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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.

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

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

Peter Dizikes | MIT News Office
June 7, 2019

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Drug makes tumors more susceptible to chemo

Compound that knocks out a DNA repair pathway enhances cisplatin treatment and helps prevent drug-resistance.

Anne Trafton | MIT News Office
June 6, 2019

Many chemotherapy drugs kill cancer cells by severely damaging their DNA. However, some tumors can withstand this damage by relying on a DNA repair pathway that not only allows them to survive, but also introduces mutations that helps cells become resistant to future treatment.

Researchers at MIT and Duke University have now discovered a potential drug compound that can block this repair pathway. “This compound increased cell killing with cisplatin and prevented mutagenesis, which is was what we expected from blocking this pathway,” says Graham Walker, the American Cancer Society Research Professor of Biology at MIT, a Howard Hughes Medical Institute Professor, and one of the senior authors of the study.

When they treated mice with this compound along with cisplatin, a DNA-damaging drug, tumors shrank much more than those treated with cisplatin alone. Tumors treated with this combination would be expected not to develop new mutations that could make them drug-resistant.

Cisplatin, which is used as the first treatment option for at least a dozen types of cancer, often successfully destroys tumors, but they frequently grow back following treatment. Drugs that target the mutagenic DNA repair pathway that contributes to this recurrence could help to improve the long-term effectiveness of not only cisplatin but also other chemotherapy drugs that damage DNA, the researchers say.

“We’re trying to make the therapy work better, and we also want to make the tumor recurrently sensitive to therapy upon repeated doses,” says Michael Hemann, an associate professor of biology, a member of MIT’s Koch Institute for Integrative Cancer Research, and a senior author of the study.

Pei Zhou, a professor of biochemistry at Duke University, and Jiyong Hong, a professor of chemistry at Duke, are also senior authors of the paper, which appears in the June 6 issue of Cell. The lead authors of the paper are former Duke graduate student Jessica Wojtaszek, MIT postdoc Nimrat Chatterjee, and Duke research assistant Javaria Najeeb.

Overcoming resistance

Healthy cells have several repair pathways that can accurately remove DNA damage from cells. As cells become cancerous, they sometimes lose one of these accurate DNA repair systems, so they rely heavily on an alternative coping strategy known as translesion synthesis (TLS).

This process, which Walker has been studying in a variety of organisms for many years, relies on specialized TLS DNA polymerases. Unlike the normal DNA polymerases used to replicate DNA, these TLS DNA polymerases can essentially copy over damaged DNA, but the copying they perform is not very accurate. This enables cancer cells to survive treatment with a DNA-damaging agent such as cisplatin, and it leads them to acquire many additional mutations that can make them resistant to further treatment.

“Because these TLS DNA polymerases are really error-prone, they are accountable for nearly all of the mutation that is induced by drugs like cisplatin,” Hemann says. “It’s very well-established that with these frontline chemotherapies that we use, if they don’t cure you, they make you worse.”

One of the key TLS DNA polymerases required for translesion synthesis is Rev1, and its primary function is to recruit a second TLS DNA polymerase that consists of a complex of the Rev3 and Rev7 proteins. Walker and Hemann have been searching for ways to disrupt this interaction, in hopes of derailing the repair process.

In a pair of studies published in 2010, the researchers showed that if they used RNA interference to reduce the expression of Rev1, cisplatin treatment became much more effective against lymphoma and lung cancer in mice. While some of the tumors grew back, the new tumors were not resistant to cisplatin and could be killed again with a new round of treatment.

After showing that interfering with translesion synthesis could be beneficial, the researchers set out to find a small-molecule drug that could have the same effect. Led by Zhou, the researchers performed a screen of about 10,000 potential drug compounds and identified one that binds tightly to Rev1, preventing it from interacting with Rev3/Rev7 complex.

The interaction of Rev1 with the Rev7 component of the second TLS DNA polymerase had been considered “undruggable” because it occurs in a very shallow pocket of Rev1, with few features that would be easy for a drug to latch onto. However, to the researchers’ surprise, they found a molecule that actually binds to two molecules of Rev1, one at each end, and brings them together to form a complex called a dimer. This dimerized form of Rev1 cannot bind to the Rev3/Rev7 TLS DNA polymerase, so translesion synthesis cannot occur.

Chatterjee tested the compound along with cisplatin in several types of human cancer cells and found that the combination killed many more cells than cisplatin on its own. And, the cells that survived had a greatly reduced ability to generate new mutations.

“Because this novel translesion synthesis inhibitor targets the mutagenic ability of cancer cells to resist therapy, it can potentially address the issue of cancer relapse, where cancers continue to evolve from new mutations and together pose a major challenge in cancer treatment,” Chatterjee says.

A powerful combination

Chatterjee then tested the drug combination in mice with human melanoma tumors and found that the tumors shrank much more than tumors treated with cisplatin alone. They now hope that their findings will lead to further research on compounds that could act as translesion synthesis inhibitors to enhance the killing effects of existing chemotherapy drugs.

Zhou’s lab at Duke is working on developing variants of the compound that could be developed for possible testing in human patients. Meanwhile, Walker and Hemann are further investigating how the drug compound works, which they believe could help to determine the best way to use it.

“That’s a future major objective, to identify in which context this combination therapy is going to work particularly well,” Hemann says. “We would hope that our understanding of how these are working and when they’re working will coincide with the clinical development of these compounds, so by the time they’re used, we’ll understand which patients they should be given to.”

The research was funded, in part, by an Outstanding Investigator Award from the National Institute of Environmental Health Sciences to Walker, and by grants from the National Cancer Institute, the Stewart Trust, and the Center for Precision Cancer Medicine at MIT.

In search of nature’s winning recipe

Graduate student Darren Parker aims to understand the ratio of ingredients that constitutes the optimal cell.

Raleigh McElvery
May 31, 2019

Fifth-year graduate student Darren Parker is as much a baker as he is a biologist — at least metaphorically speaking. He’s on a mission to understand the ratio of ingredients required to concoct nature’s winning recipe for the optimal cell. Researchers have a solid understanding of which components are essential for cellular function, but they have yet to determine whether it’s critical for cells to generate exactly the right amount of protein.

“In that way, my graduate work is actually pretty simple,” Parker says. “I just want to know if changing the amounts of a specific ingredient has an effect on the overall product.”

The oldest of four brothers, Parker grew up in a suburb just outside of Chicago. When he enrolled in the University of Illinois Urbana-Champaign for his undergraduate studies in 2009, he was considering a major in environmental science. “My high school biology classes were mostly rote memorization,” he explains, “so the molecular aspects just didn’t resonate with me. I was more interested in studying life on a larger scale.”

After his first year, he entered the Integrated Biology program, which essentially “encompassed all biology that wasn’t molecular biology.” He was still required to take an introductory molecular biology course, though, as part of the major. But this time around, something clicked.

He remembers performing his first genetic knockdown experiment, decreasing the level of dopamine receptors in roundworms and witnessing the behavioral ramifications in real time. “I finally had a handle on the molecular concepts enough to really get what was going on,” he says.

He attributed his newfound appreciation for the basic mechanisms underlying life to his fortified chemistry skills. At the beginning of his third year, he officially declared a biochemistry major, and joined a lab in the Department of Chemistry studying nucleic acid enzymes.

Parker’s job was to sift through trillions of short DNA strands, selecting only those that could act like enzymes and cut RNA. He would then home in on the nucleotide sequences within those strands that were best suited to carry out the reaction. After a year-and-a-half, he’d successfully identified a few DNA sequences that could cut RNA molecules with a distinct chemistry. After this point he was excited to try “studying life” as opposed to synthetic reactions.

Mid-way through his fourth year, he joined a biology lab in the College of Medicine probing alternative splicing in liver and heart development. It was a new group with only a few members, and Parker had more experience as an undergraduate than some of the first-year graduate students, so he hit the ground running. His last-minute switch to biochemistry meant he had five years of studies instead of the usual four — totaling six full semesters (and several summers) in lab.

After identifying a key splicing protein required for the liver to fully mature in mice and humans, Parker became even more fascinated by molecular biology and determined to pursue a career in science with bigger picture applications.

At the urging of his advisor, Parker sent in his graduate school applications. He was primarily interested in microbiology and infectious disease research — although he had no prior experience working in bacteria, only a longstanding interest in the intersection of science and society. He ultimately chose MIT Biology because of the breadth of labs. He could join a microbiology lab, or pursue an entirely different path, all within the same department. Gene-Wei Li’s lab seemed like “the perfect mix.”

“Gene was asking questions in molecular biology from the unique perspective of a physicist, looking at biological questions in a way I had never even considered before,” he says. “Gene had also just joined the department and wasn’t tied to a specific field or model organism yet, so I had the chance to build my own projects from the bottom up; I wasn’t just slotting in somewhere.”

Best of all, the Li lab was all about drilling down into to the mechanics of protein production in order to understand the cell as a whole — the bigger picture perspective that Parker was longing for.

Parker began by exploring ways to modify high-throughput RNA sequencing. He aimed to make this popular method cheaper and more scalable, in hopes of knocking out many individual genes in E. coli to test the genome-wide effects. He then pivoted his project and applied his new technique to study the effects of reducing essential genes in B. subtilis, another model bacterium. The family of enzymes that was the most interesting to him from these experiments were the aminoacyl-tRNA synthetases.

tRNAs, or transfer RNAs, carry amino acids to the ribosome so that the cell can produce proteins. This process requires the help of enzymes — tRNA synthetases — to “charge” the tRNAs with an amino acid. Only then can the ribosome transfer the amino acid from the tRNAs to the growing chain of amino acids that eventually forms the protein. Like an inquisitive baker, Parker wanted to know what would happen if he added more or less tRNA synthetase to the recipe of a bacterial cell.

His results would make Goldilocks proud. Over the past few years, he’s shown that too much or too little tRNA synthetase prevents the cell from growing at a normal rate. The amount must be just right.

“It turns out that what’s most important to the cell is maintaining the ratios of those very conserved ingredients,” Parker says. “The cell will actively use less of those ingredients if the synthetase is limiting, and this leads to a much slower growing cell. Adding too much tRNA synthetase is just a waste because the cell already has as much as it needs to sustain translation.”

This same family of tRNA synthetase proteins, he adds, are also implicated in some neurological diseases in humans, which gives him further impetus to study them.

At this point, Parker has taste-tested his fair share of biological areas, and he’s found his niche. “It was a long process,” he says. “That was probably best, though, because it gave me more time to explore.”

Once he graduates, he plans to go into industry, perhaps continuing to tweak the list of ingredients in order to engineer cells to do new things.

“The next time you’re in the kitchen and you want to add more or less of your favorite ingredient,” he urges, “just think about how the cell might feel if you did so with your favorite gene.”

Photo credit: Raleigh McElvery
Posted 5.30.19
Drug-resistant cancer cells create own Achilles heel
Nicole Giese Rura | Whitehead Institute
May 28, 2019

Cambridge, MA — The cells of most patients’ cancers are resistant to a class of drugs, called proteasome inhibitors, that should kill them. When studied in the lab, these drugs are highly effective, yet hundreds of clinical trials testing proteasome inhibitors have failed. Now scientists may have solved the mystery of these cells’ surprising hardiness. The key: Resistant cancer cells have shifted how and where they generate their energy. Using this new insight, researchers have identified a drug that resensitizes cancer cells to proteasome inhibitors and pinpointed a gene that is crucial for that susceptibility.

As cancer cells develop, they accrue multiple genetic alterations that allow the cells to quickly reproduce, spread and survive in distant parts of the body, and recruit surrounding cells and tissues to support the growing tumor. To perform these functions, cancer cells must produce high volumes of the proteins that support these processes. The increased protein production and numerous mutated proteins of cancer cells make them particularly dependent on the proteasome, which is the cell’s protein degradation machine. These huge protein complexes act as recycling machines, gobbling up unwanted proteins and dicing them into their amino acid building blocks, which can be reused for the production of other proteins.

Previously, researchers exploited cancer cells’ increased dependency on their proteasomes to develop anti-cancer therapies that inhibit the proteasomes’ function. Several distinct proteasome inhibitors have been developed, and when used in the lab, these proteasome inhibitor drugs are indeed highly effective at eradicating tumor cells. However, when administered to animal models or patients with cancer, such as multiple myeloma, proteasome inhibitors have limited efficacy and even initially vulnerable cancer cells quickly develop resistance to them. How do cancer cells so adroitly sidestep drugs that should kill them?

Exploring the gene expression of thousands of tumors and hundreds of cancer cell lines, Peter Tsvetkov, a former postdoc in the lab of late Whitehead Institute Member Susan Lindquist, has determined that the answer may lie with how and where the cells produce their energy. According to his analysis of the active genes and metabolism products generated in proteasome inhibitor-resistant cancer cells and tumors, Tsvetkov, who is currently a postdoc in the lab of Broad Institute Founding Core Member, director of the Cancer Program, and oncologist at the Dana-Farber Cancer Institute Todd Golub, concluded that such cells have shifted how they produce energy — away from breaking down the sugar glucose toward a dependency on processes within the mitochondria, the “powerhouse” part in the cell. In fact, when Tsvetkov pushed cancer cells’ metabolism to depend on the mitochondria, that change alone was sufficient to make cancer cells immune to proteasome inhibitors. Tsvetkov’s findings are described online this week in the journal Nature Chemical Biology.

In order to understand how a metabolic shift could link to proteasome inhibitor resistance, Tsvetkov screened proteasome inhibitor-resistant breast cancer cells with thousands of small molecules to identify the ones that hamper the cells’ growth or even kill the cells. One stood out in the screen: elesclomol, a small molecule that that researchers had previously evaluated as an anti-cancer agent in phase 3 clinical trials without knowing with what the drug interacts in cancer cells. To identify how elesclomol preferentially targets the proteasome inhibitor resistant cells, Tsvetkov did genome-wide CRISPR-Cas9 screens to find out which genes elesclomol requires to incapacitate resistant cancer cells. Only the gene FDX1, which encodes an enzyme in the mitochondria, came to the fore.

In collaboration with John Markley from the Department of Biochemistry at the University of Wisconsin-Madison, Tsvetkov used biochemical and biophysical systems to demonstrate that elesclomol directly binds to the mitochondrial enzyme FDX1 and impedes its natural function. In the presence of copper, elesclomol can also be altered by the FDX1 enzyme, which increases the drug’s anti-cancer toxicity. These findings led the researchers to determine that as cancer cells become overly reliant on their mitochondrial metabolism, they ramp up the FDX1 protein’s activity. Also, when the FDX1 protein interacts with copper-bound elesclomol, the protein enhances the drug’s copper-dependent toxicity. Thus, copper appears to play an essential role — when Tsvetkov removed copper, elesclomol was no longer effective.

Having established that a metabolic shift and resistance to proteasome inhibitors are linked, Tsvetkov is now interested in understanding how a change in metabolism allows cancer cells to adapt to other anti-cancer therapies and how copper-binding molecules such as elesclomol can be developed as effective anticancer agents.

This work was supported by the National Institutes of Health (NIH grant P41GM103399), University of Wisconsin-Madison Biochemistry Department, EMBO (Fellowship ALTF 739-2011), the Charles A. King Trust Postdoctoral Fellowship Program, and Howard Hughes Medical Institute (HHMI).

Written by Nicole Giese Rura

***

Susan Lindquist’s primary affiliation was with Whitehead Institute for Biomedical Research, where her laboratory was located and all her research was conducted. She was also a Howard Hughes Medical Institute investigator and a professor of biology at Massachusetts Institute of Technology.

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Citation:

“Mitochondrial metabolism promotes adaptation to proteotoxic stress”

Nature Chemical Biology, online May 27, 2019, DOI: 10.1038/s41589-019-0291-9

Peter Tsvetkov, Alexandre Detappe, Kai Cai, Heather R. Keys, Zarina Brune, Weiwen Ying, Prathapan Thiru, Mairead Reidy, Guillaume Kugener, Jordan Rossen, Mustafa Kocak, Nora Kory, Aviad Tsherniak, Sandro Santagata, Luke Whitesell, Irene M. Ghobrial, John L. Markley , Susan Lindquist, and Todd R. Golub.

Merging machine learning and the life sciences

Through computing, senior and Marshall Scholar Anna Sappington seeks answers to biological questions.

Gina Vitale | MIT News correspondent
May 22, 2019

Anna Sappington’s first moments of fame came when she was a young girl, living in a home so full of pets she calls it a zoo. She grew up on the Chesapeake Bay, surrounded by a lush environment teeming with wildlife, and her father was an environmental scientist. One day, when she found a frog in a skip laurel bush, she named him Skippy and built him a habitat. Later on, she and Skippy appeared on the Animal Planet TV special “What’s to Love About Weird Pets?”

Now a senior majoring in computer science and molecular biology, Sappington has been chosen for another prestigious honor: She’s one of five MIT students selected this year to be Marshall Scholars. She chose to study computer science because she wanted to have a role in pulling apart and understanding data, and she chose biology because of her lifelong fascination with nature, cells, genetic inheritance — and, of course, Skippy.

“My interests have grown and expanded in different ways, but they’re still kind of rooted in this natural dual passion that I have for both of these fields,” she says.

An eye for genomic research

When Sappington came to MIT, it was right after her first summer internship at the National Institutes of Health, where she examined genes that could be related to increased risk of cardiovascular disease. It was her first experience working with data on human patients, and it inspired her to continue working in medical research.

When she was a first-year student, Sappington spent the year at the Koch Institute, working with a graduate student to determine how liver cells respond to infection by hepatitis B virus. The summer after that, she went back to the NIH to contribute to a different project. This one still involved human health data, but it was more focused on building a computational tool. Sappington helped develop an algorithm that would quickly calculate how similar two genomes or proteins were to each other, a technology that could be used to screen for different bacteria strains in real-time.

“I wanted to kind of get my feet wet in all the different kinds of ways computer science and biology and human health can interact,” she says.

Since her return from the NIH at the beginning of her sophomore year, Sappington has been working in Aviv Regev’s lab in the Broad Institute of MIT and Harvard. She says Regev, a professor in the MIT Department of Biology, has been nothing short of an inspiration.

“She herself is just an incredible role model for the world of computational biology,” Sappington says.

The main initiative of Regev’s lab is an initiative called the Human Cell Atlas, which was recently named Science’s Breakthrough of the Year. It’s like a layer on top of the Human Genome Project, she says. They are working to identify and catalogue the different types of cells, such as skin cells and lung cells. The need for the cataloging comes from the fact that even though these cells have the exact same DNA genome, they have different specialized functions, and therefore can’t be identified by genome alone.

“Within a given tissue, like your skin tissue, cells are actually like a whole collage of different molecular profiles in how they express their genes,” she says. “So while the underlying genome is the same, there’s all sorts of other factors that make your cells express those genes — which turn into proteins — differently.”

Because the human body contains so many different types of cells, teams of researchers work on different pieces. Sappington works on data analysis as part of a team that is classifying retinal cells. It’s a unique challenge, she says, because the retina has more than 40 different types of cells, all of which respond to disease in different ways. While still chipping away at human retinal cell types, her team contributed to a recently published retinal cell atlas for the macaque monkey. For her undergraduate research career, Sappington was named a 2018-2019 Goldwater Scholar.

Dancing, speaking, leading

Before coming to MIT, Sappington had never been involved in dancing. But after she saw a showcase by the Asian Dance Team her first year, she decided to give it a try. After a few semesters dancing with ADT, Sappington also joined MIT DanceTroupe, where she found the culture to be creative, supportive, and incredibly fun.

“[I] just really fell in love with the community, and the general community of dancers at MIT,” she says.

Dance wasn’t the only aspect of the arts and humanities at MIT that she loved. She is also a part of the Burchard Scholars program, which allows students with a particular interest in the humanities to explore that topic. After she took a linguistics class with Professor David Pesetsky her first year, that field became her official humanities concentration. She ended up taking the next level of that class, which centered around syntax, and then she and five other students later created their own special subject class on linguistics.

“Essentially linguistics is the study of how language as a whole works, and the underlying rules that govern it,” she says. “It interfaces with brain and cognitive science, and even computer science, and how language is learned and acquired.”

Outside of class, Sappington has also been involved with TechX, a student-run organization that is responsible for many of MIT’s tech-related events, including HackMIT. Events also include the makeathon MakeMIT, the spring career fair and technology demo xFair, and high school mentoring program THINK. After serving on and running an event committee, Sappington served as the overall director for TechX in her junior year. While she’s no longer in charge, she’s still grateful to be part of the team.

“The whole thing was like one big family. … Each committee has its own intercommittee pride with the event that they run, but then everyone also has to rely on each other,” she says.

Machine learning across the pond

After graduation, Sappington will be heading off to University College London to earn her MS in machine learning. Her goal is to explore machine learning in a context that isn’t biology, so that she can learn new and different approaches that she might later be able to apply to biological challenges. The second year of her Marshall Scholarship will be spent at Cambridge University, where she will do a full year of research, likely involving machine learning applied to health care or other biological questions.

Her ultimate goal is to find new and better ways to use machine learning and technology to improve the health care system. To that end, she aims to get her MD/PhD after the next two years in England. After volunteering at the Massachusetts General Hospital and shadowing doctors in the Boston area, Sappington is pretty certain she wants a career where she can interact with patients while still being involved with computer science and biology. She’s excited to move forward with the next chapter of her life — but when it comes to leaving MIT, she’s got understandably mixed feelings.

“I think no matter where I would be going after graduation, it’s bittersweet to leave the incredible community that is the MIT community,” she says.