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Navigating new worlds in biology and at MIT

Institute Professor Sallie “Penny” Chisholm is best known for her role in discovering the tiny bacteria called Prochlorococcus — the world’s most abundant photosynthetic organism. But she has also played a pivotal role in pioneering and advocating for women’s rights at MIT and beyond.

Celina Zhao

March 31, 2022

Without the ancestors of the ocean microbe that Sallie “Penny” Watson Chisholm discovered in 1986, humans may not have ever evolved on Earth. The tiny microbe is called Prochlorococcus, and it’s full of superlatives. One hundred of them can fit on the width of a single strand of human hair, making them the smallest photosynthetic organisms on the planet. At the same time, they’re also the most abundant, comprising an integral piece of the oceans’ “invisible forest.” In fact, you can thank them for the oxygen you breathe in every twentieth breath you take.

With their population, which numbers in the billion billion billions and weighs a collective 220 million Volkswagen Beetles, you might expect Prochlorococcus to be easy to find. But they were not uncovered until the 1980s — and by accident, at that. Since that fateful discovery, Chisholm has dedicated her life and career to studying these intriguing little cells. They have earned her a National Medal of Science from former President Barack Obama, led her to a debate with the Dalai Lama, and even sparked a meeting with the Wu-Tang Clan’s GZA, a rapper interested in featuring the bacterium in his album.

This extraordinary journey, however, was not a straight path — in part because being a pioneering female researcher was no easy feat.

Early life and education

Chisholm was born on November 5, 1947 in Marquette, Michigan, a small town located on the shores of Lake Superior. While growing up, her passion was not science, but skiing, and when it came time to apply for college, she had little ambition and few dreams in higher education.

Her parents, however, intervened. Chisholm’s mother, a traditional 1950s housewife, hated not having her own job or income. In particular, she stressed to her daughter the importance of being able to get an education and career. So, Chisholm traveled east to Saratoga Springs, New York, enrolling at Skidmore College — then a private liberal arts women’s college.

Chisholm on the RV Ellen B. Scripps during her postdoctoral years at the Scripps Institute of Oceanography. Credit: David Karl, University of Hawaii

Living at Skidmore, where she studied biology and chemistry, was a formative experience. “It unconsciously builds a confidence,” Chisholm says of the absence of men competing for attention and resources. In her senior year, she participated in her first fieldwork expedition, studying the prevalence of the mineral manganese in a local lake. Noticing her interest and potential in research, her advisor suggested she attend graduate school. Though the idea had never occurred to her before, it sounded much more interesting than entering the workforce, and so she agreed.

After a year as a graduate student at Cornell University, Chisholm transferred to the State University of New York (SUNY) to study freshwater plankton. With her PhD in hand — the first PhD in her entire extended family — she moved to the sunny beaches of La Jolla, California for her postdoctoral studies. At the University of California San Diego’s Scripps Institute of Oceanography, she began studying the massive system to which she’d dedicate the rest of her career: the ocean.

Just a few months after arriving at Scripps, Chisholm sailed around the Gulf of California on her first research cruise, the R/V Alpha Helix. She stood out from most of the members of the ship in a prominent way — she was one of only a few women aboard. Women were only just starting to be allowed on research vessels in the 1970s, an imbalance that would persist on Chisholm’s other cruises at Scripps.

And, though she loved her time at Scripps, by 1976 it was time to move on. She had three options: a small marine lab in Maine, an oceanography department in Canada, or the Civil and Environmental Engineering Department at MIT. In the case of the latter, she would not simply be the only biologist; she would be the only woman. Should she choose a comfortable route, or should she choose the challenge? Then, one of her mentors at Scripps told her, “Penny, you don’t turn down MIT.” It was a once-in-a-lifetime opportunity, so she decided to give it a shot.

Settling into MIT

In 1976, Chisholm arrived at MIT to continue studying the physiology of various phytoplankton species. One of the instruments she used was a flow cytometer. Though traditionally only used in medical settings, she’d discovered that flow cytometers — with their ability to move individual cells in single file past a laser for a convenient close-up view — were also excellent for her research. In addition, she’d noticed that the unique pigments of phytoplankton fluoresced distinctive colors in the laser’s presence. For example, the green chlorophyll found in phytoplankton would emit red light when struck by a blue laser. Accessory pigments in some would emit orange light.

One day, she and her team came to a game-changing idea: “Wouldn’t it be cool if we could take an instrument like this out on a ship and just squirt sea water through it to see what the diversity of phytoplankton look like?” she mused. This idea immediately opened a whole new set of doors for possible research.

At the start of Chisholm’s career, scientists had a highly restricted picture of microbes in the ocean. This was largely due to limitations in microscope technology: phytoplankton smaller than 5 microns were extremely difficult to see using standard microscopy of the day. In 1979, however, John Waterbury of the Woods Hole Oceanographic Institution, using a technique known as epifluorescence microscopy, discovered tiny photosynthetic cyanobacteria only about 2 microns in diameter, which glowed orange. He named the bacterium Synechococcus. Chisholm was intrigued, and her team set off to the Caribbean in 1985 with their flow cytometer to study them.

While studying images of Synechococcus, they started seeing extremely tiny red signals on their instrument. They didn’t think much of it at first — assuming it was probably just electronic noise. But, as these signals kept showing up, they began to wonder: Could these signals be coming from something that was alive?

The Department of Civil and Environmental Engineering faculty picture from 1978 shows that Chisholm (middle, second row from the back) was the only female faculty member.

It was an intriguing possibility, with evidence in its favor. She and her team noticed that the signals varied depending on the depth and temperature of the water sample being analyzed. There was no reason for electronic noise to increase with depth. But there was good reason for cells to have more chlorophyll (hence the red color under the blue laser of the flow cytometer) the deeper they were under the surface of the water, in order to help with photosynthesis.

Over the next few years, collaborators discovered the same little cells in other seas across the globe. In 1988, Chisholm and her team published their findings in the journal Nature. In the paper, the researchers referred to them as a “new group of pico-plankters,” but members of the lab affectionally called them “little greens” because they contained chlorophyll b, which is a characteristic of green plant chloroplasts. For its formal name, they eventually chose “Prochlorococcus,” meaning “little round progenitors of chloroplasts,” or more colloquially “primitive green berries.”

Chisholm ultimately refocused her entire lab on Prochlorococcus, which revealed itself to be a fascinating subject. She had been looking for a phytoplankton species that could be both easily studied in the lab and easily found in the oceans. Prochlorococcus seemed like a promising model system through which she and her lab could begin understanding how the ocean works.

It turns out that Prochlorococcus wasn’t just one uniform organism, but a collective, composed of more than 30 clusters of strains called “ecotypes” with their own unique survival tactics. This collective has adapted to various environments, dividing up vast swaths of the oceans with various light, temperature, and nutrient combinations. Each ecotype is the “most efficient photosynthetic machine” at its particular conditions — and added together produce 10% of the oxygen in the atmosphere.

To Chisholm, this was an unmistakable sign that there was something truly remarkable about Prochlorococcus. But it would take a few more years for technology to develop far enough to uncover more.

flow cytometery and light microscopy image side-by-side showing red dots — The intriguing new cells glowed red under the flow cytometer (left), but appeared like mere specks of dust or electronic noise under the commonly-used light microscopes (right). Credit: Rob Olson, Woods Hole Oceanographic Institute

Taking a stance on women’s rights at MIT

Deep in the thralls of Procholorococcus research, Chisholm worked early mornings and stayed late into the night. She was in her late forties, and her life revolved around her job. In 1994, during one of those typical long days in her office, she received a phone call that dramatically changed the way she viewed her career.

It was from Nancy Hopkins, a fellow MIT professor whom she casually knew. Hopkins was rallying the support of the 17 other senior female faculty at MIT for a purpose: She believed MIT was discriminating against all of them in multiple areas, including lab space, pay, and support. Hopkins asked Chisholm if she would be willing to come to a meeting and discuss these issues.

Chisholm didn’t know what would come of the meeting, nor did she expect much change to happen. In fact, she had never really thought about what it meant for her to be among the few female faculty at MIT. “I was just doing my work,” she says, “and I liked being one of the guys. I wasn’t plugged into feminist issues or anything.”

But she agreed to attend, and in a few days, found herself in a discreet location on campus. The room was small. Some women sat on chairs, while others sprawled on the floor.

It was awkward at first. “We didn’t know each other that well, so nobody wanted to speak out. We didn’t want to be that one woman faculty member to complain because that meant you couldn’t cut it,” she recalls. But soon everyone started shedding their protective shells. Hours went by as they all found common ground.

Chisholm came to a realization, which she later articulated in her Killian Award acceptance speech: “There’s always a general sense of not being part of the club. It’s like there’s a playbook for this whole enterprise we’re involved in, and it was written by men. As a woman, you’re just constantly trying to figure out what the game is and what the playbook is.”

In her office in 1988, Chisholm holds an image of *Prochlorococcus*. Credit: Donna Coveney

Armed with a letter calling for investigation, they marched into Dean Robert J. Birgeneau’s office. One of the women even put on a skirt for the first time. They had no idea how he’d react, but preliminary evidence seemed to be on their side. Not only were there 194 tenured male professors compared to only 15 tenured women faculty in the School of Science, the percentage of female faculty hadn’t budged from 8% in 20 years.

Seeing their determination and the evidence, Birgeneau agreed to help. Together with MIT President Charles Vest, he established the MIT Committee on Women Faculty in the MIT School of Science. Birgeneau and Vest charged the committee “to study the status of women in science at MIT and, among other things, to determine the reasons for [MIT’s] failure in the School of Science to hire and promote significant numbers of women faculty.”

The committee’s findings over a two year period were published in a report in 1999. The report made headlines in nearly every major newspaper when President Vest admitted to and apologized for the gender discrimination.

“It was a shot heard around the world,” Chisholm says. And it was true — the MIT administration acted quickly and decisively to right its wrongs. Salaries were adjusted, space and equipment allocation were corrected, retirement packages were increased, among many other changes. Importantly, several other higher education institutions followed MIT’s lead.

As a result of their shared experience, the group of women faculty grew close. Chisholm says, “In my mind, that was one of the best outcomes — on top of all the positive changes by the administration — in terms of my quality of life at MIT: having a community of women that I could talk to.”

Increasing recognition for Prochlorococcus and legacy at MIT

Parallel to the push for equity for women faculty at MIT was the development of one of the most ambitious science expeditions to date — sequencing the human genome. After the Human Genome Project released the sequence of all 20,000 human genes in 2003, there was an abundance of DNA sequencing machines available for other projects. Chisholm leapt at the chance to learn more about her “little greens.” A strain of Prochlorococcus called MED4 became the second microbial genome to be sequenced.

The sequencing “completely opened up the black box,” Chisholm says. With only 1,700 genes, that strain of cyanobacteria is one of the simplest self-sustaining organisms known. Chisholm wrote in a chapter of “Microbes and Evolution: The World that Darwin Never Saw”, “This cell is truly the ‘essence’ of life. As a photosynthesizer, it can do what humans cannot, even with all of our technology: It can split water using sunlight and make hydrogen and oxygen — all with only 1,700 genes.”

The cyanobacterium Prochlorococcus was Chisholm’s muse throughout the majority of her career. Credit: Luke Thompson and Nicki Watson

Together, Chisholm and her lab eventually learned that though each Prochlorococcus strain contains fewer than 2,000 genes, the collective as a whole contains more than 80,000 — four times the size of the human genome. There is a core set of genes (about 1,200) that all Prochlorococcus share, and a few hundred more that are shared only by a subset of strains. In addition, each individual strain has an additional 80-200 genes that are completely unique to it. That incredible diversity allows Prochlorococcus to thrive in all sorts of environmental conditions, from 40 degrees north to 40 degrees south latitudes to almost 200 meters under the ocean where there’s less than 1% light penetration. As the environment shifts, so does the ecotype composition, stabilizing the total population of the species.

Additionally, it turns out that Prochlorococcus is also integral to its local environment. The 5 billion tons of living biomass it produces though photosynthesis each year is eaten by small microorganisms, then zooplankton, then fish. Ultimately, Prochlorococcus feeds 10% of all the creatures in the sea.

Over the years, Chisholm has led the charge in uncovering more about these intriguing cyanobacteria, including how they interact with other things in their environment like viruses or different microorganisms, as well as the unusual molecules Prochlorococcus produce. This persistent dedication has earned her many awards and honors. In 2011, former President Barack Obama presented her with the National Medal of Science, the White House’s highest honor for American scientists. In 2014, she won the MIT James R. Killian Faculty Award, and in 2015 she was named an MIT Institute Professor — the highest title that MIT bestows, and one that only 13 faculty presently hold. In 2019, she was awarded the Crafoord Prize in Biological Sciences by the Swedish Academy of Sciences, the equivalent of a Nobel Prize for biosciences.

As she was gaining worldwide recognition for her research, Chisholm also served as teacher and mentor to many classes of students at MIT. In 1993, she joined the Department of Biology to teach 7.014 (Introductory Biology). Her class was the only introductory biology class to feature ecology. In her lab, she advises undergraduate and graduate students with varying backgrounds, from biology, to chemistry, to oceanography, to civil and environmental engineering.

Her advocacy for women faculty’s rights at MIT has also paid off over the years, with statistics slowly but surely improving to more equal footing. As of June 2019, 250 of the approximately 1,050 faculty members are women, and within the Schools of Science and Engineering, women comprise 22% of the faculty.

And, nearly four decades later, Prochlorococcus still remains an irresistible siren to her. “I should probably be thinking about retiring, but I’m not because Prochlorococcus is too darn interesting,” Chisholm says. “I’m really very grateful to have this organism in my life.”

Posted: 3.31.22

How molecular biology could reduce global food insecurity

Mary Gehring is using her background in plant epigenetics to grow climate-resilient crops.

Summer Weidman | Abdul Latif Jameel Water and Food Systems Lab

March 30, 2022

Staple crops like rice, maize, and wheat feed over half of the global population, but they are increasingly vulnerable to severe environmental risks. The effects of climate change, including changing temperatures, rainfall variability, shifting patterns of agricultural pests and diseases, and saltwater intrusion from sea-level rise, all contribute to decreased crop yields. As these effects continue to worsen, there will be less food available for a rapidly growing population.

Mary Gehring, associate professor of biology and a member of the Whitehead Institute for Biomedical Research, is growing increasingly concerned about the potentially catastrophic impacts of climate change and has resolved to do something about it.

The Gehring Lab’s primary research focus is plant epigenetics, which refers to the heritable information that influences plant cellular function but is not encoded in the DNA sequence itself. This research is adding to our fundamental understanding of plant biology and could have agricultural applications in the future. “I’ve been working with seeds for many years,” says Gehring. “Understanding how seeds work is going to be critical to agriculture and food security,” she explains.

Laying the foundation

Gehring is using her expertise to help crops develop climate resilience through a 2021 seed grant from MIT’s Abdul Latif Jameel Water and Food Systems Lab (J-WAFS). Her research is aimed at discovering how we can accelerate the production of genetic diversity to generate plant populations that are better suited to challenging environmental conditions.

Genetic variation gives rise to phenotypic variations that can help plants adapt to a wider range of climates. Traits such as flood resistance and salt tolerance will become more important as the effects of climate change are realized. However, many important plant species do not appear to have much standing genetic variation, which could become an issue if farmers need to breed their crops quickly to adapt to a changing climate.

In researching a nutritious crop that has little genetic variation, Gehring came across the pigeon pea, a species she had never worked with before. Pigeon peas are a legume eaten in Asia, Africa, and Latin America. They have some of the highest levels of protein in a seed, so eating more pigeon peas could decrease our dependence on meat, which has numerous negative environmental impacts. Pigeon peas also have a positive impact on the environment; as perennial plants, they live for three to five years and sequester carbon for longer periods of time. They can also help with soil restoration. “Legumes are very interesting because they’re nitrogen-fixers, so they create symbioses with microbes in the soil and fix nitrogen, which can renew soils,” says Gehring. Furthermore, pigeon peas are known to be drought-resistant, so they will likely become more attractive as many farmers transition away from water-intensive crops.

Developing a strategy

Using the pigeon pea plant, Gehring began to explore a universal technology that would increase the amount of genetic diversity in plants. One method her research group chose is to enhance transposable element proliferation. Genomes are made up of genes that make proteins, but large fractions are also made up of transposable elements. In fact, about 45 percent of the human genome is made up of transposable elements, Gehring notes. The primary function of transposable elements is to make more copies of themselves. Since our bodies do not need an infinite number of these copies, there are systems in place to “silence” them from copying.

Gehring is trying to reverse that silencing so that the transposable elements can move freely throughout the genome, which could create genetic variation by creating mutations or altering the promoter of a gene — that is, what controls a certain gene’s expression. Scientists have traditionally initiated mutagenesis by using a chemical that changes single base pairs in DNA, or by using X-rays, which can cause very large chromosome breaks. Gehring’s research team is attempting to induce transposable element proliferation by treatment with a suite of chemicals that inhibit transposable element silencing. The goal is to impact multiple sites in the genome simultaneously. “This is unexplored territory where you’re changing 50 genes at a time, or 100, rather than just one,” she explains. “It’s a fairly risky project, but sometimes you have to be ambitious and take risks.”

Looking forward

Less than one year after receiving the J-WAFS seed grant, the research project is still in its early stages. Despite various restrictions due to the ongoing pandemic, the Gehring Lab is now generating data on the Arabidopsis plant that will be applied to pigeon pea plants. However, Gehring expects it will take a good amount of time to complete this research phase, considering the pigeon pea plants can take upward of 100 days just to flower. While it might take time, this technology could help crops withstand the effects of climate change, ultimately contributing to J-WAFS’ goal of finding solutions to food system challenges.

“Climate change is not something any of us can ignore. … If one of us has the ability to address it, even in a very small way, that’s important to try to pursue,” Gehring remarks. “It’s part of our responsibility as scientists to take what knowledge we have and try to apply it to these sorts of problems.”

March 29, 2022

Ragon Institute Women Make a Difference: Alison Ringel

Emily Makowski | Ragon Institue

March 25, 2022

Dr. Alison Ringel didn’t set out to exclusively choose female mentors when she started out in scientific research, but by following her research interests, that’s what happened. “I have been mentored by what I call a dream team of women faculty,” she says.

Ringel joined the Ragon in January 2022 as one of three faculty recently hired in newly created joint appointment positions between the Ragon Institute and the Department of Biology at Massachusetts Institute of Technology. She currently studies how T cells — white blood cells that help protect against infection and can help fight cancer — survive in stressful environments. Originally from Wilton, CT, Ringel’s first research experience was in yeast genetics as an undergrad at Wesleyan University. “I was really given a lot of freedom to pursue my own ideas … having that very early exposure and freedom to manipulate systems experimentally, make hypotheses, make mistakes, really solidified my interest,” she says.

Ringel graduated with two bachelor’s degrees — one in molecular biology and biochemistry, and one in physics — and completed a molecular biophysics PhD at Johns Hopkins University School of Medicine in the lab of structural biologist Cynthia Wolberger. She studied how chromatin-modifying enzymes — enzymes that modify the material that our chromosomes are made of, affecting gene expression — choose which proteins to modify. The experience was a very positive one. “Not only was that an incredibly rich environment, but she was also a very supportive mentor, and still is a supportive person in my life,” Ringel says.

As Ringel was finishing up her PhD, she became more interested in the small molecule cofactors that catalyze reactions involving these enzymes. She started to look into labs studying immunology and metabolism, and she met cell biologist Marcia Haigis, who became Ringel’s postdoctoral mentor at Harvard Medical School (HMS). Ringel, Haigis and their collaborators identified a single gene change in cancerous tumor cells that prevented T cells from functioning properly in obese mice, suggesting that obesity can have an impact on the immune system’s ability to recognize and clear a tumor.

Ringel also became a close collaborator with Arlene Sharpe, chair of the Immunology Department at HMS. Seeing how both Haigis and Sharpe were able to balance success in science with fulfilling personal lives has been a great inspiration to Ringel, who has two young sons. “Working for women who had done the whole thing — they had been amazing scientists, they had made significant discoveries that advanced their field, they all had families, they all had navigated tenure processes at really big, impactful research institutions — has been enormously helpful and inspiring to me throughout my career trajectory,” she says. Her advice for women in STEM and STEM-related fields? “Don’t be dissuaded by the challenges. Understand them and use them for your forward momentum.”

Ringel has been enjoying starting her own lab in her dual-appointment role and is currently looking at how T cells can restrict the growth of tumors. “I’m particularly excited about this connection between MIT Biology and the Ragon Institute,” she says. “I was so excited to land here because the Ragon Institute is a real powerhouse in everything immunology, and MIT Bio has the immense depth and breadth of scientific interest. This position was really unique in having both of those arms represented.”

Helping drugs play nice in the human body

Whitehead Institute

March 25, 2022

For the hundreds of thousands of people diagnosed with breast cancer each year, surgery to remove the cancerous tissue is often the best option — but this relatively simple procedure comes with some drawbacks. In more than a few cases, the surgical removal of a tumor can lead to an increased risk of the cancer reemerging in other locations in the body.

In a 2018 study, a postdoc in the lab of Whitehead Institute Member Bob Weinberg discovered that, at least in mice, this phenomenon was due to a bodily butterfly effect: the creation of a wound site in one place in the body, which necessitated subsequent wound healing, caused immune system changes affecting distant parts of the body.

These changes occurred as bone marrow cells responded to the wounding with a flood of inflammatory cells that entered into the wound site and, at the same time, scattered throughout the body. These dispersed inflammatory cells weakened the ability of the immune system to control the outgrowth of a distantly located metastatic tumor. Without this immune control, which otherwise could keep the metastasis at a very small size, the metastasis would grow out aggressively.

Hence, wounding in one part of the body provoked metastasis outgrowth at a distant site. This suggested, among other things, that the outgrowth of metastatic tumors, which is often seen in women who have recently undergone a mastectomy, might be actively provoked by the post-surgical wound-healing process.

Weinberg’s work also presented a way to potentially avoid this effect, using a preventative measure that’s probably sitting in your bathroom cabinet right now: the cheap and common class of drugs known as NSAIDS, which includes ibuprofen and aspirin. When mice were given NSAIDS before and after tumor removal surgeries, they experienced a fivefold lower rate of cancer recurrence at the site of metastasis than a control group given opioids. These NSAIDs could therefore be used in place of the opioids, which are often used to treat post-surgical pain.

The human body is full of undiscovered connections like this one and adding in foreign substances further complicates matters. While a treatment might work well in a Petri dish, researchers describe whole -body metabolism as “a whole different kettle of fish.”

The way drugs move through the body and interact with internal systems is called pharmacokinetics. When a person is given a medicine — either orally, through a chemotherapy method, or via injection — that drug must be able to find its way to its target in a high enough concentration to have an effect, and then when its purpose is served, it must be able to leave the body safely and not build up to a harmful amount.

Much like Weinberg’s work on NSAIDS in breast cancer, Whitehead Institute’s basic research has led to other surprising discoveries about drug activities in the human body. Read on to learn about research that is changing the way new drugs are designed, making existing treatments less toxic, and more.

Concentration is key

When it comes to the action of drugs in the human body, concentration is key. Just ask Rick Young, a Whitehead Institute Member and professor of biology at MIT. In 2018, Young’s lab, which had previously studied the regulatory circuitry involved in transcription (the copying of DNA into RNA), shifted its focus after discovering tiny droplets within cells that concentrate the molecular materials needed to transcribe the DNA.

The droplets, called transcriptional condensates, were the newest in a slew of recent discoveries of other such groupings of cellular components. Some of these aggregations facilitate RNA splicing while others help to form ribosomes.

For Young, the discovery of transcription-related condensates sparked an interest in how these droplets were affecting the action of drugs. Previous theories held that transcription was able to take place in cells because there was a sufficient concentration of necessary proteins, such as RNA polymerase and other accessory proteins. As the Young lab showed, these collaborating cellular players were actually being concentrated in the condensates,

In 2020, Young and Ann Boija and Isaac Klein, two postdocs in his lab, took their investigation a step further, analyzing the mechanism by which several cancer drugs are concentrated in cellular condensates, and how that concentration could affect their action in individual cells and thus in the body. They found that cancer drugs sort themselves into specific types of condensates, independently of their targets, which can allow them to build up into high concentrations in these localized areas within cells.

“This could have enormous implications for the way we discover and develop drugs,” said Rick Young. “If drugs had properties that had them partitioning into a condensate where their target lives, then they would enjoy two properties of condensates: they would be compartmentalized, and they would be at much higher concentrations than if they diffuse through the cell.”

Young’s work on condensates led him to co-create a pharmaceutical company called Dewpoint Therapeutics, with the goal of reformulating treatments for cancer or neurological conditions such as amyotrophic lateral sclerosis by targeting biomolecular condensates. Whitehead Institute Founding Member Rudolf Jaenisch serves as a scientific advisor.

Trouble in parasites

While researchers in Young’s lab investigate how drugs could be more efficiently targeted, Sebastian Lourido’s lab is taking a different tack — why do some drugs stop working as time progresses?

The malaria drug artemisinin was developed in China in the 1970s, and completely changed the way the world treated malaria. In the following decades, however, the parasites that cause malaria, several species within the genus Plasmodium, have slowly grown less susceptible to the drug.

In a paper published in September of 2020, Whitehead Institute Member Lourido and collaborators identified two parasite genes that were negatively impacting the actions of the drug in the parasite’s cells.

Researchers liken artemisinin to a “ticking time bomb,” which needs another molecule, called heme, to light its fuse. Heme, a small molecule that is one component of hemoglobin, helps transport electrons and deliver oxygen to tissues. When heme encounters artemisinin, it activates the drug, allowing the creation of small, toxic chemical radicals. These proceed to react with the parasites proteins, fats, and metabolites, eventually leading to its death.

In order to understand how some parasites were becoming less vulnerable to the drug, Lourido, along with researchers Clare Harding, Boryana Petrova and Saima Sidik, ran a genetic screen on a related parasite, Toxoplasma gondii. The screen allowed them to assess which mutations in the parasites’ genomes were beneficial for their survival and which ones were harmful.

The screen revealed two genes that affected how susceptible the parasites were to treatment with artemisinin. One, called Tmem14c, seemed to be protecting the parasites. The gene is analogous to a gene that transports heme out of mitochondria where it is generated. Lourido hypothesized that when the Tmem14c protein is working properly, it helps the cells shuttle heme and its building blocks and get them where they need to go in the cell. When this gene is knocked out or mutated, heme can build up in the parasite cells, making them more likely to activate the artemisinin “bomb.”

Another gene, when mutated, made the parasites less sensitive to artemisinin. The gene, called DegP2, encodes a protein that plays a role in heme metabolism, so when it was mutated, less heme was available in the cells to activate the drug.

This knowledge provides useful insights for treatment methods, said Lourido. For example, healthcare providers should take into consideration the fact that heme is key in artemisinin’s action, and avoid combining the drug with other treatments that might lower the amount of heme in parasite cells. “Understanding how different pathways within the cell participate to render parasites susceptible to these antiparasitic drugs helps us better pair them with other compounds that are going to be synergistic and not work against our own goal of defeating parasites,” Lourido said.

Taking the edge off toxic treatments

Another application of fundamental pharmacokinetics research involves mitigating the harmful effects of drugs. Consider the chemotherapy drug methotrexate. Methotrexate was the very first targeted drug ever made. Developed more than 60 years ago by Dr. Sidney Farber, the drug acts by inhibiting a key molecule in the metabolic process that builds DNA and RNA, thereby interfering with basic functions of the cell and with DNA synthesis, repair and replication, helping to destroy cancerous cells in the body.

Methotrexate is still a widely used component of chemotherapy cocktails, especially for pediatric leukemia. In the human body, though, methotrexate is like a bull in a china shop. It is very effective at knocking back cancer, but the drug’s life-threatening side effects, including gut, liver, kidney and brain damage, often lead doctors to terminate their patients’ treatment early, or seriously compromise the survivors’ quality of life.

The drug was much-studied in the 70s, but research trailed off in the subsequent decades due to limits on the existing technologies. Nearly fifty years later, Naama Kanarek, then a postdoctoral researcher in the lab of former Whitehead Institute Member David Sabatini, decided to take a fundamental research approach to studying the effects of methotrexate, in hopes that she might discover some way to make the drug less toxic.

“We now have access to genetic tools that allow us to address long standing questions in a way that was not possible before,” said Kanarek, who now runs her own lab at Boston Children’s Hospital. “We can use a CRISPR screen, and instead of focusing on what is known, we can ask what is unknown about the drug. We can find new genes that are involved in the response of cells to the drug that were not found before simply because the tools were not there.”

The screen revealed one gene in particular that seemed to be playing a role in how sensitive cancer cells were to methotrexate, the researchers reported in Nature in July of 2018. The cells’ sensitivity is important, Kanarek said, because if the cells can be made more vulnerable to methotrexate, the duration of treatment or required dose could be reduced. “If we can reduce dose because we can improve efficacy, then we can reduce toxicity without compromising on the cure rates and that is good news to the patients,” Kanarek said.

The gene in question, called FTCD, encodes an enzyme involved in the breakdown of the amino acid histidine. When the gene was knocked out, cancer cells were less sensitive to methotrexate. When the pathway was boosted with the addition of extra histidine, cells became more sensitive.

Former Whitehead Institute Director Susan Lindquist, who passed away 2016, performed similar work on the natural product amphotericin B, a drug which is used to treat some fungal infections. The drug is especially useful because fungi have not yet developed a resistance to it, as they have with so many other treatments. But amphotericin B also has some serious drawbacks; it can cause kidney damage, heart failure, and other serious and even fatal side effects.

These side effects mostly happened because amphotericin B works by binding to a chemical group called a sterol. In fungi, it binds to molecules called ergosterols in the cell wall, destabilizing the cells. Unfortunately humans also have a prevalent sterol: cholesterol. When amphotericin B binds to cholesterol in human cell membranes, it can damage human cells.

Using chemical synthesis methods, Lindquist and colleagues at Whitehead Institute and elsewhere were able to tweak the structure of the drug to bind only to ergosterol molecules and not cholesterol, bypassing most of the harmful side effects.

Why fundamental research

Drug development is often an extremely targeted pursuit, but for Whitehead Institute scientists, their advances have mostly come from a simple curiosity about the cellular mechanisms. For example, Rick Young didn’t set out to study condensates, but an inquiry into the fundamentals of transcription led him in this entirely new direction.

Such fundamental research has the potential to branch in any number of different ways. “Fundamental science can lead in directions that you would not foresee,” said the Institute’s Associate Director of Intellectual Property Shoji Takahashi. Basic research into drug behavior is essential and can contribute to life-changing therapies down the line.

An early diagnosis sparks a lifelong interest in science and medicine

Senior Isha Mehrotra works to discover more about autoimmune diseases, aiming for a future in which patients can be treated effectively or avoid the conditions altogether.

Alli Armijo | MIT News correspondent

March 25, 2022

“Five second rule!” her classmates shouted as they rushed to pick up some food they had dropped on the ground. At that moment, 10-year-old Isha Mehrotra knew what she wanted to do for the annual science fair.

After scouring the internet with her father, Mehrotra learned how to culture bacteria from home, first tossing food on the floor of her kitchen and swabbing samples onto agar plates — her very first microbiology project. She remembers presenting the data to her peers, watching their faces fall as they realized how much bacteria was on the food even after just five seconds. The experience kindled Mehrotra’s love of learning about the natural world, and more importantly, sharing that knowledge with others.

Now a senior studying biology, Mehrotra enjoys the investigative quality of science above all else.

“The more you study science, the more you realize what you don’t know about it,” she says.

MIT has also been a place for Mehrotra to learn more about herself. In the spring of her sophomore year, she worked in the lab of Alessio Fasano with Maureen Leonard at Massachusetts General Hospital’s Mucosal Immunology and Biology Research Center, investigating the blood microbiome of pediatric patients with an autoimmune condition called celiac disease — which Mehrotra herself was diagnosed with when she was a child.

Her diagnosis sparked an early interest in science and medicine. Today, she works to discover more about celiac, its causes, and effects on the individuals who have it, aiming for a future in which patients can be treated effectively or avoid getting the disease altogether.

Through her research experience, which has included publishing her work as a first author in the journal Current Research in Microbial Sciences, Mehrotra has learned that when presenting her findings, having faith in her work is half the battle, especially when challenging canonical scientific beliefs. “At the end of the day, you know, your data is your data. And presenting that with conviction and confidence is something that I’ve learned how to balance. I try to do that even when I’m acknowledging that there are various aspects of the work that have yet to be understood or validated,” she says.

Mehrotra also serves as a member on the Board of Directors at Boston Children’s Hospital Celiac Kids Connection, where she works to build a safe space for children with celiac. She she understands firsthand the physical and emotional toll celiac disease can have, and values the opportunity to learn more about how to support people and navigate these challenges. For instance, she recognized the connection of food insecurity to celiac early on, as celiac is treated with a gluten-free diet. One of her most fulfilling projects, funded through the PKG Center at MIT, has been helping reduce gluten-free food insecurity exacerbated by the pandemic, working with a team at Children’s to research and mitigate these food access issues.

“It comes back to looking at things in different ways. How can I have a great impact in one area if I don’t consider all the various facets of it?” she asks.

In her classes, Mehrotra has also been drawn to complex public health topics with multiple perspectives, developing an anthropology background via her HASS coursework (for which she was named a Burchard Scholar) and an entrepreneurial framework by participating in MIT Sandbox. In January 2020, she took HST.434 (Evolution of an Epidemic), travelling to South Africa to study the evolution of the HIV/AIDS epidemic in the area. The experience was eye-opening for Mehrotra; she saw firsthand the variety of factors — social, political, biological — needed to approach a singular issue.

In June of last year, Mehrotra participated in the MIT Washington Summer Internship Program, where she worked for Gryphon Scientific, studying data to see how pandemics emerge and evolve at the biological level and what can be done at the policy level to prevent them. The experience allowed Mehrotra to see how different players can influence a singular problem.

“Social processes that underlie science and medicine are really important to me to continue studying,” she says.

On campus, Mehrotra has also been working as a mentor in her dormitory, Maseeh Hall, and peer tutor. During her first year she joined dynaMIT, a STEM outreach program for middle school students in Boston through which she taught biology in ways that made it more fun and accessible. She has also found ways to bring MIT biology students together as co-president of the Biology Undergraduate Sudent Assocation and to provide funding for on-campus initiatives as a board member of the Harvard-MIT Cooperative. Mehrotra also taught chemistry and biology to students in Wales through the Global Teaching Labs program and was a teaching assistant for the biology lab course 7.002 (Fundamentals of Experimental Molecular Biology) and for 7.012 (Introduction to Biology). While she understands that not all students are excited to take a required class such as 7.012, Mehrotra enjoys helping them engage with the content in meaningful ways.

“I just don’t see a better use of gaining knowledge than spreading it to other people,” she says.

Mehrotra is also a member of MIT’s women’s lightweight crew team. As the coxswain, she steers the boat and directs the other rowers both technically and motivationally during practices and races. She says the position has helped her develop her teamwork and leadership skills and allowed her to learn something new that she had never done before MIT. “It has been a great exercise in learning to be a leader and learning what I can do to support people even if I’m not experiencing exactly what they are, which is something I will have to do long term in my career as well,” she says.

Mehrotra will attend Stanford Medical School in the fall, with the goal of becoming a physician-scientist, dedicated to sharing knowledge, doing science, and interfacing with humanistic issues. Mehrotra wants to work directly with patients and researchers to solve medical issues, discovering new information and working with people who bring diverse perspectives. In the long run, she would like to start her own multidisciplinary research practice, where she envisions being able to see and treat patients some days a week, while also running a lab with different types of researchers, such as technical and social scientists.

For now, she is savoring the last few months of her time at MIT. “I’m happiest when I’m going around doing different things. It’s a shame I have to graduate now because there’s so much more to be done!” she says.

Pioneering a deeper understanding of metabolism

Merrill Meadow | Whitehead Institute

March 23, 2022

Metabolism is the sum of life-sustaining chemical reactions occurring in cells and across whole organisms. The human genome codes for thousands of metabolic enzymes, and specific metabolic pathways play significant roles in many biological processes—from breaking down food to release energy, to normal proliferation and differentiation of cells, to pathologies underlying diabetes, cancer, and other diseases.

For decades, Whitehead Institute researchers have helped both to clarify how metabolism works in healthy states and to identify how metabolic processes gone awry contribute to diseases. Among Whitehead Founding Member Harvey Lodish’s wide-ranging accomplishments, for example, are the identification of genes and proteins involved in development of insulin resistance and stress responses in fat cells. His lab explored the hormones controlling fatty acid and glucose metabolism, broadening understanding of obesity and type 2 diabetes. In 1995, the lab cloned adiponectin, a hormone made exclusively by fat cells. A long series of studies has shown that adiponectin causes muscle to burn fatty acids faster – so they are not stored as fat – and increases the metabolism of the sugar glucose. More recently the lab identified and characterized types of RNAs that are specifically expressed in fat cells – including a microRNA unique to brown fat, which burns rather than stores fatty acids. In addition, former Member David Sabatini’s discovery of the mTOR protein and his subsequent work elaborating many ways in which the mTOR pathway affects cells function has proven to be fundamental to understanding the relationship between metabolism and an array of diseases.

Today, Institute researchers continue to pioneer a deeper understanding of how metabolic processes contribute to health and disease – with long-term implications that could range from new treatments for obesity and type 2 diabetes to methods for slowing the aging process. Here are a few examples of Whitehead Institute scientists’ creative and pioneering work in the field of metabolism.

Understanding hibernation and torpor

Research inspiration comes in many forms. For example, Whitehead Institute Member Siniša Hrvatin – who joined the faculty in January 2022 from Harvard Medical School (HMS) – was inspired to pursue his current research by science-fiction tales about suspended animation for long-term space travel. And during graduate school, he realized that the ability of some mammals to enter a state of greatly reduced metabolism – such as occurs in hibernation – was a mild but real-world form of suspended animation.

Hrvatin’s doctoral research in Doug Melton’s lab at Harvard University focused primarily on stem cell biology. But his subsequent postdoctoral research positions at Massachusetts Institute of Technology (MIT) and HMS enabled him to begin exploring the mechanisms and impact of reduced metabolic states in mammals. The timing was serendipitous, too, because he was able to use the growing array of genetic tools that were becoming available – and create some new tools of his own as well.

“To survive extreme environments, many animals have evolved the ability to profoundly decrease metabolic rate and body temperature and enter states of dormancy, such as hibernation and torpor,” Hrvatin says. Hibernating animals enter repeated states of significantly reduced metabolic activity, each lasting days to weeks. By comparison, daily torpor is shorter, with animals entering repeated periods of lower-than-normal metabolic activity lasting several hours.

Hrvatin’s lab studies the mysteries of how animals and their cells initiate, regulate, and survive these adaptations. “Our long-term goal is to determine if these adaptations can be harnessed to create therapeutic applications for humans.” He and his team are focusing on three broad questions regarding the mechanisms underlying torpor in mice and hibernation in hamsters.

First: How do the animals’ brains initiate and regulate the metabolic processes involved in this process? During his postdoctoral research, Hrvatin published details of his discovery of neurons involved in the regulation of mouse torpor. “Now we are investigating how these torpor-regulating neurons receive information about the body’s energy-state,” he explains, “and studying how these neurons then drive a decrease of metabolic rate and body temperature throughout the body.”

Second: How do individual cells – and their genomes – adapt to extreme or changing environments; and how do these adaptations differ between types of organisms?

“Cells from hibernating organisms ranging from rodents to bears have evolved the ability to survive extreme cold temperatures for many weeks to months,” Hrvatin notes. “We are using genetic screens to identify species-specific mechanisms of tolerance to extreme cold. Then we will explore whether these mechanisms can be induced in non-hibernating organisms – potentially to provide health benefits.”

Third: Can we deliberately and specifically slow down tissue damage, disease progression, and or aging in cells and whole organisms by inducing torpor or hibernation – or facets of those states? It has long been known that hibernating animals live longer than closely related non-hibernators; that cancer cells do not replicate during hibernation; and that cold can help protect neurons from the effects of loss of oxygen. However, the cellular mechanisms underlying these phenomena remain largely unknown. Hrvatin’s lab will induce a long-term hibernation-like state in mice and natural hibernation in hamsters, and study how those states affect processes such as tissue repair, cancer progression, and aging.

“In the lab, if you take many human cell types and put them in a cold environment they die, but cells from hibernators survive,” Hrvatin notes. “We’re fascinated by the cellular processes underlying those survival capacities. As a starting place, we are using novel CRISPR screening approaches to help us identify the genomic mechanisms involved.”

And then? “Ultimately, we hope to take on the biggest question: Is it possible to transfer some of those survival abilities to humans?

Solving a mitochondrial conundrum

When Whitehead Institute postdoctoral researcher Jessica Spinelli was studying cancer metabolism in graduate school, she became interested in what seemed to be a scientific paradox regarding mitochondria, the cell’s energy-producing organelles: Mitochondria are believed to be important for tumor growth; but they generally need oxygen to function, and substantial portions of tumors have very low oxygen levels. Pursuing research in the lab of former Whitehead Institute Member David Sabatini, Spinelli sought to understand how those facts fit together and whether mitochondria could somehow adapt to function with limited oxygen levels.

Recently, Spinelli and colleagues published an answer to the conundrum – one that could inform research into medical conditions including ischemia, diabetes and cancer. In a Science paper for which Spinelli was first author, the team demonstrated that when cells are deprived of oxygen, a molecule called fumarate can serve as a substitute and enable mitochondria to continue functioning.

As Spinelli explains, humans need oxygen molecules for the cellular respiration process that takes place in our cells’ mitochondria. In this process – called the electron transport chain – electrons are passed along in a sort of cellular relay race that, ultimately, allows the cell to create the energy needed to perform its vital functions. Usually, oxygen is necessary to keep that process operating.

Using mass spectrometry to measure the quantities of molecules produced through cellular respiration in varied conditions, Spinelli and the team found that cells deprived of oxygen had a high level of succinate molecules, which form when electrons are added to a molecule called fumarate. “From this, we hypothesized that the accumulation of succinate in low-oxygen environments is caused by mitochondria using fumarate as a substitute for oxygen’s role in the electron transport chain,” Spinelli explains. “That could explain how mitochondria function with relatively little oxygen.” The next step was to test that hypothesis in mice, and those studies provided several interesting findings: Only mitochondria in kidney, liver, and brain tissues could use fumarate in the electron transport chain. And even in normal conditions, mitochondria in these tissues used both fumarate and oxygen to function – shifting to rely more heavily on fumarate when oxygen was reduced. In contrast, heart and skeletal muscle mitochondria made minimal use of fumarate and did not function well with limited oxygen.

“We foresee some exciting work ahead, learning exactly how this process is regulated in different tissues,” Spinelli says, “and, especially, in solid tumor cancers, where oxygen levels vary between regions.”

Seeking a more accurate model of diabetes

Max Friesen, a postdoctoral researcher in the lab of Whitehead Institute Founding Member Rudolf Jaenisch, studies the role of cell metabolism in type 2 diabetes (T2D). An increasingly prevalent disease that affects millions of people around the world, T2D is hard to study in the lab. This has made it very challenging for scientists to detail the cellular mechanisms through which it develops – and therefore to create effective therapeutics.

“It has always been very hard to model T2D, because metabolism differs greatly between species,” Friesen says. “That fact leads to complications when we use animal models to study this disease. Mice, for example, have much higher metabolism and faster heart rates than humans. As a result, researchers have developed many approaches that cure diabetes in mice but that fail in humans.” Nor do most in vitro culture systems—cells in a dish—effectively recapitulate the disease.

But, building on Jaenisch’s pioneering success in developing disease models derived from human stem cells, Friesen is working to create a much more accurate in vitro system for studying diabetes. His goal is to make human stem cell-derived tissues that function as they would in the human body, closely recapitulating what happens when an individual develops diabetes. Currently, Friesen is differentiating human stem cells into metabolic tissues such as liver and adipocytes (fat). He has improved current differentiation protocols by adapting these cells to a culture medium that is much closer to the environment they see in the human body. Serendipitously, the process also makes the cells responsive to insulin at levels that are present in the human bloodstream. “This serves as a great model of a healthy cell that we can then turn into a disease model by exposing the cell to diabetic hyperinsulinemia,” Friesen says.

These advances should enable him to gain a better understanding of how metabolic pathways – such as the insulin signaling pathway – function in a diabetic model versus a healthy control model. “My hope is that our new models will enable us to figure out how dietary insulin resistance develops, and then identify a therapeutic intervention that blocks that disease-causing process,” he explains. “It would be fantastic to help alleviate this growing global health burden.”

Alumna, Margaret ‘Mo’ Okobi ’16, prepares for a career combining medicine and public health research to improve mental health care services in vulnerable communities

Leah Campbell | School of Science

March 22, 2022

With only one year left of medical school at Harvard, Mo Okobi ’16, took a leave of absence. She didn’t want to take a break as much as a “step back” — a moment to reassess and reframe what she was learning in school within the bigger picture of the U.S. healthcare system. During that year, Okobi earned her master’s in public health from the Harvard School of Public Health.

“It’s so important to keep a broader view of the trends in medicine,” she says, “to look at what medications and therapies we’re using and what is actually working for patients.”

When she applied to the MPH program, Okobi couldn’t have known that her year-long leave to study public health would overlap with a pandemic. Needless to say, it was good timing. Okobi’s joint training in public health and medicine has also uniquely positioned her for a career combining clinical practice and research around chronic mental illness.

Though she says she never expected to find herself on this path, Okobi’s experiences at MIT shaped her approach to medicine and her commitment to providing quality mental healthcare to underserved communities.

Okobi was interested in many aspects of medicine when she enrolled at MIT. She majored in biology, with a minor in chemistry, to explore her broad interests in STEM. She joined MIT Emergency Medical Services, a student-run, volunteer ambulance service, for the same reason.

Being a certified EMT, though, she says, was one of the most formative aspects of her MIT education. She describes it as an “intensive introduction to medicine,” cementing her excitement about her future as a doctor. It was also one of her first exposures to mental health care, and Okobi believes that mental health emergencies made up a large proportion, if not a majority, of their calls.

“MIT EMS was really my first opportunity to actually work with patients very closely and see them in their moments of need,” she says.

While deciding to become a doctor was easy, Okobi’s journey to research wasn’t so smooth. She participated in one official undergraduate research experience at MIT, admitting, “I kind of hated it.” Working in a basic science biology lab, Okobi realized that the bench wasn’t for her.

Fortunately, her mentor, Hazel Sive, a former MIT professor of biology and now Dean of the College of Science at Northeastern University, took the time to talk with Okobi and figure out where she’d thrive. Sive, a South African, connected Okobi with the MIT Africa Program, through which she spent a summer in Johannesburg with the South African National Health Laboratory Services.

That experience, which she describes as a “pivotal framing moment,” helped Okobi understand how a career combining clinical practice and research might look. She worked with scientists studying HIV transmission from mother to child, assessing the quality of testing and resource gaps across different provinces. Near the end of her internship, Okobi was able to go into an HIV clinic and do antibody testing.

“I’m looking at these numbers. I’m making all these graphs and writing this paper, but I’m also seeing the people,” she says. “I loved the clinical work. I loved meeting people and knowing their stories.”

At graduation, Okobi was recognized as a Ronald E. McNair Scholar, an award that goes every year to Black undergraduates who have excelled academically and contributed to the experience of students on campus from underrepresented groups. The award was established in honor of McNair, PhD ’77, an accomplished astronaut who received his doctorate in physics from MIT and tragically perished onboard the Challenger space shuttle in 1986.

Having found a passion for applied, public health research, Okobi spent a year before medical school at a healthcare data analytics startup called Aetion. Aetion uses data from hospitals and insurance companies to analyze healthcare trends like medication usage and clinical outcomes. For a self-described “numbers nerd” like Okobi, it was a great way to learn how healthcare studies are designed and see the big picture behind clinical decisions.

It was her second year of medical school, though, that focused Okobi’s health interests around psychiatry for marginalized populations. During her clinical rotations, she worked at Cambridge Health Alliance (CHA), a public, community-centered hospital. At CHA, she served many non-English speakers and MassHealth recipients and was able to do rotations in outpatient, inpatient, and emergency psychiatric settings.

“I really got to see it from all angles,” Okobi says of her psychiatry rotations. “I loved the practice of creating space for people to talk about their lives…. it’s about the medicine and mental illness, but it’s also about seeing the whole person.”

As for what’s next, Okobi will be heading west for her residency in psychiatry at the University of California San Francisco.

Her work with CHA convinced Okobi to apply for residencies in psychiatry. She’s primarily interested in acute care settings, particularly for those with severe, chronic mental illnesses like schizophrenia. For her, one of the joys of inpatient care is working closely with patients on a daily basis, to, as she describes it, “try to leave a positive, lasting impression on those first encountering psychiatric care.”

Yet, armed with her degree in public health, she’s also committing to combining her clinical practice with ongoing research. At Harvard, she organized a mental health survey for medical and dental students in her class to improve access to mental health resources. Since 2020, she’s been participating in research on psychiatric emergency care utilization with the Boston Emergency Services Team. In 2020, she returned to Aetion as a consultant with their new FDA-backed COVID-19 research group, to lead epidemiological studies examining COVID-19 risk factors.

Looking back, Okobi knows that it may seem like she had a clear professional plan from the get-go. But she stresses that that wasn’t her experience at all, and current students should understand that things have a way of working out if you’re open to trying things.

“My path was very much like ping pong, never knowing where I’m going next,” she says. “The uncertainty never really ends, but I take refuge in those moments of serendipity, when I find something or someone that excites me and challenges me to be a better version of myself.”

Yukiko Yamashita, unraveler of stem cells’ secrets

The MIT biologist’s research has shed light on the immortality of germline cells and the function of “junk DNA.”

Anne Trafton | MIT News Office

March 22, 2022

When cells divide, they usually generate two identical daughter cells. However, there are some important exceptions to this rule: When stem cells divide, they often produce one differentiated cell along with another stem cell, to maintain the pool of stem cells.

Yukiko Yamashita has spent much of her career exploring how these “asymmetrical” cell divisions occur. These processes are critically important not only for cells to develop into different types of tissue, but also for germline cells such as eggs and sperm to maintain their viability from generation to generation.

“We came from our parents’ germ cells, who used to be also single cells who came from the germ cells of their parents, who used to be single cells that came from their parents, and so on. That means our existence can be tracked through the history of multicellular life,” Yamashita says. “How germ cells manage to not go extinct, while our somatic cells cannot last that long, is a fascinating question.”

Yamashita, who began her faculty career at the University of Michigan, joined MIT and the Whitehead Institute in 2020, as the inaugural holder of the Susan Lindquist Chair for Women in Science and a professor in the Department of Biology. She was drawn to MIT, she says, by the eagerness to explore new ideas that she found among other scientists.

“When I visited MIT, I really enjoyed talking to people here,” she says. “They are very curious, and they are very open to unconventional ideas. I realized I would have a lot of fun if I came here.”

Exploring paradoxes

Before she even knew what a scientist was, Yamashita knew that she wanted to be one.

“My father was an admirer of Albert Einstein, so because of that, I grew up thinking that the pursuit of the truth is the best thing you could do with your life,” she recalls. “At the age of 2 or 3, I didn’t know there was such a thing as a professor, or such a thing as a scientist, but I thought doing science was probably the coolest thing I could do.”

Yamashita majored in biology at Kyoto University and then stayed to pursue her PhD, studying how cells make exact copies of themselves when they divide. As a postdoc at Stanford University, she became interested in the exceptions to that carefully orchestrated process, and began to study how cells undergo divisions that produce daughter cells that are not identical. This kind of asymmetric division is critical for multicellular organisms, which begin life as a single cell that eventually differentiates into many types of tissue.

Those studies led to a discovery that helped to overturn previous theories about the role of so-called junk DNA. These sequences, which make up most of the genome, were thought to be essentially useless because they don’t code for any proteins. To Yamashita, it seemed paradoxical that cells would carry so much DNA that wasn’t serving any purpose.

“I couldn’t really believe that huge amount of our DNA is junk, because every time a cell divides, it still has the burden of replicating that junk,” she says. “So, my lab started studying the function of that junk, and then we realized it is a really important part of the chromosome.”

In human cells, the genome is stored on 23 pairs of chromosomes. Keeping all of those chromosomes together is critical to cells’ ability to copy genes when they are needed. Over several years, Yamashita and her colleagues at the University of Michigan, and then at MIT, discovered that stretches of junk DNA act like bar codes, labeling each chromosome and helping them bind to proteins that bundle chromosomes together within the cell nucleus.

Without those barcodes, chromosomes scatter and start to leak out of the cell’s nucleus. Another intriguing observation regarding these stretches of junk DNA was that they have much greater variability between different species than protein-coding regions of DNA. By crossing two different species of fruit flies, Yamashita showed that in cells of the hybrid offspring flies, chromosomes leak out just as they would if they lost their barcodes, suggesting that the codes are specific to each species.

“We think that might be one of the big reasons why different species become incompatible, because they don’t have the right information to bundle all of their chromosomes together into one place,” Yamashita says.

Stem cell longevity

Yamashita’s interest in stem cells also led her to study how germline cells (the cells that give rise to eggs and sperm cells) maintain their viability so much longer than regular body cells across generations. In typical animal cells, one factor that contributes to age-related decline is loss of genetic sequences that encode genes that cells use continuously, such as genes for ribosomal RNAs.

A typical human cell may have hundreds of copies of these critical genes, but as cells age, they lose some of them. For germline cells, this can be detrimental because if the numbers get too low, the cells can no longer form viable daughter cells.

Yamashita and her colleagues found that germline cells overcome this by tearing sections of DNA out of one daughter cell during cell division and transferring them to the other daughter cell. That way, one daughter cell has the full complement of those genes restored, while the other cell is sacrificed.

That wasteful strategy would likely be too extravagant to work for all cells in the body, but for the small population of germline cells, the tradeoff is worthwhile, Yamashita says.

“If skin cells did that kind of thing, where every time you make one cell, you are essentially trashing the other one, you couldn’t afford it. You would be wasting too many resources,” she says. “Germ cells are not critical for viability of an organism. You have the luxury to put many resources into them but then let only half of the cells recover.”

A Picower Institute primer on ‘plasticity,’ the brain’s amazing ability to constantly adapt to and learn from experience

Picower Institute

March 17, 2022

Muscles and bones strengthen with exercise and the immune system ‘learns’ from vaccines or infections, but none of those changes match the versatility and flexibility your central nervous system shows in adapting to the world. The brain is a model remodeler. If it weren’t, you wouldn’t have learned how to read this and you wouldn’t remember it anyway.

The brain’s ability to change its cells, their circuit connections, and even its broader architectures in response to experience and activity, for instance to learn new rules and store memories, is called “plasticity.” The phenomenon explains how the brand-new brain of an infant can emerge from a womb and make increasingly refined sense of whatever arbitrary world it encounters – ranging from tuning its visual perception in the early months to getting an A in eighth-grade French. Plasticity becomes subtler during adulthood, but it never stops. It occurs via so many different mechanisms and at so many different scales and rates, it’s… mind-bending.

Plasticity’s indispensable role in allowing the brain to incorporate experience has made understanding exactly how it works – and what the mental health ramifications are when it doesn’t – the inspiration and research focus of several Picower Institute professors (and hundreds of colleagues). This site uses the term so often in reports on both fundamental neuroscience and on disorders such as autism, it seemed high time to provide a primer. So here goes.

Beginning in the 1980s and 1990s, advances in neuroanatomy, genetics, molecular biology and imaging made it possible to not only observe, but even experimentally manipulate mechanisms of how the brain changes at scales including the individual connections between neurons, called synapses; across groups of synapses on each neuron; and in whole neural circuits. The potential to discover tangible physical mechanisms of these changes proved irresistible to Picower Institute scientists such as Mark Bear, Troy Littleton, Elly Nedivi and Mriganka Sur.

Bear got hooked by experiments in which by temporarily covering one eye of a young animal, scientists could weaken the eye’s connections to the brain just as their visual circuitry was still developing. Such “monocular deprivation” produced profound changes in brain anatomy and neuronal electrical activity as neurons rewired circuits to support the unobstructed eye rather than the one with weakened activity.

“There was this enormous effect of experience on the physiology of the brain and a very clear anatomical basis for that,” Bear said. “It was pretty exhilarating.”

Littleton became inspired during graduate and medical school by new ways to identify genes whose protein products formed the components of synapses. To understand how synapses work was to understand how neurons communicate and therefore how the brain functions.

“Once we were able to think about the proteins that are required to make the whole engine work, we could figure out how you might rev it up and down to encode changes in the way the system might be working to increase or decrease information flow as a function of behavioral change,” Littleton said.

Built to rebuild

So what is the lay of the land for plasticity? Start with a neuron. Though there are thousands of types, a typical neuron will extend a vine-like axon to forge synapses on the root-like dendrites of other neurons. These dendrites may host thousands of synapses. Whenever neurons connect, they form circuits that can relay information across the brain via electrical and chemical signals. Most synapses are meant to increase the electrical excitement of the receiving neuron so that it will eventually pass a signal along, but other synapses modulate that process by inhibiting activity.

Hundreds of proteins are involved in building and operating every synapse, both on the “pre-synaptic” (axonal) side and the “post-synaptic” (dendritic) side of the connection. Some of these proteins contribute to the synapse’s structure. Some on the pre-synaptic side coordinate the release of chemicals called neurotransmitters from blobs called vesicles, while some on the postsynaptic side form or manage the receptors that receive those messages. Neurotransmitters may compel the receiving neuron to take in more ions (hence building up electric charge), but synapses aren’t just passive relay stations of current. They adjust in innumerable ways according to changing conditions, such as the amount of communication activity the host cells are experiencing. Across many synapses the pace and amount of neurotransmitter signaling can be frequently changed by either the presynaptic or postsynaptic side. And sometimes, especially early in life, synapses will appear or disappear altogether.

Moreover, plasticity doesn’t just occur at the level of the single synapse. Combinations of synapses along a section of dendrite can all change in coordination so that the way a neuron works within a circuit is altered. These numerous dimensions of plasticity help to explain how the brain can quickly and efficiently accomplish the physical implementation of something as complex as learning and memory, Nedivi said.

“You might think that when you learn something new it has nothing to do with individual synapses,” Nedivi said. “But in fact, the way that things like this happen is that individual synapses can change in strength or can be added and removed, and then it also matters which synapses, and how many synapses, and how they are organized on the dendrites, and how those changes are integrated and summated on the cell. These parameters will alter the cell’s response properties within its circuit and that affects how the circuit works and how it affects behavior.”

A 2018 study in Sur’s lab illustrated learning occurring at a neural circuit level. His lab trained mice on a task where they had to take a physical action based on a visual cue (e.g. drivers know that “green means go”). As mice played the game, the scientists monitored neural circuits in a region called the posterior parietal cortex where the brain converts vision into action. There, ensembles of neurons increased activity specifically in response the “go” cue. When the researchers then changed the game’s rules (i.e. “red means go”) the circuits switched to only respond to the new go cue. Plasticity had occurred en masse to implement learning.

Many mechanisms

To carry out that rewiring, synapses can change in many ways. Littleton’s studies of synaptic protein components have revealed many examples of how they make plasticity happen. Working in the instructive model of the fruit fly, his lab is constantly making new findings that illustrate how changes in protein composition can modulate synaptic strength.

For instance, in a 2020 study his lab showed that synaptotagmin 7 limits neurotransmitter release by regulating the speed with which the supply of neurotransmitter-carrying vesicles becomes replenished. By manipulating expression of the protein’s gene, his lab was able to crank neurotransmitter release, and therefore synaptic strength, up or down like a radio volume dial.

Other recent studies revealed how proteins influence the diversity of neural plasticity. At the synapses flies use to control muscles, “phasic” neurons release quick, big bursts of the neurotransmitter glutamate, while tonic ones steadily release a low amount. In 2020 Littleton’s lab showed that when phasic neurons are disrupted, tonic neurons will plasticly step up glutamate release, but phasic ones don’t return the favor when tonic ones are hindered. Then last year, his team showed that a major difference between the two neurons was their levels of a protein called tomosyn, which turns out to restrict glutamate release. Tonic ones have a lot but phasic ones have very little. Tonic neurons therefore can vary their glutamate release by reducing tomosyn expression, while phasic neurons lack that flexibility.

Nedivi, too, looks at how neurons use their genes and the proteins they encode to implement plasticity. She tracks “structural plasticity” in the living mouse brain, where synapses don’t just strengthen or weaken, but come and go completely. She’s found that even in adult animal brains, inhibitory synapses will transiently appear or disappear to regulate the influence of more permanent excitatory synapses.

Nedivi has revealed how experience can make excitatory synapses permanent. After discovering that mice lacking a synaptic protein called CPG15 were slow learners, Nedivi hypothesized that it was because the protein helped cement circuit connections that implement learning. To test that, her lab exposed normal mice and others lacking CPG15 to stretches of time in the light, when they could gain visual experience, and the dark, where there was no visual experience. Using special microscopes to literally watch fledgling synapses come and go in response, they could compare protein levels in those synapses in normal mice and the ones without CPG15. They found that CPG15 helped experience make synapses stick around because upon exposure to increased activity, CPG15 recruited a structural protein called PSD95 to solidify the synapses. That explained why CPG15-lacking mice don’t learn as well: they lack that mechanism for experience and activity to stabilize their circuit connections.

Another Sur Lab study in 2018 helped to show how multiple synapses sometimes change in concert to implement plasticity. Focusing on a visual cortex neuron whose job was to respond to locations within a mouse’s field of view, his team purposely changed which location it preferred by manipulating “spike-timing dependent plasticity.” Essentially right after they put a visual stimulus in a new location (rather than the neuron’s preferred one), they artificially excited the neuron. The reinforcement of this specifically timed excitement strengthened the synapse that received input about the new location. After about 100 repetitions, the neuron changed its preference to the new location. Not only did the corresponding synapse strengthen, but also the researchers saw a compensatory weakening among neighboring synapses (orchestrated by a protein called Arc). In this way, the neuron learned a new role and shifted the strength of several synapses along a dendrite to ensure that new focus.

Lest one think that plasticity is all about synapses or even dendrites, Nedivi has helped to show that it isn’t. For instance, her research has shown that amid monocular deprivation, inhibitory neurons go so far as to pare down their axons to enable circuit rewiring to occur. In 2020 her lab collaborated with Harvard scientists to show that to respond to changes in visual experience, some neurons will even adjust how well they insulate their axons with a fatty sheathing called myelin that promotes electrical conductance. The study added strong evidence that myelination also contributes to the brain’s adaptation to changing experience.

It’s not clear why the brain has evolved so many different ways to effect change (these examples are but a small sampling) but Nedivi points out a couple of advantages: robustness and versatility.

“Whenever you see what seems to you like redundancy it usually means it’s a really important process. You can’t afford to have just one way of doing it,” she said. “Also having multiple ways of doing things gives you more precision and flexibility and the ability to work over multiple time scales, too.”

Insights into illness

Another way to appreciate the importance of plasticity is to recognize its central role in neurodevelopmental diseases and conditions. Through their fundamental research into plasticity mechanisms, Bear, Littleton, Nedivi and Sur have all discovered how pivotal they are to breakdowns in brain health.

Beginning in the early 1990s, Bear led pioneering experiments showing that by multiple means, post-synaptic sensitivity could decline when receptors received only weak input, a plasticity called long-term depression (LTD). LTD explained how monocular deprivation weakens an occluded eye’s connections to the brain. Unfortunately, this occurs naturally in millions of children with visual impairment, resulting in a developmental vision disorder called amblyopia. But Bear’s research on plasticity, including mechanisms of LTD, has also revealed that plasticity itself is plastic (he calls that “metaplasticity”). That insight has allowed his lab to develop a potential new treatment in which by completely but temporarily suspending all input to the affected eye by anesthetizing the retina, the threshold for strengthening vs. weakening can be lowered such that when input resumes, it triggers a newly restorative connection.

Bear’s investigations of a specific form of LTD have also led to key discoveries about Fragile X syndrome, a genetic cause of autism and intellectual disability. He found that LTD can occur when stimulation of metabotropic glutamate receptor 5 (mGluR5) causes proteins to be synthesized at the dendrite, reducing post-synaptic sensitivity. A protein called FMRP is supposed to be a brake on this synthesis but mutation of the FMR1 gene in Fragile X causes loss of FMRP. That can exaggerate LTD in the hippocampus, a brain region crucial for memory and cognition. The insight has allowed Bear to advance drugs to clinical trials that inhibit MGlur5 activity to compensate for FMRP loss.

Littleton, too, has produced insight into autism by studying the consequences of mutation in the gene Shank3, which encodes a protein that helps to build developing synapses on the post-synaptic side. In a 2016 paper his team reported multiple problems in synapses when Shank was knocked out in fruit flies. Receptors for a key form of molecular signaling from the presynaptic side called Wnt failed to be internalized by the postsynaptic cell, meaning they could not influence the transcription of genes that promote maturation of the synapse as they normally would. A consequence of disrupted synaptic maturation is that a developing brain would struggle to complete the connections needed to efficiently encode experience and that may explain some of the cognitive and behavioral outcomes in Shank-associated autism. To set the stage for potential drug development, Littleton’s lab was able to demonstrate ways to bypass Wnt signaling that rescued synaptic development.

By studying plasticity proteins Sur’s lab, too, has discovered a potential way to help people with Rett syndrome, a severe autism-like disorder. The disease is caused by mutations in the gene MECP2. Sur’s lab showed that MECP2’s contribution to synaptic maturation comes via a protein called IGF1 that is reduced among people with Rett. That insight allowed them to show that treating Rett-model mice with extra IGF1 peptide or IGF1 corrected many defects of MECP2 mutation. Both treatment forms have advanced to clinical trials. Late last year IGF1 peptide was shown to be effective in a comprehensive phase 3 trial for Rett syndrome and is progressing toward FDA approval as the first-ever mechanism-based treatment for a neurodevelopmental disorder, Sur said.

Nedivi’s plasticity studies, meanwhile, have yielded new insights into bipolar disorder. During years of fundamental studies, Nedivi discovered CPG2, a protein expressed in response to neural activity that helps regulate the number of glutamate receptors at excitatory synapses. The gene encoding CPG2 was recently identified as a risk gene for bipolar disorder. In a 2019 study her lab found that people with bipolar disorder indeed had reduced levels of CPG2 because of variations in the SYNE1 gene. When they cloned these variants into rats, they found they reduced the ability of CPG2 to locate in the dendritic “spines” that house excitatory synapses or decreased the proper cycling of glutamate receptors within synapses.

The brain’s ever-changing nature makes it both wonderful and perhaps vulnerable. Both to understand it and heal it, neuroscientists will eagerly continue studying its plasticity for a long time to come.

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