene production and blooming, but the effect was not significant (only a few hours).

The MIT team has filed for a patent on the new sensor. The research was funded by the National Science Foundation, the U.S. Army Engineer Research and Development Center Environmental Quality Technology Program, the Natural Sciences and Engineering Research Council of Canada, and the Sao Paulo Research Foundation.

Emissions of several ozone-depleting chemicals are larger than expected

by Jennifer Chu | MIT News Office |

In 2016, scientists at MIT and elsewhere observed the first signs of healing in the Antarctic ozone layer. This environmental milestone was the result of decades of concerted effort by nearly every country in the world, which collectively signed on to the Montreal Protocol. These countries pledged to protect the ozone layer by phasing out production of ozone-depleting chlorofluorocarbons, which are also potent greenhouse gases.

While the ozone layer is on a recovery path, scientists have found unexpectedly high emissions of CFC-11 and CFC-12, raising the possibility of production of the banned chemicals that could be in violation of the landmark global treaty. Emissions of CFC-11 even showed an uptick around 2013, which has been traced mainly to a source in eastern China. New data suggest that China has now tamped down on illegal production of the chemical, but emissions of CFC-11 and 12 emission are still larger than expected.

Now MIT researchers have found that much of the current emission of these gases likely stems from large CFC “banks” — old equipment such as building insulation foam, refrigerators and cooling systems, and foam insulation, that was manufactured before the global phaseout of CFCs and is still leaking the gases into the atmosphere. Based on earlier analyses, scientists concluded that CFC banks would be too small to contribute very much to ozone depletion, and so policymakers allowed the banks to remain.

It turns out there are oversized banks of both CFC-11 and CFC-12. The banks slowly leak these chemicals at concentrations that, if left unchecked, would delay the recovery of the ozone hole by six years and add the equivalent of 9 billion metric tons of carbon dioxide to the atmosphere — an amount that is similar to the current European Union pledge under the UN Paris Agreement to reduce climate change.

“Wherever these CFC banks reside, we should consider recovering and destroying them as responsibly as we can,” says Susan Solomon, the Lee and Geraldine Martin Professor of Environmental Studies at MIT, who is a co-author of the study. “Some banks are easier to destroy than others. For instance, before you tear a building down, you can take careful measures to recover the insulation foam and bury it in a landfill, helping the ozone layer recover faster and perhaps taking off a chunk of global warming as a gift to the planet.”

The team also identified an unexpected and sizable source of another ozone-depleting chemical, CFC-113. This chemical was traditionally used as a cleaning solvent, and its production was banned, except for in one particular use, as a feedstock for the manufacturing of other chemical substances. It was thought that chemical plants would use the CFC-113 without allowing much leakage, and so the chemical’s use as a feedstock was allowed to continue.

However, the researchers found that CFC-113 is being emitted into the atmosphere, at a rate of 7 billion grams per year — nearly as large as the spike in CFC-11, which amounted to about 10 billion grams per year.

“A few years ago, the world got very upset over 10 gigagrams of CFC-11 that wasn’t supposed to be there, and now we’re seeing 7 gigagrams of CFC-113 that wasn’t supposed to be there,” says lead author of the study and MIT graduate student Megan Lickley. “The two gases are similar in terms of their ozone depletion and global warming potential. So this is a significant issue.”

The study appears today in Nature Communications. Co-authors with Lickley and Solomon are Sarah Fletcher, and Kane Stone of MIT, along with Guus Velders of Utrecht University, John Daniel and Stephen Montzka of the National Oceanic and Atmospheric Administration, Matthew Rigby of the University of Bristol, and Lambert Kuijpers of A/gent Ltd. Consultancy, in the Netherlands.

From top to bottom

The new results are based on an analysis the team developed that combines two common methods for estimating the size of CFC banks around the world.

The first method is a top-down approach, which looks at CFCs produced around the world, based on country-by-country reporting, and then compares these numbers to actual concentrations of the gasses and how long they persist in the atmosphere. After accounting for atmospheric destruction, the difference between a chemical’s production and its atmospheric concentrations gives scientists an estimate of the size of CFC banks around the world.

Based on recent international assessments that use this top-down approach, there should be no CFC banks left in the world.

“But those values are subject to large uncertainties: Small differences in production values or lifetimes or concentrations can lead to large differences in the bank size,” Lickley notes.

The second method is a bottom-up approach, which uses industry-reported values of CFC production and sales in a variety of applications such as refrigeration or foams, and estimates of how quickly each equipment type is depleting over time.

The team combined the best of both methods in a Bayesian probabilistic model — a hybrid approach that calculates the global size of CFC banks based on both atmospheric data, and country and industry-level reporting of CFC production and sales in various uses.

“We also allow there to be some uncertainties, because there could be reporting errors from different countries, which wouldn’t be surprising at all,” Solomon says. “So it’s a much better quantification of the size of the bank.”

Chasing a lost opportunity

The CFC banks, and the sheer quantity of old equipment storing these chemicals around the world, seem to be larger than any previous estimates. The team found the amount of CFC 11 and 12 stored up in banks is about 2.1 million metric tons — an amount that would delay ozone recovery by six years if released to the atmosphere. This CFC bank is also equivalent to about 9 billion metric tons of carbon dioxide in terms of its effect on climate change.

Interestingly, the amount of both CFC-11 and CFC-12 that is being emitted from these banks is enough to account for the recently observed emissions in both gases.

“It really looks like, other than the extra amount being produced in China that seems to have stopped now, the rest of what we’re seeing is no mystery: It’s just what’s coming out of the banks. That’s good news,” Solomon says. “It means there doesn’t seem to be any further cheating going on. If there is, it’s very small. And we wanted to know, if you were to recover and destroy these building foams, and replace old cooling systems and such, in a more responsible way, what more could that do for climate change?”

To answer that, the team explored several theoretical policy scenarios and their potential effect on the emissions produced by CFC banks.

An “opportunity lost” scenario considers what would have happened if all banks were destroyed back in 2000 — the year that many developed countries agreed to phase out CFC production. If this scenario had played out, the measure would have saved the equivalent of 25 billion metric tons of carbon dioxide between 2000 and 2020, and there would be no CFC emissions lingering now from these banks.

A second scenario predicts CFC emissions in the atmosphere if all banks are recovered and destroyed in 2020. This scenario would save the equivalent of 9 billion metric tons of carbon dioxide emitted to the atmosphere. If these banks were destroyed today, it would also help the ozone layer recover six years faster.

“We lost an opportunity in 2000, which is really sad,” Solomon says. “So let’s not miss it again.”

This research was supported, in part, by VoLo foundation. Solomon is also supported by a Lee and Geraldine Martin Professorship.

Bacterial enzyme could become a new target for antibiotics

by Anne Trafton | MIT News Office |

MIT and Harvard University chemists have discovered the structure of an unusual bacterial enzyme that can break down an amino acid found in collagen, which is the most abundant protein in the human body.

The enzyme, known as hydroxy-L-proline dehydratase (HypD), has been found in a few hundred species of bacteria that live in the human gut, including Clostridioides difficile. The enzyme performs a novel chemical reaction that dismantles hydroxy-L-proline, the molecule that gives collagen its tough, triple-helix structure.

Now that researchers know the structure of the enzyme, they can try to develop drugs that inhibit it. Such a drug could be useful in treating C. difficile infections, which are resistant to many existing antibiotics.

“This is very exciting because this enzyme doesn’t exist in humans, so it could be a potential target,” says Catherine Drennan, an MIT professor of chemistry and biology and a Howard Hughes Medical Institute Investigator. “If you could potentially inhibit that enzyme, that could be a unique antibiotic.”

Drennan and Emily Balskus, a professor of chemistry and chemical biology at Harvard University, are the senior authors of the study, which appears today in the journal eLife. MIT graduate student Lindsey Backman and former Harvard graduate student Yolanda Huang are the lead authors of the study.

A difficult reaction

The HypD enzyme is part of a large family of proteins called glycyl radical enzymes. These enzymes work in an unusual way, by converting a molecule of glycine, the simplest amino acid, into a radical — a molecule that has one unpaired electron. Because radicals are very unstable and reactive, they can be used as cofactors, which are molecules that help drive a chemical reaction that would otherwise be difficult to perform.

These enzymes work best in environments that don’t have a lot of oxygen, such as the human gut. The Human Microbiome Project, which has sequenced thousands of bacterial genes from species found in the human gut, has yielded several different types of glycyl radical enzymes, including HypD.

In a previous study, Balskus and researchers at the Broad Institute of MIT and Harvard discovered that HypD can break down hydroxy-L-proline into a precursor of proline, one of the essential amino acids, by removing the hydroxy modification as a molecule of water. These bacteria can ultimately use proline to generate ATP, a molecule that cells use to store energy, through a process called amino acid fermentation.

HypD has been found in about 360 species of bacteria that live in the human gut, and in this study, Drennan and her colleagues used X-ray crystallography to analyze the structure of the version of HypD found in C. difficile. In 2011, this species of bacteria was responsible for about half a million infections and 29,000 deaths in the United States.

The researchers were able to determine which region of the protein forms the enzyme’s “active site,” which is where the reaction occurs. Once hydroxy-L-proline binds to the active site, a nearby glycine molecule forms a glycyl radical that can pass that radical onto the hydroxy-L-proline, leading to the elimination of the hydroxy group.

Removing a hydroxy group is usually a difficult reaction that requires a large input of energy.

“By transferring a radical to hydroxy-L-proline, it lowers the energetic barrier and allows for that reaction to occur pretty rapidly,” Backman says. “There’s no other known enzyme that can perform this kind of chemistry.”

New drug target

It appears that once bacteria perform this reaction, they divert proline into their own metabolic pathways to help them grow. Therefore, blocking this enzyme could slow down the bacteria’s growth. This could be an advantage in controlling C. difficile, which often exists in small numbers in the human gut but can cause illness if the population becomes too large. This sometimes occurs after antibiotic treatment that wipes out other species and allows C. difficile to proliferate.

“C. difficile can be in your gut without causing problems — it’s when you have too much of it compared to other bacteria that it becomes more problematic,” Drennan says. “So, the idea is that by targeting this enzyme, you could limit the resources of C. difficile, without necessarily killing it.”

The researchers now hope to begin designing drug candidates that could inhibit HypD, by targeting the elements of the protein structure that appear to be the most important in carrying out its function.

The research was funded by the National Institutes of Health, a National Science Foundation Graduate Research Fellowship, Harvard University, a Packard Fellowship for Science and Engineering, the NSERC Postgraduate Scholarship-Doctoral Program, an Arnold O. Beckman Postdoctoral Fellowship, a Dow Fellowship, and a Gilliam Fellowship from the Howard Hughes Medical Institute.