Author: mantulin

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.

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.

Eleven MIT students accept 2019 Fulbright Fellowships

Grantees will spend the 2019-2020 academic year pursuing research and teaching opportunities abroad.

Julia Mongo | Office of Distinguished Fellowships
May 17, 2019

Eleven MIT graduating seniors and current graduate students have been named winners in the 2019-2020 Fulbright U.S. Student Fellowship Program. In addition to the 11 students accepting their awards, three applicants from MIT were selected as finalists but decided to decline their grants.

MIT’s newest Fulbright Students will engage in independent research and English teaching assignments in Brazil, the Netherlands, Spain, Russia, Taiwan, and Senegal.

Sponsored by the U.S. Department of State’s Bureau of Educational and Cultural Affairs, the mission of Fulbright is to promote cultural exchange, increase mutual understanding, and build lasting relationships among people of the world. The Fulbright U.S. Student Program offers grants in over 140 countries.

The MIT students were supported in the application process by the Presidential Committee on Distinguished Fellowships, chaired by professors Rebecca Saxe and Will Broadhead, and by MIT’s Distinguished Fellowships Office within Career Advising and Professional Development. The MIT winners are:

Annamarie “Anna” Bair ’18 earned a bachelor of science in computer science and engineering in June 2018 and will receive her master of engineering degree in computer science later this year. In Barcelona, Spain, Bair will engage in complex systems research.

Abigail “Abby” Bertics will graduate in June with a bachelor of science in electrical engineering and computer science. Her research in Yekaterinburg, Russia, will focus on natural language processing methods for understanding English second language acquisition by Russian speakers.

Hope Chen is a senior graduating with a bachelor of science in mechanical engineering. She will be going to Taiwan as an English Teaching Assistant in primary school classrooms. After completing her Fulbright program and returning to the U.S., Chen will matriculate in medical school.

Alexis D’Alessandro will graduate this spring with a bachelor of science in mechanical engineering. For her research in Aracaju, Brazil, she will develop an educational program and chemical sensing tool to promote water safety awareness among children.

Sarah DiIorio will earn her bachelor of science in biological engineering in June. She is headed to Eindhoven, the Netherlands, to conduct medical research related to cartilage regeneration for osteoarthritis.

Katie Fisher is a senior in MIT’s Scheller Teaching Education Program graduating with a bachelor of science in urban studies and planning with a concentration in education. As an English teaching assistant in the Netherlands, Fisher will work with students at a vocational college in Amsterdam.

Miranda McClellan ’18 received a bachelor of science in computer science and engineering in June 2018 and will earn her master of engineering degree in computer science this spring. McClellan will research automated scaling of 5G computer network resources in Barcelona, Spain.

Samira Okudo will graduate in June with a joint bachelor of science in computer science and comparative media studies. As an English teaching assistant in Brazil, she will work with university students training to be English-language instructors.

James Pelletier is a PhD candidate in physics. For his Fulbright research in Madrid, Spain, he will develop biophysical models to investigate how plants process information for cellular resource allocation and agricultural efficiency.

Jonars Spielberg is a third-year doctoral student in the Department of Urban Studies and Planning’s international development program. In Senegal, he will examine how the personal interactions of bureaucrats and farmers shape agricultural policy implementation in the country’s main irrigated regions.

Catherine Wu will graduate in June with a bachelor of science in biology. She will be working with university students in Brazil as a Fulbright English Teaching Assistant.

MIT students interested in applying to the Fulbright U.S. Student Program should contact Julia Mongo in Distinguished Fellowships.

Measuring chromosome imbalance could clarify cancer prognosis

A study of prostate cancer finds “aneuploid” tumors are more likely to be lethal than tumors with normal chromosome numbers.

Anne Trafton | MIT News Office
May 13, 2019

Most human cells have 23 pairs of chromosomes. Any deviation from this number can be fatal for cells, and several genetic disorders, such as Down syndrome, are caused by abnormal numbers of chromosomes.

For decades, biologists have also known that cancer cells often have too few or too many copies of some chromosomes, a state known as aneuploidy. In a new study of prostate cancer, researchers have found that higher levels of aneuploidy lead to much greater lethality risk among patients.

The findings suggest a possible way to more accurately predict patients’ prognosis, and could be used to alert doctors which patients might need to be treated more aggressively, says Angelika Amon, the Kathleen and Curtis Marble Professor in Cancer Research in the Department of Biology and a member of the Koch Institute for Integrative Cancer Research.

“To me, the exciting opportunity here is the ability to inform treatment, because prostate cancer is such a prevalent cancer,” says Amon, who co-led this study with Lorelei Mucci, an associate professor of epidemiology at the Harvard T.H. Chan School of Public Health.

Konrad Stopsack, a research associate at Memorial Sloan Kettering Cancer Center, is the lead author of the paper, which appears in the Proceedings of the National Academy of Sciences the week of May 13. Charles Whittaker, a Koch Institute research scientist; Travis Gerke, a member of the Moffitt Cancer Center; Massimo Loda, chair of pathology and laboratory medicine at New York Presbyterian/Weill Cornell Medicine; and Philip Kantoff, chair of medicine at Memorial Sloan Kettering; are also authors of the study.

Better predictions

Aneuploidy occurs when cells make errors sorting their chromosomes during cell division. When aneuploidy occurs in embryonic cells, it is almost always fatal to the organism. For human embryos, extra copies of any chromosome are lethal, with the exceptions of chromosome 21, which produces Down syndrome; chromosomes 13 and 18, which lead to developmental disorders known as Patau and Edwards syndromes; and the X and Y sex chromosomes. Extra copies of the sex chromosomes can cause various disorders but are not usually lethal.

Most cancers also show very high prevalence of aneuploidy, which poses a paradox: Why does aneuploidy impair normal cells’ ability to survive, while aneuploid tumor cells are able to grow uncontrollably? There is evidence that aneuploidy makes cancer cells more aggressive, but it has been difficult to definitively demonstrate that link because in most types of cancer nearly all tumors are aneuploid, making it difficult to perform comparisons.

Prostate cancer is an ideal model to explore the link between aneuploidy and cancer aggressiveness, Amon says, because, unlike most other solid tumors, many prostate cancers (25 percent) are not aneuploid or have only a few altered chromosomes. This allows researchers to more easily assess the impact of aneuploidy on cancer progression.

What made the study possible was a collection of prostate tumor samples from the Health Professionals Follow-up Study and Physicians’ Health Study, run by the Harvard T.H. Chan School of Public Health over the course of more than 30 years. The researchers had genetic sequencing information for these samples, as well as data on whether and when their prostate cancer had spread to other organs and whether they had died from the disease.

Led by Stopsack, the researchers came up with a way to calculate the degree of aneuploidy of each sample, by comparing the genetic sequences of those samples with aneuploidy data from prostate genomes in The Cancer Genome Atlas. They could then correlate aneuploidy with patient outcomes, and they found that patients with a higher degree of aneuploidy were five times more likely to die from the disease. This was true even after accounting for differences in Gleason score, a measure of how much the patient’s cells resemble cancer cells or normal cells under a microscope, which is currently used by doctors to determine severity of disease.

The findings suggest that measuring aneuploidy could offer additional information for doctors who are deciding how to treat patients with prostate cancer, Amon says.

“Prostate cancer is terribly overdiagnosed and terribly overtreated,” she says. “So many people have radical prostatectomies, which has significant impact on people’s lives. On the other hand, thousands of men die from prostate cancer every year. Assessing aneuploidy could be an additional way of helping to inform risk stratification and treatment, especially among people who have tumors with high Gleason scores and are therefore at higher risk of dying from their cancer.”

“When you’re looking for prognostic factors, you want to find something that goes beyond known factors like Gleason score and PSA [prostate-specific antigen],” says Bruce Trock, a professor of urology at Johns Hopkins School of Medicine, who was not involved in the research. “If this kind of test could be done right after a prostatectomy, it could give physicians information to help them decide what might be the best treatment course.”

Amon is now working with researchers from the Harvard T.H. Chan School of Public Health to explore whether aneuploidy can be reliably measured from small biopsy samples.

Aneuploidy and cancer aggressiveness

The researchers found that the chromosomes that are most commonly aneuploid in prostate tumors are chromosomes 7 and 8. They are now trying to identify specific genes located on those chromosomes that might help cancer cells to survive and spread, and they are also studying why some prostate cancers have higher levels of aneuploidy than others.

“This research highlights the strengths of interdisciplinary, team science approaches to tackle outstanding questions in prostate cancer,” Mucci says. “We plan to translate these findings clinically in prostate biopsy specimens and experimentally to understand why aneuploidy occurs in prostate tumors.”

Another type of cancer where most patients have low levels of aneuploidy is thyroid cancer, so Amon now hopes to study whether thyroid cancer patients with higher levels of aneuploidy also have higher death rates.

“A very small proportion of thyroid tumors is highly aggressive and lethal, and I’m starting to wonder whether those are the ones that have some aneuploidy,” she says.

The research was funded by the Koch Institute Dana Farber/Harvard Cancer Center Bridge Project and by the National Institutes of Health, including the Koch Institute Support (core) Grant.

Tissue chip headed to International Space Station for osteoarthritis study

Successfully launched project aims to understand why some injuries result in develop post-traumatic osteoarthritis while others heal and recover.

Daniel J. Darling | Department of Biological Engineering
May 7, 2019

On May 4, a National Center for Advancing Translational Sciences (NCATS)-supported tissue-chip system with direct clinical applications to health conditions here on Earth was launched on the SpaceX CRS 17/Falcon 9 rocket.

Hundreds of millions of people worldwide suffer from osteoarthritis (OA), and there are currently no disease-modifying drugs that can halt or reverse the progression of OA — only painkillers for short-term symptomatic relief. Millions of healthy young to middle-aged individuals develop post-traumatic osteoarthritis (PTOA) as a result of a traumatic joint injury, like a tear of the anterior cruciate ligament or meniscus, especially in young women playing sports. Exercise-related injuries are also said to be frequent sources of joint injury for crew members living aboard the International Space Station (ISS), and pre-existing joint injuries may also affect astronaut performance in space. These conditions are compounded and worsened by exposure of crew members to weightlessness and radiation on the ISS.

After a traumatic joint injury, there is an immediate upregulation of inflammatory proteins called cytokines in the joint synovial fluid, proteins which are secreted mainly by cells in the joint’s synovial lining. When mechanical trauma to cartilage caused by the initial injury is accompanied by cytokine penetration into cartilage, degradation of cartilage and subchondral bone over weeks and months often progresses to full-blown, painful PTOA in 10-15 years.

To study PTOA on Earth and in space, investigators at MIT have developed a cartilage-bone-synovium micro-physiological system in which primary human cartilage, bone, and synovium tissues (obtained from donor banks) are co-cultured for several weeks. During culture, investigators can monitor intracellular and extracellular biomarkers of disease using quantitative experimental and computational metabolomics and proteomics analyses, along with detection of disease-specific fragments of tissue matrix molecules. In addition, this co-culture system allows investigators to test the effects of potential disease-modifying drugs to prevent cartilage and bone loss on Earth and in space.

Experiments aboard the ISS utilize a Multi-purpose Variable-G Platform, made by Techshot Inc., to study the effects of microgravity and ionizing radiations on a knee tissue chip prepared using cartilage-bone-synovium tissues secured on a biocompatible material. The platform enables automated nutrient media transfer and collection for test conditions with and without disease-modifying drugs, including tests using a one-gravity control system.

These investigations on Earth and in the ISS have the potential to lead to the discovery of treatments and treatment regimens that, if administered immediately after a joint injury, could halt the progression of OA disease before it becomes irreversible. The goal is to treat the root cause of PTOA and prevent permanent joint damage, rather than mask the symptoms with painkillers later in life, as is currently done. These studies are funded by the NIH National Center for Advancing Translational Sciences and the ISS-National Lab.

A new approach to targeting tumors and tracking their spread

Researchers develop nanosized antibodies that home in on the meshwork of proteins surrounding cancer cells.

Helen Knight | MIT News correspondent
May 6, 2019

The spread of malignant cells from an original tumor to other parts of the body, known as metastasis, is the main cause of cancer deaths worldwide.

Early detection of tumors and metastases could significantly improve cancer survival rates. However, predicting exactly when cancer cells will break away from the original tumor, and where in the body they will form new lesions, is extremely challenging.

There is therefore an urgent need to develop new methods to image, diagnose, and treat tumors, particularly early lesions and metastases.

In a paper published today in the Proceedings of the National Academy of Sciences, researchers at the Koch Institute for Integrative Cancer Research at MIT describe a new approach to targeting tumors and metastases.

Previous attempts to focus on the tumor cells themselves have typically proven unsuccessful, as the tendency of cancerous cells to mutate makes them unreliable targets.

Instead, the researchers decided to target structures surrounding the cells known as the extracellular matrix (ECM), according to Richard Hynes, the Daniel K. Ludwig Professor for Cancer Research at MIT. The research team also included lead author Noor Jailkhani, a postdoc in the Hynes Lab at the Koch Institute for Integrative Cancer Research.

The extracellular matrix, a meshwork of proteins surrounding both normal and cancer cells, is an important part of the microenvironment of tumor cells. By providing signals for their growth and survival, the matrix plays a significant role in tumor growth and progression.

When the researchers studied this microenvironment, they found certain proteins that are abundant in regions surrounding tumors and other disease sites, but absent from healthy tissues.

What’s more, unlike the tumor cells themselves, these ECM proteins do not mutate as the cancer progresses, Hynes says. “Targeting the ECM offers a better way to attack metastases than trying to prevent the tumor cells themselves from spreading in the first place, because they have usually already done that by the time the patient comes into the clinic,” Hynes says.

The researchers began developing a library of immune reagents designed to specifically target these ECM proteins, based on relatively tiny antibodies, or “nanobodies,” derived from alpacas. The idea was that if these nanobodies could be deployed in a cancer patient, they could potentially be imaged to reveal tumor cells’ locations, or even deliver payloads of drugs.

The researchers used nanobodies from alpacas because they are smaller than conventional antibodies. Specifically, unlike the antibodies produced by the immune systems of humans and other animals, which consist of two “heavy protein chains” and two “light chains,” antibodies from camelids such as alpacas contain just two copies of a single heavy chain.

Nanobodies derived from these heavy-chain-only antibodies comprise a single binding domain much smaller than conventional antibodies, Hynes says.

In this way nanobodies are able to penetrate more deeply into human tissue than conventional antibodies, and can be much more quickly cleared from the circulation following treatment.

To develop the nanobodies, the team first immunized alpacas with either a cocktail of ECM proteins, or ECM-enriched preparations from human patient samples of colorectal or breast cancer metastases.

They then extracted RNA from the alpacas’ blood cells, amplified the coding sequences of the nanobodies, and generated libraries from which they isolated specific anti-ECM nanobodies.

They demonstrated the effectiveness of the technique using a nanobody that targets a protein fragment called EIIIB, which is prevalent in many tumor ECMs.

When they injected nanobodies attached to radioisotopes into mice with cancer, and scanned the mice using noninvasive PET/CT imaging, a standard technique used clinically, they found that the tumors and metastases were clearly visible. In this way the nanobodies could be used to help image both tumors and metastases.

But the same technique could also be used to deliver therapeutic treatments to the tumor or metastasis, Hynes says. “We can couple almost anything we want to the nanobodies, including drugs, toxins or higher energy isotopes,” he says. “So, imaging is a proof of concept, and it is very useful, but more important is what it leads to, which is the ability to target tumors with therapeutics.”

The ECM also undergoes similar protein changes as a result of other diseases, including cardiovascular, inflammatory, and fibrotic disorders. As a result, the same technique could also be used to treat people with these diseases.

In a recent collaborative paper, also published in Proceedings of the National Academy of Sciences, the researchers demonstrated the effectiveness of the technique by using it to develop nanobody-based chimeric antigen receptor (CAR) T cells, designed to target solid tumors.

CAR T cell therapy has already proven successful in treating cancers of the blood, but it has been less effective in treating solid tumors.

By targeting the ECM of tumor cells, nanobody-based CAR T cells became concentrated in the microenvironment of tumors and successfully reduced their growth.

The ECM has been recognized to play crucial roles in cancer progression, but few diagnostic or therapeutic methods have been developed based on the special characteristics of cancer ECM, says Yibin Kang, a professor of molecular biology at Princeton University, who was not involved in the research.

“The work by Hynes and colleagues has broken new ground in this area and elegantly demonstrates the high sensitivity and specificity of a nanobody targeting a particular isoform of an ECM protein in cancer,” Kang says. “This discovery opens up the possibility for early detection of cancer and metastasis, sensitive monitoring of therapeutic response, and specific delivery of anticancer drugs to tumors.”

This work was supported by a Mazumdar-Shaw International Oncology Fellowship, fellowships for the Ludwig Center for Molecular Oncology Research at MIT, the Howard Hughes Medical Institute and a grant from the Department of Defence Breast Cancer Research Program, and imaged on instrumentation purchased with a gift from John S. ’61 and Cindy Reed.

The researchers are now planning to carry out further work to develop the nanobody technique for treating tumors and metastases.

Study reveals how glial cells may play key epilepsy role

Mutation in disease model flies undermines maintenance of key ion balance.

David Orenstein | Picower Institute
May 2, 2019

A new study provides potential new targets for treating epilepsy and new fundamental insights into the relationship between neurons and their glial “helper” cells. In eLife, scientists at MIT’s Picower Institute for Learning and Memory report finding a key sequence of molecular events in which the genetic mutation in a fruit fly model of epilepsy leaves neurons vulnerable to becoming hyperactivated by stress, leading to seizures.

About 60 million people worldwide have epilepsy, a neurological condition characterized by seizures resulting from excessive neural activity. The “zydeco” model flies in the study experience seizures in a similar fashion. Since discovering zydeco, the lab of MIT neurobiologist Troy Littleton, the Menicon Professor in Neuroscience, has been investigating why the flies’ zydeco mutation makes it a powerful model of epilepsy.

Heading into the study, the team led by postdoc Shirley Weiss knew that the zydeco mutation was specifically expressed by cortex glial cells and that the protein it makes helps to pump calcium ions out of the cells. But that didn’t explain much about why a glial cell’s difficulty maintaining a natural ebb and flow of calcium ions would lead adjacent neurons to become too active under seizure-inducing stresses, such as fever-grade temperatures or the fly being jostled around.

The activity of neurons rises and falls based on the flow of ions — for a neuron to “fire,” for instance, it takes in sodium ions, and then to calm back down it releases potassium ions. But the ability of neurons to do that depends on there being a conducive balance of ions outside the cell. For instance, too much potassium outside makes it harder to get rid of potassium and calm down.

The need for an ion balance — and the way it is upset by the zydeco mutation — turned out to be the key to the new study. In a four-year series of experiments, Weiss, Littleton, and their co-authors found that excess calcium in cortex glia cells causes them to hyper-activate a molecular pathway that leads them to withdraw many of the potassium channels that they typically deploy to remove potassium from around neurons. With too much potassium left around, neurons can’t calm down when they are excited, and seizures ensue.

“No one has really shown how calcium signaling in glia could directly communicate with this more classical role of glial cells in potassium buffering,” Littleton says. “So this is a really important discovery linking an observation that’s been found in glia for a long time — these calcium oscillations that no one really understood — to a real biological function in glial cells, where it’s contributing to their ability to regulate ionic balance around neurons.”

Weiss’s work lays out a detailed sequence of events, implicating several specific molecular players and processes. That richly built knowledge meant that along the way, she and the team found multiple steps in which they could intervene to prevent seizures.

She started working the problem from the calcium end. With too much calcium afoot, she asked, what genes might be in a related pathway such that, if their expression was prevented, seizures would not occur? She interfered with expression in 847 potentially related genes and found that about 50 affected seizures. Among those, one stood out both for being closely linked to calcium regulation and also for being expressed in the key cortex glia cells of interest: calcineurin. Inhibiting calcineurin activity, for instance with the immunosuppressant medications cyclosprorine A or FK506, blocked seizures in zydeco mutant flies.

Weiss then looked at the genes affected by the calcineurin pathway and found several. One day at a conference where she was presenting a poster of her work, an onlooker mentioned that glial potassium channels could be involved. Sure enough, she found a particular one called “sandman” that, when knocked down, led to seizures in the flies. Further research showed that hyperactivation of calcineurin in zydeco glia led to an increase in a cellular process called endocytosis, in which the cell was bringing too much sandman back into the cell body. Without sandman staying on the cell membrane, the glia couldn’t effectively remove potassium from the outside.

When Weiss and her co-authors interfered to suppress endocytosis in zydeco flies, they also were able to reduce seizures, because that allowed more sandman to persist where it could reduce potassium. Sandman, notably, is equivalent to a protein in mammals called TRESK.

“Pharmacologically targeting glial pathways might be a promising avenue for future drug development in the field,” the authors wrote in eLife.

In addition to that clinical lead, the study also offers some new insights for more fundamental neuroscience, Littleton and Weiss said. While zydeco flies are good models of epilepsy, Drosophila’s cortex glia do have a property not found in mammals: They contact only the cell body of neurons, not the synaptic connections on their axon and dendrite branches. That makes them an unusually useful test bed to learn how glia interact with neurons via their cell body versus their synapses. The new study, for instance, shows a key mechanism for maintaining ionic balance for the neurons.

In addition to Weiss and Littleton, the paper’s other authors are Jan Melom, who helped lead the discovery of zydeco, postdoc Kiel Ormerod, and former postdoc Yao Zhang.

The National Institutes of Health and the JPB Foundation funded the research.

Three from MIT elected to the National Academy of Sciences for 2019

Faculty members Edward Boyden, Paula Hammond, and Aviv Regev recognized for “distinguished and continuing achievements in original research.”

Melanie Miller Kaufman | Department of Chemical Engineering
May 1, 2019

Three MIT professors — Edward Boyden, Paula Hammond, and Aviv Regev — are among the 100 new members and 25 foreign associates elected to the National Academy of Sciences on April 30. Forty percent of the newly elected members are women, the most ever elected in any one year to date.

Membership to the National Academy of Sciences is considered one of the highest honors that a scientist or engineer can receive. Current membership totals approximately 2,380 members and nearly 485 foreign associates.

Edward S. Boyden is the Y. Eva Tan Professor in Neurotechnology at MIT; leader of the Synthetic Neurobiology Group in the MIT Media Lab; associate professor of biological engineering and of brain and cognitive sciences; a McGovern Institute investigator; co-director of the MIT Center for Neurobiological Engineering; and a member of the MIT Center for Environmental Health Sciences, Computational and Systems Biology Initiative, and Koch Institute for Integrative Cancer Research at MIT.

Boyden develops new tools for probing, analyzing, and engineering brain circuits. He uses a range of approaches, including synthetic biology, nanotechnology, chemistry, electrical engineering, and optics to develop tools capable of revealing fundamental mechanisms underlying complex brain processes. He pioneered the development of optogenetics, a powerful method that enables neuronal activity to be controlled with light. He also led the team that invented expansion microscopy, in which a specimen is embedded in a gel that swells as it absorbs water, thereby expanding nanoscale features to a size where they can be seen using conventional microscopes. He is now seeking to systematically integrate these technologies to create detailed maps and models of brain circuitry.

Paula T. Hammond is the David H. Koch Chair Professor of Engineering and the head of the Department of Chemical Engineering; a founding member of the MIT Institute for Soldier Nanotechnology; and a member of the MIT Energy Initiative and Koch Institute.

Hammond’s research in nanomedicine encompasses the development of new biomaterials to enable drug delivery from surfaces with spatio-temporal control. She also investigates novel responsive polymer architectures for targeted nanoparticle drug and gene delivery, and has developed self-assembled materials systems for electrochemical energy devices. She has designed multilayered nanoparticles to deliver a synergistic combination of siRNA or inhibitors with chemotherapy drugs in a staged manner to tumors, leading to significant decreases in tumor growth and a great lowering of toxicity.

Aviv Regev is a professor of biology; a core member of the Broad Institute of Harvard and MIT; and aHoward Hughes Medical Institute investigator.

Regev studies the molecular circuitry that governs the function of mammalian cells in health and disease and has pioneered many leading experimental and computational methods for the reconstruction of circuits, including in single-cell genomics. Her work focuses on dissecting complex molecular networks to determine how they function and evolve in the face of genetic and environmental changes, as well as during differentiation, evolution and disease.

The National Academy of Sciences is a private, non-profit society of distinguished scholars. Established in 1863 by an Act of Congress, signed by President Abraham Lincoln, the academy was charged with “providing independent, objective advice to the nation on matters related to science and technology.” Scientists are elected by their peers to membership for outstanding contributions to research. The NAS is committed to furthering science in America, and its members are active contributors to the international scientific community.