Research Area: Human Disease

Lessons from teaching about the pandemic in real-time

Covid-19 class taps experts to help students and the public avoid misinformation as the crisis evolves.

Raleigh McElvery | Department of Biology
May 21, 2021

Just a few months after the Covid-19 pandemic took hold, Alan Grossman was already mulling over an idea for a new class to help people make sense of the virus. As head of MIT’s Department of Biology, he was aware of the key role fundamental research would play in the coming months. From RNA viruses and genomic sequencing to antibodies and vaccines, MIT students and the general public would need reliable scientific information to understand the evolving situation — and discern fact from fiction.

Not long after, the thoughts he’d feverishly scribbled on paper scraps scattered around his house began to take shape. With the support of the MIT School of Science, Accessibility Office, MIT Video Productions, and others around the institute, the Department of Biology added a new fall subject to the course catalog: 7.00 (Covid-19, SARS-CoV-2 and the Pandemic). Undergraduates could take the class for credit, as notable researchers stepped up to the virtual podium to share their expertise in front of a public livestream.

Grossman brought his nascent plans to associate department head and Whitehead Institute for Biomedical Research Member Peter Reddien, and together the two brainstormed individuals who might be willing to lead the class and queue speakers. They reached out to professor of biology and Whitehead Institute Member Richard Young, who served as an advisor to the World Health Organization and National Institutes of Health when a different virus of unknown origins was spreading — HIV. Young was also quick to mount a collaborative research campaign against SARS-CoV-2, the virus that causes Covid-19.

“I give Alan a lot of credit,” Young says. “He thought that it was the responsibility of the department to take the lead in filling the Covid-19 knowledge niche, and asked me if I would take this on and find a partner.”

Young contacted Ragon Institute Associate Director Facundo Batista, a world-class expert in immunology and infectious disease. Batista recalls being hesitant at first to co-lead the class; he couldn’t fathom condensing the global emergency into a single course. “But then I realized that the onslaught of information was the very reason we needed to organize this class — to help students and the public avoid misinformation,” he says. “We were filling a gap that the whole world was experiencing.”

Together, Batista and Young generated a list of 14 experts in an array of pandemic-related areas, including Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases, David Baltimore of Caltech, and Kizzmekia Corbett of the National Institutes of Health. Each geared their lecture toward MIT undergraduates with a minimal biology background, and defined key terms and concepts so non-biologists watching the livestream could follow along as well.

Although Batista and Young agree that remote learning pales in comparison to in-person classes, the livestream format opened the talks up to thousands more viewers, and allowed the speakers to present their work without the need for travel. The recordings of each Tuesday lecture were posted on the Department of Biology’s website shortly thereafter, permitting asynchronous viewing for people around the world. The livestream audience regularly exceeded 1,000, and the YouTube views for each recording ranged from 4,000-97,000 and climbing. In many cases, the week’s topic fortuitously coincided with current events. For instance, Corbett spoke about vaccine development just days after the results of Pfizer-BioNTech’s first clinical trial were announced. As one of the NIH scientists who collaborated with Moderna to design another important mRNA-based vaccine, Corbett was able to discuss her reaction to the news and her expectations for Moderna’s imminent clinical trial results.

In addition to the livestream audience, each week roughly 300 MIT undergraduates would enter the Zoom room and get the opportunity to ask questions during the Q&A. Participation was unusually high, Young and Batista recall, thanks to the recitation sessions led by graduate student and teaching assistant Lena Afeyan. Afeyan would walk the students through the fundamentals of molecular biology, virology, and any other topics slated to feature heavily in the upcoming lecture. She also invited trainees and medical residents from various institutions to attend, in order to introduce students to the next generation of scientists and health-care professionals. The supplementary reading materials from these sessions are still available online, so biology teachers and other members of the public can access them.

“When I heard that this class was being put together, I hoped I could help make the content more accessible for the students and anyone else joining us,” Afeyan says. “The responses we got were overwhelming. It was incredible to hear from so many teachers, researchers, and alums across the world who watched the course every week.”

Even today, Afeyan, Young, and Batista continue to receive international kudos from scientists and non-scientists alike. At one point, Young was even interviewed by a radio station in Tasmania about the course.

“I learned a lot from 7.00 — not only about Covid-19, but about immunology and biology in general,” says Lucas Marden, a first-year undergraduate who enrolled in the class. “I particularly enjoyed the focus on the real-world response to the pandemic. We learned about everything from designing and developing different tests, treatments, and vaccines, to the scale-up of these technologies. The scientific community’s response to Covid-19 has been incredibly impressive, and I loved learning about it from the people at the forefront of their fields.”

Now, Grossman says, the department is planning to offer the class again this coming fall. “The initial idea stemmed from the need to share clear and reliable information about the pandemic as it began spreading,” he explains. “Although we’ve been living with Covid-19 for over a year now, that need is still present today — perhaps more so as we continue to learn what it will take to tame the virus.”

The next iteration of 7.00 will begin in September, and likely feature some of the same speakers and topics, along with new experts in areas that have recently emerged, such as the evolving viral variants. By arming the MIT community and the public with information from leading experts, Grossman, Batista, Young, and Afeyan hope to help the world navigate this pandemic — and prevent the next one.

Childhood hobbies jump-start a research career

MIT Biology junior Eduardo Canto tinkered with science long before he started studying Treacher Collins syndrome in the Calo lab.

Saima Sidik | Department of Biology
May 19, 2021

In seventh grade, Eduardo Canto wanted a dog. His mom said no, though. She didn’t want to spend her days vacuuming fur. They reached a compromise: Canto was allowed to have pet fish. Soon Canto’s disappointment with his new pets turned to curiosity. While he couldn’t train the fish to sit or roll over, he decided that breeding the fish could be a fun pastime.

An internet search told Canto that some aquarists use dried Indian almond leaves, a traditional Asian herbal remedy, to stimulate fish breeding, although no one is quite sure how the leaves do this. However, finding Indian almond leaves presented a problem for a kid without an Amazon account living far from the tree’s native habitat. On a whim, Canto picked up some similar-looking leaves in a park near his house in Puerto Rico. He knew they weren’t from an Indian almond tree, but he put them in the tank anyhow, just to see what would happen. A few days later, he noticed a collection of eggs attached to the bottom of a leaf!

Canto often took on little experiments like this, which caused his grandfather to predict early on that he would have a scientific career. Eight years after the breeding endeavor, Canto is fulfilling his grandfather’s prediction by studying Course 7 (Biology) at MIT, where he’s currently in his third year of a bachelor’s degree. Once again, fish have come into Canto’s life — he’s working in Eliezer Calo’s lab, where researchers use zebrafish to study a genetic disorder called Treacher Collins syndrome, which causes deformities in eyes, ears, cheekbones, and chins.

Throughout middle school and high school, Canto dipped his toes into many scientific disciplines. School science fairs motivated him to build a dry ice-powered trolley, a solar-powered water heater, and start a vegetable garden.

Sometimes, he admits, his motivation for joining science clubs wasn’t lofty. “I joined the math club because I got to miss a day of school every year for their annual competition,” he says with a laugh. But he also talks excitedly about his early experiments, particularly in biology. “I’ve always loved working with my hands,” he says.

Canto’s father, a medical doctor, encouraged his son’s interest by letting Canto shadow him at work. He also started a molecular biology summer program at Canto’s high school that taught students how to pipette and do simple experiments. By the time Canto applied to college, he was convinced he wanted to study biology, and MIT drew his attention because of its reputation as a top science school with excellent biology teachers. He knew it was the right choice for him when he attended Campus Preview Weekend, and found a large Puerto Rican community ready to welcome him. Even far from the island, he felt at home.

Canto has kept up with his roots since joining MIT by playing on a soccer team for Puerto Rican students. He’s also become part of a new community in a lab run by Eliezer Calo — who is a Puerto Rican himself. The lab is interested in ribosomes, the molecular machines that build proteins. Treacher Collins syndrome arises when cells can’t make ribosomes properly, and Canto wants to understand why that is.

Before Canto joined the Calo lab, the group had already started studying a protein called DDX21 that’s involved in making ribosomes in both humans and zebrafish. When genetic mutations in zebrafish cause DDX21 to go to the wrong part of the cell, the fish develop jaw deformations that mirror Treacher Collins syndrome. The Calo lab thinks cells with mislocalized DDX21 probably don’t produce ribosomes as well as normal cells, but they’re still testing this hypothesis.

Canto wants to probe the relationship between DDX21 and Treacher Collins syndrome further, but fish reproduce slowly, so they’re not ideal organisms for his research. Instead, he’s built a strain of Escherichia coli bacteria that carry DDX21 in place of the equivalent bacterial gene. DDX21 helps these bacteria survive the stress associated with cold temperatures, so without it, the bacteria will die in the cold. Canto hopes to take advantage of this trait by finding small molecules that stop the bacteria from growing at low temperatures — just like a DDX21 mutation would. Studying how these molecules bind DDX21 will help him understand which parts of this protein are important for its function.

The possibility that this work will one day reveal how Treacher Collins syndrome develops in patients is rewarding to Canto, and in fact he hopes helping patients will soon become his life’s focus. He wants to attend medical school, and eventually become a doctor. The human physiology class he took last semester was one of his favorites, even though it was over Zoom due to the COVID-19 pandemic. Becoming a doctor will let him help others while studying topics he finds fascinating. “Medicine is like biology on steroids!” he says.

And who knows — one day after he’s a doctor, maybe he’ll even get that pet he’s always wanted. But unlike Canto’s interest in biology, some of his interests have evolved over time. These days, he prefers cats over dogs.

Photo credit: Saima Sidik
Posted: 5.19.21
Olivia Corradin

Education

  • PhD, 2015, Case Western Reserve University
  • BS, 2010, Biochemistry, Marquette University

Research Summary

Our lab studies genetic and epigenetic variation that contributes to human disease by disrupting gene expression programs. We utilize biological insights into the mechanisms of gene regulation in order to determine the impact of disease-associated variants on cellular function. We aim to identify actionable insights into disease pathogenesis by studying the confluence of genetic and epigenetic risk factors of human diseases, including multiple sclerosis and opioid use disorder.

Awards

  • NIH Director’s Pioneer Award Program Avenir Award, 2017
Spying on enzymes while they perform chemical reactions could help treat gut ailments
Raleigh McElvery
March 26, 2021

Humans breathe oxygen, but many microbes deep within in our gut don’t have access to this precious resource. Instead, they breathe sulfur compounds, releasing hydrogen sulfide in the process. This colorless gas is best-known for its rotten stench, but inside the human colon it has been linked to a thinner mucus barrier, and ailments such as inflammatory bowel disease, Crohn’s disease, ulcerative colitis, and colorectal cancer. In order to develop potential treatments, researchers are probing how microbes create hydrogen sulfide and which molecules they use.

To help further these efforts, Catherine Drennan’s lab and Heather Kulik’s lab at MIT collaborated with Emily Balskus’ lab at Harvard University to investigate the structure and mechanism of an enzyme that’s critical for hydrogen sulfide production: isethionate sulfite-lyase (IslA). The team examined IslA while it was bound to a metabolite that’s readily available in the gut — and revealed how the bacterium Bilophila wadsworthia uses this interaction to help generate the hydrogen sulfide precursor called sulfite. The researchers then compared IslA’s binding behavior to other enzymes in the same family, in order to better understand how these enzymes have evolved to perform challenging chemistry on a wide variety of molecules. Their findings were published on Mar. 26 in the journal Cell Chemical Biology.

“Although abundant, sulfide-producing bacteria are not well understood,” says Drennan, a professor of biology and chemistry and a Howard Hughes Medical Institute investigator. “By characterizing the enzymes in these bacteria that are responsible for sulfur metabolism, we can develop therapeutic strategies to limit production of hydrogen sulfide that can lead to disease.”

Although researchers have been studying bacterial sulfur respiration for decades, IslA was only recently identified. This enzyme breaks the bond between a carbon atom and a sulfur atom in a compound called isethionate, which is a prevalent metabolite in the human body. In doing so, IslA releases the sulfite that bacteria such as B. wadsworthia use to produce hydrogen sulfide.

IslA is a member of a large family of enzymes, known as glycyl radical enzyme (GREs). Scientists can learn a lot from examining the way GREs bind to other molecules, according to Christopher Dawson PhD ’20, the study’s co-first author.

GREs contain a binding site (or “active site”) where they latch onto their respective substrates to perform chemical reactions. “Understanding GREs better will aid in drug design efforts to combat the deleterious effects of some of these enzymes,” Dawson says. “It will also help to engineer enzymes that perform diverse, challenging reactions to expand the toolkit for chemical synthesis.”

To this end, Dawson wanted to compare IslA’s active site — where it binds to isethionate to break the C-S bond — to other enzymes in the GRE family. He used X-ray crystallography to visualize this interaction at the level of individual atoms. The GREs he examined shared similar “barrel-like” structures in their active sites, but used these core features in different ways, depending on the substrates they bound. For instance, isethionate bound higher in IslA’s active site compared to the way other GREs bind their respective substrates. While this aberrant binding behavior is quite unique — even among GREs — another group had found something similar when they elucidated IslA’s structure in a different bacterium. And, the Drennan lab suspects this pattern could be prevalent in other classes of enzymes as well.

Next, Dawson and his colleagues wanted to investigate how IslA goes about cleaving the C-S bond once the enzyme has bound to isethionate. Others had predicted this process would occur via a “migration” reaction. In that scenario, the sulfite leaving group first migrates to another carbon atom and then that C-S bond is cleaved to release it. However, after co-first author Stephania Irwin generated multiple IslA variants, the Kulik lab performed computational analyses, and the researchers completed structural comparisons, the team concluded that migration was not occurring. Instead, IslA appeared to be performing an “elimination” reaction that severed the C-S bond without forming another one via migration.

Now that they know more about IslA — and GREs in general — the researchers hope their insights will aid drug design.

“Understanding how pathogens use enzymes like these to extract sulfite from their hosts and fuel hydrogen sulfide production has very clear therapeutic implications,” Dawson says. “And that’s one of the things I like best about this story.”

Citation
“Molecular Basis of C-S Bond Cleavage in the Glycyl Radical Enzyme Isethionate Sulfite-Lyase”
Cell Chemical Biology, online March 26, 2021,
DOI: 10.1016/j.chembiol.2021.03.001
Christopher D. Dawson, Stephania M. Irwin, Lindsey R. F. Backman, Chip Le, Jennifer X. Wang, Vyshnavi Vennelakanti, Zhongyue Yang, Heather J. Kulik, Catherine L. Drennan, and Emily P. Balskus

Understanding antibodies to avoid pandemics

Structural biologist Pamela Björkman shared insights into pandemic viruses as part of the Department of Biology’s IAP seminar series.

Saima Sidik | Department of Biology
January 19, 2021

Last month, the world welcomed the rollout of vaccines that may finally curb the Covid-19 pandemic. Pamela Björkman, the David Baltimore Professor of Biology and Bioengineering at Caltech, wants to understand how antibodies like the ones elicited by these vaccines target the SARS-CoV-2 virus that causes Covid-19. She hopes this understanding will guide treatment strategies and help design vaccines against future pandemics. She shared her lab’s work during the MIT Department of Biology’s Independent Activities Period (IAP) seminar series, Immunity from Principles to Practice, on Jan. 12.

“Pamela is an amazing scientist, a strong advocate for women in science, and has a stellar history of studying the structural biology of virus-antibody interactions,” says Whitehead Institute for Biomedical Research Member Pulin Li, the Eugene Bell Career Development Professor of Tissue Engineering and one of the organizers of this year’s lecture series.

Immunology research often progresses from the lab bench to the clinic quickly, as was the case with Covid-19 vaccines, says Latham Family Career Development Professor of Biology and Whitehead Institute Member Sebastian Lourido, who organized the lecture series with Li. He and Li chose to focus this year’s seminar series on immunity because this field highlights the tie between basic molecular biology, which is a cornerstone of the Department of Biology, and practical applications.

“Pamela’s work is an excellent example of how fundamental discoveries can be intimately tied to real-world applications,” Lourido says.

Björkman’s lab has a long history of studying antibodies, which are protective proteins that the body generates in response to invading pathogens. Björkman focuses on neutralizing antibodies, which bind and jam up the molecular machines that let viruses reproduce in human cells. Last fall, the U.S. Food and Drug Administration (FDA) authorized a combination of two neutralizing antibodies, produced by the pharmaceutical company Regeneron, for emergency use in people with mild to moderate Covid-19. This remains one of the few treatments available for the disease.

Together with Michel Nussenzweig’s lab at The Rockefeller University, Börkman’s lab identified four categories of neutralizing antibodies that prevent a protein that decorates SARS-CoV-2’s surface, called the spike protein, from binding to a human protein called ACE2. Spike acts like the virus’s key, with ACE2 being the lock it has to open to enter human cells. Some of the antibodies that Björkman’s lab characterized bind to the tip of spike so that it can’t fit into ACE2, like sticking a wad of chewing gum on top of the virus’s key. Others block spike proteins from interacting with ACE2 by preventing them from altering their orientations. Understanding the variety of ways that neutralizing antibodies work will let scientists figure out how to combine them into maximally effective treatments.

Björkman isn’t satisfied with just designing treatments for this pandemic, however. “Coronavirus experts say this is going to keep happening,” she says. “We need to be prepared next time.”

To this end, Björkman’s lab has put pieces of spike-like proteins from multiple animal coronaviruses onto nanoparticles and injected them into mice. This made the mice generate antibodies against a mix of pathogens that are poised to jump into humans, suggesting that scientists could use this approach to create vaccines before pandemics occur. Importantly, the nanoparticles still work after they’re freeze-dried, meaning that companies could stockpile them, and that they could be shipped at room temperature.

Björkman’s talk was the second in the Immunity from Principles to Practice series, which was kicked off by Gabriel Victora from The Rockefeller University. Victora discussed how antibodies are produced in structures called germinal centers that are found in lymph nodes and the spleen.

Next in the series is Chris Garcia from Stanford University, who will speak on Jan. 19 about his lab’s work on engineering immune signaling molecules to maximize their potential to elicit therapeutic responses. To round out the series, Yasmine Belkaid from the National Institute of Allergy and Infectious Disease will speak on Jan. 26 about interactions between the gut microbiome and the pathogens we ingest. These talks complement a number of career development seminars that were organized by graduate students Fiona Aguilar, Alex Chan, Chris Giuliano, Alice Herneisen, Jimmy Ly, and Aditya Nair.

3 Questions: Phillip Sharp on the discoveries that enabled RNA vaccines for Covid-19

Curiosity-driven basic science in the 1970s laid the groundwork for today’s leading vaccines against the novel coronavirus.

School of Science
December 11, 2020

Some of the most promising vaccines developed to combat Covid-19 rely on messenger RNA (mRNA) — a template cells use to carry genetic instructions for producing proteins. The mRNA vaccines take advantage of this cellular process to make proteins that then trigger an immune response that targets SARS-CoV-2, the virus that causes Covid-19.

Compared to other types of vaccines, recently developed technologies allow mRNA vaccines to be rapidly created and deployed on a large-scale — crucial aspects in the fight against Covid-19. Within the year since the identification and sequencing of the SARS-CoV-2 virus, companies such as Pfizer and Moderna have developed mRNA vaccines and run large-scale trials in the race to have a vaccine approved by the U.S. Food and Drug Administration — a feat unheard of with traditional vaccines using live attenuated or inactive viruses. These vaccines appear to have a greater than 90 percent efficacy in protecting against infection.

The fact that these vaccines could be rapidly developed within these last 10 months rests on more than four decades of study of mRNA. This success story begins with Institute Professor Phillip A. Sharp’s discovery of split genes and spliced RNA that took place at MIT in the 1970s — a discovery that would earn him the 1993 Nobel Prize in Physiology or Medicine.

Sharp, a professor within the Department of Biology and member of the Koch Institute for Integrative Cancer Research at MIT, commented on the long arc of scientific research that has led to this groundbreaking, rapid vaccine development — and looked ahead to what the future might hold for mRNA technology.

Q: Professor Sharp, take us back to the fifth floor of the MIT Center for Cancer Research in the 1970s. Were you and your colleagues thinking about vaccines when you studied viruses that caused cancer?

A: Not RNA vaccines! There was a hope in the ’70s that viruses were the cause of many cancers and could possibly be treated by conventional vaccination with inactivated virus. This is not the case, except for a few cancers such as HPV causing cervical cancer.

Also, not all groups at the MIT Center for Cancer Research (CCR) focused directly on cancer. We knew so little about the causes of cancer that Professor Salvador Luria, director of the CCR, recruited faculty to study cells and cancer at the most fundamental level. The center’s three focuses were virus and genetics, cell biology, and immunology. These were great choices.

Our research was initially funded by the American Cancer Society, and we later received federal funding from the National Cancer Institute, part of the National Institutes of Health and the National Science Foundation — as well as support from MIT through the CCR, of course.

At Cold Spring Harbor Laboratory in collaboration with colleagues, we had mapped the parts of the adenovirus genome responsible for tumor development. While doing so, I became intrigued by the report that adenovirus RNA in the nucleus was longer than the RNA found outside the nucleus in the cytoplasm where the messenger RNA was being translated into proteins. Other scientists had also described longer-than-expected nuclear RNA from cellular genes, and this seemed to be a fundamental puzzle to solve.

Susan Berget, a postdoc in my lab, and Claire Moore, a technician who ran MIT’s electron microscopy facility for the cancer center and would later be a postdoc in my lab, were instrumental in designing the experiments that would lead to the iconic electron micrograph that was the key to unlocking the mystery of this “heterogeneous” nuclear RNA. Since those days, Sue and Claire have had successful careers as professors at Baylor College of Medicine and Tufts Medical School, respectively.

The micrograph showed loops that would later be called “introns” — unnecessary extra material in between the relevant segments of mRNA, or “exons.” These exons would be joined together, or spliced, to create the final, shorter message for the translation to proteins in the cytoplasm of the cell.

This data was first presented at the Cancer Center fifth floor group meeting that included Bob Weinberg, David Baltimore, David Housman, and Nancy Hopkins. Their comments, particularly those of David Baltimore, were catalysts in our discovery. Our curiosity to understand this basic cellular mechanism drove us to learn more, to design the experiments that could elucidate the RNA splicing process. The collaborative environment of the MIT Cancer Center allowed us to share ideas and push each other to see problems in a new way.

Q: Your discovery of RNA splicing was a turning point, opening up new avenues that led to new applications. What did this foundation allow you to do that you couldn’t do before?

A: Our discovery in 1977 occurred just as biotechnology appeared with the objective of introducing complex human proteins as therapeutic agents, for example interferons and antibodies. Engineering genes to express these proteins in industrial tanks was dependent on this discovery of gene structure. The same is true of the RNA vaccines for Covid-19: By harnessing new technology for synthesis of RNA, researchers have developed vaccines whose chemical structure mimics that of cytoplasmic mRNA.

In the early 1980s, following isolation of many human mutant disease genes, we recognized that about one-fifth of these were defective for accurate RNA splicing. Further, we also found that different isoforms of mRNAs encoding different proteins can be generated from a single gene. This is “alternative RNA splicing” and may explain the puzzle that humans have fewer genes — 21,000 to 23,000 — than many less complex organisms, but these genes are expressed in more complex protein isoforms. This is just speculation, but there are so many things about biology yet to be discovered.

I liken RNA splicing to discovering the Rosetta Stone. We understood how the same letters of the alphabet could be written and rewritten to form new words, new meaning, and new languages. The new “language” of mRNA vaccines can be developed in a laboratory using a DNA template and readily available materials. Knowing the genetic code of the SARS-CoV-2 is the first step in generating the mRNA vaccine. The effective delivery of vaccines into the body based on our fundamental understanding of mRNA took decades more work and ingenuity to figure out how to evade other cellular mechanisms perfected over hundreds of millions of years of evolution to destroy foreign genetic material.

Q: Looking ahead 40 more years, where do you think mRNA technology might be?

A: In the future, mRNA vaccine technology may allow for one vaccine to target multiple diseases. We could also create personalized vaccines based on individuals’ genomes.

Messenger RNA vaccines have several benefits compared to other types of vaccines, including the use of noninfectious elements and shorter manufacturing times. The process can scaled up, making vaccine development faster than traditional methods. RNA vaccines can also be moved rapidly into clinical trials, which is critical for the next pandemic.

It is impossible to predict the future of RNA therapies, such as the new vaccines, but there are some signs that new advancements could happen very quickly. A few years ago, the first RNA-based therapy was approved for treatment of lethal genetic disease. This treatment was designed through the discovery of RNA interference. Messenger RNA-based therapies will also likely be used to treat genetic diseases, vaccinate against cancer, and generate transplantable organs. It is another tool at the forefront of modern medical care.

But keep in mind that all mRNAs in human cells are encoded by only 2 percent of the total genome sequence. Most of the other 98 percent is transcribed into cellular RNAs whose activities remain to be discovered. There could be many future RNA-based therapies.

Vaccine Booster

Biologist Jianzhu Chen works to enhance immune response

Mark Wolverton | Spectrum
November 16, 2020

Jianzhu Chen, professor of biology and a member of the Koch Institute for Integrative Cancer Research at MIT, is pursuing a different strategy from most of his colleagues working on SARS-CoV-2, the virus that causes Covid-19. “We focus on the immune system and fundamental mechanisms as well as their application in cancer immunotherapy, vaccine development, and metabolic diseases,” he explains. Rather than trying to develop a specific vaccine, Chen is pursuing vaccine platform technologies that can be used to enhance any vaccine.

This effort is built on Chen’s previous work on dengue fever, a severe tropical disease transmitted by mosquitos. “We have been working to improve a vaccine against dengue virus infection,” he says, “which has this phenomenon called antibody-dependent enhancement,” in which “non-neutralizing” antibodies bind to the virus but do not destroy it. The immune system’s pathogen-eating macrophages then consume these virus-antibody complexes and become infected themselves, making a subsequent infection worse.

Chen’s team has identified vaccine adjuvants, or enhancing agents, that can increase neutralizing (that is, effective) antibodies while reducing non-neutralizing antibody response in mice and nonhuman primates. The team is confident that using a similar strategy against Covid-19 would improve any vaccine’s effectiveness.

Addressing cytokine storm

Chen is also focusing on the dangerous hyperinflammatory response seen in Covid-19: the cytokine storm that can result when the immune system overreacts to infection.

“We have been working on macrophage biology for quite some time,” Chen says. “SARS-CoV-2 infection is a hyperinflammatory response, and macrophages probably play a critical role in that response.”

“We have identified many compounds, including FDA-approved drugs, bioactive compounds, and natural products that can modulate macrophage activity to become anti-inflammatory,” he says. Such macrophage modulation would likely be used in conjunction with other treatments as a therapeutic strategy for already-infected patients.

A promising result from either research project could be used along with a Covid-19 vaccine to enhance immune response while preventing or reducing the severity of any possible reinfection. But it’s too early to tell what might happen. “We don’t have a vaccine yet,” Chen notes. “It’s not clear when we’ll have one. Even when we have one, it’s not clear how well it will work. It could be 95% protection; it could be 50%. Some of them may not confer much protection at all. But even 50% or 60% is a significant number of people.”

Another challenge, Chen acknowledges, is that medical research must move from theory to lab and ultimately into the real world. Vaccines can be designed and modeled on computers but eventually “we have to test them to see if they work as we expect,” he says. “You have to immunize mice or some other animals and then challenge them with SARS-CoV-2 to see whether the vaccine protects the animals from infection or dramatically minimize disease symptoms. These kinds of studies can’t be modeled computationally.”

Chen also hopes that his particular contributions will have benefits beyond the pandemic. “We’re aiming to develop a vaccine platform prototyped on SARS-CoV-2 that can be used for the development of many other vaccines as well, using the most appropriate technologies.” If that happens, science will have dug at least one substantial jewel out of the depths of an unprecedented public health crisis.

Two treatment methods enhance chemotherapy by the same means: cellular senescence
Raleigh McElvery
November 10, 2020

In 2019, cancer researchers from MIT found a drug that targeted an elusive molecular interaction previously considered “undruggable.” In so doing, they opened up a new realm of chemotherapy. This drug, called JH-RE-06, sensitized tumors to treatment, but the scientists didn’t fully understand how it exerted its effects. Now, in a pair of studies published in PNAS, the same team is closer to determining which cellular processes this drug alters to enhance cancer therapy.

Many widely-used chemotherapies, like cisplatin, kill tumors by damaging their DNA and inducing programmed cell death. But cells are resilient, and many can continue to function with the help of repair enzymes that simply bypass the damage and continue to replicate the DNA. As a result, some tumors not only defy death, but gain mutations that render them more resistant to treatment or spur new malignancies elsewhere.

“If you’re not making a patient better, it’s very likely you’re making them worse,” says Michael Hemann, associate professor of biology and co-author on both studies. Rather than fully replacing conventional DNA-damaging treatments — which could take decades — Hemann suggests an effective “medium-term” solution: augmenting low doses of cisplatin with safer agents that strengthen the chemotherapy’s tumor-killing capacity.

The team had tested this approach back in 2019, when they first identified JH-RE-06 and saw it enhanced chemotherapy treatment. These experiments revealed that JH-RE-06 bound to an especially shallow (and infamously undruggable) pocket of one DNA repair enzyme called REV1. This barred REV1 from interacting with another key enzyme, and prevented the cancer cells from recovering after cisplatin treatment. But what happened next to cause the tumors to shrink was unclear.

As they began their next round of experiments, the researchers expected to find that the drug would simply enhance the way cisplatin kills tumors via programmed cell death.

Nimrat Chatterjee, Walker’s former postdoc and lead author of the first study, treated mice and individual cells with a combination of cisplatin and JH-RE-06. She expected to see signs of programmed cell death, but for months, she saw no such markers.“We thought that if we blocked the DNA repair process with the JH compound, we’d see more programmed cell death,” says co-author Graham Walker, American Cancer Society Professor and Howard Hughes Medical Institute Professor. “As it turns out, we did see more cell death — just not the kind we were expecting.”

One evening, just as she was about to head home for the day, she peeked through her microscope at the cancer cells treated with JH-RE-06 and cisplatin. She noticed they were fluorescing a strange green color.

“At first, I didn’t know what I was seeing,” she recalls. But after some follow-up, it became clear that the mysterious green color was coming from lipid-containing residues that usually appear as cells age and stop dividing. The cells appeared to be in a permanently dormant state known as senescence — not yet dead but unable to proliferate. JH-RE-06 was altering cisplatin function by triggering a second molecular pathway independent of programmed cell death.

“That was one of the best ‘aha’ moments of my scientific career so far,” Chatterjee says. “REV1, the DNA repair enzyme that JH-RE-06 binds, may have other novel biological functions and a larger role in cancer cell etiology than we originally thought. We’re now grappling with more questions about REV1 than ever before.”

Around the same time, Faye-Marie Vassel PhD ’20, Walker and Hemann’s former joint graduate student and lead author of the second study, witnessed a similar phenomenon in her own experiments. She was investigating a different way of inhibiting the two key DNA repair enzymes that enable cancer cells to survive chemotherapy. Instead of probing JH-RE-06, which latches onto REV1, she tried deleting REV1’s binding partner, called REV7. This protein is particularly influential because it serves an important role in fixing double-stranded breaks in addition to interacting with REV1.

When Vassel deleted REV7 from mice with non-small cell lung cancer, the tumors became more sensitive to cisplatin, as expected. But, like Chatterjee, she saw signs of senescence rather than programmed cell death. The two studies had converged on a common biology: adding JH-RE-06 or deleting REV7 strengthened the effects of cisplatin by inducing this dormant state.

Cancer detection and treatment methods have improved dramatically in the last two decades, but drug-resistant cancers like non-small cell lung cancer remain difficult to combat, Vassel says. “Our experiments are the first to show that senescence induction is likely a consequence of REV7 inhibition,” she adds. “Inhibiting REV7 in tandem with cisplatin therapy may prove to be an effective strategy for enhancing a chemotherapeutic response.”

Chemotherapies that trigger programmed cell death have been the mainstay of cancer treatment for decades. But studies like these show that triggering senescence may be a promising complementary strategy. Most senescent cells are eventually cleared by the immune system, and the researchers suspect this is how cancer cells treated with JH-RE-06 or REV7 inhibitors would be eliminated from the body.

Walker and Hemann agree that, at the moment, their sister studies raise more questions than answers. As Walker explained, “We’ve pried open a new discovery, and hopefully set the stage for many exciting experiments to come.”

Top image: Genetically-engineered mouse model for lung cancer. Credit: Credit: National Cancer Institute, National Institutes of Health. NIH Image Gallery/Flickr (CC BY-NC)
The REV7 image was originally published in: “Structural basis of Rev1-mediated assembly of a quaternary vertebrate translesion polymerase complex consisting of Rev1, heterodimeric polymerase (Pol) ζ, and Pol κ.”
Journal of Biological Chemistry, online August 2, 2012, DOI: 10.1074/jbc.M112.394841
Jessica Wojtaszek, Chul-Jin Lee, Sanjay D’Souza, Brenda Minesinger, Hyungjin Kim, Alan D. D’Andrea, Graham C. Walker, and Pei Zhou.

Citations:
“REV1 inhibitor JH-RE-06 enhances tumor cell response to chemotherapy by triggering senescence hallmarks”
Proceedings of the National Academy of Sciences, online November 9, 2020, DOI: 10.1073/pnas.2016064117
Nimrat Chatterjee , Matthew A Whitman, A Harris , Sophia M Min , Oliver Jonas , Evan C Lien , Alba Luengo , Matthew G Vander Heiden , Jiyong Hong , Pei Zhou , Michael T Hemann , and Graham C Walker 

“Rev7 loss alters cisplatin response and increases drug efficacy in chemotherapy-resistant lung cancer”
Proceedings of the National Academy of Sciences, online November 3, 2020, DOI: 10.1073/pnas.2016067117
Faye-Marie Vassel, Ke Bian, Graham C. Walker, and Michael T. Hemann

Aspiring physician explores the many levels of human health

During her time at MIT, senior Ayesha Ng’s interests have expanded from cellular biology to the social systems that shape public health.

Alison Gold | School of Science
November 9, 2020

It was her childhood peanut allergy that first sparked senior Ayesha Ng’s fascination with the human body. “To see this severe reaction happen to my body and not know what was happening — that made me a lot more curious about biology and living systems,” Ng says.

She didn’t exactly plan it this way. But in her three and a half years at MIT, Ng, a biology and cognitive and brain sciences double major from the Los Angeles, California area, has conducted research and taken classes examining just about every level of human health — from cellular to societal.

Most recently, her passion for medicine and health equity led her to the National Foundation for the Centers for Disease Control and Prevention (CDC), where, this summer, she worked to develop guidelines for addressing health disparities on state and local health jurisdictions’ Covid-19 data dashboards. Now, as an aspiring physician amidst the medical school application process, Ng has a sense of how microbiological, physiological, and social systems interact to affect a person’s health.

Starting small

Throughout her entire first year at MIT, Ng studied the biology of health at a cellular level. Specifically, she researched the effects of fasting and aging on regeneration of intestinal stem cells, which are located in the human intestinal crypts and continuously self-divide and reproduce. Understanding these metabolic mechanisms is crucial, as their deregulation can lead to age-associated diseases such as cancer.

“That experience allowed me to broaden my technical skills, just getting used to so many different types of molecular biological techniques right away, which I really appreciated,” Ng says of her time at the Whitehead Institute for Biomedical Research in Professor David Sabatini’s lab.

“After some time, I realized that I also wanted to also study sciences at a broader, more macro level, instead of only the microbiology and molecular biology that we were studying in Course 7,” Ng says of her biology major.

In addition to studying the biology of cancer, Ng had developed a curiosity about the human brain and how it functions. “I was really interested in that, because my grandpa has dementia,” Ng says.

Seeing her grandfather’s cognitive decline, she was inspired to become involved in MIT BrainTrust, a student organization that offers a social support network for individuals from around the Boston, Massachusetts area who have brain injuries. “We have these meetings, in which I serve as one of only one or two students there to facilitate a safe space where we can have all these individuals with brain injury gather,” Ng says of the peer-support aspect of the program. “They can really share their mutual challenges and experiences.”

Investigating the brain

To pursue her interest in brain research and the societal impact of brain injuries, Ng traveled to the University of Hong Kong the summer after her first year as an MIT International Science and Technology Initiatives (MISTI) China Fung Scholar. Working with Professor Raymond Chang, she began to examine neurodegenerative disease and used tissue-clearing techniques to visualize 3D mouse brain structures at cellular resolution. “That was personally meaningful for me, to research about that and learn more about dementia,” Ng says.

Returning to MIT her sophomore year, Ng was certain that she wanted to continue studying the brain. She began working on Alzheimer’s research at the MIT Picower Institute for Learning and Memory in the lab of Professor Li-Huei Tsai, the Picower Professor of Neuroscience at MIT. Much existing research into Alzheimer’s disease has been at the bulk-tissue level, focusing on the neurons’ role in neurodegeneration associated with aging.

Ng’s work with Tsai considers the complexity of alterations across genes and less-abundant cell types, such as microglia, astrocytes, and other supporting glial cells that become dysregulated in the brains of patients with Alzheimer’s. Considering the interplay between and within cell types during neurodegeneration is most intriguing to her. While some molecular processes are protective, other damaging ones simultaneously occur and can exist even within the same cell type. This intricacy has made the mechanistic basis behind Alzheimer’s progression elusive and the research that much more crucial.

“It’s really interesting to see how heterogeneous and complex the responses are in Alzheimer’s brains,” Ng says of the research program with Tsai, a founding director of MIT’s Aging Brain Initiative. “I really think about these potential new drug targets to improve treatment for Alzheimer’s in the future because I have seen, with my grandpa especially, how treatment is really lacking in the neurodegeneration field. There’s no treatment that’s been able to stop or even slow the progression of Alzheimer’s disease.”

Her research project in the Tsai Lab relies on a technology called single-nucleus RNA sequencing (snRNA-seq), which extracts the genomic information contained in individual cells. This is followed by computational dimension reduction and clustering algorithms to examine how Alzheimer’s disease differentially affects genes and specific cell types.

“With that project, we’ve been able to use single-nucleus RNA sequencing to really look at the brains of human Alzheimer’s patients,” Ng says. “And with the single-cell technology, we’re able to look at brain tissue at a much higher resolution, allowing us to see that there’s so much heterogeneity within the brain.”

After conducting more than a year of Alzheimer’s research and then taking a human physiology class in her third year, Ng decided to add a second major in brain and cognitive sciences to gain deeper insight specifically into how the nervous system within the body functions.

“That class really allowed me to realize that I really love organ systems and wanted to study by looking at more physiological mechanisms,” Ng says. “It has been really great to, at the end of my college career, really delve more into a very specific system.”

Medicine and society

Having gained perspective on cellular and microbiology, and human organ systems, Ng decided to zoom out further, interning this past summer at the National Foundation for the CDC. She found the opportunity through MIT’s PKG Center, applied as one of 60 candidates, and was selected for a team of four. There, as a member of the CDC Foundation’s Health Equity Strike Team, she examined how to increase transparency of publicly available Covid-19 data on health disparities and how the narrative tied to health equity can be modified in public health messages. This involved harnessing data about the demographics of those most affected during Covid-19 — including how infection and mortality rates differ starkly based on social factors including housing conditions, socioeconomic status, race, and ethnicity.

“Thinking about all these factors, we compiled a set of best practices for how to present data about Covid-19, what data should be collected, and tried to push those out to help jurisdictions as best-practice recommendations,” Ng says. “That did really increase my interest in health equity and made me realize how important public health is as well.”

Amidst the Covid-19 pandemic, Ng is spending the first semester of her senior year at home with her family in the Los Angeles area. “I really miss the people and not being able to interact with not only other students and peers, but also faculty as well,” she says. “I really wanted to enjoy time with friends, and just explore more of MIT, too, which I didn’t always get the chance to do over the past few years.”

Still, she continues to participate in both BrainTrust and MIT’s Asian Dance team, remotely, through weekly practices on Zoom.

“I think dance is one of the biggest de-stressors for me; I had never done dance before going to college. Getting to meet this team and join this community allowed me not only to connect to my Asian cultural roots, but also just expose myself to this new art form where I could really learn how to express myself on stage,” Ng says. “And that really has been the source of relief for me to just liberate any worries that I have, and has increased my sense of self-awareness and self-confidence.”

Armed with the many experiences she has enjoyed at MIT, both in and out of the classroom, Ng plans to continue studying both medicine and public health. She’s excited to explore different potential specialties and is currently most intrigued by surgery. Whichever specialty she may choose, she is determined to include health equity and cultural sensitivity in her practice.

“Seeing surgeons, I personally think that being able to physically heal a patient with my own hands, that would be the most rewarding feeling,” Ng says. “I will strive to, as a physician, use whatever platform that I have to advocate for patients and really drive health-care systems to overcome disparities.”

Cancer researchers collaborate, target DNA damage repair pathways for cancer therapy

MIT researchers find blocking the expressions of the genes XPA and MK2 enhances the tumor-shrinking effects of platinum-based chemotherapies in p53-mutated cancers.

Koch Institute
October 2, 2020

Cancer therapies that target specific molecular defects arising from mutations in tumor cells are currently the focus of much anticancer drug development. However, due to the absence of good targets and to the genetic variation in tumors, platinum-based chemotherapies are still the mainstay in the treatment of many cancers, including those that have a mutated version of the tumor suppressor gene p53. P53 is mutated in a majority of cancers, which enables tumor cells to develop resistance to platinum-based chemotherapies. But these defects can still be exploited to selectively target tumor cells by targeting a second gene to take down the tumor cell, leveraging a phenomenon known as synthetic lethality.

Focused on understanding and targeting cell signaling in cancer, the laboratory of Michael Yaffe, the David H. Koch Professor Science and director of the MIT Center for Precision Cancer Medicine, seeks to identify pathways that are synthetic lethal with each other, and to develop therapeutic strategies that capitalize on that relationship. His group has already identified MK2 as a key signaling pathway in cancer and a partner to p53 in a synthetic lethal combination.

Now, working with a team of fellow researchers at MIT’s Koch Institute for Integrative Cancer Research, Yaffe’s lab added a new target, the gene XPA, to the combination. Appearing in Nature Communications, the work demonstrates the potential of “augmented synthetic lethality,” where depletion of a third gene product enhances a combination of targets already known to show synthetic lethality. Their work not only demonstrates the effectiveness of teaming up cancer targets, but also of the collaborative teamwork for which the Koch Institute is known.

P53 serves two functions: first, to give cells time to repair DNA damage by pausing cell division, and second, to induce cell death if DNA damage is too severe. Platinum-based chemotherapies work by inducing enough DNA damage to initiate the cell’s self-destruct mechanism. In their previous work, the Yaffe lab found that when cancer cells lose p53, they can re-wire their signaling circuitry to recruit MK2 as a backup pathway. However, MK2 only restores the ability to orchestrate DNA damage repair, but not to initiate cell death.

The Yaffe group reasoned that targeting MK2, which is only recruited when p53 function is absent, would be a unique way to create a synthetic lethality that specifically kills p53-defective tumors, by blocking their ability to coordinate DNA repair after chemotherapy. Indeed, the Yaffe Lab was able to show in pre-clinical models of non-small cell lung cancer tumors with mutations in p53, that silencing MK2 in combination with chemotherapy treatment caused the tumors to shrink significantly.

Although promising, MK2 has proven difficult to drug. Attempts to create target-specific, clinically viable small-molecule MK2 inhibitors have so far been unsuccessful. Researchers led by co-lead author Yi Wen Kong, then a postdoc in the Yaffe lab, have been exploring the use of RNA interference (siRNA) to stop expression of the MK2 gene, but siRNA’s tendency to degrade rapidly in the body presents new challenges.

Enter the potential of nanomaterials, and a team of nanotechnology experts in the laboratory of Paula Hammond, the David H. Koch Professor of Engineering, head of the MIT Department of Chemical Engineering, and the Yaffe group’s upstairs neighbor. There, Kong found a willing collaborator in then-postdoc Erik Dreaden, whose team had developed a delivery vehicle known as a nanoplex to protect siRNA until it gets to a cancer cell. In studies of non-small cell lung cancer models where mice were given the MK2-targeting nanocomplexes and standard chemotherapy, the combination clearly enhanced tumor cell response to chemotherapy. However, the overall increase in survival was significant, but relatively modest.

Meanwhile, Kong had identified XPA, a key protein involved in another DNA repair pathway called NER, as a potential addition to the MK2-p53 synthetic lethal combination. As with MK2, efforts to target XPA using traditional small-molecule drugs have not yet proven successful, and RNA interference emerged as the team’s tool of choice. The flexible and highly controllable nature of the Hammond group’s nanomaterials assembly technologies allowed Dreaden to incorporate siRNAs against both XPA and MK2 into the nanocomplexes.

Kong and Dreaden tested these dual-targeted nanocomplexes against established tumors in an immunocompetent, aggressive lung cancer model developed in collaboration between the laboratories of professor of biology Michael Hemann and Koch Institute Director Tyler Jacks. They let the tumors grow even larger before treatment than they had in their previous study, thus raising the bar for therapeutic intervention.

Tumors in mice treated with the dual-targeted nanocomplexes and chemotherapy were reduced by up to 20-fold over chemotherapy alone, and similarly improved over single-target nanocomplexes and chemotherapy. Mice treated with this regimen survived three times longer than with chemotherapy alone, and much longer than mice receiving nanocomplexes targeting MK2 or XPA alone.

Overall, these data demonstrate that identification and therapeutic targeting of augmented synthetic lethal relationships — in this case between p53, MK2 and XPA — can produce a safe and highly effective cancer therapy by re-wiring multiple DNA damage response pathways, the systemic inhibition of which may otherwise be toxic.

The nanocomplexes are modular and can be adapted to carry other siRNA combinations or for use against other cancers in which this augmented synthetic lethality combination is relevant. Beyond application in lung cancer, the researchers — including Kong, who is now a research scientist at the Koch Institute, and Dreaden, who is now an assistant professor at Georgia Tech and Emory School of Medicine — are working to test this strategy for use against ovarian and other cancers.

Additional collaborations and contributions were made to this project by the laboratories of Koch Institute members Stephen Lippard and Omer Yilmaz, the Eisen and Chang Career Development Professor.

This work was supported in part by a Mazumdar-Shaw International Oncology Fellowship, a postdoctoral fellowship from the S. Leslie Misrock (1949) Frontier Fund for Cancer Nanotechnology, and by the Charles and Marjorie Holloway Foundation, the Ovarian Cancer Research Foundation, and the Breast Cancer Alliance.