Author: mantulin

Faculty and staff recall Goldman’s unending commitment to his work for more than three decades.

Lillian Eden | Department of Biology

August 7, 2023

Last fall, Stephen “Steve” Goldman passed away at 59 after a courageous battle with amyotrophic lateral sclerosis (ALS). Prior to his passing, Goldman had worked at MIT for more than 30 years, first with Information Systems and Technology, then for the Computational and Systems Biology Initiative, and then in the Department of Biology.

“Steve was an institution,” says Stuart Levine, director of the BioMicro Center in the biology department and Goldman’s supervisor for more than a decade. According to Levine, Goldman was the type of person who had his “whole being” wrapped up in the job: “He did a little bit of everything, and that’s really hard to find these days.”

Steve Goldman was one of the first hires for the fledgling BioMicro Center, according to former supervisor Peter Sorger, whose is now the Otto Krayer Professor of Systems Pharmacology in the Department of Systems Biology at Harvard Medical School. Goldman, Sorger says, was essential for setting up the Department of Biology’s first server-based computing system.

“He brought great enthusiasm and skill to the role, and I also appreciated his sangfroid and sense of humor. This was essential because we were inventing the center’s infrastructure and mission on the fly and were often in the dark — and also down in the steam tunnels. Steve was a real pioneer,” Sorger says.

Before coming to MIT, Goldman lived in New York and worked on Wall Street. He met his wife of 32 years, Brenda Goldman (née Mahar), on a boat in the middle of the Caribbean Sea.

“He came up to me in a white tuxedo and asked me to have dinner,” Brenda Goldman recalls.

They clicked immediately. Around the time of their wedding two years later, Brenda had found a job in Cambridge, Massachusetts, and they were both eager for Steve to find work in the area, far from the high-stress environment of Wall Street.

“I found an ad at MIT and I said, ‘This sounds very much like you,’” Brenda says. After several interviews, he found out he’d gotten a job at MIT the day before their wedding — and the rest, as they say, is history.

Whether it was a weekend or a holiday, if Goldman got an alert that something was wrong, he would always try to follow up, fix the problem, or go in to offer hands-on help, according to Levine.

Brenda even accompanied him a few times, noticing that “there was always somebody around who waved or said hello. We couldn’t get out of the building without seeing someone, no matter which building it was,” she says.

Former department head Alan Grossman recalls many casual conversations about sports, especially baseball and softball.

“He always greeted me with a warm smile and ‘Hello, professor,’” Grossman says. “He truly loved working in our department, and we miss him.”

Goldman’s second love, according to Brenda Goldman, was refereeing sports. Steve would often get to work early so he could wrap up in time to referee or umpire games.

“He had something for almost every season of the year except winter,” Brenda says. “He liked it for the exercise, but he also liked it because it got him off his office chair and interacting with people.”

Steve Goldman was organized — but his workspace was notably less so. It was notorious for being filled with stuff — piles of memory sticks, CDs, cables, and devices open and in various stages of repair. However, Brenda says, “If you told him something broke, he knew what pile of things to pull the magic out of to make it work.”

Levine says Goldman’s death came as a bit of a shock: He had been answering emails just days before his passing.

“He always, always loved working for MIT,” Brenda Goldman says. “He loved computers, and the work gave his life purpose.”

Following his death, the Department of Biology made a contribution in Goldman’s memory to the ALS Association of Massachusetts. In addition to Brenda, his wife of 32 years, Goldman is survived by his children Kevin and Jason Goldman, in-laws, and many nieces and nephews.

MIT PhD student Kathrin Kajderowicz is studying how hibernation-like states could pave the way for new hypothermic therapies.

Department of Brain and Cognitive Sciences

August 4, 2023

In 2020, Kathrin “Kat” Kajderowicz’s father passed away from lung cancer. Kajderowicz was in charge of her father’s health care for as long as she can remember. While he suffered from various cardiovascular issues for several years, it wasn’t until the beginning of the Covid-19 pandemic that he was diagnosed with late-stage metastatic small-cell lung cancer. Jumping into a primary caregiver position, she closely monitored the treatments he received from doctors to no avail. “I was frustrated with the many medications he was prescribed without the doctors fully understanding how they interacted with each other,” she says. Even if a single physician had been overseeing his comprehensive treatment plan, she says, they still could not definitively say whether the medication combinations have adverse effects that outweigh any positive impact.

This frustration set her on a scientific journey that has now culminated in her research as a PhD student at MIT’s Department of Brain and Cognitive Sciences (BCS) and the Whitehead Institute for Biomedical Research. “My experience led me to a significant medical problem: How can we eventually shift the medical paradigm to develop treatments that consider not only one specific pathway or problem but contextualize systemic tissue or organ dysfunction?”

To engage with this problem, Kajderowicz studies animals uniquely adapted to handle different stressors and environments, possibly modeling human disease states. “Perhaps we can turn to nature and see how different organisms have adapted to overcome and mitigate similar challenges,” she says.

Kajderowicz now works in Professor Siniša Hrvatin’s lab at Whitehead, where she researches cold tolerance. “I’m interested in exploring the mechanisms underlying cellular cold tolerance in hibernating organisms.” Engineering cold tolerance and stasis has many potential revolutionary future applications. In the near term, her work could improve organ transplantation and cell or tissue preservation. In the longer term, she hopes her work could catalyze a shift in the medical field away from its current crisis-mode approach: “By slowing down bodily processes and disease progression, a lower metabolic state could pave the way for a new class of hypothermic therapies that induce human hibernation-like states for cells, organs, or even whole organisms.”

First-generation student and scientist

Kajderowicz’s clearheaded pursuit of fundamental, large-scale scientific questions has propelled her impressive career as a young scientist. Recently, she was awarded the Paul and Daisy Soros Fellowship for New Americans, recognizing her unique path as the daughter of immigrants from Soviet Poland. Her parents arrived in the United States without having completed higher education degrees, without any savings, knowledge of English, medical insurance, or immigration papers. They worked hard to make a living — her father was a construction worker and her mother a housekeeper — using much of their earnings to become naturalized citizens.

Kajderowicz developed an early interest in a scientific career. “My parents, who didn’t go to college, didn’t push me toward any specific profession,” she says. “This gave me the freedom to explore any field I wanted, and my curiosity naturally led me to science.”

As a teenager, she worked as a golf caddie to help her parents financially. Clients at the golf course assisted her in obtaining internships at biotech and tech companies. Having won Best in Category at the Illinois State Science Fair, Kajderowicz received a substantial scholarship to support her studies at Cornell University, but she continued working to pay for her expenses and tuition. At Cornell, Kajderowicz joined the renowned Lab of Ornithology, where she applied machine-learning techniques to study songbird communication and other behavioral patterns.

Kajderowicz’s journey as a neuroscientist began at Harvard Medical School in Professor Connie Cepko’s lab, where she studied the developmental trajectory of a population of retinal interneurons. “Learning how to identify cell signatures was a fascinating introduction to the complexity of life. But I ultimately realized I wanted to pursue the questions that kept me up at night — both how we process information and how and why these processes change during aging. For me, these are life’s biggest unanswered questions, and I believe neuroscience is the foundation for everything. This led me to MIT’s Department of Brain and Cognitive Sciences.”

Learning from hamsters

Kajderowicz applied and was admitted to over two dozen graduate programs — “but I knew I wanted to go to MIT BCS. That was a no-brainer,” she says. “The department has faculty members in all levels of neuroscience: the cellular and molecular, systems, computational, and cognitive levels. It’s amazing to have all these people under one roof.”

Shortly after starting her graduate work at MIT, Kajderowicz realized she wanted to focus on the cellular level. “I think it’s important first to understand how things work within cells before focusing on function and systems.” She also seeks a translational avenue connecting theory and therapy, bridging the gap between basic science and applied treatment.

Kajderowicz found what she sought at the Whitehead Institute’s Hrvatin Lab and Weissman Lab. “It’s truly unique to have access to two very different communities at MIT. In BCS, I am seen as a biologist, while at the Whitehead Institute, I am more of a neuroscientist. It’s great having folks from different training backgrounds challenging my ideas and work.”

Instead of working directly on how cognition is encoded at the cellular level, Kajderowicz decided to embark on a project that would allow her to figure out how different species survive extreme stressors and environments. She is now developing tools to study cold tolerance across several species on the cellular level.

“Hibernating hamsters can safely endure prolonged durations during which their body temperature drops to 4 degrees [Celsius]. By taking a comparative species approach, I want to identify whether hibernators are uniquely genetically programmed to withstand these conditions or whether non-hibernators don’t activate these genetic pathways,” she says. Next, Kajderowicz hopes to figure out how to transfer or activate cold-protective effects to human cells and, someday, whole humans. While she isn’t directly studying the root of cognition, she hopes her research will help maintain or enhance cognitive functioning throughout aging by pushing the boundaries of the types of medicines and therapeutics available.

Building a scientific community

Kajderowicz’s involvement in the scientific community extends beyond her immediate work. At the height of the pandemic, she initiated a digital platform facilitating conversations on biotechnology trends among researchers, biotech professionals, venture capitalists, and others interested in staying updated on cutting-edge developments. Known as “DNA Deviants,” the community she built consists of several thousand active members on several social media platforms.

“It started with an informal journal club I had with some friends, where we would meet over coffee and discuss new papers. Then, when the pandemic shut down everything, I started a real-time podcast on the Clubhouse app with a friend, discussing emerging biotech trends. Eventually, it became an online journal club, and people just kept joining. We got experts to serendipitously join conversations within their realm of expertise from around the world.” Today, almost a dozen PhD, MD-PhD, and motivated undergraduates worldwide take turns leading conversations with different paper authors.

“It’s been incredibly rewarding to remain connected not only to my work, but also to gain a comprehensive understanding of what’s happening in the world,” Kajderowicz says. “You always need to look beyond your immediate circle.”

MIT researchers find timing and dosage of DNA-damaging drugs are key to whether a cancer cell dies or enters senescence.

Bendta Schroeder | Koch Institute

July 31, 2023

Despite the proliferation of novel therapies such as immunotherapy or targeted therapies, radiation and chemotherapy remain the frontline treatment for cancer patients. About half of all patients still receive radiation and 60-80 percent receive chemotherapy.

Both radiation and chemotherapy work by damaging DNA, taking advantage of a vulnerability specific to cancer cells. Healthy cells are more likely to survive radiation and chemotherapy since their mechanisms for identifying and repairing DNA damage are intact. In cancer cells, these repair mechanisms are compromised by mutations. When cancer cells cannot adequately respond to the DNA damage caused by radiation and chemotherapy, ideally, they undergo apoptosis or die by other means.

However, there is another fate for cells after DNA damage: senescence — a state where cells survive, but stop dividing. Senescent cells’ DNA has not been damaged enough to induce apoptosis but is too damaged to support cell division. While senescent cancer cells themselves are unable to proliferate and spread, they are bad actors in the fight against cancer because they seem to enable other cancer cells to develop more aggressively. Although a cancer cell’s fate is not apparent until a few days after treatment, the decision to survive, die, or enter senescence is made much earlier. But, precisely when and how that decision is made has not been well understood.

In an open-access study of ovarian and osteosarcoma cancer cells appearing July 19 in Cell Systems, MIT researchers show that cell signaling proteins commonly associated with cell proliferation and apoptosis instead commit cancer cells to senescence within 12 hours of treatment with low doses of certain kinds of chemotherapy.

“When it comes to treating cancer, this study underscores that it’s important not to think too linearly about cell signaling,” says Michael Yaffe, who is a David H. Koch Professor of Science at MIT, the director of the MIT Center for Precision Cancer Medicine, a member of MIT’s Koch Institute for Integrative Cancer Research, and the senior author of the study. “If you assume that a particular treatment will always affect cancer cell signaling in the same way — you may be setting yourself up for many surprises, and treating cancers with the wrong combination of drugs.”

Using a combination of experiments with cancer cells and computational modeling, the team investigated the cell signaling mechanisms that prompt cancer cells to enter senescence after treatment with a commonly used anti-cancer agent. Their efforts singled out two protein kinases and a component of the AP-1 transcription factor complex as highly associated with the induction of senescence after DNA damage, despite the well-established roles for all of these molecules in promoting cell proliferation in cancer.

The researchers treated cancer cells with low and high doses of doxorubicin, a chemotherapy that interferes with the function with topoisomerase II, an enzyme that breaks and then repairs DNA strands during replication to fix tangles and other topological problems.

By measuring the effects of DNA damage on single cells at several time points ranging from six hours to four days after the initial exposure, the team created two datasets. In one dataset, the researchers tracked cell fate over time. For the second set, researchers measured relative cell signaling activity levels across a variety of proteins associated with responses to DNA damage or cellular stress, determination of cell fate, and progress through cell growth and division.

The two datasets were used to build a computational model that identifies correlations between time, dosage, signal, and cell fate. The model identified the activities of the MAP kinases Erk and JNK, and the transcription factor c-Jun as key components of the AP-1 protein likewise understood to involved in the induction of senescence. The researchers then validated these computational findings by showing that inhibition of JNK and Erk after DNA damage successfully prevented cells from entering senescence.

The researchers leveraged JNK and Erk inhibition to pinpoint exactly when cells made the decision to enter senescence. Surprisingly, they found that the decision to enter senescence was made within 12 hours of DNA damage, even though it took days to actually see the senescent cells accumulate. The team also found that with the passage of more time, these MAP kinases took on a different function: promoting the secretion of proinflammatory proteins called cytokines that are responsible for making other cancer cells proliferate and develop resistance to chemotherapy.

“Proteins like cytokines encourage ‘bad behavior’ in neighboring tumor cells that lead to more aggressive cancer progression,” says Tatiana Netterfield, a graduate student in the Yaffe lab and the lead author of the study. “Because of this, it is thought that senescent cells that stay near the tumor for long periods of time are detrimental to treating cancer.”

This study’s findings apply to cancer cells treated with a commonly used type of chemotherapy that stalls DNA replication after repair. But more broadly, the study emphasizes that “when treating cancer, it’s extremely important to understand the molecular characteristics of cancer cells and the contextual factors such as time and dosing that determine cell fate,” explains Netterfield.

The study, however, has more immediate implications for treatments that are already in use. One class of Erk inhibitors, MEK inhibitors, are used in the clinic with the expectation that they will curb cancer growth.

“We must be cautious about administering MEK inhibitors together with chemotherapies,” says Yaffe. “The combination may have the unintended effect of driving cells into proliferation, rather than senescence.”

In future work, the team will perform studies to understand how and why individual cells choose to proliferate instead of enter senescence. Additionally, the team is employing next-generation sequencing to understand which genes c-Jun is regulating in order to push cells toward senescence.

This study was funded, in part, by the Charles and Marjorie Holloway Foundation and the MIT Center for Precision Cancer Medicine.

A new approach opens the door to a greater understanding of protein-microbe interactions.

Lillian Eden | Department of Biology

July 19, 2023

Your mouth is a crucial interface between the outside world and the inside of your body. Everything you breathe, chew, or drink interacts with your oral cavity — the proteins and the microbes, including microbes that can harm us. When things go awry, the result can range from the mild, like bad breath, to the serious, like tooth and gum decay, to more dire effects in the gut and other parts of the body.

Even though the oral microbiome plays a critical role as a front-line defense for human health and disease, we still know very little about the intricacies of host-microbe interactions in the complex physiological environment of the mouth; a better understanding of those interactions is key to developing treatments for human disease.

In a recent study published in PNAS, a team of scientists from MIT and elsewhere revealed that one of the most abundant proteins found in our saliva binds to the surface of select microbes found in the mouth. The findings shed light on how salivary proteins and mucus play a role in maintaining the oral cavity microbiome.

The collaboration involved members of the labs of Barbara Imperiali in the MIT Department of Biology and Laura Kiessling in the MIT Department of Chemistry, as well as the groups of Stefan Ruhl at the University at Buffalo School of Dental Medicine and Catherine Grimes at the University of Delaware.

The work is focused on an abundant oral cavity protein called zymogen granule protein 16 homolog B (ZG16B). Finding ZG16B’s interaction partners and gaining insight into its function were the overarching goals of the project. To accomplish this, Soumi Ghosh, a postdoc in the Imperiali lab, and colleagues engineered ZG16B to add reporter tags such as fluorophores. They called these modified proteins “microbial glycan analysis probes (mGAPs)” because they allowed them to identify ZG16B binding partners using complementary methods. They applied the probes to samples of healthy oral microbiomes to identify target microbes and binding partners.

The results excited them.

“ZG16B didn’t just bind to random bacteria. It was very focused on certain species, including a commensal bacteria called Streptococcus vestibularis,” says Ghosh, who is first author on the paper.

Commensal bacteria are found in a normal healthy microbiome and do not cause disease.

Using the mGAPs, the team showed that ZG16B binds to cell wall polysaccharides of the bacteria, which indicates that ZG16B is a lectin, a carbohydrate-binding protein. In general, lectins are responsible for cell-cell interactions, signaling pathways, and some innate immune responses against pathogens. “This is the first time that it has been proven experimentally that ZG16B acts as a lectin because it binds to the carbohydrates on the cell surface or cell wall of the bacteria,” Ghosh highlights.

ZG16B was also shown to recruit Mucin 7 (MUC7), a salivary glycoprotein in the oral cavity, and together the results suggest that ZG16B may help maintain a healthy balance in the oral microbiome by forming a complex with MUC7 and certain bacteria. The results indicate that ZG16B regulates the bacteria’s abundance by preventing overgrowth through agglutination when the bacteria exceed a certain level of growth.

“ZG16B, therefore, seems to function as a missing link in the system; it binds to different types of glycans — the microbial glycans and the mucin glycans — and ultimately, maintains a healthy balance in our oral cavity,” Ghosh says.

Further work with this probe and samples of oral microbiome from healthy and diseased subjects could also reveal the lectin’s importance for oral health and disease.

Current attention is focused on developing and applying additional mGAPs based on other human lectins, such as those found in serum, liver, and intestine to reveal their binding specificities and their roles in host-microbe interactions.

“The research carried out in this collaboration exemplifies the kind of synergy that made me excited to move to MIT five years ago,” says Kiessling. “I’ve been able to work with outstanding scientists who share my interest in the chemistry and the biology of carbohydrates.”

Kiessling and Imperiali, both senior authors of the paper, came up with the term for the probes they’re creating: “mGAPS to fill in the gaps” in our understanding of the role of lectins in the human microbiome, according to Ghosh.

“If we want to develop therapeutics against bacterial infection, we need a better understanding of host-microbe interactions,” Ghosh says. “The significance of our study is to prove that we can make very good probes for microbial glycans, find out their importance in the front-line defense of the immune system, and, ultimately, come up with a therapeutic approach to disease.”

This research was supported by the National Institute of Health.

With a minor in literature and environmental sustainability, the biology alumna considers perspectives from Charles Darwin to Annie Dillard.

Lillian Eden | Department of Biology

July 6, 2023

Growing up in Los Angeles about 10 minutes away from the Ballona Wetlands, Andrea Lo ’21 has long been interested in ecology. She witnessed, in real-time, the effects of urbanization and the impacts that development had on the wetlands.

“In hindsight, it really helped shape my need for a career — and a life — where I can help improve my community and the environment,” she says.

Lo, who majored in biology at MIT, says a recurring theme in her life has been the pursuit of balance, valuing both extracurricular and curricular activities. She always felt an equal pull toward STEM and the humanities, toward wet lab work and field work, and toward doing research and helping her community.

“One of the most important things I learned in 7.30[J] (Fundamentals of Ecology) was that there are always going to be trade-offs. That’s just the way of life,” she says. “The biology major at MIT is really flexible. I got a lot of room to explore what I was interested in and get a good balance overall, with humanities classes along with technical classes.”

Lo was drawn to MIT because of the focus on hands-on work — but many of the activities Lo was hoping to do, both extracurricular and curricular, were cut short because of the pandemic, including her lab-based Undergraduate Research Opportunities Program (UROP) project.

Instead, she pursued a UROP with MIT Sea Grant, working on a project in partnership with Northeastern University and the Charles River Conservancy with funding support from the MIT Community Service fund as part of STEAM Saturday.

She was involved in creating Floating Wetland kits, an educational activity directed at students in grades 4 to 6 to help students understand ecological concepts,the challenges the Charles River faces due to urbanization, and how floating wetlands improve the ecosystem.

“Our hope was to educate future generations of local students in Cambridge in order for them to understand the ecology surrounding where they live,” she says.

In recent years, many bodies of water in Massachusetts have become unusable during the warmer months due to the process of eutrophication: stormwater runoff picks up everything — from fertilizer and silt to animal excrement — and deposits it at the lowest point, which is often a body of water. This leads to an excess of nutrients in the body of water and, when combined with warm temperatures, can lead to harmful algal blooms, making the water sludgy, bright green, and dangerously toxic.

The wetland kits Lo worked with were mini ecosystems, replicating a full-sized floating wetland. One such floating wetland can be seen from the Longfellow Bridge at one end of MIT’s campus — the Charles River floating wetland is a patch of grass attached to a buoy like a boat, which is often visited by birds and inhabited by much smaller critters that cannot be seen from the shore.

The Charles River floating wetland has a variety of flora, but the kits Lo helped present use only wheat grass because it is easy to grow and has long, dangling roots that could penetrate the watery medium below. A water tray beneath the grass — the Charles river of the mini ecosystem — contains spirulina powder for replicating algae growth and daphnia, which are small, planktonic crustaceans that help keep freshwater clean and usable.

“This work was really fulfilling, but it’s also really important, because environmental sustainability relies on future generations to carry on the work that past generations have been doing,” she says. “MIT’s motto is ‘mens et manus’ — education for practical application, and applying theoretical knowledge to what we do in our daily lives. I think this project really helped reinforce that.”

Since 2021, Lo has been working in Denmark in a position she learned about through the MIT-Denmark program.

She chose Denmark because of its reputation for environmental and sustainability issues and because she didn’t know much about it except for it being one of the happiest countries in the world, often thought of synonymously with the word “hygge,” which has no direct translation but encapsulates coziness and comfort from the small joys in life.

“At MIT, we have a very strong work-hard, play-hard culture. I think we can learn a lot from the work-life balance that Denmark has a reputation for,” she says. “I really wanted to take the opportunity in between graduation and whatever came after to explore beyond my bubble. For me, it was important to step back, out of my comfort zone, step into a different environment — and just live.”

Currently, her personal project is comparing the conditions of two lagoons on the island of Fyn in Denmark. Both are naturally occurring, but in different states of environmental health.

She’s been doing a mix of field work and lab work. She collects sediment and fauna samples using a steel corer, or “butter stick” in her lab’s slang. In the same way that one can use a metal tube-shaped tool to remove the core of an apple, she punches the steel corer into the ground, removing a plug of sample. She then sifts the sample through 1 millimeter mesh, preserves the filtered sample in formalin, and takes everything back to the lab.

Once there, she looks through the sample to find macrofauna — mollusks, barnacles, and polychaetes, a bristly-looking segmented worm, for example. Collected over time, sediment characteristics like organic matter content, sediment grain size, and the size and abundance of macrofauna, can reveal trends that can help determine the health of the ecosystem.

Lo doesn’t have any concrete results yet, but her data could help researchers project the recovery of a lagoon that was rehabilitated using a technique called managed realignment, where water is allowed to reclaim areas where it was once found. She says she’s glad she gets a mix of field work and lab work, even on Denmark’s stormiest days.

“Sometimes there are really cold days where it’s windy and I wish I was in the lab, but, at the same time, it’s nice to have a balance where I can be outside and really be hands-on with my work,” she says.

Reflecting her dual interests in the technical and the innovative, she will be back in the Greater Boston area in the fall, pursuing a master of science in innovation and management and an MS in civil and environmental engineering at the Tufts Gordon Institute.

“So much has happened and changed due to the pandemic that it’s easy to dwell on what could’ve been, but I tell myself to be optimistic and take the positive aspects that have come out of the circumstances,” Lo says. “My opportunities with the Sea Grant, MISTI, and Tufts definitely wouldn’t have happened if the pandemic hadn’t happened.”

Biology graduate student Tong Zhang has spent the last two years learning the intricacies of how bacteria protect themselves.

Lillian Eden | Department of Biology

June 12, 2023

For the past two and a half years, graduate student Tong Zhang has been figuring out how bacteria protect themselves against phages — the viruses that infect them. All the while, doing so as a student far from her hometown of Beijing, China.

Phages and bacteria are in a constant arms race, which those in the field call the Red Queen Conflict: Alice in Wonderland running to stay in place, the queen making chase. Both the infector and the infected are constantly forced to adapt — the host and the parasite persistently co-evolving.

Perhaps the best-known anti-phage defense systems are called restriction modification systems, and much of the influential work on those systems was done by Salvador Luria, the longtime MIT professor and founding director of what is now called the Koch Institute for Integrative Cancer Research. Those anti-phage defense systems can distinguish self DNA from foreign DNA; they are always active, in surveillance mode, ignoring the host DNA but on the hunt for foreign DNA to slice up to protect the host.

Other anti-phage systems, however, require activation. Although researchers have characterized systems that protect bacteria from phage, many questions remain about how those systems become activated during infection.

Unlocking phage science

In an open-access paper published last year, Zhang, along with collaborators, found that during infection, the capsid protein that coats the outside of the phage directly triggers activation of a toxin-antitoxin system called CapRel, where the N-terminus of the protein is the toxin and the C-terminus is the antitoxin; the C-terminus works as both infection sensor and inhibitor of the toxic N-terminus. The capsid protein of some phages infecting Escherichia coli, the bacteria studied for the paper, will bind to the C-terminal domain, which triggers activation of the toxic N-terminus defense system to restrict infection by blocking phage replication.

“The capsid is essential for the phage and is the most abundant thing in the phage.” Zhang says. “The bacteria are sensing something that the phage cannot just get rid of and still be happy, so this really limits the possibility that the phage can overcome this defense system.”

Before Tong’s paper, it was unclear that phage proteins could directly activate this defense system.

Although the details and molecules are different for different immune systems, the concept of sensing foreign invaders and responding to infection is conserved across all domains of life.

“It’s a testament to how hard she works, how smart she is, and how dedicated she is, that this project resulted in a paper in just two years — and started during a pandemic,” Laub says.

From Beijing to MIT

Zhang has thought biology was “cool” since long before she arrived at MIT. She hails from Beijing and was an undergraduate at the University of California at Berkeley, where her mentor gave her the perfect mix of guidance and independence.

“I think that experience made me realize that trying to figure out a problem is like solving a puzzle,” she says. “What I’m interested in is understanding mechanisms, the details of how different systems work. In my current research, there are a lot of open questions like that, which is really exciting.”

Laub says Zhang was the driving force behind the project, but collaborations also helped move the project along.

Although the pandemic posed a lot of challenges for research, it also changed the scales of distance: certain things work well in a virtual format. Laub was able to participate in a thesis defense abroad from the comfort of his desk in Cambridge, for example, and Zhang’s project came about in part because Laub served as an outside examiner for a lab in Sweden that had been studying CapRel.

But some things just don’t work on Zoom — like going home.

“There have been some unique challenges for Tong — and for all of our international students. They’re a long way from home, a long way from family,” Laub says. “The courage and the tenacity that it takes to not only do this work but to thrive and to succeed the way she has is remarkable.”

Zhang, like many international students pursuing education in the United States, has not been home in more than three years; in contrast, as an undergraduate, she went home for extended periods at least twice a year.

“I think that’s the most challenging part,” she says of her time at MIT.

She arrived in the United States to attend UC Berkeley having never visited the campus before. Zhang, used to sitting in the same classroom with the same group of people all day, was surprised to find that not only did she have the flexibility to pick out her course schedule, she also had to go to different places to attend classes, each with their own group of people.

“I’m really glad I went to UC Berkeley. There were a ton of opportunities and the science there was amazing. Obviously there were difficulties navigating a huge university and overcoming language barriers, but I think that also trained me to be more proactive in finding resources, finding help, looking for opportunities, and working to get them,” she says.

Laub says she’s just the type of student that MIT’s graduate programs are a good fit for.

“Our graduate program attracts people like Tong who are super rigorous scientists that really want to push that deep mechanistic, incisive understanding of things.”

Zhang is currently hard at work on her next project with “cool data” already in hand, Laub says.