Fellows - Jane Coffin Childs Memorial Fund

Class of 2026

Kevin Aris, Ph.D. Robertson Foundation - Jane Coffin Childs Fellow

University of California, Berkeley

Exploring the epigenetic role of DNA topology in gene regulation and disease

DNA usually forms a right-handed double-helix, known as the canonical B-form. But DNA can also be wound more tightly or more loosely, called positive and negative supercoiling. DNA supercoiling can impact how genes are regulated yet is difficult to study in its native cellular context.

During his thesis research in Zev Bryant, Ph.D.’s lab at Stanford University Kevin Aris examined how DNA supercoiling affects the energetics of DNA-protein interactions. He showed that DNA shape, or topology, affects how genes can be edited by different mechanisms. Specifically, Aris demonstrated that DNA supercoiling imparts physical reasons for why enzymes, such as Cas9 and Cas12a, naturally differ in how they bind to their DNA target.

As a Robertson Foundation – Jane Coffin Childs Fellow in Aaron Streets’ lab at UC Berkeley, Aris will use his expertise in the CRISPR-Cas gene editing system not just to edit genes, but as a tool to measure DNA supercoiling across the genome in living cells. His goal is to build a genome-wide map of DNA shape to understand how it affects binding by gene regulators (like transcription factors). In addition to providing fundamental new knowledge about DNA shape in cells and gene regulation, Aris will investigate if and how this parameter is impacted in diseases such as cancer.

Minwoo Bae, Ph.D. Robertson Foundation - Jane Coffin Childs Fellow

Yale University

De Novo Designed Trojan-Horse Protein Antibiotics Against Gram-Negative Bacteria

Minwoo Bae, Ph.D., believes microbes contain a huge, largely unexplored supply of proteins that can be discovered and engineered for new medical and biotech uses. His past work found microbial proteins with unusual functions. Now, as a Robertson Foundation – Jane Coffin Childs Fellow, he plans to build “Trojan-horse” delivery systems inspired by microbial toxins that can smuggle next-generation antibiotics into bacteria.

As a graduate student in Emily Balskus’s lab at Harvard, Bae identified gut microbial enzymes that break down dietary polyphenols. He first found an enzyme that metabolizes hydrocaffeic acid abundant in coffee, and later discovered multiple enzymes that convert ellagic acid into urolithin A, a compound linked to anti-aging and anti-inflammatory effects. This work helps explain how the gut microbiome changes the chemistry of what we eat and shows that microbes have evolved proteins that can carry out rare, complex chemical reactions.

Because many clever microbial tools come from bacteria competing with each other, Bae joined Joseph Mougous’s lab at Yale to study and repurpose these systems. Antibiotic resistance is a major global health challenge, including for Gram-negative pathogens whose outer membranes are an impenetrable fortress keeping antibiotics out. His goal is to engineer microbial protein toxins that can pass through outer-membrane transporters, enabling antibiotics to be brought inside “by deception.” He’s especially interested in a pathogen associated with colorectal cancer, and his work could support both new antibiotic development and potential new strategies related to colorectal cancer.

Jenna Beyer, Ph.D. Robertson Foundation - Jane Coffin Childs Fellow

Oregon State University

Resolving cardiac Protein Kinase A signaling using a stable phosphoserine analog in mammalian cells

Jane Coffin Childs Fellow Jenna Beyer, Ph.D. believes that we are in a golden age of chemical biology, which is a field that uses chemical approaches to manipulate and understand complex biological systems. The illuminating tools that Beyer developed during her Ph.D. research and is developing during her Robertson Foundation – Jane Coffin Childs Fellowship, are unquestionably helping this field shine bright.

During her graduate work in George Burslem’s lab at the University of Pennsylvania she generated a new way to edit protein sequences directly inside living mammalian cells. This method quickly adds chemical labels, like biotin or fluorescent dyes, to proteins, which helps researchers study them using tools like pull-down assays or microscopy. Compared with older approaches, her method works faster, lets scientists control timing more precisely, and avoids using large tags or antibodies that can interfere with a protein’s normal function.

For the fellowship in Ryan Mehl’s lab at Oregon State University, Dr. Beyer will develop new tools to study phosphorylation at specific spots on proteins. Phosphorylation is when a phosphate group is added to an amino acid, and it can happen at many places on many proteins. Most current methods are “all-or-nothing”: they change a kinase, which is an enzyme that adds a phosphate group to a protein, and end up affecting lots of proteins at once. Beyer is creating a way to add a stable phosphate mark at one chosen site on one protein inside mammalian cells—more like a precise scalpel than a blunt tool. To show it works, she will first study how Protein Kinase A (PKA) may help protect against cardiovascular disease. Beyer’s approach should also help researchers understand the role of phosphorylation in many other diseases.

Laura Blasco Chamarro, Ph.D. Hope Funds for Cancer Research-Jane Coffin Childs Fellow

Dana Farber Cancer Institute

Targeting Developmental GABAergic Signaling in Diffuse Hemispheric Gliomas with H3G34 Mutations

Pediatric brain tumors arise in the developing brain, yet how they interact and communicate with their neighboring cells to promote tumor growth is not well understood. In Laura Blasco-Chamarro’s previous research she discovered how neural stem cells pause cell division to maintain a quiescent state. Now, as a Hope Funds for Cancer Research – Jane Coffin Childs Fellow, Blasco-Chamarro will study how pediatric brain tumors, called gliomas, misuse normal developmental programs to trigger abnormal cell division.

As a graduate student in Isabel Fariñas’ lab at the University of Valencia, Blasco-Chamarro explored how localized cues support neural stem cell (NSC) quiescence. She found that in response to a specific signal, NSCs secrete a supportive material, called the extracellular matrix (ECM) that induces quiescence. This matrix then activates specific proteins called YAP and TAZ, which move into the nucleus and turn on genes that reinforce the resting state. Her work showed how a cell’s environment can push neural stem cells toward staying inactive.

In Dr. Mariella Filbin’s lab at Dana-Farber Cancer Institute, Blasco-Chamarro will study the opposite process: how pediatric high-grade gliomas activate developmental signaling to keep dividing. She will map how tumor cells interact with surrounding cells in the tumor microenvironment and identify the signals that promote tumor growth. She expects that blocking these support signals could slow or stop tumor growth. This research could lead to new treatments for pediatric high-grade gliomas and offer a broader strategy for targeting similar, lineage-specific signaling pathways in other cancers.

Annalise Bond, Ph.D. Jane Coffin Childs Fellow

Salk Institute for Biological Studies

Hypothalamic inflammation and metabolism in sepsis outcomes

There are two ways the body survives an infection, the immune system can kill the germ, or the body can reduce harm from the infection even if the germ isn’t eliminated.
Annalise Bond, Ph.D., created a new research tool during her Ph.D. that improved our understanding of how immune cells identify and destroy targets. As a Jane Coffin Childs Fellow, she will now focus on the second strategy—helping the body tolerate infection and limit damage, known as “cooperative defense”.

During Bond’s graduate work in Meghan Morrissey’s lab at UC Santa Barbara, she studied how macrophages (immune cells that act as the first responders) pick out pathogens among many healthy cells. She realized that the field lacked a tool to precisely control the duration and intensity of macrophage signaling, so she designed a synthetic, light-activated switch to turn on the signal. Using it, she showed that earlier activation can “prime” macrophages to engulf more of their target (in her experiments, cancer cells). She also found this priming works through a fast mechanism and a longer-lasting one, making the effect both quick and durable. These insights could help researchers design better ways to regulate immune responses, including against cancer.

Much less is known about the mechanisms of cooperative defense, which also means that this strategy remains essentially untapped in terms of therapeutic interventions. Dr. Bond will shift her studies to cooperative defense in Janelle Ayres, Ph.D.’s lab at the Salk Institute using a mouse model of sepsis. By analyzing neural-system signaling that correlates with survival, Bond is uncovering how the nervous and immune systems communicate to help the host survive an infection. In addition to discovering fundamental principles about cooperative defense, her work may lead to new ideas for improving outcomes for people with sepsis.

Matthew Capek, Ph.D. Jane Coffin Childs Fellow

Harvard University

Molecular mechanisms underlying ancient cross-kingdom interactions and terrestrial life

Matthew Capek, Ph.D. believes that by examining how organisms sense and respond to their closest neighbors we can deepen our understanding of basic biology while also gaining insight into human health, disease, and ecosystem stability. During his graduate research he uncovered the distinct ways through which flies sense and adapt to environmental temperatures. Now, as a Jane Coffin Childs Fellow, Capek will investigate the adaptation and cooperation between some of the first plant and animal pioneers to transition from living in the waters to living on land.

As a graduate student in Marco Gallio, Ph.D.’s lab at Northwestern University, Capek showed how responses to temperature evolved in fly species hailing from different environments, from temperate forests to hot deserts. Flies from mild climates avoid heat and have molecular differences in their receptors that directly sense temperature. Mojave Desert flies are instead attracted to heat, and this shift in behavior arises from a change in how the brain processes and interprets the signal. He also studied the cold-adapted fly Chionea alexandriana, showing that they generate heat in response to rapid cold challenges, carry molecular changes in pathways to cope with stress, and produce antifreeze proteins that prevent freezing in sub-zero temperatures.

For his fellowship in Nicholas Bellono’s lab at Harvard University, Capek will focus on understanding how interactions between mosses and springtails established the first terrestrial ecosystems. In water, moss sperm can swim to eggs to achieve fertilization, but life on land makes that journey far more difficult. Springtails help mosses reproduce on land by carrying sperm between moss sex organs. Capek will examine how mosses compel springtails to facilitate their reproduction, and determine what benefit motivates the springtails’ efforts. He predicts that understanding this ancient plant-animal cooperation will yield a new framework for understanding how molecular communication drives the evolution of complex life.

Ruoyu Chen, Ph.D. Jane Coffin Childs Fellow

Harvard University

Neural and molecular mechanism of social drive

Biology often reuses the same basic “building blocks” for similar functions. Dr. Ruoyu Chen studied RNA–protein clusters (called RNP granules) in fruit fly reproductive cells and made a surprising discovery that changed how scientists think these granules work. Because similar granules also play important roles in neuronal functions, Chen became interested in neuroscience and now wants to study the cellular and molecular underpinnings of the drive for social interaction.

As a graduate student in Ruth Lehmann’s lab at the Whitehead Institute for Biomedical Research, Chen studied RNP granules, which are small cell compartments made of RNA and RNA-binding proteins. Scientists had long thought these granules turn off protein production from the RNAs inside them. Chen found the opposite in fly germ cells: the RNAs in these granules are actively being used to make proteins. This was a paradigm-shifting finding for the field and led Chen to consider other areas of biology where this kind of translational regulation is important.

Since similar RNA granules help move RNAs around long nerve cells and make proteins in specific places, Chen began focusing on how these processes affect brain function and behavior. As a Jane Coffin Childs Fellow in Catherine Dulac’s lab at Harvard, he will study the brain circuits and molecular signals that control the desire for social interaction. He will use social isolation to probe these systems, with the hope of understanding why loneliness is linked to poor health and some mental health disorders.

Ryan Chow, M.D., Ph.D. JJJ Charitable Foundation - Jane Coffin Childs Fellow

University of Pennsylvania

De novo design of peptides to perturb oncogenic transcriptional condensates

As a hematology and oncology fellow, Ryan Chow, M.D., Ph.D., is often faced with the limitations of our current cancer therapies. His goal as a JJJ Charitable Foundation- Jane Coffin Childs Fellow is to build on his graduate work of identifying genetic insults to develop a new class of anti-cancer therapies that function by disarming oncogenic transcription factors.

In Sidi Chen’s lab at Yale University, Chow created new CRISPR screening methods to study which genes drive cancer. It should be noted that Chow’s overwhelming research production as a graduate student cannot be completely covered in this space, but we’ll look at a few examples. For example, he used AAV viruses to deliver CRISPR tools into animals and find tumor-suppressor genes in glioblastoma and liver cancer. Then, Chow adapted his CRISPR screens to enable stepwise mutation of multiple genes which can capture the sequential nature of mutations, for instance in non-small cell lung cancer. While Chow’s findings emphasize the power of CRISPR screens in revealing novel cancer genetics, he quickly realized the impracticality of this modality for cancer therapies.

Now in Pranam Chatterjee’s and Katalin Susztak’s labs at the University of Pennsylvania, Chow is taking a different approach: designing brand-new peptides to target cancer-driving transcription factors. These proteins are important targets but have been hard to drug with traditional medicines because they are flexible and located in the cell nucleus. Chow plans to use deep learning to design peptides that bind these transcription factors and test whether they can rewrite cancer gene programs and eliminate tumors.

Adam Fenton, Ph.D. Achelis and Bodman - Jane Coffin Childs Fellow

Weill Cornell Medicine

Determining the cause and consequence of cancer cells co-opting neuronal vesicle trafficking mechanisms

Kinesins are motor proteins that “walk” along microtubules to carry cargo inside cells. Adam Fenton, Ph.D., studied how kinesins move mitochondria (the cells’ power source) to where cells need energy. As a Jane Coffin Childs Fellow, he will now investigate a surprising possibility: that a neuron-specific kinesin also helps cancer cells invade other tissues.

In Erika Holzbaur’s and Thomas Jongens’s labs at the University of Pennsylvania, Fenton found several key things about kinesin motors and mitochondrial transport in neurons. In addition to his work on mitochondrial fission in neurons, he learned that a kinesin is turned on by a protein that connects it to mitochondria. He found that some ALS-linked kinesin mutations make this kinesin too active by removing a normal “off” mechanism.

Next, in Samara Reck-Peterson’s lab at Weill Cornell Medicine, Fenton will study cancer progression. Early evidence suggests cancer cells may increase organelle-transport systems that are usually only active in neurons. He will test how a neuron-specific kinesin and its partner proteins contribute to cancer cell invasion and test ways to block this process in tumor organoid models. Fenton anticipates that his research will uncover novel roles for organelle transport in cancer cell biology and may illuminate the path toward new cancer therapies.

Christopher Giuliano, Ph.D. Jane Coffin Childs Fellow

Rockefeller University

Tracking and perturbing metabolic exchanges in cancer

What does microbial metabolism have to do with finding cancer therapies? Dr. Chris Giuliano thinks studying how microbes share and trade nutrients can help reveal novel ways to treat cancer. His goal is to find important metabolic “give-and-take” interactions between tumors and healthy tissues that could be targeted with drugs.

As a graduate student in Sebastian Lourido, Ph.D.’s lab at the Whitehead Institute for Biomedical Research, Giuliano studied the parasite Toxoplasma gondii. Because very little of its genome had been tested for genes that help it cause disease, he used a genome-wide CRISPR screen during infection and identified 300+ previously unknown virulence factors. He then studied three of these genes in depth and suggested a possible way to block infection.

Now as a Jane Coffin Childs Fellow in Kivanç Birsoy’s lab at The Rockefeller University, Giuliano will shift his focus to metabolic exchange across human organs. He wants to create an unbiased method to detect metabolic exchange between organs and tissues, using an idea inspired by microbial metabolism. He will apply this novel approach to cancer—studying how tumors interact metabolically with nearby cells, with immune cells, and even with distant organs—to uncover metabolic vulnerabilities that could be disrupted for therapy.

Jacob Klemm, Ph.D. Robertson Foundation - Jane Coffin Childs Fellow

Duke University

Uncovering tissue-specific tRNA regulation and function in animal development

Fly and worm researchers have long debated the unique advantages of their favorite model organism. Dr. Jake Klemm finds that flies provide a powerful genetic toolkit to study animal physiology. He previously used flies to find unexpected roles for proteins involved in cell death processes in tissue repair and regeneration. As a Robertson Foundation – Jane Coffin Childs Fellow, he will use fruit flies and mammalian cells to study how tRNAs, small RNA molecule that act as a physical adaptor during protein synthesis, help control which proteins are made in specific tissues.

Klemm developed his appreciation for flies during his thesis research in Rob Harris, Ph.D.’s lab at Arizona State University. Klemm built a fly model, using the fly wing, to study the tissue response to necrotic injury (a type of cell death different from apoptosis). He unexpectedly found that necrosis can trigger apoptosis in cells far away from the injury, something he called “necrosis-induced apoptosis.” He also showed this process is required for tissue regeneration, and that enzymes called caspases are important for regeneration. This suggested that molecules best known for killing cells can also help tissues regrow.

Now in Don Fox’s lab at Duke University, Klemm will study “tissue-adapted” tRNAs, which may help regulate gene expression in a tissue-specific way. Instead of being just routine parts of the protein-making machinery, these tRNAs may influence what gets translated in different cell types. He will test this idea in both reproductive (germ) cells and specialized (differentiated) cells, aiming to build a strong model for understanding how tRNAs function in animal development and physiology.

Frank Lanfrachi, Ph.D. Robertson Foundation - Jane Coffin Childs Fellow

Stanford University

Recurrent circuit dynamics underlying internally generated actions

Francesco (Frank) Lanfranchi, Ph.D. is baffled by how little we truly understand about the neural mechanisms underlying behavior. As a Robertson Foundation – Jane Coffin Childs Fellow, Lanfranchi wants to help fill this knowledge gap by understanding the neural circuits that facilitate how internal goals are maintained and translated into action – one of the fundamental functions that neurological diseases disrupt.

During his graduate studies in Doris Tsao’s lab at UC Berkeley, Lanfranchi investigated how visual information is transformed into meaningful object representations across mammalian species. Lanfranchi studied how brains turn visual input into recognizable objects. Comparing macaques with tree shrews, he found that tree shrews can show primate-like abilities such as recognizing objects and faces. This suggests that “hierarchical” visual processing is conserved, but more compact, in the smaller tree shrew brain.

In Tirin Moore’s lab at Stanford University, Lanfranchi will study how the brain uses sensory information to guide actions—especially when sensory cues aren’t available. For example, you can still write your name with your eyes closed because the goal is internally maintained. He will map the circuits that support this kind of goal-directed behavior in macaques, with the hope that understanding these normal circuits will help explain why internally driven actions are especially affected in Parkinson’s disease.

Mengyao Li, Ph.D. Robertson Foundation - Jane Coffin Childs Fellow

Broad Institute

Decoding the Spatiotemporal Translational Landscape of Early Mammalian Embryogenesis via Developing Spatial Translatomics

How does a single cell develop into a complete and complex organism? Dr. Mengyao Li is fascinated by the question of how cells, despite sharing an identical genome, achieve such distinct identities and tissue types through epigenetic regulation. During her graduate studies in Fuchou Tang’s lab at Peking University and Kehkooi Kee’s lab at Tsinghua University, she traced the epigenetic dynamics and lineage differentiation that guide cell fate decisions during early mammalian embryogenesis, utilizing an ultra-sensitive long-read sequencing-based chromatin accessibility profiling method she developed for scarce, single-cell-input samples. This method enabled her to dissect the epigenetic regulation of repetitive elements and the X chromosome, systematically delineating the cell-type-specific transcription factor regulatory networks that drive early development.

As a Robertson Foundation – Jane Coffin Childs Fellow in Xiao Wang’s lab at the Broad Institute and MIT, she seeks to decipher the hidden spatial code governing how cells translate RNA into functional proteins. By exploring how the subcellular organization of transcripts dictates their translation kinetics, she aims to uncover how dynamic shifts in RNA translational efficiency ultimately orchestrate cellular states, tissue architecture, and disease.

Jing Li, Ph.D. Robertson Foundation - Jane Coffin Childs Fellow

University of California, Berkeley

Synthetic modulation of cGAS signaling in mammalian cells

Cells are constantly threatened by pathogens, so they need ways to sense danger and turn on defenses at the right time. In her graduate work, Jing Li, Ph.D., elucidated elegant and mechanistic details of how bacteria know when to fight back against invading bacteriophages. As a Robertson Foundation – Jane Coffin Childs Fellow, Li will leverage insight from her previous studies to reengineer human cells to explore the programmable activation of immune defense.

As a graduate student in Longfei Wang’s lab at Wuhan University, Li revealed how bacterial defense systems sense when to activate. She solved a number of novel and insightful structures of the GajA/GajB proteins with different cofactors and substrates. Her structures showed that when ATP is abundant, GajA remains in a closed, inactive state. However, when ATP is depleted during phage infection, GajA converts into an open state which binds to and cleaves DNA, thereby activating GajB and leading to prokaryotic cell death. This research helped Li appreciate the role of small molecules, such as ATP, to act as information-rich signals that gate biological decisions.

Now in Shiyu Xia’s lab at UC Berkeley, Dr. Li plans to bring similar “small-molecule control” ideas into human cells. She will build synthetic protein circuits to reprogram the cGAS–STING immune pathway so she can choose when it turns on and how strongly it responds. Because cGAS–STING is involved in cancer, aging, autoimmune disease, and infections, this controllable system could help researchers understand these conditions and eventually support new therapies.

Ke Liang, Ph.D. Jane Coffin Childs Fellow

Harvard Medical School

Mechanistic Analysis of Peroxisomal Protein Import Receptor Recycling

Ke Liang, Ph.D. studies how proteins are transported in cells and why these processes matter for human disease. In her earlier work, Liang used structural biology to map major protein-transport machines. As a Jane Coffin Childs Fellow, she will focus on how proteins are transported into peroxisomes, small organelles found in the cytoplasm that act as the cell’s “cleanup crew,” breaking down and detoxifying substances generated by metabolic processes.

As a graduate student in Yigong Shi’s and Zhen Yan’s labs at Westlake University, Liang’s research illuminated different mechanisms for protein transport across organelle boundaries. She made key contributions to determining the structures of the frog cytoplasmic, inner, and nuclear rings of the nuclear pore complex (NPC), providing unprecedented insights of the organization of this complex. Additionally, Liang’s structures of chloroplast protein import complexes in land plants and green algae demonstrated how related transport systems are conserved and specialized across species.

Now as a JCC Fellow in Tom Rapoport’s lab at Harvard Medical School, Liang will investigate protein import into peroxisomes. Peroxisomes are unusual because they can import fully folded proteins using receptors that shuttle in and out and must be extracted and recycled. Liang aims to clarify how these steps work. Because failures in peroxisomal import cause serious diseases with few or no treatments, her work could also point toward new therapeutic ideas.

Jialin Liu, Ph.D. Jane Coffin Childs Fellow

University of Michigan

Lineage-Guided Evolving CAM Codes in Wiring the Drosophila Brain

Jialin Liu, Ph.D., has been building “snapshots” of brain development using single-cell and spatial gene-expression data. But because those datasets were incomplete, he often had to infer how development unfolded rather than directly observe it. Now he aims to create a new way to track neuronal development in space over time inside an intact brain.

In Joshua Welch, Ph.D.’s lab at The University of Michigan Liu developed computational tools to analyze cell states based on gene expression. Examples include a pipeline that jointly analyzes single-cell sequencing data from a variety of experiments and can be used by all scientists, as well as a model for inferring spatial and temporal dynamics of cell states from spatial transcriptomic data. Liu’s research has provided incredibly useful and broadly accessible tools for analyzing cell state based on gene expression, which can be used to infer cell state transitions among other purposes.

In Tzumin Lee’s lab at The University of Michigan, Liu will generate the kind of data his models need: 3D spatial transcriptomics across multiple time points during fruit fly brain development, both in normal flies and in flies with targeted genetic changes. With these richer datasets and new analysis tools, he hopes to produce a “ground-truth” map of how cell lineages and brain wiring develop over time—more like watching the whole movie rather than predicting from a few frames.

Adam Lowet, Ph.D. Jane Coffin Childs Fellow

University of California, Berkeley

Neural Mechanisms of Naturalistic Social Decision-Making

Adam Lowet, Ph.D. is fascinated by the neural and computational basis of social behavior in both health and disease. During his graduate work, Lowet used insights from AI to uncover a novel way in which the brain learns from rewards and punishments. As a Jane Coffin Childs Fellow, Lowet will now investigate the computational and biological mechanisms underlying social decision-making using an unorthodox model system: the Egyptian fruit bat, a highly social animal.

Lowet’s graduate research in Naoshige Uchida’s lab at Harvard University was motivated by the observation that many AI algorithms are significantly improved when considering the entire probability distribution of outcomes rather than just their mean value. Lowet thought this principle might apply to how our brains work and investigated this hypothesis in the context of the mesolimbic dopamine system. Lowet demonstrated that the brain indeed encodes more than just the mean and uses this distributional information to speed up learning. Surprisingly, Lowet discovered that the upper and lower tails of reward distributions are encoded in different types of neurons, suggesting brain information processing is organized in a more detailed way than previously understood.

Now in Michael Yartsev’s lab at UC Berkeley, Lowet will use the Egyptian fruit bat, an ultrasocial mammal, as a model for studying social decision behavior. Lowet will record behavior and neural activity while groups of bats forage collectively and compare these to normative models of social decision-making from machine learning and behavioral ecology. Ultimately, Lowet hopes that this foundational research into how healthy brains coordinate with others will eventually inform approaches to disorders where this ability is compromised.

Heankel Lyons, Ph.D. Jane Coffin Childs Fellow

Stanford University

Mechanisms of Transcriptional Dysregulation in Neurodegeneration

Heankel Lyons, Ph.D. became motivated to do biomedical research while growing up due to a family member developing a rare neurodegenerative disease. As a JCC Fellow, she will take her expertise from her graduate work on how biomolecular condensates regulate gene activity to ask how condensates regulate neuronal gene expression, how these processes shape normal cell biology, and how their dysregulation leads to brain disease.

As a graduate student in Ben Sabari’s lab at UT Southwestern, Lyons uncovered fundamental principles into how biomolecular condensates, membrane-less compartments that gather specific molecules, help regulate transcription. She found that condensates formed by a protein called MED1 recruit RNA polymerase II and helpful regulators while keeping out inhibitors. Impressively, Lyons also identified amino-acid “patterns” that determine which proteins get recruited, and showed how cancer fusion proteins exploit similar patterns to drive cancer-related gene programs.

Now as a JCC Fellow in Aaron Gitler’s lab at Stanford University, Lyons returns to the subject that originally spurred her interest in science: neurodegeneration. She’ll focus on a central protein in amyotrophic lateral sclerosis (ALS), named TDP-43. TDP-43 forms condensates, and most research in the neurodegeneration field has focused on TDP-43’s role as an RNA-binding protein, yet this protein was originally discovered as a DNA-binding protein. Lyons will use her expertise in transcription and condensates to define TDP-43’s role in neurons and investigate how transcriptional dysregulation involving TDP-43 contributes to ALS.

Kira Marshall, Ph.D. Jane Coffin Childs Fellow

Stowers Institute for Medical Research

Molecular mechanisms of fertilization dynamics and prezygotic barriers in Acropora millepora

Dr. Kira Marshall has combined her desire to do rigorous molecular research with her passion to preserve threatened species. As a graduate student, Marshall provided keen insights into the molecular mechanisms of spermatogenesis in marsupial and placental mammals. Now, she’ll return to the sea to gain a better understanding of coral reproduction, to uncover ways to mitigate the rapidly declining coral populations around the world.

Marshall’s graduate studies in Bluma Lesch’s lab at Yale University provided fine detail into gene expression during sperm development – a deeply conserved process with obvious implications for fitness. By characterizing this process in the marsupial opossum and in mouse, a placental mammal, Marshall was able to compare spermatogenesis across the placental-marsupial split. She uncovered a gene program that’s conserved in both species, as well as genes that appear to contribute to the placental mammalian lineage. Marshall’s findings furthered our understanding of germ cell biology as well as infertility.

As a JCC Fellow at the Stowers Institute in Matt Gibson’s lab, Marshall will extend her research on reproduction to a different branch of the evolutionary tree by studying Acropora millepora, a hermaphroditic free spawning coral species. These organisms release bundles of eggs and sperm into the water, yet self-fertilization is exceedingly rare, suggesting that there are mechanisms that control gamete attraction and compatibility. Marshall will investigate the fertilization of this coral species and decipher the means by which they ensure proper mating. Ultimately, Marshall aims for her research to have a direct and positive effect on marine ecosystems by helping to preserve threatened coral species.

Sasha McDowell, Ph.D. Jane Coffin Childs-Merck Fellow

Harvard Medical School

A thirst for blood: structural mechanisms of human hunting by mosquitoes

Taste can be instructive: for example, the taste of a calorie-rich pastry is highly pleasurable while spoiled food is off-putting. Sasha McDowell, Ph.D.’s graduate research revealed the molecular details of how fruit flies are repelled by too much salt yet attracted to just the right amount. As a Jane Coffin Childs-Merck Fellow McDowell will now explore a related mechanism for how mosquitoes are attracted to the odor of their human prey.

During her thesis research in Michael Gordon’s lab at the University of British Columbia, McDowell investigated how fruit flies taste and respond to salt. She identified the first salt-specific receptor in Drosophila melanogaster and demonstrated how this ionotropic receptor (IR) functions to avoid high salt concentrations. McDowell then investigated a related receptor which is involved in salt attraction. She found that the receptor activity is tuned in response to prior salt consumption. Together, McDowell’s studies reveal how IRs are involved in both salt attraction and repulsion to balance overall dietary intake.

Near the end of her graduate research McDowell contracted dengue fever through a mosquito bite. Naturally, she was curious about what attracts mosquitoes to their human prey, which will be her focus in Josefina del Mármol’s lab at Harvard. Previous research had shown that a mosquito IR is involved in their attraction, though it remains unclear what component of human odor this receptor detects. Dr. McDowell aims to discover this missing attractant, understand how the receptor binds to the attractant, and find inhibitors that prevent mosquitoes’ attraction to humans. In addition to providing fundamental information about mosquito biology, McDowell’s research may reveal new strategies for bio-control efforts.

Sandra Nakandakari-Higa, Ph.D. Jane Coffin Childs Fellow

University of Rochester Medical Center

In vivo mapping of lung microenvironmental interactions controlling CD8⁺ tissue-resident memory persistence

Dr. Sandra Nakandakari-Higa wants to understand how a cell’s fate and function are determined. This process is not shaped in isolation; rather, it is shaped through continuous interactions with neighboring cells, forming dynamic networks of communication that orchestrate development, homeostasis, and immune responses. As a Jane Coffin Childs Fellow, she’ll use Labeling Immune Partnerships by SorTagging Intercellular Contacts (LIPSTIC), an approach she improved in her graduate work, to evaluate the persistence of memory T cells within the lung.

Using LIPSTIC, Nakandakari-Higa studied how brief interactions between immune cells and their cellular partners shape lasting immune responses during her graduate work in Gabriel Victora’s lab at The Rockefeller University. Nakandakari-Higa redesigned LIPSTIC so it no longer depends on one specific receptor–ligand pair. This made it broadly applicable for many types of cell interactions. She used this “universal” LIPSTIC to follow how dendritic cells activate T cells and how virus-specific T cell interactions change over time, and the tool can now help other researchers track immune contacts in detail.

As a JCC Fellow in Minsoo Kim’s lab at the University of Rochester, Nakandakari-Higa will focus on a key aspect of protective immunity: the generation and persistence of memory T cells in the lung. Infection with respiratory viruses generates these T cells and provides protection against reinfection. However, over time the numbers of these T cells wane which limits their effectiveness. Nakandakari-Higa will use her universal LIPSTIC technology to map the cellular interactions of memory T cells in the lung, and to analyze how those interactions change. She’ll also invert LIPSTIC to determine how signals delivered by the local microenvironment contribute to T cell survival. Her research may provide new clues that could inform ways to make vaccine protection last longer.

Kangbo Ng, Ph.D. Robertson Foundation - Jane Coffin Childs Fellow

Whitehead Institute for Biomedical Research

Mechanisms and functions of soma-to-germline mitochondrial transfer

KangBo Ng, Ph.D., has long been fascinated by how somatic cells, the non-reproductive cells of the body, and germ cells, the reproductive cells, work together to ensure the proper development of an organism. During his graduate research, Ng studied how these cells organize themselves in space to build the embryo. Now, as a Robertson Foundation – Jane Coffin Childs Fellow, Ng will investigate how somatic and germ cells exchange metabolic resources to help kick-start embryonic development.

Ng’s thesis research in Nathan Goehring’s lab at the Francis Crick Institute addressed how cell polarity shapes animal development. Because polarity systems are used across many different cellular contexts, they must be able to respond sensitively to spatial cues while still producing stable outcomes. Ng demonstrated that oscillatory polarity feedback, coupled to the cell cycle, allows cells to resolve these seemingly contradictory requirements. He also found that mechanical flows generated during cell division can directly transport polarity proteins to organize the embryo. Altering these flows changed division patterns, suggesting a simple mechanism by which embryos could generate different body plans.

In Ruth Lehmann’s lab at the Whitehead Institute, Ng will focus on metabolic communication between somatic and germ cells. Germ cells switch between phases of rest, division, and quality control, and somatic cells appear to help control these transitions, but the underlying mechanism remains unclear. Ng hypothesizes that somatic cells may orchestrate these processes by transferring metabolic resources to germ cells. His work could reveal new principles of embryo development and inform future research into reproductive health.

Jordan Ngo, Ph.D. Robertson Foundation - Jane Coffin Childs Fellow

California Institute of Technology

Molecular mechanisms of de novo peroxisome biogenesis

Jordan Ngo, Ph.D. is interested in uncovering the mechanistic principles that govern organelle biogenesis and membrane assembly in both normal physiology and human disease. As a graduate student, Ngo provided important insight into how extracellular vesicles are formed and how the plasma membrane is repaired. As a Robertson Foundation – Jane Coffin Childs Fellow, Ngo will continue to study organelle biogenesis, investigating how peroxisomes, membrane-bound organelles that play essential roles in human physiology, form.

During Ngo’s thesis research in Randy Schekman’s lab at UC Berkeley, he made important discoveries around extracellular vesicles and the plasma membrane. First, Ngo discovered that exosomes, a specific subtype of extracellular vesicles, form in response to plasma membrane damage and that the protein Annexin A6 is crucial for this process. Then, he demonstrated that the selective autophagy receptor p62 is important for sorting protein and RNA cargo into exosomes. Finally, he identified sorcin as a scaffold that couples Annexin A11 recruitment to ESCRT-III assembly for plasma membrane repair.

For his Robertson Foundation – Jane Coffin Childs Fellowship in Rebecca Voorhees’s lab at Caltech, he will search for genes that control peroxisome assembly and build a new test to study how early peroxisome-related vesicles form. Because defects in peroxisome formation cause serious disorders, such as Zellweger spectrum disorders, and have been implicated in cancer progression, this work could clarify how peroxisome problems contribute to disease.

Andreas Obers, Ph.D. Jane Coffin Childs Fellow

Icahn School of Medicine at Mt. Sinai

Uncovering cellular stress programs governing intestinal resilience and aging

Andreas Obers, Ph.D. investigates the biological mechanisms that determine whether tissues recover after injury and inflammation or become trapped in persistent, maladaptive states that contribute to chronic disease and aging. Inspired by his graduate research showing that biological responses are shaped by local tissue environments and prior experiences, Obers now explores how a key regulator of cellular stress responses influences the balance between tissue repair and persistent dysfunction.

Obers conducted his doctoral research in the laboratories of Laura Mackay and Christoph Wilhelm through a joint program between the University of Melbourne and the University of Bonn. In his first-author work, he revealed that retinoic acid, a metabolite derived from vitamin A, shapes the durability and distribution of immune surveillance across tissues. In related work, he contributed to the discovery that immune cells occupying the same tissue can adopt distinct functional identities, allowing them to either promote tissue protection or contribute to disease.

Now in the laboratory of Shruti Naik at Mount Sinai, Obers studies a key regulator of cellular stress responses whose expression is consistently elevated in aged tissues. Although it is widely associated with aging, scientists are only beginning to explore whether it has functions beyond its classical role. By investigating how inflammation reshapes its localization and activity within cells, Obers aims to uncover how tissues transition from successful repair to persistent dysfunction and chronic disease.

Francis Belén Pacheco Fiallos, Ph.D. Jane Coffin Childs Fellow

Massachusetts Institute of Technology

Recognition and Attenuation of Pervasive Transcription by the Restrictor Pathway

Belén Pacheco-Fiallos, Ph.D. studies how gene activity is regulated. Although scientists know the structures of many individual parts, a major next step is learning how these molecular “machines” work together. In graduate school, she studied how cells export the right messenger RNAs (mRNAs) from the nucleus out of roughly 20,000 different transcripts. As a Jane Coffin Childs Fellow, she will now study how cells prevent unhelpful (“non-productive”) transcription from happening everywhere in the genome.

In Clemens Plaschka’s lab at the Research Institute of Molecular Pathology in Vienna, Austria, Pacheco-Fiallos studied selective mRNA transport via the Transcription and Export (TREX) complex. She demonstrated that TREX lives up to its name by being an enormous oligomeric complex that’s approximately 2 megadaltons in size. Using cryo-electron microscopy and tomography Pacheco-Fiallos revealed how TREX selectively recognizes mature mRNA-protein complexes for export to the cytosol and eventual translation of the transcript. Her research stresses the importance of studying molecular machines in relevant conditions and at the appropriate level of molecular complexity.

Pacheco-Fiallos will continue this approach to tackle a different selectivity problem in gene expression at Seychelle Vos’s lab at MIT. There she will study a different selectivity problem: RNA polymerase II makes full mRNAs from genes, but it also makes very short, non-coding transcripts at enhancers and promoters. How the cell stops transcription in those regions isn’t well understood. She will test whether a Restrictor complex helps recognize and shut down this inappropriate transcription, using integrative structural biology to figure out how the complex assembles and works.

Ian Price, Ph.D. Jane Coffin Childs Fellow

University of North Carolina, Chapel Hill

Secreted proteins from tardigrades as potent protectants in extreme conditions

Jane Coffin Childs Fellow Ian Price, Ph.D., studies how living things survive extreme stress. He focuses on tardigrades, microscopic animals that can survive the vacuum of space, extreme radiation, and being dried out completely for years before rehydrating and carrying on living.

For his thesis research in Wen Tang’s lab at The Ohio State University Price examined protein-RNA assemblies called germ granules in C. elegans. He discovered novel proteins that regulate germ granule assembly, demonstrated that germ granules contribute to developmentally-appropriate gene silencing, and defined the molecular interactions that scaffold germ granule assembly. This work highlighted how powerful model organisms are for discovering new biology.

As a JCC Fellow in Bob Goldstein’s lab at UNC, Chapel Hill, Price is investigating extremophile tardigrades, colloquially known as water bears. Tardigrades can tolerate drastic conditions including complete dehydration and levels of radiation that are one thousand times higher than what humans can survive. Previous work from the Goldstein lab demonstrated that a secreted protein is crucial for desiccation tolerance in tardigrades. Price suspects there are more protective secreted proteins and is searching for them to understand how they work. If some of these proteins protect other organisms too, they could be useful for preserving cells, medicines, and other medical materials.

Amy Prichard, Ph.D. Jane Coffin Childs Fellow

University of California, Los Angeles

Keep your enemies close: How does Flock House Virus replicate on mitochondrial membranes?

Amy Prichard, Ph.D., aims to understand how viruses reorganize their host cells to protect themselves from host defenses. During her Ph.D. research, Prichard examined how a family of bacteriophage, viruses that infect bacteria, build replication compartments in bacterial cells to shield viral genome replication from host defenses. Now, as a Jane Coffin Childs Fellow, Prichard will focus on how viruses that infect animals create a different type of replication compartment and how that may also allow them to evade host defenses during infection.

Prichard’s graduate research in the labs of Joe Pogliano, Ph.D., and Elizabeth Villa, Ph.D., at UC San Diego investigated a family of bacteriophage that they named Chimalliviridae. This viral family is unique in that they form a nucleus-like replication compartment within bacteria. Prichard defined the core genes encoded by these bacteriophage, including chimallin, the namesake of this family, which is the major structural protein that forms the replication compartment. Additionally, Prichard and her colleagues revealed how chimallin self-assembles to form this subcellular compartment. Overall, her work clarified which viruses share this unique lifestyle and how these viruses protect their genome replication from the host.

During her JCC Fellowship in the lab of Lena Pernas, Ph.D., at UCLA, Prichard will investigate a different type of virus-induced subcellular compartment. Nodaviruses, such as Flock House Virus and Nodamura Virus, are unique in that they form replication compartments on the outer mitochondrial membrane. Prichard suggests that this location is an unusual “choice” for a viral replication site since mitochondria are home to an essential anti-viral signaling protein. Also, because mitochondria have their own genomes, they use cellular resources that other organelles do not, which could put them in direct competition with these viruses. Her project will examine how and why Nodaviruses replicate in this high-risk location, offering a clear example of how our cells’ organelles, such as mitochondria, can help us fight off viral infection, and how viruses attempt to subvert these defenses by hiding their replication within subcellular compartments. By better understanding the ways viruses hijack our cells, scientists can build a biological toolkit to gain new ways to prevent disease.

Rohith Rajasekaran, Ph.D. Robertson Foundation - Jane Coffin Childs Fellow

University of California, San Francisco

Reprogramming STAT signaling using engineered fusion proteins to tune CAR T cell antitumor activity

Rohith Rajasekaran, Ph.D., wants to study how naturally evolved molecular systems can be redesigned to program new cellular behaviors. Rajasekaran’s previous research repurposed a bacterial positioning system to turn mammalian cells into “two-way radios” that can send and receive biological information. Now, as a Robertson Foundation – Jane Coffin Childs Fellow, Rajasekaran will rewire T cell signaling in modular, tunable ways to improve their efficacy, durability, and safety in cancer immunotherapies.

Rajasekaran’s thesis research in Scott Coyle’s lab at the University of Wisconsin—Madison ported two bacterial proteins (MinD and MinE) into mammalian cells. MinD and MinE are normally involved in establishing bacterial polarity, but Rajasekaran repurposed them to control and pattern intracellular mammalian biology. He used them to track signaling (like kinase activity) and to organize processes such as condensate formation and actin filament growth. He also built genetic circuits that linked natural cellular processes to MinD/MinE signaling patterns, allowing those signaling “rhythms” (frequency and strength) to serve as a readout of cellular activity, revealing when genes turn on, how proteins are broken down, and how stem cells develop into different cell types.

In Kole Roybal’s lab at UCSF, Rajasekaran will apply similar ideas to chimeric antigen receptor (CAR) T cell therapies. CAR T cancer therapies have shown great promise yet are only effective for a subset of patients and have limited duration for responding patients. Rajasekaran will build on the Roybal Lab’s finding that oncogenic fusion genes enhance CAR T therapies, he will design synthetic fusion proteins that adjust the strength and timing of key signaling pathways in T cells. By linking signaling patterns to T cell behavior, he aims to create better, longer lasting, and safer CAR T therapies for more patients.

Molly Sargen, Ph.D. Jane Coffin Childs Fellow

Princeton University

Cross-Domain Chemical Communication Drives Host-Virus Interactions

Viruses have immense potential to influence the fates of individual cells, multicellular communities, and entire organisms. Nonetheless, vast gaps exist in our understanding of the interactions between viruses and their host cells. Molly Sargen, Ph.D., is specifically fascinated by how some viruses can co-exist with their hosts even though the interests of a virus and a cell are usually incompatible. Her goal is to use models of bacteria and their viruses (phages) to define the principles that drive host-virus interactions, including how each entity manipulates the interaction to its own advantage.

As part of her Ph.D. research in Sophie Helaine’s lab at Harvard Medical School, she showed that phages that are embedded in Salmonella block other phages from infecting the same bacterium through defense mechanisms that they strategically avoid during their own replication. She found that phages also deploy these defense mechanisms to compete with other phages that inhabit the same host. Strikingly, these phage-phage interactions occur while Salmonella infects mammalian immune cells called macrophages and thereby can influence the outcome of Salmonella infections. Thus, Sargen showed how host-virus interactions have implications beyond one host cell and one virus.

Now as a Jane Coffin Childs Fellow in Bonnie Bassler’s lab at Princeton University, Sargen will investigate how phages eavesdrop on bacterial communication called quorum sensing to inform their behavior: namely, whether they stably replicate with the host or undergo lytic replication that kills the host. In particular, she is interested in uncovering the mechanisms by which different cues influence these divergent virus lifestyles. Sargen notes that beyond advancing our basic understanding of viral behavior, her discoveries have the potential to inform the development of biomedical therapies that use or control viruses.

Francisco Tenjo Castano, Ph.D. Jane Coffin Childs-Merck Fellow

Columbia University

Retro but never outdated: Biology and applications of the human LINE-1 retrotransposon

Francisco Tenjo Castaño, Ph.D. studies how DNA changes over time. In graduate school, he solved new protein structures showing how CRISPR-associated transposons (CAST) insert new DNA into the genomes of their bacterial hosts. As a Jane Coffin Childs-Merck Fellow, he will now study LINE-1, a major human DNA “jumping gene” that can reshape our genome and contribute to disease.

In Guillermo Montoya, Ph.D.’s lab at the University of Copenhagen, Tenjo Castaño used biochemistry and structural biology to reveal the molecular mechanism of CAST DNA insertions. First, he solved the structure of the CAST catalytic protein TnsB bound to the transposon ends and the target DNA, and found that the enzyme only becomes conformationally active when it is properly attached to the target DNA. Tenjo Castaño proposed that this coupling serves as a safety feature to ensure that CAST only starts integrating new DNA into the genome once the complex is in the proper location. Then, he reconstituted the complete ~1 MDa CAST system with target DNA and solved several structures of the entire complex and assembly intermediates at different stages. These results explained the fine details of DNA target detection and insertion site regulation. This work could help advance future gene-editing technologies.

During his thesis research, Tenjo Castaño increasingly appreciated the potential of transposons in gene therapy but also as drug targets. In Akanksha Thawani’s lab at Columbia University, he will focus on LINE-1, the only active autonomous human retrotransposon, which has made up almost one-third of the human genome over evolutionary time. He will identify human proteins that help LINE-1 function, study how LINE-1 works using structural and biochemical methods and look for small-molecule drugs that inhibit it. Because LINE-1 activity is linked to cancer, neurodegeneration, and inflammation during aging, this research could point toward new treatments.

James Whitley, Ph.D. Jane Coffin Childs Fellow

Rutgers University

Population Codes and Communication Subspaces in Motor Control

James Whitley, Ph.D. has always been a fan of the underdog, and he notes that in neuroscience this tag applies broadly to any structure outside of the cortex. In his Ph.D., he showed that these regions do more than pass information along. As a Jane Coffin Childs Fellow, he will now study the brainstem, asking whether it plays a sophisticated role in filtering motor commands.

Historically the thalamus has been seen as a passive relay conveying sensory information to the cortex. Whitley’s graduate research in Martha Bickford’s lab at the University of Louisville challenged this passive view and established a more active, regulatory role for two visual thalamic nuclei. First, he demonstrated that the dorsal lateral geniculate nucleus enhances the flow of visual information following gaze shifts. Then, Whitley revealed an integrative role for the pulvinar nucleus whereby top-down and bottom-up signals are processed in the same neuron.

As Whitley has learned and discovered more about how information is transferred between different regions of the brain, he’s come to the realization that traditional models fail to account for the diversity of behaviors and limit functional flexibility. In Ian Oldenburg’s lab at Rutgers University, Dr. Whitley will examine information transfer between the cortex and the brain stem. He thinks motor commands may be represented as patterns of activity across groups of neurons, and he will test this idea using multiple methods. His goal is a better overall understanding of motor control and movement disorders.

Airi Yoshimoto, Ph.D. Jane Coffin Childs Fellow

Stanford University

Respecifying connections of hypothalamic thirst and warmth circuits

Airi Yoshimoto, Ph.D. was influenced by her pharmacy training and a patient experience that showed her how early-life stress can affect brain development. Inspired by this experience, Yoshimoto focused her graduate work on how the brain controls body functions like heart rate. As a Jane Coffin Childs Fellow, she will study how hypothalamic circuits form during development and how they control basic needs such as thirst and temperature regulation.

During Yoshimoto’s thesis research in Yuji Ikegaya’s lab at The University of Tokyo she discovered the neural relay that allows voluntary control of one’s heart rate. Heart rate and other physiological parameters are usually controlled by the autonomic nervous system. However, specialized training such as for free diving or meditation can teach individuals to voluntarily regulate these parameters. Yoshimoto developed a rat model of heart rate biofeedback, and used her model to uncover how the signal traveled through anterior cingulate cortical neurons through several relay stations all the way to parasympathetic neurons in the heart.

Now in Liqun Luo’s lab at Stanford University, Yoshimoto will examine neurons in the hypothalamus that regulate homeostatic functions. Neurons that are thirst- and warmth-activated are anatomically intermingled in the hypothalamus, but are, by definition, triggered by different stimuli. Yoshimoto predicts that the presence of distinct surface adhesion proteins distinguishes these neural populations, and will build genetic mouse models to rewire hypothalamic circuits such that thirst will activate warmth-sensitive neurons. Yoshimoto’s research promises to provide novel insight into the molecular mechanisms that dictate hypothalamic circuit specificity.

Class of 2025

Aurora Alvarez-Buylla, Ph.D. Jane Coffin Childs Fellow

University of California, Berkeley

Harnessing long-range hormone signaling for therapeutic delivery

What do poisonous frog toxins have to do with drug delivery? More than you might think, according to Jane Coffin Childs Fellow Dr. Aurora Alvarez-Buylla.

During her thesis research in Dr. Lauren O’Connell’s lab at Stanford, Alvarez-Buylla identified the first toxin binding protein in poison frogs. This protein, a serine protease inhibitor, or serpin, binds to toxins in the blood, and delivers them to skin glands for bioaccumulation. Interestingly, Alvarez-Buylla found that this frog protein is very similar to mammalian hormone carrier proteins that facilitate the transport of lipid-soluble hormones in the bloodstream and their delivery to target cells.

For the fellowship in Alanna Schepartz’s lab, Dr. Alvarez-Buylla plans to reconstruct the evolutionary trajectory of mammalian hormone carrier proteins. Like frog poison, many therapeutics are toxic when delivered systemically, therefore it is desirable to sequester these therapeutics until delivered to a particular organ. By understanding the range of small molecules that these proteins could possibly bind to, and how their release can be triggered, Alvarez-Buylla’s research will establish a framework for rationally engineering proteins to serve as novel drug delivery agents for many therapeutic molecules.

Nathan Bullen, Ph.D. Jane Coffin Childs Fellow

University of Colorado, Boulder

Unlocking the Bacterial Vault: Novel Organelles Involved in RNA Repair

It has been said that RNA is the central molecule in genetic transfer and cellular processes; Dr. Nathan Bullen’s past and planned future research certainly support that sentiment.

During his thesis research in Dr. John Whitney’s lab at McMaster University, Bullen discovered the role of an RNA-modifying enzyme in microbial warfare. Bacteria compete with one another in a microscopic turf war of sorts. One of the ways they combat their foes is by injecting toxins into nearby bacterial cells. Bullen demonstrated that one of these toxins is an enzyme called RhsP2 which works to inhibit protein synthesis or translation in neighboring cells.

As a Fellow in Aaron Whiteley’s lab at the University of Colorado, Dr. Bullen is going on the defensive—asking: how do organisms survive when their RNA is under attack? Intriguingly, the proteins that repair RNA are conserved from bacteria to humans, and Bullen has reason to believe that these systems operate in remarkably similar ways, despite billions of years of evolution. By studying these pathways in bacteria—whose genes are easier to manipulate—his cutting-edge research is shedding light on fundamental processes of RNA metabolism across the tree of life, with far-reaching implications for health, disease, and beyond.

Emre Caglayan, Ph.D. HHMI-Jane Coffin Childs Fellow

Boston Children's Hospital, Harvard Medical School

Uncovering oligodendrocyte lineage dynamics in the human brain using somatic mutations

Human brain development is challenging to study for many reasons. Dr. Emre Caglayan’s project as an HHMI-JCC Fellow aims to overcome experimental limitations related to studying brain development and provide unprecedented insight into how a brain develops over the human lifespan.

As a Ph.D. student in Dr. Genevieve Konopka’s lab at UT Southwestern Medical Center, Caglayan investigated human brain evolution. Using advanced genomics technologies, he found that human brains have unique functionalities used for the development and maturation of specialized cells relative to other closely related species.

Dr. Caglayan notes that the absence of non-invasive molecular tools has prevented further exploration of the human brain, and was captivated by the approach of Christopher Walsh’s lab to use somatic mutations as a “barcode” to trace cell lineages. This approach will enable Caglayan’s investigation into brain dynamics so that they can investigate how new mature oligodendrocytes are generated throughout a human lifespan. This research will provide fundamental insight into neurodevelopment and may reveal novel clues about how these processes go awry during neurodegeneration.

Brendan Camellato, Ph.D. Jane Coffin Childs Fellow

Memorial Sloan Kettering Cancer Center

Recording cell states and signaling events to reveal cell fate decisions during pancreatic islet differentiation

Gene transcription, the process of copying DNA into RNA for gene expression, is a complicated process that relies on sequences of DNA known as enhancers to help regulate the process. Enhancers are non-coding stretches of DNA that regulate the expression of a subset of genes.

Dr. Brendan Camellato made crucial insights into enhancer-mediated regulation during his thesis research in Dr. Jef Boeke’s lab at NYU Langone Health. In one of his projects, Camellato investigated transcriptional regulation across various species. In addition to being an impressive technical advance, this approach provided insight into a plausible mechanism for how genetic information is transferred and regulated in yeast and mouse embryonic stem cells.

Now, as a Fellow in Junhong Choi, Ph.D.’s lab at Memorial Sloan Kettering Cancer Center, Dr. Camellato will use enhancers as a tool to record cellular histories during normal development, and in diseased states. Using the recently developed ENhancer-based Genomic Recording of transcriptional Activity in Multiplex (ENGRAM), Camellato will investigate how cell signaling drives stem cell differentiation with single-cell resolution. His research promises to advance these important technologies, as well as provide unprecedented insight into human development.

Lews Caro, Ph.D. HHMI-Jane Coffin Childs Fellow

University of Utah

Evolution of receptor-ligand selectivity to evade bacterial ligand mimicry

Dr. Lews Caro is fascinated with the molecular arms race that occurs between a host and pathogen and how it shapes their evolution. Caro hypothesizes “that by understanding the molecular mechanisms of evolutionary phenomena, we can actually gain more insight into the evolutionary process itself.”

Caro’s graduate research in Michael Ailion’s lab at the University of Washington uncovered the mechanism of a toxin-antidote system in C. elegans. While such systems are widespread in bacteria and fungi, relatively few examples have been discovered in animals, and those few examples remain poorly characterized.

As a Fellow in Nels Elde’s lab at the University of Utah, Dr. Caro will explore the relationship between a special type of transmembrane protein, called ligand receptors, and the ligand itself. Pathogens secrete toxic ligand imitators which bind to host receptors and hijack normal host signaling. This exerts an evolutionary pressure on the receptor to escape activation by pathogen toxic ligands while retaining responsiveness to host ligands. Caro will use a combination of evolutionary analyses, functional and binding assays, and structural biology approaches to determine how receptors resolve this evolutionary conflict.

Ya'el Courtney, Ph.D. Jane Coffin Childs Fellow

Stanford University

Deciphering the Role of EBV-Infected B Cells and Autoimmunity in Post-Infectious Syndromes and Developing a Targeted Elimination Strategy

Illness can interfere with the brain’s ability to function properly, affecting much more than just clear thinking. Dr. Ya’el Courtney’s fellowship research is uncovering how immune responses to illness contribute to neurological dysfunction and may even trigger neurodegenerative processes, revealing new connections between the immune system and the brain.

During her thesis research in Dr. Maria Lehtinen’s lab at Harvard University, Courtney revealed how the choroid plexus, a specialized brain structure that produces cerebrospinal fluid is regulated. She found that secreted factors stimulate the development of specialized neural cells and alter their developmental trajectory. Interestingly, environmental factors such as maternal exposure to certain drugs or immune activation in response to illness also trigger secretion of factors and, eventually, can influence offspring behavior.

Dr. Courtney will examine immune-neurological interplay in Dr. William Robinson’s lab at Stanford University in a different context. There, she’ll examine how autoimmune responses in chronic post-infectious syndromes, such as post-treatment Lyme disease or long COVID, drive neurological manifestations. Courtney’s research has the potential to uncover novel immune-neurological connections and may elucidate novel and therapeutically tractable targets for patients with these long-lasting post-infection syndromes.

Pascal Devant, Ph.D. Jane Coffin Childs-Merck Fellow

Gladstone Institutes

Engineering CAR T cells for Enhanced Cancer Immunotherapy via Protein Interaction Network Analysis

Cancer immunotherapies, such as chimeric antigen receptor (CAR) T cell therapies, have shown great promise against malignancies of the blood but have struggled to effectively treat solid tumors. During his fellowship, Dr. Pascal Devant will focus on understanding how T cells work in an effort to engineer CAR T cell therapies that can better attack solid cancers.

Devant developed his expertise in immunology during his graduate research in Dr. Jonathan Kagan’s lab at Harvard Medical School. There, he focused on caspases, key enzymes that work as the body’s early warning system of invaders. Devant discovered that inflammatory caspases are key enzymes in mammalian innate immunity, providing an alternative activation route to what was previously described. He structurally characterized a caspase complex, providing novel insights into substrate capture and processing.

Now, in Dr. Alex Marson’s lab at Gladstone Institutes, Dr. Devant will generate quantitative protein-protein interaction networks to identify key interactions that regulate T cell function. Devant will leverage this information, using gene editing and preclinical CAR T cell models, to engineer the next generation of CAR T cell therapies for the treatment of solid tumors. In addition to providing fundamental insight into how T cells work, Devant’s work holds great promise in clinical translation for cancer patients.

Meagan Esbin, Ph.D. Jane Coffin Childs Fellow

University of Washington

“Healthy aneuploidy”: Discovering strategies from the placenta to regulate aneuploidy tolerance

Most human cells have two copies of each chromosome, and the loss or gain of entire chromosomes, known as aneuploidy, can often be a characteristic of cancer cells. However, in the placenta, many cells exhibit a high degree of aneuploidy and chromosomal instability. For her fellowship, Dr. Meagan Esbin will study how the cells of the placenta tolerate such high levels of aneuploidy.

During her thesis research, Dr. Esbin studied transcriptional regulation in the joint lab of Drs. Robert Tjian and Xavier Darzacq at UC Berkeley. First, she helped solve the structure of a regulatory hub involved in gene regulation, the human SAGA complex. Then, motivated in part by her passion to improve women’s health and make pregnancy safer, Esbin demonstrated that a human transcription factor (TFEB) plays an essential role in placental cell-cell fusion. This finding reveals new possibilities for rescuing defective cell fusion that can occur in preeclampsia.

In Dr. Min Yang’s lab at the University of Washington, Esbin will take a new angle on understanding placental biology. Using novel cell models, genetic screening, and live imaging she will attempt to define the rules of aneuploidy development and tolerance in the placenta. Her research will provide insight into this life-giving, yet understudied organ. Ultimately, she aims for her research to reveal how we can improve pregnancy outcomes and manage aneuploid cancer cells.

Elayne Fivenson, Ph.D. Jane Coffin Childs Fellow

Massachusetts Institute of Technology

Illuminating the cell envelope architecture and assembly of a tick-borne pathogen

The bacterial cell surface plays a critical role in bacterial physiology and represents a key target for many antibiotics. However, the properties of many bacterial cell surfaces are not well characterized. Dr. Elayne Fivenson’s fellowship project aims to learn more about the cell surface of Rickettsia parkeri, a tick-transmitted bacteria that is a model system for the more pathogenic species Rickettsia rickettsii that causes the deadly Rocky Mountain Spotted Fever (RMSF).

Fivenson developed her expertise in bacterial cell surfaces in Dr. Thomas Bernhardt’s lab at Harvard Medical School. There, Fivenson demonstrated how an inner membrane protein functions to regulate the synthesis of the outer layer of many Gram-negative bacteria. Next, she investigated how the synthesis of the outer membrane and cell wall are coordinated. While it has long been appreciated that the cell wall impacts cell morphology, Fivenson’s results indicate that the outer membrane also contributes to cell shape.

Now in Dr. Rebecca Lamason’s lab at Massachusetts Institute of Technology, Fivenson will study R. parkeri, a model system for the more pathogenic rickettsial species that cause RMSF. She will use structural and proteomic approaches to reveal the composition of the R. parkeri cell envelope. Then, she will use genetic approaches to dissect cell envelope synthesis pathways with the goal of identifying therapeutic targets. As tick range expands due to climate change, RMSF prevalence has increased. Fivenson’s research promises new insights towards the eventual therapeutic inhibition of these deadly bacteria.

Grace Hibshman, Ph.D. HHMI-Jane Coffin Childs Fellow

University of California, Berkeley

From Bacteria to Biotechnology: Harnessing Retrons for Precision Medicine

CRISPR-Cas systems have revolutionized how specific genes can be precisely edited. Dr. Grace Hibshman’s fellowship project is focused on how to develop the next generation of genome editors.

During her graduate work in Dr. David Taylor’s lab at the University of Texas, Austin, Hibshman became an expert in the structural and functional characterization of CRISPR-Cas systems.

First, she engineered a more specific genome editing tool with less off-target effects. Then, in a tour de force, Hibshman determined the precise 3D structures of this tool in real-time to understand how it recognizes specific sequences of DNA. Her studies have provided crucial insight into how to improve CRISPR-Cas systems for genome editing.

Now, during her postdoctoral research in Dr. Eva Nogales’s lab at UC Berkeley, Hibshman will study a different set of genetic editing tools focusing on retrons, bacterial elements that can fuse multiple enzymatic activities into a single protein. She’ll use biochemical, structural, and high-throughput mutagenesis approaches to characterize and optimize one such retron. Hibshman’s research may provide us with the latest and greatest genome editor, and she’s betting on its applications in a wide variety of diseases such as cystic fibrosis, Alzheimer’s, and Duchenne muscular dystrophy.

Hannah Itell, Ph.D. Jane Coffin Childs Fellow

Vanderbilt University Medical Center

Defining the targets of the antibody response to natural Oropouche virus infection

Dr. Hannah Itell’s passion for understanding the “ever-evolving virus-host arms race” started during her undergraduate global health studies in India, South Africa, and Brazil. Seeing the impact of viral infection on individuals, families, communities, and entire countries, motivated Itell to dedicate her research career to preventing viral transmission.

In her graduate research in Dr. Julie Overbaugh’s lab at the Fred Hutchinson Cancer Center, Itell focused on identifying human traits that limit HIV severity. She discovered that many virus-fighting genes seen in lab-grown cells function differently than real human immune cells,, demonstrating that common lab models may not reflect what really happens in the body. Next, she identified a gene that regulates a pattern in HIV transmission that was not previously understood.

Now as a Fellow in Dr. Ivelin Georgiev’s lab at Vanderbilt, Itell has switched her focus to the Oropouche virus which is endemic to Brazil.There are currently no vaccines or specific treatments available to prevent or treat infection. Itell will find out how many virus types can be blocked by antibodies and where on the virus the antibodies attach. Itell’s efforts will provide fundamental knowledge about host response to Oropouche virus and directly inform rational vaccine design in the development of antibody therapeutics.

Madeleine Junkins, Ph.D. HHMI-Jane Coffin Childs Fellow

Yale University

Uncovering the principles of immune sensing within the central nervous system

Dr. Madeleine Junkins is intrigued by brain-body interactions and how this relationship enables complex behaviors and functions. During her graduate research she investigated thirst suppression in ground squirrels, a hibernating species that can forgo water for months. During her fellowship, Junkins will interrogate collaborative immune-neural responses to illness.

During her thesis research in Dr. Elena Gracheva’s lab at Yale University, Junkins demonstrated that a specialized subset of neurons are activated at low temperatures during hibernation and promotes the release of a hormone that tells the body to hold onto water. Additionally, she found that thirst-sensing neurons in specialized brain areas called the circumventricular organs are functionally suppressed during hibernation. Collectively, Junkins’ research provided a major leap forward for understanding the neural regulation of thirst suppression during hibernation.

As a postdoc in Dr. Ruslan Medzhitov’s lab at Yale, Dr. Junkins will now study how our immune and neural systems collaborate to engage defenses when we’re sick. She will uncover the molecular and cellular components that transform inflammatory signals into neural activity. By manipulating the communication between the immune and neural systems during inflammation, Junkins will provide insight into how these two major body systems interact. This understanding could lead to the identification of novel therapeutic targets for neuroimmune disorders.

Shoshanna Kahne, Ph.D. Jane Coffin Childs Fellow

University of Washington

Investigation of immune systems in multicellular bacteria

Dr. Shoshanna Kahne is interested in bacterial pathways and determining how they change in response to their environment. From Mycobacterium tuberculosis to cyanobacteria, Kahne’s research is creating powerful insights with implications ranging from human disease to environmental impacts.

Kahne’s Ph.D. research in Dr. Heran Darwin’s lab at NYU focused on how proteins are marked for breakdown in the bacteria that causes tuberculosis, Mycobacterium tuberculosis. Kahne discovered a protein that regulates marking an important vitamin-making enzyme for degradation in response to the abundance of the vitamin it helps synthesize. Her findings could help identify new ways to treat this deadly disease.

Now, in Dr. Alex Meeske’s lab at the University of Washington, Kahne will study how cyanobacteria defend themselves against infection by viruses. She is investigating species in the order Nostocales and has identified numerous and diverse potential defense systems in their genomes.

Kahne will test Nostocales hosts against diverse viruses to characterize how they succeed or fail to prevent infection. This work may reveal strategies to harness useful qualities of Nostocales, such as their abilities to fix atmospheric carbon and nitrogen, as well as combat their toxic overgrowths which can poison plants, animals, and humans.

David Klawon, Ph.D. Hope Funds for Cancer Research-Jane Coffin Childs Fellow

Massachusetts Institute of Technology

Role of neoantigen-nonspecific Passenger T cells in cancer-associated immunity and tumor progression

Dr. Dave Klawon is fascinated with the critical, yet disparate roles that our immune system plays in resolving or mediating different diseases. He hypothesizes that comparing productive immune responses during infections with immune responses that fail to resolve in autoimmunity or become dysfunctional in cancer will “reveal precise therapeutic targets capable of tuning the immune response at will”.

Klawon developed his immunology expertise during his graduate research in Dr. Peter Savage’s lab at the University of Chicago. His research there focused on understanding how the immune system recognizes proteins from invaders like viruses or bacteria but knows not to attack the body’s own proteins. Klawon found that a special type of adaptive immune cell, regulatory T cells, selectively suppress self-reactive immune responses during infection to prevent autoimmune disease, thereby providing crucial mechanistic insight into self/non-self discrimination by the immune system.

During his fellowship in Dr. Tyler Jacks’s lab at MIT, Klawon will adjust his research focus to the immune system’s role in cancer. Immunotherapy is a burgeoning and incredibly promising cancer treatment modality, yet many patients fail to respond to current therapeutic options. Klawon notes that tumor-infiltrating T cells are a heterogeneous population that include subsets that either combat tumor growth or suppress the immune response allowing tumors to flourish. His research aims to identify factors driving tumor-enrichment of these disparate populations and reveal novel therapeutic targets that would both promote anti-tumor T cells and inhibit immunosuppressive T cells.

Anna Lebedeva, Ph.D. Jane Coffin Childs Fellow

Harvard Medical School

Organisational logic of the spino-parabrachial pathway for light touch

The way our brain senses a soothing touch differs from how it senses a painful one, but how these signals are processed are not well understood. Dr. Anna Lebedeva’s fellowship will leverage novel tools developed during her graduate work to answer this question in conscious, freely behaving mice.

Lebedeva developed her expertise in neuroscience and tool development in Dr. Kenneth Harris’s lab at University College London. There she helped develop Neuropixels 2.0, an implant that can steadily track brain activity in thousands of neurons for over two months. Importantly, this miniaturized implant does not constrain animal behavior, enabling measurements in conscious, freely moving mice and rats. Lebedeva then applied her new tool to uncover why mice make certain behavioral choices versus others that have a greater reward output.

During her postdoctoral research in Dr. David Ginty’s lab at Harvard, Dr. Lebedeva will apply Neuropixels 2.0 to understand how the brain processes signals resulting from touch. The brain region called the parabrachial nucleus (PBN) is thought to be important in this process, yet it is unknown how this information is filtered. Lebedeva will be able to monitor thousands of neurons in the PBN to decipher how touch is communicated in response to different stimuli such as light touch, pinching, and heating or cooling. This research will provide unprecedented detail into neural processing of the light touch pathway.

Amir Levi, Ph.D. Jane Coffin Childs Fellow

University of California, San Francisco

Neuronal mechanisms of simulations in the brain of sleeping mice

Dr. Amir Levi is interested in understanding the neural mechanisms underlying complex behavior. In his thesis research, Levi used innovative techniques to make keen insights into how we learn. In his fellowship, Levi’s research will provide important insight into how our brains generate “internal models”—mental simulations that allow us to predict and control movements and adapt to changing environments.

During his graduate research in Dr. Eran Stark’s lab at Tel Aviv University, Levi focused on neural mechanisms of learning. Learning is frequently understood as the brain adapting to external cues, yet Levi’s approach involved direct manipulation of neuronal networks and subsequent assessment of behavioral performance. Levi created a visual test where mice choose between two options, and found that they can learn the task in just one session, depending on their past experience and how hard the rule is. He also demonstrated how specific brain circuits can transmit neuronal signals with remarkable accuracy and precision, highlighting the brain’s ability to maintain and even enhance signal integrity during processing. His work suggests that using brain activity to guide learning may help us understand how brain signals lead to behavior.

Now in Dr. Massimo Scanziani’s lab at UC San Francisco, Levi will dissect the neural mechanisms involved in generating internal models. Normally, these internal simulations occur together with actual physical movement, making it challenging to study prediction separately from action. Levi will overcome this limitation by studying mice while they sleep. During sleep, internal models are still generated, but no physical movement occurs. Thus, Levi’s clever approach will enable him to tease apart the neural mechanisms for these distinct functions. His research will help us understand how the brain anticipates events, coordinates movements, and processes experiences during dreams.

Diego Lopez, Ph.D. Jane Coffin Childs Fellow

University of Utah, Huntsman Cancer Institute

The early-life microbiome regulates β-cell function and type-1 diabetes via gamma-aminobutyric acid

Environmental interactions during prenatal development have important implications that often last well into adulthood. Dr. Diego López’s research has shown how infections can alter this developmental trajectory, impacting immune function and influencing the development of asthma. In his fellowship he will investigate how our microbiome impacts developmental trajectories and metabolic outcomes in adulthood.

López’s graduate research began in Dr. Anna Beaudin’s lab at UC Merced focused on how maternal immune activation and inflammation have lasting impacts that continue well into the offspring’s adulthood.

In one project, Lopez found that when a mother’s immune system is activated, it causes an increase in certain early immune cells—and this increase lasts into adulthood. Additionally, he demonstrated that maternal inflammation expands and hyperactivates a specific population of innate immune cells that cause their offspring to have increased risk for developing asthma in adulthood. Collectively, López’ results reveal the long-lasting consequences of maternal immune activation on offspring fitness.

Now in Dr. June Round’s lab at the University of Utah, López will shift his focus to a different type of environmental interaction: our microbiome. This collection of trillions of microorganisms in our gastrointestinal tract plays a key role in the development of numerous diseases, including type-1 diabetes. Recently, the Round lab demonstrated that loss of early-life microbial diversity during a critical developmental window results in lifelong metabolic dysfunction due to reduced beta cell development. López will investigate the molecular crosstalk between specific microbes, immune cells, and pancreatic beta cells. His research will increase our understanding of the development of type-1 diabetes, and may reveal novel therapeutic targets for treating this disease.

Tomer Milo, Ph.D. Jane Coffin Childs Fellow

The Ragon Institute of MGH, MIT, and Harvard

A spatial stochasticity theory resolves how host-protective T cell responses emerge amid regulatory T cell immunosuppression

Dr. Tomer Milo appreciates distilling simplicity out of complex biological systems. During his graduate work, Milo developed elegant theories for a variety of human diseases and collaborated with experimentalists to validate them. In his fellowship he will develop his own experimental expertise and combine it with his theoretical expertise to tease apart immune processing of self vs. foreign antigens.

During Dr. Milo’s thesis research in Dr. Uri Alon’s lab at the Weizmann Institute of Science he “studied design principles of physiological systems to better understand complex human diseases.” His work provided groundbreaking insight into the tumor microenvironment, bipolar disorder, and autoimmune disease. In his work, Milo used mathematical modeling to identify molecular players and cellular interactions critical in a host of biological diseases.

As a postdoc in Dr. Harikesh Wong’s lab at the Ragon Institute and Mass General, Dr. Milo will focus on systems immunology. Milo will investigate how a specific immune cell population, regulatory T cells, prevents autoimmune responses to self antigens while allowing appropriate immune responses against pathogenic non-self antigens. He thinks that the spatial segregation of the lymph node is crucial for this discrimination and will use high-resolution imaging and mouse models to tackle this question. Milo’s research will answer critical and fundamental questions in immune biology and provide insight into immune responses at homeostasis, during infection, and in autoimmune disorders.

Toshitaka Nakamura, Ph.D. Jane Coffin Childs Fellow

Rockefeller University

A genetic approach to study metabolite sensing and regulation in organelles

Dr. Toshitaka Nakamura is interested in understanding protein-chemical interactions that mediate how cells sense stress. During his graduate work he found and characterized new compounds that kill cancer cells by triggering a type of cell death called ferroptosis. In his fellowship, he is interested in understanding how cells handle iron and glutathione, a crucial antioxidant and detoxifying agent, to mitigate stress responses.

In Dr. Nakamura’s graduate research in Dr. Marcus Conrad’s lab at Helmholtz Munich, he investigated the role of the protein ferroptosis suppressor protein (FSP1) in halting ferroptosis, a form of cell death that functions by damaging cell membranes. Nakamura discovered molecules that block FSP1, which induces cancer cell death. He showed that these molecules work by moving FSP1 away from cell membranes, inactivating the inherent enzymatic activity that protects them from damage. Then, by studying FSP1 mutations from cancer patients and lab experiments, he found another inhibitor and identified out how both types work. Collectively, his research provided groundbreaking insight into the role of FSP1 in ferroptosis, and revealed how this protein can be therapeutically targeted in cancer treatments.

Now, as a fellow in Dr. Kıvanç Birsoy’s lab at Rockefeller, Nakamura will study how cells sense metabolites in different cellular compartments. To facilitate his studies Nakamura will develop a CRISPR-Cas9-based genetic screening platform that can target specific organelles. Then, he’ll leverage his platform to investigate iron and glutathione sensing in mitochondria. In addition to providing a novel, widely applicable research tool, Nakamura’s studies may provide new insights and identify tractable therapeutic targets in diseases like cancer and neurodegeneration.

Vanha Pham, Ph.D. Ludwig Cancer Research-Jane Coffin Childs Fellow

Princeton University

Biochemical basis and function of lipid spatial localization within the brain

Dr. Vanha Pham hypothesizes that there are many molecular examples of the “Goldilocks principle” in cell biology. During her graduate research she demonstrated how the right amount of formaldehyde mediates functional epigenetic signaling, while too much leads to general toxicity. In her fellowship, Pham will investigate how lipids in the brain are organized to maintain homeostasis and the functional and disease implications that result when they are not.

Pham’s thesis research in Dr. Chris Chang’s lab at UC Berkeley, focused on the role of small molecules and metal ions in helping the body’s cells carry out chemical processes. Pham discovered that formaldehyde can block an enzyme needed to make SAM, a key molecule in one-carbon metabolism. Surprisingly, this didn’t cause widespread changes in gene regulation, but instead affected only specific spots on certain genes.

As she transitions to Dr. Joshua Rabinowitz’s lab at Princeton University, Pham will shift her studies to the interplay between proteins and lipids. Using the brain as a model system, she’ll investigate why lipids are spatially enriched in different layers of the brain using a novel approach that maps lipids and gene activity in specific parts of a tissue in combination with genetic screens.

Additionally, she will investigate what happens when certain lipid patterns are disrupted. Pham anticipates that her findings will reveal important insights on how lipids impact membrane protein function, regulate cell morphology, and modulate physiology and disease.

Matthew Reynolds, Ph.D. Jane Coffin Childs Fellow

Washington University in St. Louis

Structural mechanisms for higher-order microtubule assembly function in parasites

Dr. Matthew Reynolds is fascinated with the elegant structures of our cytoskeleton – a large network consisting of protein fibers and associated proteins that gives shape and structure to cells. During his thesis research he developed machine-learning based techniques to enable the structural determination of curved and bundled actin structures. In his fellowship, Reynolds will detail specialized cytoskeleton super-assemblies from parasitic cells.

During Reynolds’ thesis research in Dr. Greg Alushin’s lab at Rockefeller University, he made important contributions to processes involved in cryo-EM structure determination. Reynolds developed computational techniques that were crucial in reconstructing bent F-actin segments and bundled F-actin that help shape and move cells.

Now, in Dr. Rui Zhang’s lab at Washington University in St. Louis, Reynolds will apply his structural biology expertise to more complex cellular systems. He will continue to investigate the cytoskeleton and will use a combination of cryo-EM and cryo-electron tomography (cryo-ET) to examine microscopic single-cell organisms. These studies will provide mechanistic insights into the nanoscale protein-protein interactions that drive micron-scale cytoskeleton organization in single-celled parasites. His research will likely push forward technological development in structural determination via cryo-EM and cryo-ET. Reynolds anticipates that his findings will inform parasitic disease models and may reveal novel therapeutic targets.

Heegwang Roh, Ph.D. HHMI-Jane Coffin Childs Fellow

University of California, Berkeley

Discovery of silencing factors of the unfolded protein response in cancer

Dr. Heegwang Roh recalls how the COVID-19 pandemic hit during a pivotal moment of his graduate training. During the lockdown, he devoted considerable effort to reading literature on basic biology and became interested in the unfolded protein response (UPR), a cellular stress response triggered by the accumulation of unfolded or misfolded proteins in a cell.

Roh’s thesis research in Dr. Alice Ting’s lab at Stanford University involved a number of innovative projects covering a broad swath of chemical biology. In one project, he created a better way to tag nearby proteins using an enzyme called laccase, fixing safety problems seen in older methods. This new system works well for studying proteins and viewing cells under powerful microscopes. In another project, Roh turned a harmless version of botulinum toxin into a tool for delivering proteins inside cells.

As he transitions to Dr. Michael Rape’s lab at UC Berkeley, Roh will utilize his expertise in tool development to interrogate the UPR. This response is important for cells to respond to stress stimuli, yet the molecular mechanisms by which the UPR is suppressed after the stress is resolved is unknown. Roh will use genetic screens to identify novel UPR suppressors and develop chemical inhibitors for the UPR suppressors. In addition to uncovering novel UPR biology, Roh’s studies will provide new tools for studying UPR in cancer cells and perhaps reveal lead molecules for cancer drug development.

Wesley Saintilnord, Ph.D. Jane Coffin Childs-Merck Fellow

Washington University in St. Louis

The functional role of transposable element-derived transcripts in cancer progression

Dr. Wesley Saintilnord is interested in how transposable elements (TEs), DNA sequences that can move from one location in a genome to another, can exploit epigenetic pathways that then lead to their aberrant reactivation in cancer cells to rewire gene expression programs. In his fellowship, Saintilnord will examine how TEs functionally contribute to cancer progression.

Saintilnord developed his expertise in epigenetic mechanisms during his Ph.D. research at the University of Kentucky in Dr. Yvonne Fondufe-Mittendorf’s lab now at the Van Andel Institute. In his first project, Saintilnord showed that cadmium exposure changes how many genes are turned on during sperm development by affecting DNA methylation. In another study, he found that certain cancer-associated variants of a histone protein make DNA wrap more tightly, changing how genes are expressed. Collectively, his research demonstrates how environmental exposure, and oncogenic mutations rewire gene expression through epigenetic pathways.

Now, in Dr. Ting Wang’s lab at Washington University in St. Louis, he will dissect why cancer cells take control of TEs for gene regulation and how TE-generated transcripts drive tumorigenesis. He will develop a high-throughput screen to evaluate tumor-enriched TE transcripts in classical cancer phenotypes. Then, Saintilnord will evaluate which of these transcripts encode functional proteins that modulate cell signaling and chromatin dynamics. Saintilnord’s studies will provide fundamental insights into TE biology in cancer cells and may reveal novel therapeutic strategies to combat TE-mediated oncogenic programs.

Ellen Shrock, Ph.D. Jane Coffin Childs Fellow

University of Washington

Decoding the Structural Basis of Immunogenicity

Dr. Ellen Shrock envisions a future where novel therapeutics are not seen as dangerous by the immune system. While studying the immune response to SARS -CoV2 in her graduate work, she recognized that even different individuals responded in the same way to the virus. In her fellowship, Shrock is systematically characterizing immunogenicity, the ability of a substance to provoke an immune response, and training models to predict antibody recognition, with the long-term goal of avoiding such features in protein therapeutics.

During her thesis research in Dr. Stephen Elledge’s lab at Harvard Medical School, Shrock studied antibodies from people who had COVID-19 and found they targeted over 800 parts of the virus. She also showed that some parts of these antibodies are built into our genes and help the immune system recognize viruses quickly. Shrock’s research is a giant step forward in understanding immune recognition, with important implications for viral immunoevasion and the design of immunosilent protein therapeutics.

As a postdoc in Dr. David Baker’s lab at the University of Washington, Shrock is taking a systematic approach to more broadly understand antibody recognition. She will execute a large-scale screen to characterize the antibody response against a diverse array of proteins. Shrock will then characterize the epitopes within these proteins and use her results to train an AI model to predict immunogenicity. In addition to providing fundamental learnings on immune recognition, Shrock’s findings will empower the design of future protein therapeutics that are invisible to our immune systems.

Patrick Steadman, M.D., Ph.D. HHMI-Jane Coffin Childs Fellow

Stanford University

Disrupting neuron-glioma interactions in the thalamus for thalamic pediatric low-grade glioma therapy

Dr. Patrick Steadman is passionate about neuroscience and the interplay between neurons and glial cells (support cells in the brain) in physiology and disease. During his graduate research, he examined the interaction between these cell types in normal memory consolidation. In his fellowship, Steadman will now investigate how this interplay impacts pediatric low-grade gliomas.

Steadman’s thesis research in Dr. Paul Frankland’s lab at the University of Toronto, focused on the importance of a specialized glial cell, myelin-forming oligodendrocytes, in memory consolidation. He showed that oligodendrogenesis and de novo myelination in the cortex are promoted by learning. Importantly, when he prevented learning-induced increases in oligodendrogenesis, this impaired memory consolidation. Steadman’s results emphasize the role of glial cells in fine-tuning neural circuits for memory consolidation and retrieval.

Now in Dr. Michelle Monje’s lab at Stanford University, Dr. Steadman will continue to examine glial-neuronal interactions, but in the pathological context of pediatric low-grade gliomas. Recent work from the Monje lab demonstrated that gliomas increase neuronal excitability which promotes tumor growth and disrupts normal brain function. Steadman will investigate the molecular mechanisms mediating glioma progression, and test targeted therapies’ impacts on glioma progression and brain function. This research will provide new insight into pediatric gliomas while taking into account the cognitive impact of potential treatments on patients – an important consideration since children with this disease are typically quite young.

Shivang Sullere, Ph.D. HHMI-Jane Coffin Childs Fellow

Harvard University

Understanding energetic and vascular constraints on neurophysiology, encoding and behavior

The brain is a remarkable organ; it shapes our perceptions, memories, and cognitive functions, yet these functions come at a high energetic cost. During Dr. Shivang Sullere’s graduate research he discovered a novel mechanism for pain relief that provides significant insight into the role of endogenous cholinergic circuit, while serving as a potential alternative to opioids. During his fellowship, he will investigate the metabolic, neurophysiological and behavioral consequences of deficient energy supply to active brain regions.

During his Ph.D. research in Dr. Daniel McGehee’s lab at the University of Chicago, Sullere used neurophysiological approaches to explore cholinergic circuits involved in central pain signaling. He identified that activating certain cholinergic centers in the brain helped reduce pain, even in conditions in which opioids no longer worked. He then identified the receptor mechanisms mediating the analgesic effects of this cholinergic circuit.

As he transitions to Dr. Chengua Gu’slab at Harvard University, Sullere will adjust his focus to neurovascular coupling (NVC): a dynamic process that matches local blood flow to areas with high neural activity. He will use genetic mouse models and optical methods to disrupt NVC and evaluate how NVC impacts brain function at metabolic, neurophysiological and behavioral levels. Sullere’s studies will provide foundational insights into NVC and may reveal strategies for correcting metabolic deficits in diseases like Alzheimer’s, dementia, diabetes, and atherosclerosis.

Shih-Yi Tseng, M.D., Ph.D. HHMI-Jane Coffin Childs Fellow

University of California, San Francisco

Dynamic interactions of hippocampal-prefrontal circuits for flexible behavior

Dr. Shih-Yi Tseng is interested in how the brain coordinates the many functions we use to navigate our way through the world. During her Ph.D. research she studied a large population of neurons to illustrate that neural coding enables these functions and is distributed throughout the cortex. In her fellowship, Tseng will now decipher how two areas of the brain work together to enable the flexible behavior required for navigation.

Tseng’s thesis research in Dr. Christopher Harvey’s lab at Harvard University examined the functional organization of the cortex in supporting sensing, planning, and action to navigate towards a goal location in dynamically changing environments. By tracking the activity of 90,000 brain cells in mice, Tseng found that information about tasks and behavior is spread out across the cortex. Her work suggests that this part of the brain possesses a vast capacity to integrate complex features of behavior and surroundings to guide decisions.

In Dr. Loren Frank’s lab at UC San Francisco, Tseng will now investigate the dynamic interactions between the hippocampus (HPC) and prefrontal cortex (PFC) to enable flexible behavior. The HPC is important for learning and memory, whereas the PFC is crucial for decision-making. These regions need to coordinate during tasks such as navigation, yet how such coordination occurs is not known. Tseng will use multi-area electrophysiology, optogenetic manipulations, and computational methods to determine the HPC-PFC interactions needed for flexible behavior, and to evaluate how their coupling enables these regions to perform their individual functions. This research will provide fundamental insights into HPC-PFC coupling and may reveal ways in which this process goes awry in neuropsychiatric disorders.

Yu Wang, Ph.D. HHMI-Jane Coffin Childs Fellow

Stanford University

Neural mechanism of behavioral exhaustion

Focusing on a task can often leave us exhausted despite low physical exertion. Dr. Yu Wang is investigating the source of this type of behavioral exhaustion. Building off her thesis research on neural sensing of peripheral metabolic states, she’s primed to make key insights into the brain’s metabolic deficiencies that may lead to our fatigue.

Wang developed her expertise in the neural integration of metabolic states during her Ph.D. research in Dr. Ardem Patapoutian’s and Dr. Li Ye’s labs at The Scripps Research Institute. Specifically, she was interested in how sensory neurons regulate peripheral metabolism, metabolic processes that occur in tissues and organs outside of the central nervous system, and how these neurons coordinate intracellular energy use to sustain activity. Wang demonstrated that somatosensory neurons enervate adipose tissue and modulate adipocyte function by acting as a break on the sympathetic system. Interestingly, she found that the mechanoreceptor PIEZO2 is highly expressed in these neurons, and is required for their brake-like function. Collectively, her research has provided keen insight into the interplay between neural function and peripheral metabolic states.

As a postdoc in Dr. Karl Deisseroth’s lab at Stanford University, Wang will examine the neural mechanisms of behavioral exhaustion. She hypothesizes that repetitive behaviors deplete local energy resources in specific brain regions, ultimately leading to behavioral exhaustion. Wang will combine different mouse models with repetitive behaviors, and assess metabolic and energetic states using metabolomics and imaging. Wang’s studies will provide novel insight into behavioral fatigue, and may inform on better intervention strategies.

Bailey Weatherbee, Ph.D. Jane Coffin Childs Fellow

Cincinnati Children's Hospital

Multifunctional RNA-binding transcription factors coordinate cell states in development

Human development at the earliest stages is a complicated process with many intrinsic and extrinsic cell signals. For her fellowship, Dr. Bailey Weatherbee will investigate the molecular mechanisms of lineage-defining transcription factors that enable early embryonic development.

During her Ph.D. research in Dr. Magdalena Zernicka-Goetz’s lab at the University of Cambridge, Weatherbee developed a cellular model of the human post-implantation embryo. By combining various types of stem cells made by turning on certain genes, she created cell clusters that mimic important stages of early embryo development. Furthermore, Weatherbee used cell models and embryos to investigate the requirement of specific signaling pathways for different cell types in early development. These studies are a major step forward in modeling the earliest steps in embryonic development and will enable numerous follow-up studies by the broader scientific community.

Now, in Dr. Aaron Zorn’s lab at Cincinnati Children’s Hospital, Weatherbee will investigate the molecular mechanisms of two critical lineage-defining transcription factors (TFs). She hypothesizes that in addition to their canonical DNA-binding activities, binding to RNA is also crucial for their function. Weatherbee will use cell and animal models to evaluate the developmental significance of TF-RNA interactions and identify partner proteins that mediate their function. Since mutations that impact RNA regulation occur in several congenital diseases and cancers, Weatherbee anticipates that her findings will inform on novel therapeutic strategies to treat these conditions.

Class of 2024

Stephen Abini-Agbomson, Ph.D. Jane Coffin Childs Fellow

Max Planck Institute of Immunobiology and Epigenetics

Direct Visualization of DNA Methyltransferase Oligomerization and Its Influence on Neuronal Gene Regulation

Epigenetic modifications are changes that affect how our genes are turned on or off,
without changing the underlying DNA sequence. These changes can be influenced
by factors like our environment, diet, and lifestyle. The epigenetic modifications of
DNA and chromatin-associated proteins play a crucial role in regulating cell-type
specific gene expression. Methylation of DNA, for example, is associated with
turning genes off via transcriptional repression. In most cells, DNA methylation
occurs in the context of “CG” dinucleotides. Neurons, however, are also methylated
at “CA” sequences.

Dr. Stephen Abini-Agbomson predicts that the oligomerization, or the
process of small molecules joining together to form a larger structure, of DNA
methyltransferases (DNMT) is important for their appropriate genomic localization
and activity. He will use cutting edge single-molecule approaches to investigate the
role of DNMT oligomerization in gene expression during neuronal development
in Dr. Ibrahim Cissé’s lab at the Max Planck Institute of Immunobiology and
Epigenetics. Mis-regulation of DNA methylation is frequently observed in
neurodevelopmental disorders and many types of cancer. Dr. Abini-Agbomson’s
findings may produce new mechanistic insights to inform future therapeutic
targeting of these diseases.

Abini-Agbomson honed his expertise in epigenetics and chromatin biology as
a graduate student in Dr. Karim-Jean Armache’s lab at the New York University
Grossman School of Medicine. There, he demonstrated that the histones encoded
by giant viruses can form nucleosomes. This was quite surprising as previously it
was thought that only eukaryotes have nucleosomes. Additionally, Abini-Agbomson
showed that the lysine methyltransferase SUV420H1 impacts chromatin dynamics
through both enzymatic and non-enzymatic mechanisms. With this research
background, Abini-Agbomson is poised to make breakthrough discoveries on the
impact of epigenetic protein oligomerization in neurodevelopment.

Green Ahn, Ph.D. Jane Coffin Childs - HHMI Fellow

University of Washington/Institute for Protein Design

De novo design of extracellular effector for modulating distinct outputs of cell-surface proteins

Cell surface proteins can drive diametrically opposed phenotypic outcomes when bound by ligands, distinct molecules that attach to other specific molecules. Therefore, efforts to rewire membrane protein signaling, introducing a specific function could improve and change how we develop treatments.

Dr. Green Ahn will engineer novel membrane protein effectors in Dr. David Baker’s lab at the University of Washington. Using artificial intelligence protein design tools, Dr. Ahn will design a library of de novo extracellular effectors against particular ectodomains of cell surface proteins and investigate how those effectors impact downstream function. Ahn’s studies will provide fundamental insight into membrane protein signaling and set the stage for future therapeutic targeting of these pathways.

Ahn’s expertise in targeting membrane proteins stems from her graduate studies in Dr. Carolyn Bertozzi’s lab at Stanford University. There Ahn developed the first cell-type-specific degrader for a membrane protein. Ahn built on that study to discover cellular factors that are required for targeted membrane protein degradation. She also helped develop the first de novo designed proteins that trigger membrane protein degradation in collaboration with Dr. David Baker’s lab. With this experience Dr. Ahn is poised to make future discoveries with implications for our fundamental knowledge of protein membrane biology as well as future therapeutic strategies.

Ibraheem Alshareedah, Ph.D. Jane Coffin Childs - HHMI Fellow

Boston Children's Hospital/Harvard Medical School

Protein-DNA interactions in DSB repair across scales

Homologous recombination (HR) is an important pathway for error-free DNA strand break repair. Proper repair of DNA breaks is crucial for preventing cancer, as indicated by the number of frequent genetic mutations in this pathway that lead to breast, ovarian, and other types of cancer. Therefore, a better mechanistic understanding of DNA break repair may open up new avenues for therapeutic targeting of cancer.

Dr. Ibraheem Alshareedah is taking a novel approach to investigate DNA break repair in Dr. Taekjip Ha’s lab at Harvard Medical School. It is known that BRCA2 loads RAD51 onto single-stranded DNA (ssDNA), yet HR still occurs in BRCA2-mutant cancers, suggesting that there is redundancy in this pathway. Dr. Alshareedah hypothesizes that RAD52 nanoclusters in cells recruit RAD51 and load it onto ssDNA, even in the absence of functional BRCA2. To investigate this hypothesis, Alshareedah will examine if RAD51, ssDNA, and other DNA-break repair proteins are recruited to RAD52 nanoclusters in cells. He will then determine which RAD52 protein features are required for cluster formation. By understanding the partial redundancies in the DNA repair pathway, Alshareedah’s research may reveal novel targets for treating BRCA2-mutant cancers.

Alshareedah’s expertise in protein and nucleic acid clusters stems from his Ph.D. research in Dr. Priya Banerjee’s lab at the University at Buffalo. There, Alshareedah focused on the formation and material properties of protein-nucleic acid biomolecular condensates. He developed an in-condensate passive micro rheology assay and showed that condensates behave as an elastic solid on short time scales, but like a viscous liquid on long time scales. Alshareedah also used this method to probe the aging process of condensates, which is thought to be related to protein aggregation in neurodegenerative diseases. Now in his postdoctoral research, Alshareedah will investigate the functional importance of RAD52 condensates in BRCA2-mutant cancers.

Meenakshi Asokan, Ph.D. Jane Coffin Childs Fellow

Princeton University

Hormone-mediated changes in neural computations that drive flexible social behaviors

Social interactions and behaviors are mediated by a hormone-sensitive brain network. For example, female mice are sexually receptive only during a certain phase of their estrous cycle around ovulation. Yet, it is still unclear how hormones modulate this network’s circuit architecture and dynamics to dictate changes in behavior.

Dr. Meenakshi Asokan will examine this missing link in Dr. Annegret Falkner’s lab at Princeton University. Dr. Asokan hypothesizes that sex hormones reorganize neural dynamics and functional coupling in crucial hubs for top-down control of sociability to drive flexible female social choice. Asokan will use a behavioral assay and computational tools to quantify the hormone-dependent changes in social motivation and preference. She will then pinpoint the location of these differences in the brain, address how these neural ensembles alter the coding of social interactions and manipulate these regions to verify their causal role in hormone-dependent changes in social behaviors. These studies will provide fundamental insight into how sex hormones rewire information processing to impact social behaviors. This information will be invaluable in situations where steep changes in hormone levels are linked to depressive symptoms such as during post-partum, perimenopausal, and pre-menstrual stages in women.

Asokan built her expertise in understanding how neural circuits influence perception and behaviors in Dr. Daniel Polley’s lab at Harvard University. During her graduate studies, Asokan focused on neural substrates that underlie changes in perception following noise-induced hearing loss. She localized this change to layer 5 cortico-collicular axons that innervate the amygdala and striatum, which explains the exacerbated sound-triggered anxiety and aversiveness in hearing loss patients. Additionally, through multi-regional extracellular recordings and optical measurements, Asokan discovered cooperative plasticity in inputs to amygdala as mice learn to reappraise neutral stimuli as possible threats. Asokan will now use her expertise in linking brain regions to changes in social behavior to investigate how sex hormones influence these processes during her postdoctoral research.

Divya Bezwada, Ph.D. Jane Coffin Childs-Merck Fellow

The Scripps Research Institute

Illuminating cryptic functional pockets in the human proteome with electrophilic stereoprobes

Allostery is a fundamental biochemical process in which one site on a protein influences the function of a different site on the same protein, even if they are far apart. Given this relationship, allosteric sites are versatile drug targets as they can activate, inhibit, or even provide a new function to the protein depending on the specific ligand. Yet, therapeutic cooption of allosteric sites remains limited, in part, due to the prevalence of invisible, cryptic allosteric sites that only appear upon ligand binding.

Dr. Divya Bezwada aims to transform our understanding of cryptic allosteric sites in Dr. Benjamin Cravatt’s lab at The Scripps Research Institute. There Dr. Bezwada will use a chemoproteomic approach to investigate the prevalence of cryptic allosteric sites across protein paralogs. Bezwada’s research will provide first principles regarding the evolution of cryptic allosteric sites and develop novel chemical tools with broad relevance for biological understanding and therapeutic applications.

Bezwada provided novel insight into cancer metabolism during her doctoral research in Dr. Ralph DeBerardinis’ lab at UT Southwestern Medical Center. There she found that clear cell renal cell carcinomas (ccRCC) have defects in the electron transport chain which suppresses oxidative phosphorylation. This result is consistent with decades of research into cancer metabolism. Unexpectedly, Bezwada found that ccRCC metastases upregulate oxidative phosphorylation and that this change is functionally important for metastasis. Bezwada’s discovery has crucial and paradigm-shifting implications for cancer patient treatment. Now, Bezwada will leverage chemical biology techniques to make her next important insights into human biology and disease during her postdoctoral research.

Julian Braxton, Ph.D. Jane Coffin Childs Fellow

California Institute of Technology

Defining the role of protein homeostasis in spermatogenesis

Traditionally, structural biology efforts have been limited to studying purified samples in isolation. While we have learned a great deal via these efforts, such approaches unfortunately strip away much of the biological context from the sample of interest.

Dr. Julian Braxton will overcome these limitations by using cryo-electron tomography (cryo-ET) to examine proteostasis, or the process by which cells maintain the proper balance, folding, and function of proteins, within sperm cells in Dr. Zhen Chen’s lab at the California Institute of Technology. Proteostasis plays important yet understudied roles in cellular development processes, as the proteome must be reprogrammed to enable new functions. Braxton will apply cellular cryo-ET to analyze such developmental processes in mammalian sperm, where highly specialized functional compartments are assembled. This research will provide foundational understanding into the posttranslational regulation of sperm maturation and expand the frontier of cryo-ET development and analysis.

Braxton’s expertise in proteostasis stems from his graduate studies in Dr. Daniel Southworth’s lab at the University of California, San Francisco. There, Braxton used the related structural technique cryo-EM to reveal the intricate details of how the autophagy-related adapter UBXD1 regulates the hexameric AAA+ chaperone p97. His findings revealed that UBXD1 separates two adjacent p97 protomers to open the p97 ring, allowing for a new mode of substrate entry and/or exit into the p97 central pore. In a related project, Braxton revealed a novel asymmetric state of the mitochondrial chaperone Hsp60 that enables client refolding. In his postdoctoral work, Braxton will expand his structural biology toolkit to include cryo-ET and use this technique to provide unprecedented insight into the role of nuclear proteasomes in spermatogenesis.

Yi Fu, Ph.D. Jane Coffin Childs - HHMI Fellow

University of Washington

Deciphering the dynamic regulation of mitochondrial genomes

Mitochondria are cellular organelles that house their own DNA. There are hundreds to thousands of copies of the mitochondrial genome (mtDNA) in each cell. Often, mtDNA copies are not the same; rather, a fraction of them carries mutations. Moreover, the composition of mtDNA varies drastically across cells and cell types. Mitochondrial diseases manifest when the pathogenic mutations reach a high percentage in a substantial fraction of cells. However, it is still unclear how mtDNA mutations expand and how cell-to-cell variation of mtDNA composition is formed.

Dr. Yi Fu will address these questions in Dr. Jay Shendure’s lab at the University of Washington. Dr. Fu will develop a method to accurately genotype mtDNA at single-cell resolution and employ this method to monitor mtDNA mutations during differentiation. Fu will also combine this approach with CRISPR perturbation to identify factors that impact the mitochondrial mutation burden in various cell types. These experiments will uncover cell type-specific regulation of mitochondrial genome maintenance. Furthermore, Fu’s research may provide insight into novel therapeutic approaches for mtDNA-associated diseases.

Fu’s expertise in mtDNA stems from her graduate studies in Dr. Agnel Sfeir’s lab at New York University and Memorial Sloan Kettering Cancer Center. There Fu discovered that double-strand breaks in mtDNA activate the integrated stress response, highlighting the cellular program to cope with defective mitochondrial genome. Fu also investigated mtDNA deletions and their impact on cellular metabolism. Now, Fu will leverage genomics and single-cell technologies to elucidate the dynamic regulation of mtDNA during her postdoctoral research.

Jarvis Dawson Hill, Ph.D. Jane Coffin Childs-Merck Fellow

Yale University

Novel Chemical Tools for Targeted Eradication of DNA Repair Proteins and Application to Chemosensitization

Glioblastoma is one of the deadliest forms of brain cancer. All glioblastomas contain fast-growing and aggressive tumor cells. The current standard of care, temozolomide (TMZ), extends patient’s lives by a median of 7 months; however, this chemotherapy only works for a subset of patients, and many of those patients rapidly acquire resistance to this treatment. Additional, more efficacious treatments are direly needed for glioblastoma patients.

Dr. Jarvis Hill’s postdoctoral research in Dr. Seth Herzon’s lab at Yale University aims to enable the next generation of glioblastoma therapies. The Herzon lab recently identified a novel small molecule, KL-50, that is effective against glioblastomas lacking the O6-methylguanine-DNA-methyltransferase (MGMT). However, this small molecule does not work on MGMT-positive glioblastomas. In this research, Dr. Hill will develop tumor-specific MGMT inhibitors that can be combined with KL-50 to treat patients with MGMT-positive glioblastoma.

Part of Dr. Hill’s interest in brain tumors grew out of his Ph.D. research in Dr. David Crich’s lab at the University of Georgia. As an organic chemist, Hill devised a novel synthesis for trisubstituted hydroxylamines. Recognizing that these are underrepresented functional groups in medicinal chemistry, Hill next evaluated the drug-like properties of molecules where he replaced hydrocarbons, ethers, or amines with a trisubstituted hydroxylamine. In contrast with long-standing expectations, Hill found that these substitutions were stable and generally well tolerated. Then, Hill used the trisubstituted hydroxylamine motif as a key structural unit to develop an epidermal growth factor receptor (EGFR) inhibitor with excellent brain penetration, which may be useful for treating brain metastases driven by aberrant EGFR. Now, Dr. Hill will turn his dual focus on synthetic medicinal chemistry and neuro-oncology towards finding glioblastoma therapeutics during his postdoctoral research.

Tom Hindmarsh Sten, Ph.D. Jane Coffin Childs - HHMI Fellow

Stanford University

Neural Circuit Mechanisms for Balancing Instinct with Experience

Neural circuits have been honed by evolution to enable animals to instinctively survive and reproduce in the world that surrounds them. Mammals, however, also have a distinct ability to weigh primal instinct against experience, allowing us to learn how to appropriately respond based on our unique knowledge of the dynamic world around us. However, how the mammalian brain balances the innate robustness of neural circuits with the flexibility afforded by learning remains unclear.

Dr. Tom Hindmarsh Sten aims to answer these questions as a JCC-HHMI Fellow in Dr. Liqun Luo’s lab at Stanford University. To investigate how instinctive behaviors can be modified by learning, Dr. Hindmarsh Sten will leverage natural variation in the ability of mice to suppress their innate fears and learn how to hunt live prey. He will delineate an anatomical blueprint of neural circuits that mediate evasion and predation, and pinpoint the plastic nodes impacted by learning. These studies will reveal how neural circuits, which have been refined by eons of evolution, are modulated to meet immediate and novel demands in the present.

As a Ph.D. candidate in Dr. Vanessa Ruta’s lab at Rockefeller University, Hindmarsh Sten investigated neural circuits mediating reproduction in fruit flies. He pioneered a novel virtual reality-based behavioral preparation which revealed that sexual arousal in male flies reconfigures how they see and respond to female flies. Additionally, Hindmarsh Sten examined how male flies coordinate aggression amongst rivals with courtship towards females in competitive environments where more than one male fly is vying for each female’s attention. This study revealed neural populations that allow males to rapidly switch between aggression and courtship. With this background, Hindmarsh Sten is primed to investigate how learning modulates innate instinct in mammals.

Caroline Holmes, Ph.D. Jane Coffin Childs Fellow

Harvard University

Learning structure in genotype to phenotype maps

Inferring the genetic basis of quantitative traits is foundational to understanding the biological mechanisms that underlie complex phenotypes such as behavior, homeostasis, and disease. Mapping genotype to phenotype has been transformational for understanding and treating diseases controlled by a single gene, or monogenic. However, understanding complex, highly polygenic phenotypes with currently available approaches can take decades of research from fields of researchers to make progress, if the problem is even solvable with current methodologies.

Dr. Caroline Holmes will transform the process of unraveling polygenic phenotypes in Dr. Michael Desai’s lab at Harvard University. Dr. Holmes will develop new computational approaches and use high-throughput experiments to learn the structure of interactions between genes involved in a particular phenotype. Holmes then will test her predictions of interactions with mutational perturbations. Ultimately, Holmes will develop methods to improve the generalizability of genotype to phenotype maps and test their accuracy on a distinct microbe that was not used to train the system. If successful, Holmes’ methods would rapidly catalyze the process of understanding and rationally perturbing polygenic phenotypes.

Holmes’ longstanding interest in both biology and physics dates back to her studies and research as an undergraduate student at Emory University. Her graduate studies emphasized the physics side as Holmes mainly used theoretical approaches in the labs of Dr. Bialek and Dr. Palmer at Princeton University. However, many of Holmes’ research applications were still biological in nature. For example, Holmes demonstrated that non-24 hour circadian periods can compensate for systematic error that arises as a result of seasonality. Holmes will now develop quantitative experimental systems during her postdoctoral research and combine this with her expertise in theoretical approaches to make inroads into complex polygenic phenotypes.

Amer Azim Hossain, Ph.D. Jane Coffin Childs Fellow

Memorial Sloan Kettering Cancer Center

Mechanisms and consequences of APOBEC3 targeting of extrachromosomal DNA

Extrachromosomal DNAs (ecDNAs) are circular DNA elements that amplify oncogenes and mediate chemotherapy resistance. Despite their importance in cancer, currently no therapies directly target these aberrant molecular structures.

Dr. Amer Hossain will investigate innate immune system recognition of ecDNAs to limit their oncogenic potential in Dr. John Maciejowski’s lab at Memorial Sloan Kettering Cancer Center. Dr. Hossain’s research will provide a fundamental understanding of the recognition and processing of ecDNAs by the immune system. Furthermore, his studies may provide insight into defects in this process that lead to cancer, and into therapeutic strategies to reinforce immune clearance of ecDNAs.

Hossain studied bacteria-phage conflicts as a graduate student in Dr. Luciano Marraffini’s lab at The Rockefeller University. Specifically, he developed a novel functional assay to screen for antiphage defense elements, and discovered a DNA glycosylase that inhibits phage replication. At first glance, this might seem like a distant subject from cancer biology. Yet, Hossain notes in many ways the immune-ecDNA conflict mirrors the host-pathogen conflict in that they both involve recognition and degradation of DNA substrates. Therefore, Hossain will apply his expertise to cancer biology during his postdoctoral research.

Yanyan Hu, Ph.D. Jane Coffin Childs - HHMI Fellow

Dana-Farber Cancer Institute & Harvard Medical School

Unveiling Novel Therapeutic Targets in Cancer Through Cell-Surface Proteomic Profiling

Dr. Yanyan Hu’s research focuses on discovering new biomarkers to help diagnose, monitor, and treat cancer. In particular, Dr. Hu hypothesizes that studying the tumor cell surface proteome will reveal an abundance of potential therapeutic and diagnostic targets against cancer.

In Dr. William Kaelin, Jr.’s lab at Dana-Farber Cancer Institute, Hu has devised a proximity labeling method that enables the direct quantification of proteins on the surface of cancer cells. Hu will now use this method to examine two types of cancer: clear cell renal cell carcinoma, and tumors with homologous recombination defects. In addition to revealing novel and fundamental information on cancer cell surface proteomes, Hu’s research has direct implications for future diagnostic and therapeutic approaches.

Hu’s Ph.D. research in Dr. Sheng Ding’s lab at Tsinghua University focused on totipotent stem cell biology. Totipotent stem cells are capable of producing every kind of differentiated cell in both embryonic and extraembryonic tissues. Previously, they had only been generated through IVF or SCNT using germline cells. Hu discovered a cocktail of three small molecules that converted mouse pluripotent stem cells into totipotent stem cells. Now Hu will apply her expertise of stem cell biology to explore similar mechanisms – such as cellular plasticity, self-renewal, and differentiation – to cancer biology during her postdoctoral research.

Shijia Liu, Ph.D. Jane Coffin Childs - HHMI Fellow

Harvard Medical School

Time to stop: neural mechanisms of action termination

Sometimes less is more. Our ability to stop an action is an important aspect of executive control, and the lack of this ability is linked to neuropsychiatric disorders like Obsessive-Compulsive Disorder and Attention-Deficit/Hyperactivity Disorder. Yet, it remains unclear how we make and execute stop decisions.

Dr. Shijia Liu will investigate the neural mechanisms and pathways underlying voluntary stop decisions in Dr. Bernardo Sabatini’s lab at Harvard Medical School. Dr. Liu will focus her studies on how mice voluntarily stop licking in response to the absence of water, as a specific instantiation of the broader question. Liu has designed a “licking-for-water” task that will enable her to dissect this process temporally and in different contexts. She will identify the modes of action and neural pathways that mediate stop decisions using optogenetics, large-scale neural recording, and real-time decoding approaches. Liu’s research will improve our understanding of voluntary stop decisions, related neuropsychiatric disorders, and computational mechanisms for context-dependent behavioral switching.

Liu’s expertise in neuroscience stems from her Ph.D. research in Dr. Sung Han’s lab at the Salk Institute for Biological Studies. Her graduate studies focused on the neural connection between perceived pain and breathing, and how opioid drugs impact this connection. Liu identified two subpopulations of lateral parabrachial nucleus (PBL) neurons that express the m-opioid receptor and project to pain and breathing centers. By manipulating activity at the cellular and molecular levels, Liu discovered how to decouple morphine administration and respiratory depression, which would prevent opioid overdose deaths. With this expertise in involuntary physiological-behavioral connections, Liu will now focus on voluntary decisions and their impact on behavior during her postdoctoral research.

Tianyang Mao, Ph.D. Jane Coffin Childs Fellow

Broad Institute

LIGHTing up tumor-associated tertiary lymphoid structures through cytokine pharmacokinetic engineering

Proper functioning of our immune systems depends on the precise timing of an orchestra of molecular events. One such important event is the release of cytokines, which are signaling molecules, into the extracellular space to mediate intercellular communication. For cytokines to exert appropriate immunomodulatory roles, their bioavailability must be strictly yet dynamically regulated in space and time. However, the mechanisms by which the immune system interprets the timing of cytokine release remain poorly understood.

Dr. Tianyang Mao will investigate the temporal encoding of cytokine signaling in anti-tumor immunity in Dr. Darrell Irvine’s lab at the Massachusetts Institute of Technology. Dr. Mao will use a novel controlled drug release technology which enables programmable control over the duration of cytokine exposure in vivo. This unique approach will allow Mao to make novel insights into how cytokine temporal dynamics shape cancer immunosurveillance. Better understanding of the immunological impact of cytokine release kinetics will guide the development of temporally reprogrammed cytokine therapeutics for cancer treatment.

Mao’s expertise in immunology emerged as a graduate student in Dr. Akiko Iwasaki’s lab at Yale University. There Mao developed an intramuscular prime–intranasal boost vaccine strategy for SARS-CoV-2 termed “prime and spike,” which leverages preexisting immunity generated by primary mRNA-LNP vaccines to elicit mucosal immunity within the respiratory tract using unadjuvanted intranasal spike boosters. In addition, he developed several antiviral strategies that trigger type I interferon-based immune protection against SARS-CoV-2, including a short stem-loop RNA agonist for the innate immune receptor RIG-I and an aminoglycoside antibiotic with unexpected antiviral properties. Collectively, these strategies hold great promise to not only prevent disease, but also viral transmission. Now, Mao will build on this experience, using novel bioengineering techniques in the Irvine Lab, to make new inroads into the importance of timing in immune responses to cytokines.

Marija Nadjsombati, Ph.D. Jane Coffin Childs Fellow

University of Utah

Ron Tyrosine Kinase deficiency uncovers a critical regulator of anti-tumor T Cell responses

Metastasis, which includes the dissemination of tumor cells from a primary site and subsequent colonization of faraway sites, is the primary cause of cancer deaths. This process requires a failure of our immune system to recognize and destroy metastasizing cancer cells. As such, targeting cancer during the metastasis step will help create therapies for patients with many different types of cancers (breast, prostate, colon, etc.).

Dr. Marija Nadjsombati will investigate the immune response during metastasis in Dr. Alana Welm’s lab at the University of Utah. Dr. Nadjsombati will use mouse models of breast cancer which faithfully recapitulate metastatic propensity. Nadjsombati will develop new cancer models and investigate their transcriptional regulatory networks to decipher the role of T cell regulation in metastasis. These studies will provide novel insights on both T cell regulation and on targeted therapies for cancer immunology.

Nadjsombati built her expertise in immunology as a graduate student in Dr. Jakob von Moltke’s lab at the University of Washington. There she studied a specialized type of epithelial cells, called tuft cells, which initiate immune responses in the small intestine. Nadjsombati discovered that succinate triggers the downstream signaling in tuft cells that initiates a type 2 immune response. Additionally, by comparing different mice strains, and performing genetic crosses, Nadjsombati showed that Pou2af2 isoform expression is a key regulatory mechanism that determines tuft cell frequency. With this strong immunological background, Nadjsombati is poised to make new breakthrough discoveries on the immune regulation of metastasis.

Victor Naturale, Ph.D. Jane Coffin Childs Fellow

NIH/NICHD

Linking Parts to Process: Probing the Cell-Biological Basis for Tissue Patterning in Developing Mesenchyme

Organismal development is an elegant progression from a single cell to billions or trillions of different cells that form our tissues and organs. While much is known about development at the molecular level, important questions remain about how subcellular molecular inputs integrate with “supracellular” physical behaviors of large cell collectives to shape our tissues. Little is known about how subcellular and supracellular dynamics relate among the mesenchymal cell types that give rise to all connective tissues including skin.

Dr. Victor Naturale will make inroads into these questions using a novel vertebrate skin cell platform developed in Dr. Amy Shyer’s and Dr. Alan Rodrigues’ lab at The Rockefeller University. Dr. Naturale expects that understanding how biological organization translates across length scales will provide novel insight into diverse areas including cancer microenvironments and mesenchymal birth defects that lack a single genetic cause.

Naturale developed his interest in developmental biology as a graduate student in Dr. Jessica Feldman’s lab at Stanford University. Working largely at the molecular to cellular scale, Naturale discovered that in C. elegans the polarity scaffold PAR-3 and the transmembrane protein HMR-1/E-cadherin collaboratively build polarity networks at epithelial cell-cell contacts. He demonstrated that HMR-1 also communicates cell polarity at the tissue level. Importantly, Naturale additionally identified a novel symmetry breaking cue arising at the supracellular scale due to emergent cell-cell contact patterns. This research, and the beautiful images within, were highlighted on the journal cover. In his postdoctoral research, Naturale will translate his experience identifying supracellular cues to a novel model system with relevance to cancer and developmental diseases.

Jung-Un Park, Ph.D. Jane Coffin Childs - HHMI Fellow

University of California, Berkeley

Redesigning RNA-guided DNA integration system using protein engineering

CRISPR-Cas systems have revolutionized genetic engineering and led to novel genetic medicines. As powerful as these systems are, they have some disadvantages such as their large size and a lack of orientation bias which limits their therapeutic usage. CRISPR-associated transposons (CASTs) are mobile genetic elements that use CRISPR-Cas systems for RNA-guided transposition. CASTs may represent the next generation of genome editors due to their enhanced features relative to CRISPR-Cas. Yet, CASTs still require further optimization to realize this potential.

Dr. Jung-Un Park will engineer novel forms of CASTs to optimize properties for genome editing in Dr. David Savage’s lab at the University of California, Berkeley. Using structural biology, biochemistry, and protein engineering approaches, Dr. Park will enhance the activity of individual CAST proteins, as well as tune the functional association between different CAST proteins. Ultimately, Park’s research will provide vast insight into genome editing and may result in the next generation of gene editing technologies.

Park’s interest in CAST biology stems from his graduate work in Dr. Elizabeth Kellogg’s lab at Cornell University. There, he solved structures for CAST that informed on both RNA-guided and RNA-independent transposition. Park will leverage his extensive knowledge of CAST structural details to optimize this system for genome editing during his postdoctoral work.

Noah Pettit, Ph.D. Jane Coffin Childs - HHMI Fellow

Harvard Medical School

Neural circuit computations underlying memory-guided navigation

In adaptive behavior, we take in information from the world around us and use that information to execute certain actions to interact with the surrounding environment. For example, successful navigation requires us to remember the spatial position of a goal and transform that information into actions that will move us towards that goal. Mechanistically, it is still unclear how neural circuits perform these computations.

Dr. Noah Pettit will approach this question using fruit fly interaction with wind direction in Dr. Rachel Wilson’s lab at Harvard Medical School. Dr. Pettit hypothesizes that specific cell types form a circuit that encodes wind direction, maintains it in memory, and transforms this information to influence body movement. Pettit will use multisensory virtual reality, two-photon imaging, and genetic silencing approaches to investigate this circuit at the cellular and molecular levels. These studies will provide a detailed description of how environmental perception is sensed, stored, and translated into action, thereby providing a general framework for understanding these computations in different systems and organisms.

Pettit generated expertise in the underlying neurobiology of spatial learning in Dr. Christopher Harvey’s lab at Harvard Medical School. During his graduate studies, he examined the role of Fos, a transcription factor implicated in memory and spatial learning. Pettit discovered that Fos-induced neurons are more likely to be place cells – cells that are activated when an animal experiences a certain place in its environment. Additionally, Pettit found that the place code degrades when mice voluntarily disengage from a spatial task, suggesting that the internal state exerts a strong influence on place cell activity. With this experience, Pettit will now transition to fruit flies and understanding how these animals transform and respond to external cues.

Daniel Richard, Ph.D. Jane Coffin Childs Fellow

Stanford University

Decoding Aging Neurogenic Niches: Unraveling Somatic Mutations, Clonal Dynamics, and Functional Decline

Aging is associated with decreased cognitive ability and enhanced risk of developing neurodegenerative diseases such as Parkinson’s and Alzheimer’s. The declining function of neural stem cells (NSCs) is partially responsible for these trends in the aging brain. While much is known about the genetics of late-stage neurodegenerative diseases, relatively little is known about changes that lead to the decline in NSC function.

Dr. Daniel Richard will investigate the accumulation of somatic mutations in NSCs in Dr. Anne Brunet’s lab at Stanford University. He will examine how these mutations change NSC gene expression and neuron production. Additionally, Dr. Richard will explore strategies to genetically manipulate somatic mutations to potentially enhance NSC function. Richard’s studies will provide much-needed insight into fundamental NSC biology during aging and may reveal novel therapeutic strategies for neurodegenerative diseases and cognitive decline.

Richard’s interest in the link between genetic changes and aging emerged from his graduate studies in Dr. Terence Capellini’s lab at Harvard University. There, Richard focused on the genetic regulation of knee development. By comparing functional regulatory regions in human and mouse fetal limbs, Richard discovered mutations associated with an increased risk for osteoarthritis later in life. Now, Richard will shift his focus to aging-related biological changes in NSCs and neurodegenerative diseases during his postdoctoral research.

Emily Jane Rundlet, Ph.D. Jane Coffin Childs Fellow

The University of Texas at Austin

Structure-based vaccine design targeting mpox antigen A27

The international outbreak of mpox (monkeypox) in 2022 incited global health concerns and underscored the need for an innovative vaccine. However, little is known about potential vaccine targets within the causative orthopoxvirus, mpox virus.

Dr. Emily Rundlet will explore the structure and function of potential mpox vaccine targets in Dr. Jason McLellan’s lab at the University of Texas at Austin. Dr. Rundlet will structurally characterize antigen complexes using cryo-EM and X-ray crystallography, which will enable her to probe their function in the viral lifecycle and design vaccine candidates. In sum, Dr. Rundlet’s work is expected to provide valuable insights into mpox biology and pave the way for future mpox vaccines.

Dr. Rundlet developed her expertise in structural biology in Dr. Scott Blanchard’s lab at Weill Cornell Medicine. During her graduate studies, Dr. Rundlet used cryo-EM and single-molecule FRET assays to make important discoveries about protein translation. With these methods, Dr. Rundlet elucidated how the ribosome initiates movement of tRNAs during protein synthesis and demonstrated that mRNA decoding by ribosomes is kinetically and structurally different in humans and bacteria. Now Dr. Rundlet is using her expertise to uncover the structural secrets of orthopoxviruses to guide vaccine design and prevent future outbreaks.

Trey Scott, Ph.D. Jane Coffin Childs Fellow

Harvard University

Secretory cell innovation in a symbiotic interaction

Social interactions between distinct species are important at ecological scales yet are mediated at the molecular level by the transfer of biomolecules such as small chemicals and proteins between organisms. Symbiosis is an example of a relationship among species where both species benefit from a social behavior or interaction.

Dr. Trey Scott will examine the symbiotic relationship between butterfly larvae in the Lycaenidae family and ants in Dr. Naomi Pierce’s lab at Harvard University. Lycaenid caterpillars secrete nutritious and psychoactive substances that are ingested by ants. Ants, in return, protect their renewable food source, the caterpillar, during its vulnerable developmental stage. Dr. Scott will determine the molecular, cellular, and evolutionary bases for this example of symbiosis. Scott’s research will provide novel insight into social interactions, broadly speaking, including their evolution.

Scott examined social interactions as a graduate student in Dr. Joan Strassmann’s and Dr. David Queller’s labs at Washington University. Although the above example of symbiosis between ants and Lycaenid butterflies is relatively straightforward, most examples of social interactions contain context-dependent elements of both cooperation and conflict. Using Dictyostelium discoideum amoebae and Paraburkholderia bacteria as a model for social interactions, Scott discovered that the bacteria may benefit or be harmed by the amoebae depending on current environmental conditions – in this case, rainfall. Scott proposed that this flexibility helps the amoebae host survive in harsh soils with variable prey. Furthermore, Scott showed how long-term social interactions influence evolutionary adaptation. With this extensive background in social interactions, Scott is poised to make breakthroughs investigating the evolution of symbiosis between butterflies and ants during his postdoctoral research.

Bing Shui, Ph.D. Jane Coffin Childs Fellow

Massachusetts Institute of Technology

Understanding tissue damage in the pre-neoplasia to neoplasia transition of colorectal cancer

Tissue regeneration, in a normal developmental context, and cancer are both forms of cellular proliferation. However, tissue regeneration is regulated and responsive to the surrounding environment, whereas cancer sheds these restraints. Understanding the commonalities and the differences between tissue regeneration and cancer may provide insight into novel avenues for cancer therapeutics.

Dr. Bing Shui will investigate the role of tissue damage in facilitating the early pre-neoplastic to neoplastic transition in colorectal cancer in Dr. Tyler Jacks’ lab at the Massachusetts Institute of Technology. Dr. Shui will examine how tissue damage cooperates with oncogenic mutations to initiate cancer. He will also compare damaged mutant and wildtype cells to identify vulnerabilities that can be leveraged to selectively destroy precancerous cells. Ultimately, a better understanding of the role of tissue damage in this early precancerous transition may reveal novel prophylactic cancer treatments.

Shui’s interest in the relationship between tissue regeneration and cancer burgeoned in Dr. Kevin Haigis’ lab at Harvard University. During his Ph.D. studies, he examined the role of microRNAs (miRNAs) in colon regeneration and colon cancer. First, Shui demonstrated that miRNAs are required for tissue regeneration and miRNA suppression exacerbated colon damage due to failed regeneration. Next, he examined the role of miRNAs in colon cancer and discovered a novel form of posttranslational regulation mediated by oncogenic K-Ras that governs global miRNA function. Now Shui will use his expertise in tissue damage and regeneration to identify vulnerabilities in colorectal cancer during his postdoctoral research.

Donte (Alex) Stevens, Ph.D. Jane Coffin Childs Fellow

The Scripps Research Institute

Towards a novel tauopathy therapeutic: harnessing biomolecular condensates for targeted protein degradation.

Tauopathies are diseases such as Alzheimer’s that are characterized by the aggregation of tau protein. Unfortunately, no disease-modifying therapies currently exist for tauopathies, and the impact of these diseases will increase as the global population trends towards an aging demographic.

Dr. Alex Stevens will investigate a novel mode for treating tauopathies in Dr. Keren Lasker’s lab at the Scripps Research Institute. Autophagy-based degradation methods are making progress, yet a hallmark of tauopathies is that these solid tau aggregates resist degradation. To circumvent this issue, Dr. Stevens will engineer biomolecular condensates to clear tau aggregates. Stevens’ research will set the foundation for next generation tauopathy therapies and provide a general framework using biomolecular condensates to modulate pathological events.

Stevens investigated how viruses hijack cellular transport mechanisms during his Ph.D. research in Dr. Samara Reck-Peterson’s lab at the University of California, San Diego. By exploring the conflicts between viruses and the host intracellular transport machinery, Stevens discovered a previously unknown transport mechanism that potentiates the innate immune response. His research provides insight into how cells mount a defense against infecting viruses and highlights the important role of cellular transport in this process. Now, Stevens will attempt to rationally hijack autophagy to enable degradation of aggregated tau.

Jonathan Tullis, Ph.D. Jane Coffin Childs Fellow

Oregon Health and Science University

Mechanisms of Type I PARP1 Inhibitors in Regulating Cell Fate Decisions in Cancer

Poly ADP-ribose polymerase 1 (PARP1) is a protein involved in the DNA damage response and an important drug target against many cancers. There are a number of PARP1 inhibitors, but current drugs targeting PARP1 can have limited therapeutic potential due to cancer cells frequently acquiring resistance to these drugs.

Dr. Jonathan Tullis aims to understand the mechanistic details of a class of PARP1 inhibitors in Dr. Michael Cohen’s lab at Oregon Health and Science University. PARP1 inhibitors are thought to function by inhibiting the enzymatic activity of this protein. However, “type I” inhibitors exhibit an additional feature – they lock PARP1 onto sites of DNA damage. Dr. Tullis will use mechanistic studies to tease apart the relative importance of these two features – enzymatic inhibition vs locking PARP1 onto DNA – for therapeutic efficacy. These detailed studies promise to reveal novel information about PARP1 biology and may pave the path for more effective PARP1 drugs in the future.

Tullis’ passion for mechanistic studies dissecting protein function stem from his graduate research in Dr. Ulli Bayer’s lab at the University of Colorado. His Ph.D. focused on a protein kinase, CaMKII, that is crucial for long-term potentiation, a fundamental process in learning and memory. It was thought that CaMKII’s kinase activity was required for long-term potentiation. Using careful biochemical and chemical biological approaches, Tullis convincingly demonstrated that it is actually a structural role of CaMKII that is required for inducing long-term potentiation and its enzymatic activity was only required to enable that role. Next, Tullis will leverage his expertise in mechanistic studies to tease apart the important functions of PARP1 inhibitors during his postdoctoral research so that more efficacious targets against cancer cells can be developed.

Ivan Zheludev, Ph.D. Jane Coffin Childs Fellow

Gladstone Institute

The molecular biology of Obelisk RNAs

The first century of molecular biology discoveries was enabled by the study of Nature’s original molecular biologists: viruses. Viruses and their simpler cousins, sub-viral RNAs are extremely well adapted to manipulate their host cell. By studying how these agents alter their host, scientists have been able to both understand the mechanisms of diseases as well as derive tools to fight them. Yet there is still much we don’t know about viruses, but even less-so about sub-viral RNAs. Obelisk RNAs are a recently discovered class of widespread sub-viral RNAs with small, structured genomes that seem to bear no resemblance to any known biological entity. The study of Obelisk biology then might reveal molecular mechanisms that have yet to be seen.

Dr. Ivan Zheludev will characterize a novel class of sub-viral RNAs, termed Obelisk RNAs, in Dr. Melanie Ott’s lab at the Gladstone Institute of Virology using a model Obelisk-host system based on a human oral bacterium. Using this system, Zheludev will probe how Obelisk RNA replicates and spreads between cells, the function of the Obelisk-encoded protein Oblin-1, and how Obelisk RNA impacts the host bacterium within complex microbial communities such as the human oral microbiome. Zheludev’s studies will provide foundational knowledge for understanding Obelisk RNAs and provide a general framework for investigating sub-viral RNAs.

Zheludev’s interest in sub-viral RNAs stems from his Ph.D. research in Dr. Andrew Fire’s lab at Stanford University. There, Zheludev created a bioinformatic discovery tool and used it to discover a new class of sub-viral RNAs that he named “Obelisk” RNAs. He demonstrated that Obelisk RNAs are widespread, with examples found on every continent, and that they are diverse, having identified roughly 30,000 distinct Obelisks. Further, they are also found in the microbiomes of between five to fifty percent of assayed human donors. Now in his postdoctoral research, Zheludev will investigate Obelisk molecular biology and their host interactions.

Zhuoning Zou, Ph.D. Jane Coffin Childs - HHMI Fellow

The University of Chicago

Spatially resolved de novo single-cell translatomics to dissect translational control in cancer

Translation is a key step in gene regulation that dynamically responds to cell stress, signaling, and metabolic alterations. While there are techniques that allow for investigating transcription with single-cell resolution, similar tools for examining translation are lacking.

Dr. Zhuoning Zou will develop a method for analyzing translation in single cells from complex samples in Dr. Chuan He’s lab at the University of Chicago. Dr. Zou’s method will use in situ reverse transcription to develop a spatially resolved single-cell translatome profiling method. This method will enable measuring differences in translation between distinct types of cells in a heterogeneous mixture. For example, Zou will apply her method to patient biopsies and surgical colon cancer samples. In such samples this method will distinguish translation between different individual cancer cells as well other types of cells in the tumor microenvironment. This research will uncover the translation landscape in real human tissues, provide novel insights into translation regulation in the tumor microenvironment, and may reveal potential biomarkers for cancer prognosis and targets for future therapies.

Zou developed sensitive methods for monitoring translation and applied them to rare and heterogenous samples in Dr. Wei Xie’s lab at Tsinghua University. During her graduate studies she helped pilot a method that investigates translation of a single mouse oocyte. Zou then applied that method to human oocytes and early embryos to reveal novel and dynamic translational regulation in early embryogenesis. Now Zou will apply her expertise to examine translational regulation in cancer cells and other cells in the surrounding tumor microenvironment during her postdoctoral research.

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