Kumayl Alloo | Research-Scholar, Columbia University Credit: Emma Asher, 2025
For decades, Parkinson’s disease (PD) research has centered primarily around the disease’s hallmark motor symptoms, including tremors, rigidity, and bradykinesia. However, nonmotor symptoms of the disease—such as anxiety, depression, and cognitive impairments—have remained largely unexplored. Though less visible, these symptoms profoundly affect quality of life, often preceding motor dysfunction and providing critical clues about PD progression.
Kumayl Alloo, a research scholar at the Benson and Huntley Labs at Columbia University and the Icahn School of Medicine at Mount Sinai, is helping address this critical gap in knowledge, delving into the complex interplay between genetic and environmental risk factors in shaping PD’s broader, nonmotor impact on the brain.
“For years, our lab has focused on how the LRRK2-G2019S mutation, a key genetic risk factor for PD, interacts with chronic stress, a prominent environmental risk factor, to drive nonmotor symptoms of the disease,” Alloo explained. “Our earlier studies revealed behavioral and neurological changes in mouse models exposed to both factors, but we lacked clarity on which brain regions or synapses were responsible. Put simply, we knew what was happening, but we didn’t know where.” This mystery formed the foundation of Alloo’s PD research, aimed at pinpointing the specific neural mechanisms driving these observed differences.
In their latest study (Guevara, Alloo, et al., 2025), Alloo and his lab uncovered critical insights into how these risk factors interact in sex-specific ways. Their research demonstrated that the LRRK2 mutation and chronic stress together altered synaptic activity in regions like the medial prefrontal cortex (mPFC), nucleus accumbens (NAc), and basolateral amygdala (BLA)—areas crucial for emotional regulation and cognition. These changes were linked to heightened anxiety-like behaviors in male models, while females showed variable resilience or susceptibility depending on the nature of the stressors.
The findings from this research offer a clearer picture of how risk factors converge to alter brain circuits before motor symptoms emerge, opening doors to earlier intervention strategies and informing future experiments crucial for PD detection, classification, and treatment. “After all, now that we know where the issue is, future therapeutic research would know where to target,” Alloo notes.
A Parkinson’s Foundation Fellow, Saltzman Scholar, Pucker Fellow, and FlexMed Scholar, Alloo’s contributions exemplify the importance of fostering early-career researchers to tackle pressing challenges in neurodegeneration. His contributions are helping to redefine our understanding of PD.
“My long-term goal is to be a physician-scientist—at the intersection of research and treatment,” he says. “This unique overlap between medicine and research allows me to address the clinical needs of patients in the hospital while conducting research tailored to those needs in the lab. The integration of bench-to-bedside approaches—where care and cure inform each other—promises novel cures and therapies built on two different approaches toward disease.”
As Kumayl and his lab continue to advance our understanding of PD, their work exemplifies the power of integrating academic science research with clinical aspirations to address one of the most challenging neurodegenerative disorders of our time.
Join us to celebrate the winners of the BSDB postdoc poster prize from the Biologists @ 100 conference. The webinar will be chaired by Abigail Tucker (King’s College London).
Wednesday 4 June – 15:00 BST
Giulia Paci (University College London) ‘3D cell topology regulates signalling range to promote precise patterning of wing sensory organs’
Shifaan Thowfeequ (University of Oxford) ‘Visualising calcium dynamics in the developing embryo : from fertilisation to the first heartbeat’
At the speakers’ discretion, the webinar will be recorded to view on demand. To see the other webinars scheduled in our series, and to catch up on previous talks, please visit: thenode.biologists.com/devpres
The winners of the Young Embryologist Network (YEN) 2025 Image Competition have been announced at the conference today held at the Francis Crick Institute.
Please check out the top 10 images that have received the most votes from attendees of the YEN 2025 Conference.
We thank those who sent us their images and attendees of YEN 2025 for helping us select these images. If you would like to learn more about YEN visit www.youngembryologists.org
YEN Image Competition winner:
Théo Morel (PARCC Paris, Inserm-UMR970, France) A 3D view beyond the skin What if we could directly visualize the arterial and nervous systems behind the skin of a mouse embryo? To make this possible we used a iDISCO clearing protocol on a 15 dpc mouse embryo, followed by whole mount co-staining with ASMA (light blue, marking arteries) and TH (purple, marking the sympathetic nervous system). The embryos were imaged using light-sheet microscopy and reconstructed in 3D using Imaris software.
Runner-up:
Lisa Leinhos (University of Oxford, UK) Cosmic life Drifting in the womb like an astronaut in space, the embryo floats peacefully, a moment of cosmic calm in the universe of early life. This image portrays a dissected mouse embryo at E14.5, captured through a Nikon camera on a binocular microscope system. The focus of this experiment is to investigate gene expression at different stages of embryonic development using bulk RNA sequencing. What makes this image particularly compelling is the contrast between its scientific significance and emotional depth. Although the embryo is no longer alive, the image portrays a moment of serene stillness, almost as if it were still within the womb. It captures the profound beauty of life’s early stages while highlighting the mysteries that science seeks to understand. At the same time, there is an inherent sadness, as this specimen, like many others, has been sacrificed in the name of advancing our knowledge of developmental processes. This delicate balance of scientific discovery and respect for life makes the image not only visually striking but also emotionally resonant.
Runner-up:
Andrea Krstevski (Institute of Child Health, UCL, UK) Minnie’s Bow Neural crest cells play a crucial role in neural tube development as they are a population of multipotent cells that emerge from the dorsal neural tube. These cells migrate to various regions of the embryo and differentiate into a diverse array of tissues, including neurons, glial cells, and components of the peripheral nervous system. Their proper development and migration are essential for the correct patterning and function of the nervous system. Any disruption in neural crest cell development can lead to a variety of congenital disorders and malformations. The image shown is a E8.5 mouse embryo displaying actin in black and migrating neural crest cells using marker Pax3 in red. The Zeiss LSM 880 upright confocal multiphoton microscope was used to capture the image.
Swanee Douglas and Dr Tom Pettini (Department of Genetics, University of Cambridge, UK) Segment-polarity stripes Drosophila embryo with immunostaining of cell membranes (grey) and 5-plex HCR in situ hybridization to visualize segmentation genes (blue = engrailed mRNA, green = paired + snail mRNA, magenta = odd-skipped mRNA, yellow = wingless mRNA, red = sloppy-paired 1 mRNA) with minimal crosstalk, Microscope: 40X Z-stack on Stellaris 5 confocal microscope (sum projection here), Processing: Python and Fiji
David Grainger (Institute of Developmental and Regenerative Medicine, University of Oxford, UK) SMILE This image showcases a vibratome section of an E9.5 mouse embryo, where KDR immunostaining (magenta) delineates endothelial progenitors and TUBB3 (green) marks developing neurons. Captured using a Zeiss LSM980 confocal microscope, a maximum intensity projection and horizontal mirroring were applied to optimize signal and symmetry.
Francesca Montesi (The Francis Crick Institute, UK) A blossom of stem cells Human embryonic stem cells differentiating on a 1000 µm-diameter hydrogel micropattern. Cells differentiate and form hollow cysts at the periphery, while they remain pluripotent at the core of the colony (CDX2, gold; BRA, blue; SOX2, red). Imaged on a spinning disk confocal microscope and processed with Imaris.
Jinlong Qiu (Hull York Medical School) Blossoming Embryo A fluorescence microscopy representation of a bovine blastocyst, stained with Hoechst 33342, Alexa Fluor 488 conjugated with NANOG and Alexa Fluor 568 conjugated with GATA6. The image was captured using a Zeiss LSM710 confocal microscope and later artistically modified. Tree-like branches were digitally illustrated using Adobe Illustrator, and further contrast adjustments and artistic enhancements, including the ‘Glow Edges’ effect, were applied in PowerPoint. This fusion of science and art transforms the cellular organization of early embryonic development into a vibrant visualization of growth and differentiation, resembling a flourishing tree of life.
Achira Karunaratna (Institute of Child Health, UCL, UK) Crest Nebula Cranial neural crest explant visualized via immunofluorescence after staining for marker proteins. The image was captured on the Nikon eclipse Ti2 series epifluorescence microscope housed at UCL GOS ICH at 20x followed by gaussian stack focusing of a Z series. Explanting is a widely used ex-vivo approach to study neural crest development in animal models. The neural crest, regarded as the ” fourth germ layer”, gives rise to multiple important cell types within vertebrate bodies, including the craniofacial cartilage, peripheral nerves, and pigment cells among others. This explant experiment is part of a wider attempt to understand the mechanisms of neural crest migration that contributes to neural tube defects in mammalian embryos by understanding cytoplasmic protein methylation in migrating g neural crest cells. Visualised in yellow are neural crest cells (stained for neural crest marker sox10 ) emerging out of the mouse cranial neural folds. Tinges of green at the outer edges represent phalloidin staining marking F-actin localization in cells. The faint red hue marks another membrane-bound protein SETD2, a methyltransferase, within the explant and in migrating cells. The circular looping where neural crest cells emerge is reminiscent of areas of clouds of gas and dust that form when stars are born in nebulae in the pitch-dark corners of our universe. Hence, aptly named a crest nebula, a factory for neural crest cell production.
Malgorzata Borkowska (MRC Laboratory of Medical Sciences, Imperial College London, UK) Metaphase Monroe Metaphase spread of 2i/LIF grown mouse embryonic stem cells image obtained with Leica SP5 confocal and processed in Fiji for chromosome counting.
All the world’s a metabolic dance, early career scientists are leading the way!
Emerging perspectives in metabolism
Dr. Holly Thorpe
This week we’ll meet Dr. Holly Thorpe, newly minted PhD from the Chow lab at the University of Utah, who is now continuing her research there as a postdoctoral fellow. Holly’s path into rare disease research began as an undergraduate when she studied multiple sclerosis through computational genetics. A paper from the Chow lab showing how a simple sugar rescued a rare metabolic disorder in flies sparked her fascination towards studying metabolism and rare diseases. Now a freshly minted PhD continuing as a postdoc, Holly models rare disorders like Phosphatidylinositol glycan biosynthesis class A congenital disorder in Drosophila, using the power of fly genetics to uncover disease mechanisms and therapeutic targets. The Chow lab specializes in precision medicine for rare diseases, using advanced genetic tools – demonstrating how basic science is actively curing diseases and impacting human health. Driven by curiosity and compassion, Holly’s research shows how foundational discoveries can become lifelines for patients with no other options. Check out more work from the Chow lab here!
What was your first introduction to the field of metabolism – what’s your first memory? Could you share your journey into studying metabolism using Drosophila and what inspired you to specialize in the field of rare diseases?
For my undergraduate research, I worked in a lab that used computational genetics to study Multiple Sclerosis. I knew from this experience that I wanted to work in a human disease genetics lab for graduate school, but I wanted to have a mix of dry and wet lab in my research. When I found the Chow lab, they had recently published a paper showing that supplementation of N-acetyl glucosamine rescued a Drosophila model of another rare glycosylation disorder. The idea that something as simple as adding a specific sugar to the diet could have an effect was so exciting to me. I knew I wanted to study rare metabolic disorders.
Walk us through the process of studying rare diseases and creating personalized therapies.
Many of the patients reach out to Dr. Chow for help. The rare disease world is interesting because oftentimes the parents of these patients have found each other and started their own communities and foundations. We have had multiple different foundations reach out to Dr. Chow about the running screens for their gene of interest. To screen for phenotypes, we typically start with an RNAi model and knock down the gene ubiquitously and in multiple different tissues in the fly such as the eye, neurons, and muscle cells. Then we look for any phenotypes that might arise. We have successfully used the Drosophila Genetic Reference Panel (DGRP), a group of wild-derived, inbred, fully sequenced flies, to look at the effects of natural genetic variation on the phenotypes. From that we are able to run statistical analyses, such as a genome wide association study (GWAS) to identify potential candidate modifiers.
Tell us how Drosophila serves as an extremely advantageous model for conducting studies on rare genetic disorders.
I think Drosophila are such a good model organism. Roughly 70% of human disease genes have a human orthologue, so we are able to study a lot of different disorders. Most of the disorders we focus on have neuronal phenotypes, and we are able to take advantage of the ability to mimic these phenotypes such as neuromuscular issues and seizures.
Tell us about Phosphatidylinositol glycan biosynthesis class A congenital disorder of glycosylation (PIGA-CDG). How did you work towards characterizing and establishing Drosophila model of PIGA-CDG and how do you think it will be a help in understanding of the pathogenesis of this understudied rare disorder?
PIGA-CDG is an ultra-rare neurodevelopmental disorder. It is caused by loss of function mutations in the gene PIGA which encodes a necessary protein in the glycosylphosphatidylinositol (GPI) anchor synthesis pathway. Patients typically present with seizures, hypotonia, and neurodevelopmental delay. In developing a PIGA model, we found that ubiquitous loss of PIGA in Drosophila was lethal, so we decided to look at more cell-type specific loss. Because of the neurological phenotypes seen in patients, a previous graduate student in the lab performed neuronal- and glial–specific knockdown of PIGA and identified a climbing and seizure defect, respectively. We also had a heterozygous knockout model created to see if ~50% loss of PIGA would give any phenotypes since homozygous knockout flies are lethal. We again found a seizure phenotype. Using these models, and other cell specific models, we can start to tease apart which tissues PIGA is important in and we can run modifier and drug screens to identify other interacting pathways and novel therapeutic targets.
In one of your works, you used pedigree analysis to identify potential protective modifier genes, including a null variant in CNTN2 – walk us through the process and tell us how you genetically validated CNTN2 as a target which could rescue most of the PIGA-associated phenotypes. What were your key findings and what are the future metabolic mechanisms remaining to be uncovered in this regard?
In our study, we used pedigree analysis in a family with variable expression of PIGA-CDG to identify potential protective genetic modifiers. Whole-genome sequencing revealed a null variant in CNTN2 that was present in asymptomatic carriers but absent in the probands. To test the interaction between PIGA and CNTN2, we used tissue specific Drosophila models where knockdown of the CNTN2 ortholog rescued key PIGA-related phenotypes like eye size, seizures, and motor defects. This showed that CNTN2 is a genetic modifier of PIGA, but the mechanism of interaction is still unclear. CNTN2 is a GPI-anchored protein, so it is possible the interaction could be broadly found across many GPI-anchored proteins. The interaction could also be CNTN2 specific and more related to its specific function in the nervous system.
Tell us about your work on evolutionary rates of glycosylation genes. What factors contribute to evolutionary rate differences among glycosylation genes – what are the consequences? How will identifying genetic modifiers of CDG enable our understanding of broad clinical spectrum seen in the patients? What tools have you used for these studies and what future studies should be done to expand these studies to develop targets for CDGs and other rare metabolic diseases?
We used evolutionary rate covariation (ERC) analysis to identify potential genetic modifiers of glycosylation genes. ERC is a computational method that identifies functionally related genes by measuring how similarly their evolutionary rates have changed across species over time. The more similar the evolutionary pattern, the more likely there is a genetic interaction. We discovered that glycosylation genes, particularly those involved in GPI anchor synthesis and N-linked glycosylation, exhibit high ERC values, indicating shared evolutionary pressures and functional interdependence. By identifying genes with high ERC to known glycosylation genes, we pinpointed potential modifiers that may contribute to the clinical variability observed in CDG patients. To validate these findings, we employed Drosophila models, confirming that several candidate genes modulate CDG phenotypes. Glycosylation affects many different genes and biological pathways. Modifier genes can help us to narrow down which pathways may be more important for CDG pathophysiology. Similar pipelines could be applied to other rare metabolic disorders in order to identify modifier genes and potential therapeutic targets.
Tell us about the unique experimental approaches you have taken throughout your work – what tools are you using, how difficult some of these experiments are – did you have to deal with midnight timepoints or require an army of undergrads/ long hours, had to use some un-conventional/creative tools to overcome experimental challenges?
Luckily using Drosophila there are a lot of readily developed tools. Most of the genetic constructs we needed had already been developed, and the different assays we ran are pretty common in the Drosophila world. While there were definitely quite a few weekends and long days, I managed to design my experiments so there were no midnight timepoints.
What are your upcoming plans? What metabolic pathways or signals do you aim to investigate further?
I just defended my PhD, so I will continue to work in the Chow lab as postdoc focusing on a more therapeutic targeted look at a new CDG. I’ll still be using natural genetic variation as an exploratory method, but with the hope of contextualizing and identifying therapeutic targets.
Your work intersects metabolism and genetic variation. How do these fields overlap and how do you integrate these disciplines in your research, and what unique insights have emerged from this approach?
Genetic variation plays a significant role in shaping metabolic function, as variants in metabolic genes can impact numerous interconnected pathways. In my research, I investigate how these genetic differences influence disease risk and severity, particularly by identifying modifiers that alter metabolic outcomes. This approach highlights the importance of studying disease within the context of diverse genetic backgrounds to better understand variability in clinical presentation and therapeutic response.
What role does curiosity play in your life, both within and outside of science? How important it is for you to answer basic science questions on metabolic signaling and how do you see its impact on animal health/relevance on human health?
I was definitely one of those kids that always asked a million questions, so I think my curiosity has really driven my work as a scientist. I think metabolism has such a huge impact on human health. Understanding these basic mechanisms is crucial, as they have direct relevance to human conditions like the rare diseases I study, and more common diseases such as diabetes, obesity, and cancer. Both in and out of the lab, curiosity keeps me asking meaningful questions and pushing for insights that can lead to real-world impact.
What changes have you seen in the scientific community in regard to studying these unique aspects of metabolic signaling in flies? Are we moving toward a more nuanced understanding, or do you see potential pitfalls?
Drosophila offers powerful tools to dissect conserved metabolic pathways in vivo, allowing for high-throughput and genetically precise studies. However, a potential pitfall is oversimplifying or overgeneralizing findings without considering species-specific differences—while flies are incredibly informative, translating insights to human biology still requires careful validation.
Tell us about how you see the future of metabolism evolve with the new upcoming tools – what techniques have you used and which tools are you most excited about?
I think ERC is an incredibly powerful and versatile tool—it can be applied to virtually any gene of interest to uncover new functional relationships and reveal previously unknown aspects of its biology.
Were there any pivotal moments that shaped your career path? What’s an unexpected place you’ve found inspiration for your work?
I’ve always had a passion for science, but I realized I wanted to pursue a PhD in genetics after a conversation with one of my undergraduate professors about her career path. She invited me to join her research lab—an opportunity I hadn’t previously considered—which ultimately opened the door to an entirely new trajectory for me. Rare disease remains an understudied area with immense potential for discovery. In particular, many metabolic rare disorders present rich opportunities for investigation through both computational and experimental approaches.
Tell us about what experiences/results/training motivated you to push forward in grad school?
I have been so lucky in joining the lab that I did. We are all great friends who help encourage each other to keep going. I definitely would not have made it through without the people in my lab.
How do you maintain a balance between your rigorous research activities and personal life? Are there hobbies or practices you find particularly rejuvenating?
The work-life balance is one of my favorite parts of doing grad school in Utah. I work right by the mountains, so all year long, I’m able to go hiking, rock climbing, and paddle boarding. And we frequently take weekend trips to one of the many national parks in the state. It’s always refreshing to get out in nature after a long day, and in Utah it’s so accessible.
If you hadn’t embarked on a career in biological research, what other profession might you have pursued, and why?
If I hadn’t studied science, I would have loved to open up a bakery. The method of baking is so therapeutic to me. I have always loved tinkering with recipes to try and find the best one.
Last week we learnt about the impact of environmental toxins on animal development and their resilient coping mechanisms from “genotypic” to “phenotypic” perspective. Check out the article –From shifting Skies to Toxic Tides (Lautaro Gandara)
A deep-dive into the many cool (and free) resources available to zebrafish researchers!
Disclaimer:This is not a comprehensive list but a list of useful websites that are free (or have free versions that are useful)
Featured Resources
“The Mothership” – ZFIN (https://zfin.org/): Contains vital resources such as The Zebrafish Book, Thisse’s expression data & curated publications.
Homepage of ZFIN (Hosted by the University of Oregon and Alliance of Genome Resources, as part of the Global Core Biodata Resource)
“The Central Hub of Model Organism Databases” – Alliance of Genome Resources (https://www.alliancegenome.org/): The future of MODs.
Homepage of Alliance of Genome Resources (Hosted by NIH, NHGRI & NHLBI)
“Disease Modeling on Steroids” – MARRVEL (https://marrvel.org/ ): Super powerful resource including links to OMIM & ClinVar.
Homepage of MARRVEL (Hosted by Baylor College of Medicine Department of Pediatrics and the Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital)
“Ol’ Reliable Genome Browsing” – Ensembl (https://www.ensembl.org/Danio_rerio/Info/Index): Contains current & past genome assemblies in a easy(-ish) format. BLAST/BLAT is a powerful tool for queries.
Homepage of Ensembl (Hosted by EMBL-EBI)
“Simplified Genome Browsing Software” – Integrative Genomics Viewer (https://igv.org/): Better as a desktop app. Lovely interface.
Download page of IGV Desktop Application (Hosted by UC San Diego and the Broad Institute)
“Genome Browsing With Bells and Whistles” – UCSC Genome Browser (https://genome.ucsc.edu/): Contains custom tracks such as ‘DANIO-CODE’ & ‘ZebrafishGenomics’ with super helpful CRISPR/Cas9 guide predictions via CRISPRscan.
Homepage of UCSC Browser with some useful custom tracks (Hosted by The Regents of the University of California)
“One Repository to Rule Them All” – GEO DataSets (https://www.ncbi.nlm.nih.gov/gds): Shared resource for the life sciences & beyond.
Homepage for GEO DataSets (Hosted by NLM & NIH)
“The Exclusive Fishy Repository” – DANIO-CODE (https://danio-code.zfin.org/): Contains multiple stages across lifespan.
Homepage of DANIO-CODE (Hosted by ZENCODE-ITN, BBSRC & ZFIN)
“Work-(sea)horse of Bioinformatics” – DAVID (https://davidbioinformatics.nih.gov/): A beast of a website. A free alternative to Ingenuity Pathway Analysis.
“The Controversial (sgRNA Predictions)” – CHOPCHOP (https://chopchop.cbu.uib.no/): Fantastic for selecting guides for generating F0 crispants and CRISPR knock-ins.
Homepage of CHOPCHOP (Hosted by Valen Lab, Department of Informatics, Computational Biology Unit, University of Bergen)
“All Hail the UMAP!” – Daniocell (https://daniocell.nichd.nih.gov/): Turning into the gold-standard for zebrafish transcriptomics during early development.
Homepage of Daniocell (Hosted by Farrell Lab at NIH/NICHD)
“Into the Multi-Ome” – Zebrahub (https://zebrahub.sf.czbiohub.org/): The future is here! Dynamic repository of development. And you must check out the videos!
Homepage of Zebrahub (Hosted by Chan Zuckerberg Biohub San Francisco – Royer Group)
“Never-ending Search for Antibodies” – CiteAb (https://www.citeab.com/): If a zebrafish antibody does exist, it exists here.
Homepage of CiteAb (Hosted by CiteAb Limited)
“Regeneration Rules!” – ZF REG DATABASE (http://zfregeneration.org/ ): See if your gene-of-interest has a role in regeneration across tissues.
Homepage of ZF REG DATABASE (Created by Rocío Nieto-Arellano & Héctor Sánchez-Iranzo; prev. University of Heidelberg)
“Missed Connection” – STRING (https://string-db.org/ ): Finds the common link (e.g. expression data or literature reference) between your gene-of-interest & other potential hits in your datasets.
Homepage of STRING (Hosted by Swiss Institute of Bioinformatics, CPR – Novo Nordisk Foundation Center Protein Research & EMBL – European Molecular Biology Laboratory)
“Trusted Resource for Craniofacial Researchers” – FaceBase (https://facebase.org/): Comparative dataset of musculoskeletal tissues across species.
Homepage of FaceBase (Hosted by National Institute of Dental and Craniofacial Research – NIDCR)
The 2025 Developmental Biology Gordon Research Seminar (GRS) was held on March 29-30 2025. This year, the GRS co-chairs Ana R. Hernandez Rodriguez and Anastasia Repouliou decided to organise an image competition by asking the GRS participants to submit their images and vote for their favourite.
“I have always believed that one of the great strengths of developmental biology is its remarkable visual appeal. The Developmental Biology GRC was a wonderfully diverse meeting with a variety of established and emerging model organisms, and we wanted to provide a platform for researchers to share captivating images of their work. These images were displayed throughout the week during breaks and poster sessions, creating an inspiring backdrop for cutting edge scientific discussions and highlighting the diversity and creativity within our community.”
Ana Hernandez (Co-Chair GRS Developmental Biology 2025)
Among the great selection of images, Paul Bump’s “Life as a drop in the ocean” won the most votes – congratulations!
You can browse through all the great entries to the competition in the image gallery below.
Browse through the image gallery (click to expand)
“Life as a drop in the ocean” This image is from an embryo of the marine acoel worm Hofstenia miamia, with cell membranes and nuclei highlighted. Early in development nuclei are shaped as rosettes but reasons or consequences for this remain mysterious. – Paul Bump“Human segmentoid” Organoids recapitulating human axial elongation and segmentation derived from induced pluripotent stem cells – Yuchuan Miao“Drosophila embryo Zipper” The Drosophila embryo central nervous system (CNS) stained with anti-body BP102 – Huangping An“Cycling through the cell cycle” Somite formation in chicken embryos. The pre-somitic mesoderm, the somites and the notochord are clearly visible, as the embryo grows towards the posterior, the anterior tissues mature. FUCCHI chicken line developed at the NARF and the Roslin Institute. Green marks cells in G2/M, Red marks cells in G1. – Ana R. Hernandez Rodriguez“Developing Neural Kaleidoscope in Drosophila melanogaster” Neuronal markers (TfAP-2 (red); Vsx1 (green); Ap (blue)) in the larval optic lobe of Drosophila melanogaster. Imaging was done with a Leica SP8 confocal microscope and processed with the LAS X and Fiji imaging software. – Yen-Chung Chen“Chicken Aurora” Tail of chicken embryo electroporated with Brainbow plasmids – Prikshit“Implantation Infrastructure: Uterine Glands and Vessels around the mouse embryo implantation chamber” Uterine Glands (Blue branched structures) and Blood Vessels (Pink) surround the elongating V-shape embryo implantation chamber (in the center) and are critical for supporting early pregnancy in the mouse. – Harini Raghu Kumar (Arora Lab)“A detour on the path to reproductive system morphogenesis in C. elegans” A young adult hermaphrodite C. elegans expressing markers for the somatic gonad (green) and germ cells (magenta) and carrying a mutation causing turning defects in gonad morphogenesis. – Noor Singh“Lateral neighbors” Developing zebrafish embryo showing the expression patterns of twist1 (magenta) and hand2 (green), dorsal view, anterior to the top. – Amanda Garfield“Fiery fish” A fire filter applied to a gene expressed in neurons and muscles along with DAPI to stain nuclei in a 24 hours old zebrafish embryo. – Zainab Afzal“Multichromatic Acacia” E6 chick embryo spinal cord electroporated with next generation Brainbow transgenes. This whole-mount acquisition allows tracing of neural progenitors to migrating neurons, following with axonal projections, showcasing lineage dynamics during development. – Thea Chrysostomou“Gradients” This image reveals the spatial coordination of BMP signaling and gene expression during early embryonic development. Dorsal view of a Drosophila melanogaster embryo at nuclear cycle 14, stained with anti-pSMAD antibody and smFISH for a BMP target gene. Captured using a Leica Stellaris confocal microscope and post-processed in Fiji. – Susanna Brantley“Symmetry on the Brain” This is a coronal section of a mid gestational embryonic piglet brain stained with DAPI in dark blue, phosphorlated s6 kinase in green, PROX1 in red, and NR2F2 in cyan to label different neuronal progenitor classes. Image aquired on a Leica Steallaris laser scanning confocal microscope then stitched and processed using ImageJ. – Emma Horton“Shaping it up like clockwork” Somite-forming organoids derived from human pluripotent stem cells allow the modelling of early vertebrate development and congenital disorders affecting the spine. Somites are transient block-like structures formed periodically, like clockwork, stacked on top of one another during early development, later developing into the vertebral column. The image shows a somitoid throughout its development from an oval spheroid to a stack of somites. Somite cells (magenta) develop on the anterior end, and progenitor populations (co-stained by cyan and yellow, which appear green) necessary for somite formation mark the posterior end. – Pranav S. Ramesh“Salivary cauliflower” Mouse embryonic salivary gland stained for Hes1 (blue) and p63 (yellow). Imaged using a 40x objective on a Zeiss LSM780 on the PICT Core facility at Institut Curie, Paris. – Robin Journot“Fishing for sex chromosomes” The X chromosomes (green) and Y chromosomes (magenta) painted by DNA FISH in a E3.5 mouse blastocyst; DNA stained with Hoechst (blue). – Aurélien Courtois“Radially migrating cortical neurons” After being born, the cerebral cortical projection neurons migrate from the proliferative zone of developing cortex to destined cortical layers. This extended depth of focus image shows these radially migrating cortical neurons at embryonic day 17 which are labelled with GFP expressing plasmid through in-utero electroporation. The staining in red shows EdU positive cells. This image has been taken using AXR Nikon microscope at CEAF Confocal facility, IIT Kanpur, India. – Nitin Agnihotri“Craniofacial mesenchyme”Craniofacial mesenchyme of HH16 chick embryo stained for ALX1 (magenta), ALX4 (green), PITX2 (red) and DAPI (blue). Image acquired with Nikon confocal microscope and processed with NIS element and FIJI. – Shirley Ee Shan Liau“Neural connections in the developing frog head” Stage 40 Xenopus laevis head labeled with an anti-neurofilament antibody, highlighting several neuronal connections. Antibody used: DHSB 3A10 (AB_531874). – Sudipta Mukherjee“Coming Together” This image captures the process during which the embryonic foregut forms an epithelial septum to give rise to the esophagus and trachea. Cells coming together in the septum remodel their Golgi apparatus (magenta), losing the tubular morphology and apical localization to the nucleus (cyan) characteristic of other epithelial cells, and resemble the surrounding mesenchymal cells. – Rui Yan“An Ewing Fish” Ewing sarcoma development through NCCs reprogramming. a massive green tumor driven by the expression of human oncofusion in neural crest cells. This fish also has an ectopic extra-dorsal fin, demonstrating an intriguing connection between normal development and tumorigenesis. – Elena Vasileva“Love on the Brain” Maximum intensity projection of an adult D. melanogaster brain from a fly carrying a GAL4 insertion crossed to a UAS-mCD8::GFP fluorescent reporter, expressing membrane-targeted GFP (in green) stained against phalloidin (in magenta) showing that the GAL4 insertion drives expression in the mushroom body of the fly brain. – Anastasia Repouliou“Web of Life” 20 days old zebrafish heart ventricle, membranes of cardiomyocytes are marked by fluorescent protein, imaged at 40x zeiss 980 and image rendered on Imaris. – Kirti Gupta“C. elegans digestive tract” – Lauren Cote– Catherine Pei-Ju Lu“The Developing Vasculature in Zebrafish” – Elithabeth Jones“The saga of bone genes and proteins” – Pragati Shekhar“Toroidal Hydra” – Daniel Pearce– Lucia RivasSomites and PSM eletroporated in chicken embryo (Gallus gallus). – Nisia MartinsFast green image of collagen in yellow and nuclei stained with DAPI in the suture mesenchyme of the mouse E15.5 skull. – Sasha Degtyareva Actin cytoskeleton in a developing Drosophila embryo – Nilay Taneja (No ratings yet) Loading...
About 6.5 years ago now, I wrote my first post for the Node, ‘Hello from Alex‘, introducing myself as a new Reviews Editor for Development. I was thrilled by the opportunity to stay in touch with the science I first came across at university and with which I instantly fell in love. In the years that followed, I’ve enjoyed helping authors publish their review-type articles, interviewing leaders of the field from all career stages and meeting the community at conferences. Six years is a relatively short time, but I’ve seen single-cell sequencing go from state-of-the-art technology to an almost routine approach, an explosion in the development of stem cell-based systems and a renaissance of fundamental aspects of biology, such as metabolism, genetics and mechanics, interrogated from new perspectives and with new tools. My hairline may have receded over these years, but my love for developmental biology, and indeed for the journal, has only grown. It’s been a journey of continuous learning and constant discovery where I’ve been able to get to grips with the wonderful world of plant biology, finally understand the complex anatomy of an early mammalian embryo and even grasp some mathematics.
It was – is – the perfect job and although I thought that, one day, I might attempt the leap to Executive Editor, I was fully prepared to wait another 20 years for the chance. So, when it was announced that Development’s previous Executive Editor, Katherine Brown, was moving on to a new post within The Company of Biologists, it came as a surprise. For over a decade, Katherine has been a pillar in the colosseum that is our community and the centre pole in the tent that is Development. It is, indeed, the end of an era. As much as I loved being a Reviews Editor, I’ve learned that personal and professional growth can only come through change and challenge – by venturing from the comfortable. I had hestitations about whether I was ready, but I’m fortunate in that, throughout my career (in addition to the privileges afforded to me as a cis white man), I’ve had supervisors and mentors like Katherine willing to take a risk with me, and I’ve tried my best to live up to that potential. I can’t hope to emulate Katherine, nor will I try, but the best news for me is that, as the Publishing Director at the Company, she will remain a source of guidance, expertise and superhuman capability.
What does this change mean for the journal? In the short term, my focus will be on keeping business as usual during this transition and supporting our excellent team of academic Editors in handling your papers. Real change, in whatever form that might be, occurs on a longer timescale. I bring with me a few ideas (and one or two of those, I hope, are actually sensible), but the main purpose of my role is to bring about the vision of James Briscoe, Editor-in-Chief; I’ve quoted below an article published earlier this year about the history of Development in which James talks about the future.
Over the next few years, we can expect continued change in the business models supporting scientific publishing, whether this is in new forms of OA or further innovation in publishing pathways. We are committed to being as inclusive as possible and giving all authors, wherever you are in the world, options that allow you to publish in Development. Preprints present new ways to enhance scientific communication and new approaches to peer review, and we will continue to develop new ways to help researchers navigate and use the preprint literature effectively. Over the next few years, we also expect to see innovative use of artificial intelligence in scientific publishing, complementing human experts. These technologies are emerging as valuable tools for information and literature discovery, manuscript processing, and journal production, offering possibilities to improve scientific publishing while maintaining rigorous standards.
Development has a long-held reputation for being respected and trusted, but the journal has not rested on its laurels. The journal has regularly introduced practices and polices to make publication easier and more transparent for authors, such as format-free submission, cross-referee commenting and publishing referee reports. It is my plan to continue these efforts, to turn avid readers of Development into frequent authors and to tackle the misconception that publishing in Development is ‘hard’. I’ve been overwhelmed by the response from the community about my appointment, and it’s a priority of mine to meet even more of you. I look forward to hearing your ideas, suggestions, queries and indeed your grievances so that the journal might continue to develop.
Finally, if you love developmental and stem cell biology, wish to remain in the community but not in the lab, and want to join our new, enthusiastic and supportive team on this new journey, we are currently recruiting a Community Manager for the Node.
I was excited to be in Liverpool for the Biologists @ 100 meeting this past March. Not only is a meeting organised by The Company of Biologists always guaranteed to be friendly and exciting, this was also my first science-related activity back in the UK since I started a postdoc in Boston last November, so I was doubly happy to be there.
Sunny views on the River Mersey, Liverpool’s aquatic pride and joy.
The most intriguing aspect of the meeting for me was the fact that it drew together an unusually broad range of scientists – this wasn’t your average BSDB/BSCB joint meeting! It was a celebration of the 100 years since the founding of The Company of Biologists and the 5 journals that are published under its umbrella. Accordingly, in addition to the cell and developmental biology track, there were three more included in the meeting, each in reality a mini symposium or satellite meeting: sensory perception (the Journal of Experimental Biology’s symposium), interdisciplinary approaches to combatting antimicrobial resistance (Disease Models & Mechanisms’ symposium), and experimental biology and impact: solutions to climate change and biodiversity loss, organised by the Society of Experimental Biology.
The ACC, venue of the conference.Talks in the ACC.
Bringing together many different groups of scientists that might not typically encounter each other at meetings and pooling resources has some practical perks: firstly, the meeting was held in the ACC, a big, comfortable, and supremely well-located venue right on the River Mersey. We were also very close to the Museum of Liverpool, where a welcome reception was held at the end of the first day, and St George’s Hall, where the conference’s gala dinner was held on the penultimate day of the conference.
St George’s Hall, where the gala dinner was held.
However, what I appreciated most was getting to hear about many different types of science that I would not have normally expected to hear at a conference (and especially at the same conference!). The biodiversity and climate change plenary lectures by Jane Francis of the British Antarctic Survey, and Hans-Otto Pörtner from the Alfred Wegener Institute for Polar and Marine Research in Germany were on the one hand fascinating, and on the other hand greatly sobering. They highlighted the essential role every scientist (not just climate scientists) should play in disseminating accurate information about the climate catastrophe our planet is suffering, and what we should be doing to combat it.
The parallel session format of the conference meant that you could hop between tracks several times throughout the day and take in all the different types of science that converged at the meeting. For example, the sessions on sensory perception were very comprehensive, with talks on vision, light pollution, thermosensation, sound perception, magnetic and chemical senses. There were also talks and posters on insect behaviour and insect-plant parallel evolution – this is a very subjective opinion, but butterflies always make a conference more fun. I was also excited to attend one of the sessions on drug discovery and ‘omics. Talks ranged from large-scale efforts to combat the development of antimicrobial resistance, to systematically exploring the breadth of organic chemistry to discover new drugs. This might not be news to some readers, but I was not aware of the tendency of microbes that develop drug resistance to concomitantly become more sensitive to other classes of drugs. This is something that researchers are actively investigating in their efforts to combat antibiotic resistance.
There was also a handful of plant-themed posters and a couple of talks on plant biology. There I heard the best description of leaves from Dr Chris Whitewoods from the Sainsbury Lab in Cambridge: “kind of green, kind of flat, sort of pretty in the sunshine.” For someone who gave a talk on leaf air space development, it was hilarious to get such a fun, entry-level description of leaves. Speaking to the (relatively few) plant scientists that were present at the meeting, I wondered why there tend to be such few plant researchers at developmental and cell biology conferences. They shared with me that they tend to congregate at plant science conferences instead, so this is my personal plea to plant scientists and developmental biology conferences: please sign up for dev bio conferences / invite plant scientists to speak at them! It is so refreshing to hear about research in non-animal models (and this is coming from someone with a passion for animal development).
Overall, the Biologists @ 100 conference was a big success. It was fantastic to see old colleagues and former lecturers, meet new people and discuss potential collaborations, and above all be exposed to an unusually broad suite of scientific investigation. There is nothing quite as inspiring as sharing one’s excitement about research with others!
All the world’s a metabolic dance, early career scientists are leading the way!
Emerging perspectives in metabolism
Dr. Lautaro Gandara, Postdoctoral researcher, EMBL, Heidelberg.
This week we will get to know insights from Dr. Lautaro Gandara, who is a postdoctoral researcher in the Crocker lab at EMBL Heidelberg. Lautaro’s work delves into the profound interplay between metabolism, toxicology, and development. As he prepares to establish his own lab, Lautaro is driven by a deep curiosity about how life adapts to environmental challenges, and how metabolic shifts shape the very essence of biological resilience. From his studies of Drosophila melanogaster to the impact of environmental stressors on insect populations, his research questions the fundamental nature of life’s response to stress and transformation. For Lautaro, science is not just a pursuit of answers but a journey of discovery, where each question unfolds new dimensions of understanding. He believes that the study of metabolism and development is not merely academic—it’s a window into the intricate ways life connects, adapts, and evolves. Follow his journey as he continues to explore these deep questions and check out his work here.
Could you share your journey into studying metabolism and what inspired you to specialize in metabolic studies using Drosophila melanogaster.
When I took an introductory course in chemical biology as an undergrad, I remember being less than enthusiastic about the field. Metabolism was presented as a completed research program—a field in which human metabolic maps had already been established, flux control theory had provided all the relevant dynamical information, and the only open questions were clinical ones. It was only after I started my PhD work in Pablo Wappner’s lab that I got access to the then-new research showing how metabolism, far from being a housekeeping process, can actually transmit information by regulating gene expression, signaling pathways, and so on. At the time, I was studying the response to oxygen deprivation (hypoxia) in flies, and we soon realized that many metabolic facets of this process remained unexplored. Drosophila larvae can perform lactic acid fermentation in hypoxic environments, but at that time there was little information on the spatial and temporal properties of this metabolic switch. These questions became the focus of my work as a grad student.
How did you get interested in the field of toxicology and impact of chemicals on insect health and metabolism? How do you think toxicology and metabolism fields overlap and how they regulate each other or how they are connected?
I have always been fascinated by the way in which life actively responds to environmental change—its intrinsic ability to preserve itself by regulating its own activities and structures. When you look at these processes more closely, all the reductionist metaphors of “life as mere machines” start to crumble, right? This is where my interest in the hypoxia response originally came from. So as a postdoc in Justin Crocker’s lab at EMBL, I wanted to expand on the approaches I had used as an undergraduate to further explore these phenomena. Instead of focusing on just one environmental perturbation (hypoxia) and one phenotype (metabolism), we decided to test more than 1000 different chemical stressors and measure how the effects induced by these molecules propagate across the different scales of biological organization.
High spatial resolution MALDI-imaging analysis of a Drosophila larva (scale bar = 100 μm). The images show relative intensities of individual lipid species, each for an individual m/z value: upper panel = 544.3373 (C26H52NO7P); middle panel = 177.0158 (C7H6O4); lower panel =744.5537 (C41H78NO8P). Image source: LG.
Tell us about how you see the future of metabolism evolve with the new upcoming tools like the FRET biosensors you worked on. What changes have you seen in the community regarding exploring metabolic aspects of development ?
I consider the development of tools to be an essential driver of science, and I think that the interplay between development and metabolism is a paradigmatic case of this phenomenon. In the first half of the 20th century, embryologists such as Joseph Needham studied the metabolic facets of development using the technology available at the time (calorimetry, respirometry, etc.). However, as embryology was transformed into developmental biology, and the focus shifted from organismal-level processes to gene- and cell-level phenomena, this set of tools proved ill-suited for exploring metabolism at this scale. As a result, questions about the role of metabolism during development were put on hold. Recently, the combination of metabolic FRET sensors, spatial omics techniques (especially spatial metabolomics), and flux analysis by isotope tracing has reignited interest in these old questions and revitalized the field. Ongoing research by many different groups working on different model systems around the world is providing priceless information about the precise role of metabolism in the development of multicellular organisms.
One of your reviews is titled “Metabo-Devo: A metabolic perspective of development”. Could you elaborate on the key findings and their implications for the field? How do you integrate different disciplines – metabolism, development, and evolution in your research, and what unique insights have emerged from this approach?
In that review article, we proposed a conceptual framework to discuss how metabolism interacts with developmental processes. We classified these interactions as either 1) bioenergetic functions, 2) regulation of gene expression through changes in the epigenome, or 3) signaling functions.
Bioenergetic processes are those that provide energy or building blocks to developing tissues. Many cell populations that proliferate at high rates acquire a particular metabolic state, called aerobic glycolysis, that allows them to synthesize macromolecules at the right pace. This metabolic switch was reported ~100 years ago in the context of cancer biology (i.e. the Warburg effect), but it is now becoming clear that aerobic glycolysis is also required for cell proliferation in developing organisms. Ongoing research efforts aim to elucidate the developmental processes during which this metabolic transition occurs, and how it is regulated.
In addition to this bioenergetic role, specific metabolic pathways can directly regulate gene expression. Certain metabolites have been shown to act in developmental contexts as rate-limiting substrates for histone and DNA modification. And this metabolic control of gene expression has been shown to play an essential role in key developmental processes, such as the zygotic genome activation. Similarly, many metabolites are directly involved in the post-translational modification of signaling-related proteins, while several metabolic enzymes have been reported to act as multifunctional “moonlighting” proteins that can perform alternative functions not necessarily related to metabolism. Thus, metabolites and metabolic enzymes have the potential to modulate signaling pathways that are essential for development.
Although we think that the classification described above provides a useful conceptual framework for designing and discussing experiments, dissecting the actual role of metabolism in specific processes remains challenging, especially because the same metabolites and enzymes may simultaneously play bioenergetic and signaling roles that affect the same developmental phenomenon. In any case, the emerging view is that metabolism and development are deeply intertwined processes that cannot be disentangled. Thus, this observation highlights the need for a discipline or research area—developmental metabolism or “metabo-devo”—that directly addresses these issues.
You are currently studying the impact of toxic substances from genotypic to phenotypic perspectives and your work suggests the use of agrochemicals is the root cause of insect decline. Can you briefly discuss this work ?
We decided to focus on agrochemicals (i.e. insecticides, fungicides, plant growth regulators, etc.). Increased use of pesticides has been proposed as a potential cause of the widespread declines in insect populations, but studies investigating the effects of these molecules on insects are often limited to a few chemicals and a single insect species. We started with a screen that tested the effects of 1024 agrochemicals on the behavior of Drosophila larvae. Behavioral changes often have a mechanistic basis at simpler phenotypic levels, and thus monitoring behavior can provide important information about the state of the biological system as a whole. Surprisingly, we found that ~60% of the molecules in our library significantly alter larval behavior! And these effects are not limited to flies—we also detected similar sublethal behavioral changes in mosquitoes and butterflies, suggesting a generalizable effect on insect populations.
By exploring some of the screen hits further, we found that the effects go well beyond behavior. Exposure to sublethal doses triggered widespread phosphoproteomic changes, revealing how these chemicals affect many different physiological processes. And chronic exposure led to delayed development and reduced reproductive output, potentially contributing to the decline in insect populations. Thus, the study showed that even non-insecticidal pesticides at field-realistic sublethal concentrations can have profound ecological consequences, highlighting the need for better safety assessments that take sublethal effects into account.
How difficult some of those experiments work – did you have to deal with midnight timepoints or require an army of undergrads/ long hours ?
The behavioral screen was very time consuming. We ended up testing 3072 different conditions (different molecules and concentrations), so including replicates and controls, we ran more than 10000 individual assays… It was a lot of work, but I got a lot of help from everyone in the lab, and fortunately we managed to get it done in just a few months. It was truly a collaborative effort!
Can you shed light on the big picture of the field, what are you most excited about and how does it all connect to impacting insect/human health.
Understanding how animal systems respond to stress is becoming increasingly important in the current context of human-induced global environmental change. Going back to my fascination with the resilience of biological systems, I think our previous work has opened up an exciting opportunity to test some of the open questions in the field of stress response. There is this idea that multicellular organisms need to activate a system-level stress response to restore homeostasis. This process would be based on the well-known “integrated stress response” pathway—a process that occurs at the cellular level—but would also involve organismal level stress defense systems involving cell differentiation processes, metabolic switches, physiological changes, and even behavioral effects. Testing this hypothesis, however, is not straightforward because it would require measuring the degree of interconnectedness among all these different processes across a wide range of environmental perturbations. By performing the behavioral screen I mentioned earlier, we have defined a panel of chemicals that induce widespread systemic changes in fly larvae, but at sublethal concentrations, meaning that these animals can orchestrate a successful response to these stressors and recover from these injuries. Thus, this panel of chemicals can be used next to explore the level of integration between the different stress defense systems operating at the organismal level. I hope to start my own group soon, and this is one of the first problems I’d like to tackle.
What advice would you offer to students and early-career scientists interested in exploring the intersections of metabolism, development, and evolution?
I’d tell them to have fun! These are indeed exciting times to be doing metabolic research in developmental systems. New technologies are allowing us to explore the various ways in which metabolism transfers information not only across space (inter-organ communication, metabolic coupling between cell types, etc.), but also across time (developmental and cell differentiation processes). I think this is the time to be bold and creative in finding ways to make the most of this technological advantage.
What role does curiosity play in your life, both within and outside of science? How important is it for you to answer basic science questions about behavioral and metabolic aspects of toxicology and how are you planning to use insect models to bridge basic science and applied research ?
Curiosity does play an essential role in my life and in my research. The project I mentioned earlier, in which we studied the sublethal effects of agrochemicals on insects, has some facets that are obviously relevant to the community as a whole. But I strongly disagree with the idea that it’s only worth studying certain natural phenomena if they affect us directly, or if we can use them for our direct benefit in the short term. Basic and applied research aren’t in opposition to each other—on the contrary, they are involved in a dialectical feedback in which the former feeds the latter with information about how fundamental processes work, while the latter not only highlights which questions are most pressing, but also drives the development of new tools and methods that can then be applied to basic research. Hypoxia research is a good example. The oxygen sensor—the molecule that allows cells to determine oxygen availability and trigger an appropriate response when oxygen levels become too low—was identified more than 20 years ago in fundamental work on C. elegans. Years later, this molecular machinery was found to have enormous clinical relevance, as it could be manipulated to induce angiogenesis and treat the symptoms of cardiovascular disease or prevent it and limit tumor growth. But this useful knowledge first came from curiosity-driven research on basic genetics.
Were there any pivotal moments that shaped your career path? What’s an unexpected place you’ve found inspiration for your work?
It may sound simple, but for me the most important source of scientific inspiration is talking to other people. I can think about some problems for hours, but in my case, ideas really take shape when I express them, either by writing them down or by discussing them with someone else. It’s as if, by trying to communicate my thoughts, I organize them into a coherent narrative—a logical structure—from which new ideas can occasionally emerge. And then different people, with different backgrounds and different opinions, will steer your train of thought in completely different directions, certainly leading to unexpected places… But I’m not talking about big meetings full of people here—it’s the one-on-one discussions that force you to interact longer with a single concept and exhaust all its multiple possibilities that are often more productive for me.
If you hadn’t embarked on a career in biological research, what other profession might you have pursued, and why?
I don’t really see myself doing anything other than biological research. But if it weren’t for biology, I think I would have pursued a career in the social sciences. Human societies are incredibly complex entities, but understanding how they work is not just a matter of academic curiosity. Especially now, looking at the current times, explaining how society, economics, or history actually works has become a pressing issue. I think that on an individual level—and as citizens —we can’t afford to ignore these problems any longer.
Anything you’d want to highlight for the future.
I’m currently looking for a place to set up my own lab. Aside from the global uncertainty we discussed earlier, I think these are exciting times to start a group. New technologies are making old questions experimentally tractable, new species are being proposed all the time as novel model systems, and AI promises to change the way we approach data analysis. There’s no doubt that the way we do science is going to change dramatically in the coming years, and that’s an idea I find particularly appealing.
Last week we learnt about how males and females are metabolically differently rewired – from the perspective of lipid storage and utilization – The Fat of the Matter (Lianna Wat)
In our recently published paper ‘Ectoderm barcoding reveals neural and cochlear compartmentalization‘, we utilized ultrasound-guided in utero nano injections to deliver heritable DNA barcodes to cells exposed to the amniotic fluid, performing the first high-throughput single cell lineage tracing study of the developing nervous system and inner ear. Our results led to the reclassification of cell lineages in the cochlea and provided a comprehensive single-cell atlas of neural and cochlear clonal relationships.
Sandra’s perspective: Work related to this publication already started a long time before I (Sandra) joined Emma R. Andersson’s lab back in 2019 to pursue my PhD studies. Work done by Katrin Mangold and Jingyan He, PhD students in the lab at the time, laid the foundation for successful in utero injections into the amniotic cavity to target the neural plate (Mangold et al, 2021). Like the neural plate, the progenitors of the inner ear are exposed to the amniotic fluid during an early time window of development (~E7 – E9) and we therefore hypothesized that we would be able to target the otic placode and manipulate progenitors of the inner ear using this technique. In fact, preliminary data from a Master’s student, Sanne Stokman, showed some targeting of the vestibular system of the inner ear. This data hinted that we should be able to target the cochlea as well – and laid the foundation to further explore this during my PhD studies. Drawing on expertise from two laboratories—the Andersson lab at the Karolinska Institute, specializing in developmental biology, Notch signaling, and in utero injection techniques, and Matt Kelley’s lab at the National Institutes of Health, experts in inner ear developmental biology—the first experiments targeting the cochlea were conducted in 2019. I vividly recall witnessing the targeting of the cochlea, for the first time, using low-titer H2B-GFP lentivirus injections performed by Jingyan. The mosaic-like targeting of hair cells along the cochlear spiral was truly remarkable (Fig. 1). I remember sharing these initial positive results with Emma via text while at the confocal microscope. Together with Jingyan, who truly mastered the injection technique, and together with the Infinigene core facility (established by Emma), we optimized our injection strategy to target the inner ear, including the injection volume, embryonic stage and viral titer. This journey was, of course, not without its challenges. At times, we faced difficulties with mouse breeding, low viral titers, and, not to forget, a pandemic that occurred along the way. Finally, in 2022, injections using high-titer virus yielded high-targeting efficiencies – of over 90% of the hair cells and supporting cells in the Organ of Corti. I remember observing the high efficiency targeting, quantifying targeting efficiencies late at night the same day, and presenting the results the next day over Zoom during the Kelley lab meeting – excited to share the new results.
Fig1: First cochlear targeting results using low-titer H2B-GFP lentivirus. Injections performed at embryonic day 8, collection at postnatal day 0. Hair cells shown in magenta, GFP-labelled cells shown in green. DAPI (nuclei) in blue
Using viral delivery of heritable DNA barcodes, we were able to perform high-throughput lineage trace studies in the inner ear for the first time, answering fundamental questions about inner ear development. I am still thrilled that we could apply this advanced method to explore lineage relationships within the inner ear. Although we initially focused on the divergence of medial and lateral cochlear cells, we soon realized that the most intriguing findings came from cells outside the Organ of Corti, including Hensen’s cells and populations within the stria vascularis. One of my favorite insights is the classification of Hensen’s cells. At the time, more research was performed on this specific population of cells in the cochlea, but no consensus existed on whether this cell type should be considered a supporting cell subtype or grouped with cells lateral to the Organ of Corti. Our data indicated that Hensen’s cells should be classified as lateral to the Organ of Corti, rather than being a supporting cell subtype of the Organ of Corti – if basing this definition on lineages. This classification might be relevant for future strategies focusing on regeneration and differentiation of cells within the cochlea. These findings also nicely aligned with results from another project of my PhD studies, in which we showed that Hensen’s cells respond differently to the loss of Jag1-mediated Notch activation compared to lateral supporting cells (De Haan et al 2024, Development).
As dissociation of cochlear cells relies on physical dislocation through microdissections, we inadvertently included cell types in our analysis that were not initially the focus of the study, including spiral ganglion neurons and glia. The analysis of barcode sharing between these populations proved to be quite complex. Contamination between spiral ganglion neurons and glia cells often occurs in single-cell preparations, so we investigated the barcode sharing between these populations to determine whether it was due to contamination or if subtypes of neurons might share a common origin with glia cells, which would challenge the current view. Ultimately, this experience taught me the importance of remaining open to new discoveries while ensuring that data collection and experimental design are well-suited to address the research questions. It highlighted the need for careful experimental planning, robust data collection and validation to draw accurate conclusions from complex datasets.
Jingyan’s perspective: While contributing to the inner ear lineage tracing project, I (Jingyan) was also focused on the overarching goal of my PhD projects: advancing the in utero injection technique to label non-ectodermal cells, building upon previous success in ectoderm targeting. By exploring different injection approaches, I successfully established a technique to label diverse cell types with other embryonic origins (ongoing work). As part of this highly ambitious project, we lineage traced tall ectoderm-derived cells using amniotic cavity injections at E7.5. We collected whole embryos at E9.5 and E10.5 after barcode labeling at E7.5 with amniotic cavity injection. This approach allowed us to study the lineage relations of central nervous system, neural crest-derived cells, as well as various epithelial lineages, including the otic lineage. This part of data was later incorporated into the inner ear lineage tracing paper to add a more comprehensive understanding of neurodevelopment and illustrate the potential clonal relations between otic epithelial lineages and other cell types.
One of the key challenges in this work was balancing the viral transduction efficiencies across different collection time points to ensure an optimal number of labeled cells for the single cell RNA sequencing and clonal analyses. Although E9.5 and E10.5 are just one day apart, the difference in total cell number is substantial. We had to pool a few E9.5 embryos to obtain sufficient cell numbers for clonal analyses. However, for E10.5, if we used the same amount of viral particle and reached the same transduction efficiency as E9.5 collection, a single E10.5 embryo yielded so many labeled cells that we needed to split them into multiple reactions when preparing the sequencing libraries.
Viral transduction efficiency itself was influenced by a variety of factors, such as the subtle differences of the embryos’ stages when injecting, viral storage time, freeze-thaw cycles and the variability between different virus production batches, making it difficult to consistently control the number of transduced cells recovered from each injection.
Collection days were always highly intense and stressful, involving a full workflow from the setting up of the cell sorter, embryo collection, dissection, dissociation, cell sorting, to library preparation, all within a tight window to preserve cell viability and RNA quality. Sandra and I always teamed up to streamline the workflow, assisting each other with reagent preparation, cell counting, and other time-sensitive steps.
Joint perspective: The manuscript, initially focused on cochlea only, was submitted shortly before Sandra’s successful PhD defense in August 2024. The E9.5/E10.5 ectodermal lineage tracing data was initially intended for a separate publication, but in response to reviewer and editorial feedback, we decided to incorporate it into the current paper during the revision process. This addition significantly enriched the manuscript and provided a more comprehensive understanding of neurodevelopment. As a result, Jingyan and Sandra shared the first authorship of the paper, highlighting the collaborative nature of our research and the importance of these findings.
Now that the paper has been published and new projects are underway in the Andersson lab applying this technique to different tissue systems, we are both excited to see how the technology will be used, further developed, and what biological insights it will uncover. We’re proud that our work also laid the foundation for an ERC Consolidator Grant to the Andersson lab, who will continue to push the frontiers of the technology – and the lab is looking for post docs!
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