HHMI Invests $300 Million in 33 New Investigators

Summary

The scientists come from 21 US institutions and will join a community of Investigators who are tackling some of the most challenging problems in biomedical research.

The 2021 Howard Hughes Medical Institute (HHMI) Investigators are diving deep into tough questions that span the landscape of biology and medicine. And the new cohort of 33 scientists that HHMI announced today represents outstanding science from across the United States.

In North Carolina, a psychiatrist is examining the role of brain electricity in mental health disorders. An Arizona scientist is probing how bacteria can become permanent fixtures inside host cells. And a California biologist is on a mission to heal diseased hearts.

These scientists and their fellow 2021 Investigators could radically change how we think about biology, human health, and disease. HHMI will invest at least $300 million in these new Investigators, who come from 21 US institutions and will join HHMI’s Investigator community, which currently includes approximately 250 scientists.

“HHMI is committed to giving outstanding biomedical scientists the time, resources, and freedom they need to explore uncharted scientific territory,” says HHMI President Erin O’Shea. By employing scientists as HHMI Investigators, rather than awarding them research grants, she says, the Institute is guided by the principle of “people, not projects.”

HHMI selected the new Investigators because they’re thoughtful, rigorous scientists who have the potential to make transformative discoveries over time, says David Clapham, HHMI’s vice president and chief scientific officer. “We encourage Investigators to follow new directions, learn new methods, and think in new ways,” he says. “This could lead to scientific breakthroughs that benefit humanity.”

Each new Investigator will receive roughly $9 million over a seven-year term, which is renewable pending a successful scientific review. HHMI selected the new Investigators from more than 800 eligible applicants.

To date, 32 current or former HHMI scientists have won the Nobel Prize – most recently, Jennifer Doudna in 2020 for the development of a method for genome editing. Investigators have made significant contributions across many research areas, including HIV vaccine development, microbiome and circadian rhythm research, immunotherapy, SARS-CoV-2 biology, and potential therapies and vaccines for COVID-19, among other fields.

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HHMI is the largest private biomedical research institution in the nation. Our scientists make discoveries that advance human health and our fundamental understanding of biology. We also invest in transforming science education into a creative, inclusive endeavor that reflects the excitement of research. HHMI’s headquarters are located in Chevy Chase, Maryland, just outside Washington, DC.

2021 HHMI Investigators

Emily Balskus, PhD

Harvard University

Chemistry is happening all around us – and even inside us. Harvard University chemical biologist Emily Balskus is revealing the hidden chemical reactions carried out by microbes deep inside our guts.

Like trillions of tiny chemists, microbes are continuously building or breaking down molecules. These microscopic organisms can manufacture enzymes capable of chemical feats the human body can’t pull off alone. Scientists are still cataloging these microbes, called the gut microbiome, and know that they play a role in disease. But just how the microbiome influences human health remains a mystery. One challenge is teasing apart the different jobs microbes perform in the complex environment of the intestines.

“As a chemist, I can bring a unique perspective to this problem,” Balskus says. She and her team have figured out important aspects of microbial metabolism, such as how an enzyme in gut bacteria breaks down cholesterol, which is linked to heart disease. Engineering probiotics that contain the cholesterol-busting enzyme could potentially help lower people’s cholesterol levels.

Balskus’s lab has also uncovered how some bacteria convert the Parkinson’s drug levodopa to a different molecule, reducing the drug’s effectiveness. And by puzzling out the action of a particular cluster of genes, her team learned how certain gut bacteria produce colibactin, a molecule that scientists have implicated in colorectal cancer. The team discovered that colibactin damages the DNA of host cells, and then they designed a molecule to block its action.

Now, Balskus says, she’s excited to develop new strategies to harness the microbiome for improving human health.

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Gregory Barton, PhD

University of California, Berkeley

Before a person’s immune system launches an attack, it must answer a crucial question: friend or foe? Make the wrong choice, and a pathogen could sneak through, or the person’s own cells could come under fire. Greg Barton of the University of California, Berkeley, is learning how the immune system makes these choices.

The human immune system uses two main strategies: the innate immune system is pre-programmed to recognize broad categories of pathogens, and the adaptive immune system learns about specific pathogens as they’re encountered. Barton and his team focus on how the innate immune system recognizes microbes, and how the innate and adaptive systems work together.

Barton studies two related mysteries in the immune system’s workings. One is that immune cells recognize pathogens by sensing their genetic material, even though similar material exists within our own cells. Also, the body tends not to attack harmless gut bacteria, suggesting that immune cells can distinguish “friendly” bacteria from harmful ones.

His team has discovered genes and molecular processes that allow the immune system to distinguish between pathogen genetic material and our own, and showed how breakdowns in these mechanisms lead to attacks on the body’s cells. He has also identified gut bacteria that trigger the immune system, and is learning from them how the immune system knows whether a microbe is harmful.

“Our ultimate goal is to leverage our discoveries … for therapeutic benefit,” Barton says. For instance, certain gut microbes might one day be harnessed to boost immunity, and a better understanding of autoimmunity could spark new treatments for immune disorders.

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Diana Bautista, PhD

University of California, Berkeley

Diana Bautista wants to understand what’s driving unpleasant and sometimes deadly immune responses. In conditions like eczema, asthma, and COVID-19, for example, the nervous and immune systems go into overdrive, prompting an exaggerated reaction that can be harmful.

The first member of her family to attend college, Bautista has been studying cell signaling since graduate school. Now a cell and molecular neurobiologist at the University of California, Berkeley, she’s focused on untangling the complex cellular and molecular interactions that contribute to chronic inflammation, where the nervous and immune systems are doing more harm than good.

Bautista first tackled this issue in eczema, a chronic itch disorder. She found that a signaling molecule released by epithelial skin cells directly activates immune cells and the nervous system. Neurons send out inflammatory signals that make eczema flare up, Bautista’s lab showed. They then looked at airway neurons and lung epithelial cells, as many children with eczema go on to develop asthma and allergies. The team found similar neuronal signaling in those cells as well.

When the pandemic hit in 2020, Bautista’s lab began to research the new threat – COVID-19 can cause deadly lung inflammation, too. “As a woman of color, with a diverse group of trainees in my lab, we felt first-hand the disparities of COVID-19 in our own families and communities,” says Bautista. By looking at cellular-level changes from when infection begins to when breathing problems develop, she hopes to untangle the ways SARS-CoV-2 impacts the nervous system and triggers inflammation.

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Trevor Bedford, PhD

Fred Hutchinson Cancer Research Center

Trevor Bedford changed history with a Twitter thread on February 29, 2020, sounding the alarm on the first known community transmission of COVID-19 in the United States. The warning, spurred by a disease surveillance network his team built, touched off emergency lockdowns and other preventative public health measures in Seattle and beyond.

It was just the latest example of the life-saving roles Bedford’s research has played in improving the world’s ability to spot and respond to deadly scourges. A computational biologist at the Fred Hutchinson Cancer Research Center, Bedford had once felt frustrated that genetic analyses of emerging viruses were typically done too late to help quash the outbreaks. Far better, he thought, to set up a surveillance system that includes genome sequencing to rapidly track worrisome new viral strains. Such a system could provide “insights into an outbreak that are unobtainable by any other approach,” he explains, like where it began and how it spreads. He co-developed a software platform, Nextstrain, to create such a global surveillance network, and also started the Seattle Flu Study to detect and interrupt transmission of influenza in that vicinity.

The projects led to improved methods for forecasting flu mutations, now used by the World Health Organization to inform vaccine design. His team also has monitored spatial spread of the Ebola virus, uncovered extensive “cryptic” transmission of the Zika virus, and charted outbreaks of West Nile and dengue viruses. And since COVID-19 struck, Bedford’s analyses have been crucial to understanding the evolution and transmission of SARS-CoV-2.

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Flaminia Catteruccia, PhD

Harvard University

Mosquitoes have threatened human health for centuries, transmitting pathogens like malaria. By learning more about the biology of Anopheles mosquitoes and the malaria parasite that develops inside them, Flaminia Catteruccia hopes to find new solutions for disease control that are less harmful to the environment.

Female mosquitoes must nourish their developing eggs, and human blood provides an ideal source of nutrients. Yet that blood often brings malaria parasites with it. At Harvard University, Catteruccia is piecing together the basic biology of how the eggs developing in the female mosquito’s ovaries tolerate the malaria parasites multiplying in her gut.

To better understand the interplay between these two pathways, Catteruccia tapped into mosquitoes’ mating behavior. She and her team identified a male steroid hormone that is transferred to the female mosquito during sex. It protects females’ eggs from damage by the malaria parasite and also blocks female mosquitoes from mating again. “Males and females are together for only 17 seconds, but it completely changes female physiology and behavior,” Catteruccia says.

Going forward, the team’s insights into mosquito reproduction and parasite biology will help them develop more targeted antimalarial compounds. Such tools could crack down on the parasite without having broader health effects on mosquitoes, other insects, or humans. By aiming at the parasite, rather than the mosquito, Catteruccia wants to minimize the emergence of resistance to antimalarial compounds. Ultimately, she hopes her work can rein in “the deadliest parasite in the history of humankind.”

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Xin Chen, PhD

Johns Hopkins University

In our bodies, nature is continually performing an amazing feat of renewal. Stem cells constantly divide to create two genetically identical daughter cells. One daughter is another stem cell. But a mysterious transformation converts the other into something more specialized, like a skin cell or blood cell. How is this molecular sleight of hand achieved when both cells have identical DNA?

In award-winning research at the Johns Hopkins University, biologist Xin Chen has shown that the answer involves proteins called histones. Scientists have long known that histones act like a spool around which strands of DNA wrap. But the proteins also contain crucial instructions known as epigenetic information.

When the stem cell copies its genes and histones in order to divide, the original histones go to the daughter that remains a stem cell. Discoveries in Chen’s lab have revealed that histones in the other daughter are altered. This alteration, they’ve found, starts at replication, thus reprogramming the epigenetic information and creating a more specialized cell.

Using new methods and tools developed or refined in her lab, Chen has made the first direct observations of this so-called asymmetric epigenetic inheritance in living organisms. She’s also spotted the mechanism in creatures ranging from fruit flies to mice, providing “exciting preliminary data that this could be a fundamental property of stem cells that is conserved across species,” she says.

The research offers a possible new window into diseases that might be caused when this molecular mechanism goes awry, such as cancer or tissue degeneration.

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Rhiju Das, PhD

Stanford University

Uncovering the three-dimensional structures of biological molecules can bring valuable insights into their function. A detailed 3-D map of a virus’s RNA could reveal vulnerable nooks and crannies that might be targets for pathogen-neutralizing drugs. In the past, most RNA molecules have resisted giving up their structural secrets. But “the dream – and the major goal of my research – has been to be able to take any RNA sequence and rapidly figure out its 3-D structure,” says Stanford University biochemist Rhiju Das.

Das is now close to realizing that dream. His team began by adapting computational methods previously used to predict protein shapes. These tools helped reveal the shapes of entire viruses and key biological machines like telomerase – and helped the Das lab win numerous competitions predicting structures of RNA molecules.

Still, the shapes of most RNA molecules remain elusive. So Das and his colleagues doubled down on an imaging technique called cryo-electron microscopy. The effort finally nailed the structure of the first RNA-only enzyme discovered, 40 years after it was first identified. Now, Das’s team hopes to build a 3-D atlas of all of nature’s RNA molecules.

When the COVID-19 pandemic struck in 2020, Das quickly pivoted to study the new threat, seeking the 3-D structures of key segments of coronavirus RNA. His lab and colleagues identified “tantalizing holes and crevices” that could be binding sites for drugs, Das says. They’re now developing anti-viral drugs based on those discoveries, as well as probing and improving COVID-19 mRNA vaccines.

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Kafui Dzirasa, MD, PhD

Duke University

In recent decades, psychiatry has focused on the role of brain chemistry in mental illness. But chemistry is only a part of the picture in the brain, says Duke University psychiatrist Kafui Dzirasa. Electrical signals also define neural activity.

Dzirasa’s research poses the question: What if psychiatric disorders are electrical in nature?

His interest is personal. Dzirasa says his work is “motivated and informed by my experiences caring for people and family members with profound emotional disruptions.” Also a neurophysiologist and biomedical engineer, Dzirasa and his team are examining the role of electricity in mental health disorders. They record the millions of electrical changes that cross the brains of mice every second and then analyze the rhythmic patterns of those brain waves.

The scientists have identified distinct electrical signatures in mice that exhibit symptoms of depression. Dzirasa’s team discovered that they could disrupt these signatures to restore normal electrical activity and behavior. They also identified a different signature in healthy mice prone to developing depressive behavior. His team has linked different emotional states to specific signatures, dubbed the “electome.” They are now working to compile an encyclopedia of brain wave signatures relevant to psychiatric disorders including bipolar disorder, schizophrenia, substance abuse, and autism.

Over the long term, Dzirasa hopes to devise new treatments for such conditions based on what his team learns about how brain electrical activity gets disrupted. “My aspiration,” he says, “is to advance curative treatment strategies for psychiatric disorders.”

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Nels Elde, PhD

University of Utah

When mortal enemies, infectious microbes and their hosts are locked in an ever-escalating conflict. Nels Elde, an evolutionary geneticist at the University of Utah, studies the cellular innovations that result from this arms race. He’s interested in how the biology of host cells changes to prevent pathogens from replicating.

“Our research points to a central role for microbes in shaping our own cell biology,” Elde says. And it raises the possibility that interactions with microbes have more widely shaped cells’ basic functions – “an emerging view with the potential to disrupt textbook concepts in genetics and cell biology.”

His lab has discovered a genetic mutation in mice and monkeys that illustrates such a maneuver. A duplicated gene encodes an altered protein that delays the process cells use to bud off pieces of their membranes. The change interferes with the ability of viruses such as HIV and Ebola to coopt this process and escape an infected cell. Elde and his team believe this represents a new type of immunity that arises quickly to protect against short-lived threats.

Elde’s lab also studies adaptations that result from infections by bacteria and fungi. One such project focuses on evolutionary changes to a key physiological process – the intestine’s absorption of water – that ward off diarrhea caused by E. coli.

To overcome host defenses, our adversaries change too – sometimes in sneaky ways. Viruses, for example, are known to capture host genes in their own genomes. Elde’s lab is exploring the mechanisms that make these genetic acquisitions possible.

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Cagla Eroglu, PhD

Duke University

How do billions of neurons establish the trillions of connections that make up a human brain? The answer could involve sprawling, star-shaped brain cells called astrocytes, says Duke University neuroscientist Cagla Eroglu.

“Traditionally, astrocytes were viewed as inert support cells,” she says. Now, scientists know that astrocytes aren’t just the glue that holds neurons together – they actually help construct an intricate web of neural circuitry. By developing new techniques to visualize these cells and study their interaction with neurons, Eroglu’s team is learning how astrocytes shape communication networks in the brain.

Neurons communicate via junctions between cells. Chemical or electrical signals zip through these gaps, called synapses, sending information through the brain’s circuits. A single human astrocyte may interact with two million synapses. Eroglu’s team discovered that neurons rely on chemical signals from astrocytes to form these communication junctions. And the relationship between the two cell types goes both ways, the researchers have shown. Astrocytes grow to their full size and complexity only if neurons are present.

To detect and respond to neurons, astrocytes rely on the coordinated action of many different genes. Scientists have linked some of these genes to autism. By uncovering the genes’ functions, Eroglu’s work could expand our understanding of autism and other disorders rooted in brain connectivity, such as epilepsy and pain caused by damaged nerves.

Deciphering the details of how astrocytes sculpt neural connections and influence brain circuitry will open up exciting possibilities for future investigations, Eroglu says. “We have only begun to explore astrocyte biology.”

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Cassandra Extavour, PhD

Harvard University

In complex organisms like animals, specialized cells called germ cells make the eggs and sperm that enable sexual reproduction. Harvard University biologist Cassandra Extavour is investigating the ancient origins of germ cells.

No other cells in the body pass on their genes, making germ cells central to the process of evolution. Extavour studies the evolutionary processes that led to the formation of the first egg cell. “Like the ‘One Ring’ of Tolkien’s Middle Earth,” she says, “the germline unites and guides the function and evolution” of all other cells in the body as well as the subsequent germline — and ultimately, the future of the species. She wants to understand germ cell evolution on as many different levels as possible, from individual molecules and genes all the way up to ecological interactions between organisms. To do this, her lab uses an array of tools spanning such disciplines as molecular genetics, protein chemistry, and mathematical modeling.

At the molecular level, Extavour’s team discovered that the path to the first egg cell involved repurposing existing genetic networks, but also added entirely new genes assembled from portions of bacterial and animal genes. On an ecological scale, she’s shown newfound ways that environmental pressures on reproduction rate help steer evolution.

Extavour investigates ancient questions of evolutionary biology, but her findings could potentially influence applied medical research as well. “While my research program is devoted to understanding the fundamentals of germline evolution,” Extavour says, “these factors are also highly relevant to infertility and other pathologies of human reproduction.”

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Chenghua Gu, PhD

Harvard University

Neurons in the brain are highly sensitive to their surroundings. To maintain a controlled chemical environment and protect the brain from toxic or unwanted signals, the blood-brain barrier selectively allows only certain molecules to enter the brain from the blood.

In her lab at Harvard University, neuroscientist Chenghua Gu studies how the brain establishes this protection. “Having a tightly controlled barrier is no doubt very important for normal brain function,” she says. “At the same time, it is the biggest obstacle to delivering drugs into the brain.”

The blood-brain barrier is formed by endothelial cells that line the walls of brain blood vessels. To enter the brain, molecules in the blood must either go between these cells or through them. Neuroscientists thought blood vessels stopped unwanted traffic by keeping endothelial cells locked tightly together, preventing most molecules from slipping through.

Gu and her team have discovered that’s only part of the story. Most endothelial cells in the body have a transport system that ferries molecules from one side to the other. The team showed that this system is actively suppressed in brain endothelial cells to prevent unwanted trafficking. They also found unique molecular pathways present only in the brain endothelial cells that control this process.

Gu’s discovery suggests that scientists could alter the blood-brain barrier by manipulating the molecular pathways that inhibit trafficking across endothelial cells. That control could allow easier delivery of needed medications. It could also help tighten the barrier when it becomes leaky, which occurs in certain neurodegenerative diseases.

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Sun Hur, PhD

Boston Children’s Hospital

Sun Hur is solving the immune system’s most perplexing mysteries.

When fighting an invading pathogen, the body must be careful not to attack itself. Distinguishing its own molecules from those of a foreign organism is “a fundamental basis for defense against microbial infection,” says Hur, a biochemist at Boston Children’s Hospital.

One way the immune system can spot a viral invader is by recognizing its double-stranded RNA. Protein sensors detect the RNA, kicking off an immune response. But how the immune system coordinates this response – and differentiates viral RNA from RNA made by the body – is not well understood, Hur says.

Her team has discovered a key part of this viral detection process. The immune system’s virus-spotting machinery includes receptor molecules that bind to double-stranded RNA. The receptors form filaments during that binding process, Hur’s team determined. The filaments then go through a series of molecular steps that identify the virus to the immune system.

Each step functions as a checkpoint, Hur says, giving the immune system several chances to ensure the target is foreign. She calls this molecular pathway “powerful yet dangerous.”

The receptors can trigger a useful immune response that researchers could potentially tap to fight viral infections, as well as inflammatory diseases and cancers. But there are several ways for the detection process to go off course, she notes, possibly leading to inflammatory disorders. By exploring such processes, Hur hopes her work will lead to new ways to keep the immune system on target.

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Martin Jonikas, PhD

Princeton University

Plants transform carbon dioxide from the atmosphere into sugars. This process, called photosynthesis, lets plants feed much of life on Earth. But single-celled microorganisms called algae can suck up this gas more efficiently than land plants. That’s because the microbes rely on a tiny molecular compartment called the pyrenoid.

Princeton University molecular biologist Martin Jonikas believes that engineering the pyrenoid into crops like rice and wheat could revolutionize agriculture.

Jonikas wasn’t always into plants. Motivated by a childhood love of robotics, he studied aerospace engineering in college. But after taking a required molecular biology class, Jonikas was hooked. “The most amazing machines on Earth are living organisms,” he says.

In plants and algae, an enzyme called Rubisco converts carbon dioxide into biomass. But Rubisco runs slowly, limiting how quickly many crops can grow. Algae have figured out a way to make the enzyme run faster. They cluster their Rubisco molecules within pyrenoids and force-feed the enzyme carbon dioxide.

Jonikas and his team’s near-term goal is to engineer working pyrenoids into plants. Already, they have identified 90 pyrenoid proteins, accounting for most of its known components. Jonikas’s lab has also overturned the 50-year-old assumption that the pyrenoid is a crystalline solid. Instead, they’ve shown, it behaves like a liquid.

Now, his lab has begun to examine another crucial pyrenoid component: the network of tiny tubes that anchor it and supply it with carbon dioxide. Jonikas hopes his team’s work will unlock pyrenoids’ power, ultimately allowing scientists to supercharge crops.

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Cigall Kadoch, PhD

Dana-Farber Cancer Institute

Although often depicted as a linear piece of code, DNA has 3-D structure when packed within chromosomes. Dana-Farber Cancer Institute molecular biologist Cigall Kadoch studies an influential molecular machine that alters this structure to control gene activity.

Known as SWI/SNF or BAF complexes in mammals, this diverse family of protein assemblies governs the architecture of the genome, turning genes on and off, and dialing activity up or down at the right times.

SWI/SNF complexes are critical for the development of virtually every type of tissue. When they malfunction, the consequences can be devastating. Mutations affecting SWI/SNF contribute to more than 20 percent of human cancers and are frequently found in neurodevelopmental disorders and immune conditions. The complex is also complicated. Encoded by 29 genes, it assumes three primary forms, which can exist in more than 1,000 different configurations, likely each with specific roles.

Kadoch’s lab uses human disease genetics as an entry point to study how SWI/SNF works. Her team’s studies have uncovered the biochemical, structural, and functional consequences of SWI/SNF subunit aberrations, each of which contributes to disease in distinct manners.

Now, Kadoch’s group is defining the mechanisms underpinning SWI/SNF complex disruptions. They aim to fully delineate how the complex functions in human health and disease, which could offer hope to many patients. The team’s discoveries could lead to new treatments that target specific mutations responsible for different cancers. In fact, Kadoch says, understanding SWI/SNF complex features “serves as a powerful foundation for defining new therapeutic opportunities across a wide range of human diseases.”

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Shingo Kajimura, PhD, ScD

Beth Israel Deaconess Medical Center

To many people, fat is a four-letter word. But to Shingo Kajimura, fat is the ticket for solving many ailments plaguing society today. At Beth Israel Deaconess Medical Center, Kajimura’s work highlights the critical role fat cells play in energy metabolism – and how these cells might unlock new treatments for metabolic diseases.

Kajimura uses fat as a model to study bioenergetics. White fat stores energy and thickens waistlines; brown and beige fat burn energy and generate heat. This heating power comes from tiny cellular furnaces called mitochondria, which give brown fat its color. Exposure to cold can prompt white fat to create mitochondria, turning it beige. Kajimura’s work poses the new idea that brown and beige fat are “good fat” that go far beyond heat generation.

His team has shown that beige fat collects sugar and other metabolites, removing them from the bloodstream where they can wreak havoc on the body. This discovery suggests that beige fat could counteract diabetes. Now, Kajimura’s team is pinpointing the molecular players that might help brown and beige fat ward off metabolic diseases. They have discovered the master regulator of brown and beige fat development, and the molecule that transports fuel inside these cells.

Kajimura’s overarching goal is to generate molecular blueprints that illustrate how white fat is remodeled into beige fat and how such processes go awry in disease. Mapping out these events could one day enable scientists to rewire a person’s metabolic circuitry, potentially improving their metabolic health.

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Daniel Kronauer, PhD

The Rockefeller University

Over the past 18 years, Daniel Kronauer has observed army ants in many marvelous places, from the rainforests of Costa Rica to the Konza Prairie of Kansas. He has described how these social insects, which form societies of up to 20 million members, can overwhelm larger prey in spectacular feats of cooperation and battle prowess.

These remarkable behaviors stem from ants’ ability to work as a group, segregating into castes with different roles that help their colony thrive. At the Rockefeller University, Kronauer studies the genetic and neural mechanisms that determine how ants adapt, develop, and interact. He’s investigating how ants take on specialized jobs in a colony – such as foraging or nursing – and how they use what he calls a “dazzling array of pheromones” to communicate with each other and generate colony-level decisions.

Kronauer has shown that clonal raider ants – an army ant relative – reproduce by making clones of themselves. Offspring are genetically identical to the parent, yet new ants can take on different jobs. That sparks an intriguing question: If genes don’t dictate an ant’s job in a colony, what does?

Kronauer developed the clonal raider ant as an unconventional laboratory model to unravel this mystery, and to study complex social behavior. Now, his team can begin to understand how genes and the environment influence an individual ant’s identity, while also letting millions of ants coordinate their behavior and act as one. The work, he says, could help scientists understand the origins of insect social life in unprecedented depth and detail.

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Frederick Matsen IV, PhD

Fred Hutchinson Cancer Research Center

Researchers trying to answer big scientific questions often collect huge amounts of data.

Making sense of all this information can become a very hard math problem, says Frederick Matsen IV, a mathematician at the Fred Hutchinson Cancer Research Center. And that, he adds, can block progress in understanding biology. Matsen has dedicated his career to finding and solving such problems.

Take the vital task of charting a virus’s evolution. Scientists can use genomic mutations to computationally reconstruct a virus’s evolutionary tree. This reconstruction is inherently uncertain, Matsen says. So, scientists use a tool called Bayesian phylogenetics to find the set of trees that credibly explain the data.

But when researchers have amassed thousands of genome sequences, as with the Ebola virus, results can take weeks to compute. And in the case of the SARS-CoV-2 virus, where scientists have sequenced more than 2.5 million genomes, “classical Bayesian computation is unthinkable,” Matsen says.

Matsen and his team are developing new approaches to this problem, creating computational algorithms to analyze large sets of genetic data from an evolutionary perspective. The goal is to track viral evolution using Bayesian methods in real time, such as during an outbreak.

Matsen is also applying his mathematical wizardry to immunology. He wants to figure out how immune cells rapidly mutate to produce antibodies that can fight off new pathogens. “I’ve been absolutely captivated by those cells,” he says. Matsen’s team is creating new, sophisticated statistical models of this process, and testing them with data from collaborating laboratories.

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Ian Maze, PhD

Icahn School of Medicine at Mount Sinai

Serotonin and dopamine govern our moods, our motivations, and our movements. These neurotransmitters rein in or spur on the signals that race through the brain’s neural circuits. But Ian Maze, a neurobiologist at the Icahn School of Medicine at Mount Sinai, is more interested in what else they are doing in the brain. “What if this is only half of the story?” he asks.

Inside neurons, Maze has found something surprising: serotonin and dopamine clinging to DNA-packaging proteins called histones. There, the tag-along molecules act as regulatory marks that influence which genes get switched on.

Scientists knew that cells can regulate gene activity by decorating the genome with certain chemicals. But no one knew that these chemicals included serotonin and dopamine. Maze’s findings suggest that these chemical marks may have implications for brain function and psychiatric health. For example, they could play a role in driving drug addiction, his team has discovered.

Some of the chemical relatives of serotonin and dopamine can also attach to histones, Maze’s lab has reported. He is now studying this family of chemicals, called monoamines, to understand how, when, and where they link up with histones, as well as how the cell’s machinery “reads” them once they are in position.

Maze’s team is also looking beyond monoamines’ unexpected impact on gene regulation and investigating what happens when they glom on to other proteins in the brain. “We are excited to be at the forefront of this burgeoning field,” he says.

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John McCutcheon, PhD

Arizona State University

John McCutcheon studies bacteria with a complicated living arrangement: They reside within the cells of sap-eating insects called mealybugs, where they provide nutrients that the insects can’t make themselves or get from food. In return, the insects supply materials the bacteria can’t make on their own. McCutcheon is exploring this partnership to better understand events that occurred more than a billion years ago.

Back when all life was single-celled, one cell engulfed another and struck up a relationship that eventually gave rise to mitochondria, internal energy plants that power organisms from yeast to humans. Millions of years later, a different cell took in a photosynthetic bacterium, eventually leading to chloroplasts – an essential step in the evolution of plants and algae.

“We’re trying to understand how an independent organism becomes so intimately associated with its host cell that it becomes part of it,” says McCutcheon, a biologist at Arizona State University. “We think that what we discover will give us some hints about how mitochondria and chloroplasts came to be.” Symbiotic relationships between insects and intracellular bacteria might represent an in-between stage of this transformation.

The bacteria McCutcheon studies have tiny genomes. He’s found that they rely on proteins made by their mealybug hosts, which has enabled them to downsize their DNA. This parallels the import of cellular materials into chloroplasts or mitochondria, which have tiny genomes of their own. As McCutcheon looks for clues to the evolutionary past within this long-standing symbiotic relationship, he is also exploring newer insect-bacteria partnerships, hoping to learn how organisms adapt as symbioses become established.

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Michelle Monje, MD, PhD

Stanford University

Gliomas don’t just grow within the brain’s circuitry – they become part of it. Stanford University neurobiologist Michelle Monje studies these often aggressive brain cancers, which begin in precursors to the glial cells that surround and support neurons. She’s found that gliomas and neural circuits are so intimately integrated that activation of nearby neurons can send electrical signals flowing through the tumor – and spur its growth.

To improve patient outcomes, scientists need to know more about gliomas’ interactions with the nervous system, says Monje, who is also a pediatric neuro-oncologist. “This cancer is an electrically active tissue,” she says. “We must understand the neuroscience of this malignant circuitry.”

Monje’s glioma research complements her work on healthy neurodevelopment. She discovered that when neurons fire, it encourages the development of glial cells that will insulate and protect them. Because insulation speeds the transmission of neurons’ electrical signals, this is one way that experience tunes neural circuits. More recently, she’s found that signals from activated neurons also stimulate growth and spread of glioma. In animal models, silencing neuron-glioma communication dramatically slows tumor growth. This discovery led Monje’s team to the identification of a promising therapeutic target for malignant gliomas, and the launch of a clinical trial evaluating a potential treatment for children with the disease.

As she investigates the intersection between neuroscience and cancer biology, Monje also expects to learn more about healthy neuron-glia interactions. That, in turn, could further our understanding of how the brain adapts and neural circuits change in response to experience and activity.

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Daniel Mucida, PhD

The Rockefeller University

The intestines are home to an ever-changing ecosystem. Trillions of microbes reside there, and new ones – most of them harmless – arrive every day, along with a rich assortment of nutrients from digested food. Within this mix, it’s the immune system’s job to keep track of friend and foe. Daniel Mucida has made it his job to figure out how.

“The main function of the immune system is to provide resistance, or protection, against invading pathogens,” Mucida says. But it must also learn to tolerate beneficial microbes and molecules from the diet, he adds.

Mucida wants to understand what happens when this equilibrium fails. It’s an important question, because when the immune system launches an unnecessary attack, it can trigger food allergies or celiac disease. Too much immune activity in the gut can also lead to inflammatory bowel disease and increase the risk of cancer.

In his lab at the Rockefeller University, Mucida is charting the signals that help immune cells both steer clear of innocuous molecules and protect the gut from microbial interlopers. He’s shown that the immune system preps some immune cells to tolerate dietary nutrients encountered in the small intestine, while readying other cells to deal with microbes found in the large intestine.

Even the nervous system gets involved. Microbe-sensing neurons embedded in the intestines can direct nearby immune cells’ response, Mucida’s team has discovered. Now, he is investigating how cross talk among microbes, neurons, and immune cells shapes neural circuitry – within the gut and beyond.

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Dana Pe’er, PhD

Memorial Sloan Kettering Cancer Center

The cells of a young embryo have nearly unlimited potential. As those cells begin to establish their identities, their choices narrow. A single stem cell may become any kind of cell – but once it’s on its way to becoming a blood cell, for example, it’s unlikely to ever be a neuron.

Dana Pe’er, a computational biologist at Memorial Sloan Kettering Cancer Center, studies how cells travel their developmental paths. She’s interested in how healthy cells shape their identities, and how cancer cells abandon those identities to take on dangerous new abilities. Pe’er’s work combines mathematical approaches with a range of emerging technologies that enable large-scale analyses of single cells.

Her methods recognize and help explain the complexity of biological systems, such as how cells gradually adopt new properties over time, rather than abruptly switching between cell types. While statistical models often focus on trends and dismiss outlying data points, Pe’er does the opposite. “In biology, rare events matter,” she says. By developing techniques that highlight rare events, Pe’er helps scientists distinguish the events from noise in their data.

This approach has highlighted ways in which cancer cells misuse developmental pathways. For instance, cancer cells can tap into the cellular plasticity usually found only in developing or regenerating tissues. This lets the rogue cells access genes that help them metastasize or develop drug resistance.

For Pe’er, context is key. She seeks to understand how the tissue environment influences an individual cell’s fate. Now, her lab is charting how cells organize themselves, and what happens when this goes awry.

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Kristy Red-Horse, PhD

Stanford University

Kristy Red-Horse is on a mission to heal diseased hearts. Her focus: collateral arteries, blood vessels that can re-route blood to flow around blockages.

Formation of collateral arteries varies from person to person – some individuals grow many, while most develop few, if any. Red-Horse, a Stanford University biologist, has been studying how collateral arteries form and whether inducing their growth might repair damage caused by coronary heart disease, the leading cause of death worldwide.

For years, these arteries were thought to be transformed capillaries – blood vessels that connect arteries and veins. Instead, Red-Horse and her team found that the building blocks of collateral arteries are actually the same cells that make up typical arteries. In newborn mice, they showed they could trigger the formation of collateral arteries by creating a blockage. The newly formed collateral arteries developed from cells that detached from the lining of regular arteries and migrated to the damaged area.

Her team later discovered that the protein CXCL12 makes the feat possible. They injected CXCL12 into adult mice after a heart attack and showed that the molecule induces collateral artery formation. There was one drawback: computer modeling indicated that induced collateral arteries in newborn mice didn’t work as well as the natural versions. Red-Horse is now looking for other proteins and pathways that may be relevant in mice. She’s also studying the hearts of guinea pigs, which sport extensive collateral arteries from birth. She hopes her research in such model organisms could one day help in developing therapies for patients.

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Vanessa Ruta, PhD

The Rockefeller University

In nature, even the most closely related species can sometimes display surprisingly different behaviors. Among fruit fly species, for instance, all males perform an elaborate ritual to woo females. But some flap their wings to produce distinct songs while others silently flaunt their wings in a visual display.

Vanessa Ruta, a neuroscientist at the Rockefeller University, is studying the brains of courting Drosophila melanogaster males to understand what’s prompting this diversity. “Almost nothing is known about how evolution has tinkered with brain circuits to produce such endless variation,” she says. Her team is investigating how evolution tailors the nervous system to shape distinct behaviors across different species.

In male D. melanogaster, only 1,500 neurons control courtship behaviors. Switching on neurons known as P1 drives courtship in D. melanogaster and multiple closely3 related species, Ruta’s team has found. P1 neurons get switched on by the sight of a female and the “taste” of pheromone chemicals coating her body.

Ruta and her team discovered that each species’ P1 neurons are tuned to slightly different female cues, allowing males to select the right mate to court. That’s a surprise, Ruta says. It suggests that simply fiddling with preexisting circuits is enough to produce vastly different behaviors.

Next, her team plans to study how the intensity of P1 activation determines whether a Drosophila male sings or chases the female during courtship and how females use a male’s performance to select worthy mates. Decoding fruit flies’ elaborate courtship rituals offers “a window into the neural mechanisms of behavioral evolution,” she says.

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David Savage, PhD

University of California, Berkeley

David Savage wants to make crops more productive – and he thinks bacteria could help.

Like plants, water-dwelling cyanobacteria can photosynthesize, transforming sunlight, water, and carbon dioxide into sugar. But the bacteria do it better. Savage, a biochemist at the University of California, Berkeley, has spent the last decade studying one key component that makes cyanobacteria so efficient.

Inside tiny compartments called carboxysomes, bacteria concentrate carbon dioxide molecules, making them readily available for photosynthesis. Savage’s team is working toward installing this capable compartment into plants.

Nearly 20 genes play a role in manufacturing a functional carboxysome, he and his colleagues have discovered. The team has also figured out how to transfer this molecular machinery from one bacterial species to another that lacked it. They were able to transform Escherichia coli into bacteria that captured carbon dioxide from the air to fuel its growth. This work is a first in the field and “lays the groundwork for moving these components into plants,” Savage says.

The task isn’t straightforward. It would require transforming a plant’s chloroplast, the compartment that houses its photosynthesis machinery. Scientists would need to swap out some chloroplast genes with those that produce functioning bacterial carboxysomes. Every plant cell contains up to 100 chloroplasts, each with multiple genomes, making such an engineering feat challenging.

Savage and his team are now deploying sophisticated genome editing tools to tackle the problem. He hopes that one day the work could enhance plants’ photosynthesis abilities, so that farmers can harvest more from crops using less land.

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Mikhail Shapiro, PhD

California Institute of Technology

Mikhail Shapiro uses sounds waves to paint pictures of how cells function. A biochemical engineer at the California Institute of Technology, Shapiro and his team are figuring out new ways to see cells in live animals.

Most imaging relies on light waves. But light scatters and bounces against living tissue, similar to the way headlights bounce off rain and distort a driver’s vision. It can be hard to get clear, detailed images of cells deep inside a tissue. Ultrasound can probe beneath the surface without light’s glare. But while ultrasound is good at imaging muscles and organs, it hasn’t been useful for visualizing specific cells.

Shapiro’s team is changing that. They are pioneering a method that uses ultrasound to image and track cells in living animals. “My dream is that someday biology labs are going to have ultrasound systems standing right next to their optical microscopes,” says Shapiro.

To visualize cell activity with ultrasound, they found a molecule that sound waves can detect and cells can produce. The molecule came from a bacterium that evolved gas-filled protein sacs to float on water.

Shapiro has since engineered animal versions of the genes to manufacture that protein, and used it to image tumors in live mice. Recently, he has used ultrasound to track the activity of enzymes.

Currently, doctors have few ways to track the progression of microscopic medical treatments like stem cell therapy or engineered tissues. Cellular-level ultrasound could eventually make these therapies easier to monitor and control — giving listening to your body an entirely new meaning.

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Vincent Tagliabracci, PhD

University of Texas Southwestern Medical Center

Enzymes, and their ability to speed up chemical reactions, are a cornerstone of high school biology classes. Yet there is much about them that scientists still don’t understand, despite their important roles in many human diseases.

Vincent Tagliabracci, a biochemist at the University of Texas Southwestern Medical Center, is hunting down answers to these molecular mysteries. He focuses on protein kinases, a superfamily of enzymes that influences almost every aspect of cell life, from communication to division. So far, scientists have found hundreds of protein kinases – but they suspect there are many more yet to be discovered.

Identifying more of these catalysts and defining their jobs could lead to a greater understanding of major diseases such as cancer, diabetes, and rheumatoid arthritis.

It’s well understood that protein kinases do their work inside cells. Recently, researchers have realized that some protein kinases work outside of cells. Earlier in his career, Tagliabracci discovered a family of those external protein kinases linked to several developmental disorders.

Since then, his lab team has combed the genomes of humans, the SARS-CoV-2 virus, the bacterium responsible for Legionnaire’s disease, and a plant pathogen. They’ve identified some 30 new families of enzymes that look like protein kinases, though some of the enzymes are performing different chemical reactions.

Tagliabracci’s goal now is to test those enzymes to understand their chemistry and biology. This work has the potential to “fundamentally change the way we think about cellular signaling, regulation, and host-pathogen interactions,” says Tagliabracci. It could also lead to new tools for diagnosing and treating disease.

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Benjamin Tu, PhD

University of Texas Southwestern Medical Center

Benjamin Tu’s work is revealing that there’s more to metabolism than scientists once suspected. Rather than simply a way for the body to make energy, metabolism also steers key facets of cellular life.

Tu’s biochemistry lab at the University of Texas Southwestern Medical Center is drawing connections between metabolism and fundamental processes in cells, such as DNA replication and cell division. In short, whether a cell grows or dies depends on its metabolism. “My lab has discovered numerous examples of the overlooked influence of metabolism on a variety of life processes,” Tu says.

The metabolic chemicals acetyl-CoA and SAM, for instance, act as nutritional sensors in yeast, his team has found. When key nutrients are lacking, these chemicals’ levels wane, telling cells to halt growth. Acetyl-CoA and SAM “represent the metabolic currency of the cell,” Tu says. Without this currency on hand, cells cannot grow.

Tu and his colleagues have helped explain how this process works. His team was one of the first to demonstrate that acetyl-CoA can influence epigenetic modifications, the chemical tags on DNA that change how a gene is read. High acetyl-CoA levels, they’ve shown, stimulate epigenetic changes to a set of more than 1,000 growth genes.

Tracking down metabolic pathways that affect growth could lead to new targets for treating cancer and other diseases, he says. Now Tu’s group is studying mice, in addition to yeast, to learn more about these connections in mammals. He hopes paying closer attention to how cells synchronize energy use may help explain many mysterious and debilitating conditions.

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Kay Tye, PhD

Salk Institute for Biological Studies

Kay Tye is revealing the neural circuitry behind loneliness.

Her team is uncovering how our brains respond and adapt to shifting social scenes, and what happens when animals are isolated for too long. According to her research, we may want to add game nights and group meals to our lists of essential activities.

“Many of the most successful species on the planet live in social groups,” says Tye, a behavioral neuroscientist at the Salk Institute for Biological Studies. Too much alone time can be devastating for animals adapted to regular interaction. In humans, shorter life spans, mood disorders, and cancer are all connected to isolation. But scientists know little about the mechanisms underpinning why loneliness is harmful, or how gregarious species like ours form intricate, stable societies.

Tye is studying natural animal behavior to learn how individuals get the right quality and quantity of social contact. This balancing act is known as social homeostasis. She has discovered that stimulating an understudied population of neurons to release dopamine can spark a need for social connection. Increased activity in this neural circuit signals social craving in both mice and humans, her team has found.

Tye is also looking at how animals bounce back from short-term solitude or become antisocial after extended isolation. Understanding loneliness has gained new urgency amid global social distancing, she says. Tye hopes that her work studying how the brain adapts to new social settings will help guide both mental health care and future policy decisions that support mental health.

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David Veesler, PhD

University of Washington

David Veesler’s mission is to eradicate infectious disease in people. His team is mining bat viruses and the immune responses they elicit to combat future viral outbreaks.

Bats carry a disproportionately large and diverse array of viruses. While most of those pathogens don’t sicken bats, many are deadly to us. And as people convert bat habitat into cities and farms, society could encounter new and dangerous pathogens. The COVID-19 pandemic, which began in bats, is a stark example of this animal-to-human spillover.

“Many viruses found in bats are of major public health concern, with no approved vaccines or specific therapeutics available to protect humans,” says Veesler, a biochemist at the University of Washington. Understanding how bats are impervious to so many viruses could translate into tools for protecting people when spillovers occur.

Veesler’s lab focuses on how pathogens access host cells and how the immune system responds. Specifically, they look at the spike proteins that let coronaviruses enter cells. Soon after researchers genetically sequenced SARS-CoV-2, the virus that causes COVID-19, Veesler’s team revealed the architecture of its spike protein structure. Based on that work, his group developed a so-called subunit vaccine, which uses a spike protein fragment attached to a protein nanoparticle. The vaccine is currently being evaluated in clinical trials.

Now, Veesler plans to analyze the genetic makeup of thousands of bat viruses. He hopes this data-intensive approach will uncover the pathogens most genetically suited for infecting humans. Tools emerging from that work could not only help prepare for future outbreaks, but also predict their arrival.

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Elizabeth Villa, PhD

University of California, San Diego

Elizabeth Villa is in the tool-building business. A biophysicist at the University of California, San Diego, Villa develops new techniques to visualize cellular machinery, like the molecules that transport compounds within cells and through their membranes.

Such machinery consists of bulky molecular complexes made up of proteins, carbohydrates, lipids, and nucleic acids. Early in Villa’s career, she began building the microscopy and computational tools needed to understand all those parts in action. “We want to find ways to look at these molecules and their mechanisms in context – inside of cells,” she says.

Villa and her colleagues helped develop a technique called cryo-FIB milling, launching what she calls “the next resolution revolution.” First, researchers use a focused ion beam to blast ultrathin layers off frozen cells. They then take images of the sample from various angles using a transmission electron microscope. Computational tools combine those two-dimensional images into a 3-D picture, or tomogram, of cellular structures in their natural environment.

Villa and her team use this technique – and related cryo-electron microscopy and visualization methods – to examine everything from bacterial transport structures to human proteins linked to disease. Her lab recently determined the structure of the human LRRK2 protein, a major driver of Parkinson’s disease. Until now, the protein had eluded scientists’ efforts to study its structure. Now, Villa’s team plans to investigate LRRK2’s function and whether it plays a role in transporting cellular compounds.

She calls this project, and the approach she brings to all her work, “bringing structure to cell biology.”

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Jochen Zimmer, PhD

University of Virginia

In the right hands, polysaccharides are much more than sugars chained together like beads on a string. For insects, these molecules can become hard, chitinous exoskeletons. For plants, they can support firm yet pliable cell walls. And for microbes, they can create extracellular coats that protect against antibiotics.

Jochen Zimmer, a molecular biologist at the University of Virginia, is investigating how these compounds are made and integrated into cells’ exteriors.

A major focus for his team is cellulose, which consists of hundreds to thousands of linked glucose molecules. Ubiquitous in plants and microbes, cellulose is the most abundant biopolymer on Earth.

In the past, Zimmer’s team has unraveled the mechanisms behind the synthesis of cellulose. Plants and microbes turn cellulose into a wide array of complex materials, and now, Zimmer’s lab investigates the variation in cellular machinery that creates such diversity.

For example, his team is interested in how bacteria produce cellulose-based biofilms, and how plants spin cellulose into fibers that serve as load-bearing supports in cell walls. They’re exploring how the cellular machinery in both types of organisms deposits polysaccharides onto the cell surface. And they’re studying how vertebrates and some bacteria build extracellular scaffolding that is rich in hyaluronan, a massive polysaccharide.

“We know very little about how extracellular polysaccharides are synthesized, secreted, and assembled, and how they perform their biological functions,” Zimmer says. He hopes that understanding these essential processes will one day help scientists develop new biomaterials for medicines, food, and energy.

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