Author: mantulin

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.

Department of Biology hosts second annual Science Slam

Eight biology contestants get one slide and three minutes to explain their research and impress their listeners.

Raleigh McElvery | Department of Biology
April 30, 2019

Trainees recently took over the Tuesday Biology Colloquium for the second annual Science Slam, hosted by MIT’s Department of Biology. Topics ranged from the science behind cancer metastasis to parasites, hangovers, and, notably, poop.

A science slam features a series of short presentations where researchers explain their work in a compelling manner, and — as the name suggests — make an impact. These presentations aren’t just talks, they’re performances geared towards a science-literate but non-specialized public audience. In this case, competitors were each given one slide and three minutes to tell their scientific tales and earn votes from audience members and judges.

The latter included Mary Carmichael, founder and CEO of the strategic communications consultancy Quark 4; John Pham, editor-in-chief of Cell; and Ari Daniel, an independent science reporter who crafts digital videos for PBS NOVA and co-produces the Boston branch of Story Collider.

Among the competitors were six graduate students and two postdocs who hailed from labs scattered throughout Building 68, the Whitehead Institute, and the Koch Institute for Integrative Cancer Research at MIT. In order of appearance:

  • Rebecca Silberman, from Angelika Amon’s lab, who spoke about how there is something special about cancer cells that allows them to thrive with the wrong number of chromosomes;
  • Tyler Smith, from Sebastian Lourido’s lab, who spoke about his organism of choice, Toxoplasma gondii, and how these parasites provide insights into fundamental biology that classic “model” organisms do not;
  • Jasmin Imran Alsous, from Adam Martin’s lab, who spoke about the coordinated cellular interactions required for fruit fly egg development;
  • Darren Parker, from Gene-Wei Li’s lab, who spoke about the ratio of ingredients needed to concoct nature’s winning recipe for the perfect cell;
  • Sophia Xu, from Jing-Ke Weng’s lab, who spoke about the molecules responsible for the kudzu flower’s capacity to alleviate hangovers;
  • Jay Thangappan, from Silvi Rouskin’s lab, who spoke about the importance of RNA structure in splicing and its consequences for many important biological processes;
  • Lindsey Backman, from Catherine Drennan’s lab, who spoke about the biochemical processes carried out by gut bacteria that make poop smell bad; and
  • Arish Shah, from Eliezer Calo’s lab, who spoke about how developing zebrafish clear maternally-contributed molecules and replace them with their own, thus becoming “independent from mom.”

The event was moderated by former Slammers, postdoc Monika Avello and graduate student Emma Kowal. The duo joined forces with the Building 68 communications team and Biology Graduate Student Council to publicize the event and host two pre-slam workshops and a practice session.

Kowal, last year’s winner, was motivated to mentor this year’s cohort because, as she puts it, most scientists either don’t recognize the importance of clear communication or don’t recognize the challenge of doing it well.

“It is rare to see graduate programs devote training time to this,” she says, “but I believe it’s worth the effort. Taking the time to distill what excites and motivates us in our research not only inspires people to value science and even become scientists, but also helps us connect with each other — and remember why we love doing science in the first place.”

Avello recalls signing up for last year’s slam at the last minute, and “loving the experience.”

“I wanted to facilitate the experience of thinking hard about science communication in a fun and inclusive way for other graduate students and postdocs,” she says. “I really enjoyed watching everyone wrestle with the challenge of presenting their science in such a tight, condensed format, and ultimately developing their own unique story and style.”

There were two prizes, one awarded by the three judges and another awarded by the audience. Silberman, a fifth-year graduate student whose talk was titled “Does Chromosome Imbalance Cause Cancer?,” took home the Judges’ Prize, while third-year graduate student Sophia Xu claimed the Audience Prize with her talk, “Plant Natural Products and Human Ethanol Metabolism.”

Silberman said her favorite part was watching her fellow participants’ talks develop over time during the consecutive practice sessions. “Getting the opportunity to workshop my ideas and get input from Emma, Moni, and the other participants made the final presentation much less terrifying than it would have been otherwise, and made my talk much better,” she says.

Xu saw the Slam as an opportunity to practice presenting her research in an engaging way, and take a small step toward conquering her fear of public speaking. “I was overwhelmed by the support I received, not only from the organizers, but also from the other speakers,” she says. “It felt much like what I imagine a collaborative, friendly British cooking show would be like.”

Silberman encourages Department of Biology trainees considering participating in next year’s slam to “go for it.” She adds: “As grad students, we often aren’t challenged to distill our research down to its simplest terms. It was both harder and more fun than I expected.”

The fluid that feeds tumor cells

The substance that bathes tumors in the body is quite different from the medium used to grow cancer cells in the lab, biologists report.

Anne Trafton | MIT News Office
April 16, 2019

Before being tested in animals or humans, most cancer drugs are evaluated in tumor cells grown in a lab dish. However, in recent years, there has been a growing realization that the environment in which these cells are grown does not accurately mimic the natural environment of a tumor, and that this discrepancy could produce inaccurate results.

In a new study, MIT biologists analyzed the composition of the interstitial fluid that normally surrounds pancreatic tumors, and found that its nutrient composition is different from that of the culture medium normally used to grow cancer cells. It also differs from blood, which feeds the interstitial fluid and removes waste products.

The findings suggest that growing cancer cells in a culture medium more similar to this fluid could help researchers better predict how experimental drugs will affect cancer cells, says Matthew Vander Heiden, an associate professor of biology at MIT and a member of the Koch Institute for Integrative Cancer Research.

“It’s kind of an obvious statement that the tumor environment is important, but I think in cancer research the pendulum had swung so far toward genes, people tended to forget that,” says Vander Heiden, one of the senior authors of the study.

Alex Muir, a former Koch Institute postdoc who is now an assistant professor at the University of Chicago, is also a senior author of the paper, which appears in the April 16 edition of the journal eLife. The lead author of the study is Mark Sullivan, an MIT graduate student.

Environment matters

Scientists have long known that cancer cells metabolize nutrients differently than most other cells. This alternative strategy helps them to generate the building blocks they need to continue growing and dividing, forming new cancer cells. In recent years, scientists have sought to develop drugs that interfere with these metabolic processes, and one such drug was approved to treat leukemia in 2017.

An important step in developing such drugs is to test them in cancer cells grown in a lab dish. The growth medium typically used to grow these cells includes carbon sources (such as glucose), nitrogen, and other nutrients. However, in the past few years, Vander Heiden’s lab has found that cancer cells grown in this medium respond differently to drugs than they do in mouse models of cancer.

David Sabatini, a member of the Whitehead Institute and professor of biology at MIT, has also found that drugs affect cancer cells differently if they are grown in a medium that resembles the nutrient composition of human plasma, instead of the traditional growth medium.

“That work, and similar results from a couple of other groups around the world, suggested that environment matters a lot,” Vander Heiden says. “It really was a wake up call for us that to really know how to find the dependencies of cancer, we have to get the environment right.”

To that end, the MIT team decided to investigate the composition of interstitial fluid, which bathes the tissue and carries nutrients that diffuse from blood flowing through the capillaries. Its composition is not identical to that of blood, and in tumors, it can be very different because tumors often have poor connections to the blood supply.

The researchers chose to focus on pancreatic cancer in part because it is known to be particularly nutrient-deprived. After isolating interstitial fluid from pancreatic tumors in mice, the researchers used mass spectrometry to measure the concentrations of more than 100 different nutrients, and discovered that the composition of the interstitial fluid is different from that of blood (and from that of the culture medium normally used to grow cells). Several of the nutrients that the researchers found to be depleted in tumor interstitial fluid are amino acids that are important for immune cell function, including arginine, tryptophan, and cystine.

Not all nutrients were depleted in the interstitial fluid — some were more plentiful, including the amino acids glycine and glutamate, which are known to be produced by some cancer cells.

Location, location, location

The researchers also compared tumors growing in the pancreas and the lungs and found that the composition of the interstitial fluid can vary based on tumors’ location in the body and at the site where the tumor originated. They also found slight differences between the fluid surrounding tumors that grew in the same location but had different genetic makeup; however, the genetic factors tested did not have as big an impact as the tumor location.

“That probably says that what determines what nutrients are in the environment is heavily driven by interactions between cancer cells and noncancer cells within the tumor,” Vander Heiden says.

Scientists have previously discovered that those noncancer cells, including supportive stromal cells and immune cells, can be recruited by cancer cells to help remake the environment around the tumor to promote cancer survival and spread.

Vander Heiden’s lab and other research groups are now working on developing a culture medium that would more closely mimic the composition of tumor interstitial fluid, so they can explore whether tumor cells grown in this environment could be used to generate more accurate predictions of how cancer drugs will affect cells in the body.

The research was funded by the National Institutes of Health, the Lustgarten Foundation, the MIT Center for Precision Cancer Medicine, Stand Up to Cancer, the Howard Hughes Medical Institute, and the Ludwig Center at MIT.