This is part of the ‘Lab meeting’ series featuring developmental and stem cell biology labs around the world.

Where is the lab?

Andrea: You can find the Ditadi lab at Ospedale San Raffaele, as part of the San Raffaele Telethon Institute for Gene Therapy, in the north-east corner of Milan, Italy. Milan is a great spot for both science and life, with a myriad of places to visit, plenty of things to do and a rich community of great labs to collaborate with.

Regarding us, you can find more on our LinkedIn page and our official website.

Research summary

Andrea: We want to understand how human blood cells form. For this, we use human pluripotent stem cells as a model, integrating developmental, cell and molecular biology, as well as a bit of immunology. We study human developmental biology in a dish: we study early mesoderm patterning and follow the process all the way to mature blood cells, including hematopoietic stem cells, trying to work out which signals guide each step. We are developmental biologists working at an institute that focuses on genetic diseases and their therapy, so we also use the cells we generate to look at diseases from a developmental perspective. At the same time, we explore how to engineer and arm these cells in unique ways so they can be used in clinical settings in the future.

Lab roll call

Let’s start in order of length of service in the lab.

We have Lauren Randolph, post-doctoral fellow, who is studying how hemogenic cells give rise to blood.

Claudia Castiglioni, PhD student, who aims to identify the earliest commitment to blood cell fate.

Riccardo Piussi, former Master’s student now PhD student-wannabe (and hopefully soon-to-be), working to decipher the regulation of self-renewal in emerging HSCs.

Deborah Donzel, a postdoctoral fellow, and Nikita Pinto, another former Master’s student now turned research assistant, are partners in modeling a ribosomopathy that affects red blood cells only postnatally to decipher proteostasis regulation across different stages of hematopoietic development.

Elena Morganti, a postdoctoral fellow, and Bianca Nesti, a Master’s student, who teamed up to model a pediatric autoimmune disease as a way to understand the role of embryonic lymphocytes in health and disease.

Alessandra Guerreschi, a Master’s student who recently joined our lab and is gearing up to investigate the multiple roles of Notch signaling in hematopoietic development.

Favourite technique, and why?

Andrea: It is not exactly a technique, but my favourite moment in the lab is simply watching cells under the microscope. We do not do much imaging; most of our days are spent in the hood doing cell culture. Even now, when I am sadly not doing many experiments any longer, I still have this habit that I actually stole from my postdoc advisor. When I need a break from the desk and the administrative tasks, I go to the lab for what I call a bit of “cell therapy”. I grab a few plates and spend some time simply looking at cells under the microscope. I love it. Observing cells in cultures is very informative, cells talk to us all the time.

If I need to choose a proper technique, I would choose flow cytometry. We use it a lot. It may not be as high-throughput as some newer methods, but it gives us robust full gene expression data at the single-cell level, and we can learn a lot from what comes out of the cytometer.

Andrea, apart from your own research, what are you most excited about in developmental and stem cell biology?

Andrea: Recently, I have been following the evo-devo field with a lot of interest. I find it fascinating to think about how cells and tissues evolved, and for a lab like ours that tries to recreate how blood cells are formed in vitro, understanding how they appeared in the first place feels very relevant.

Another field that I find extremely exciting is synthetic biology. I am fascinated by how we can now “prod” cells and systems and modify their responses. I remain a developmental biologist at heart, but the environment where we work has opened my eyes to how we can push the boundaries of therapeutic innovation. Alongside the clinical application of stem cells, synthetic biology is transforming the way we think about medicine and how we might design future therapies.

Andrea, how do you approach managing your group and all the different tasks required in your job?

Andrea: I am not sure I can say I am set into one approach, at least yet. I think it is always evolving, as the people in the lab, as well as the lab itself, need change over time. In general, I try to spend time getting to know the people in my group, recognizing the strengths and weaknesses, and trying to exploit the former while helping them work on the latter. I often think of the group as an orchestra or a music band. First, I need to hear the sound of each instrument, help them get tuned and then my job is to compose some music that fits them. Let’s say that some composition takes more time than others. But in the end, the goal is to nurture the love and passion for the true privilege of doing research for everyone.

As for managing the different tasks, I often wish I had more hours in the day; that would be a great superpower. So, I try to clear out the things I do not enjoy, the administrative duties and emails, as quickly as possible. This gives me protected time for what I love: reading, thinking and spending time with the team in the lab. I am not sure I always find enough time for that, but I try very hard.

What is the best thing about where you work?

AD: Without a doubt, being surrounded by young and bright people. It is energizing and another privilege of this job.

CC: The thing I value most about being at SR-Tiget is the stimulating environment, where science truly comes alive. Ideas are shared freely, we have the resources to bring them to life, and we constantly get to learn from seminars by scientists from around the world.

NP: The best thing about working at SR-Tiget in Milan is the combination of different scientific topics and a truly collaborative environment, where you can walk into a lab or an office to ask for help and know that someone will genuinely take the time to help you solve a problem.

RP: What I like most about where I work is the general drive of the institute to do high-level science and to set ambitious goals. In the lab, I really appreciate the way we reason scientifically and the fact that we constantly challenge our ideas by asking questions every day.

LNR: The best thing about where I work is the science and the people. I really enjoy the project that I am working on and find it both challenging and engaging. I am also really lucky to work with incredibly collaborative and supportive colleagues who really treat the lab as a family. It makes it a joy to spend time with them, both in and out of work, and to do and talk science together.

DD: The best things about where I work are the research topic and the people I work with. My enthusiasm for the project keeps me focused and driven, even during challenging periods. I’m also fortunate to work with colleagues who are open to sharing ideas and knowledge, which creates a collaborative environment that helps us move forward together.

BN: What I appreciate most about working at SR-Tiget is the highly stimulating scientific environment, both at the institute level and within my own laboratory. The presence of diverse expertise, frequent seminars and strong resources fosters a continuous exchange of ideas and supports high-quality research.

EM: What I like most about where I work is the young and supportive environment. I feel that people around me are genuine and open-minded, and this makes my days very pleasant and enjoyable.

AG: Even though I haven’t been here long, I’ve really noticed how welcoming and supportive everyone is. It makes it easy to ask questions, learn quickly and feel like part of the team right away.

What’s there to do outside of the lab?

AD: Despite being in love with my job and not feeling the need to escape, life is too short, and I have so many interests – books, music, sport, hiking, biking, food, friends, etc. – so I try to do a bit of it all. To be coordinated with the family, in particular, two kids who keep me happy and busy.

CC: Outside of the lab, I really enjoy canoeing on the Navigli, the famous canals in Milan. Being on the water allows me to slow down and take a break from the busy pace of the lab. I love the feeling of paddling along the canals, enjoying the surroundings and reconnecting with the city.

NP: Having grown up in Milan, I sincerely love this city and everything it offers. Outside of the lab, I like different things, from baking and crocheting to spending time with family and friends while enjoying the city’s cultural life, like its aperitivo culture and different neighborhoods. Recently, I also joined the Red Cross as a volunteer, where I am involved in social inclusion activities with homeless people, as well as assistance roles during public events. These experiences help me stay grounded, connected to the community and maintain balance alongside research.

RP: This job takes a lot of time and energy, but outside of the lab I really enjoy spending time with my family and friends. I also love fishing. I enjoy it for its unpredictability and complexity; it requires analyzing many variables and accepting failure without expectations. Every small decision can make a difference, and while nothing is guaranteed, everything is possible, like in science.

LNR: Outside of the lab, I enjoy traveling, reading, and all things food-related. In Milan, I particularly enjoy access to the ballet, opera, and theater.

DD: Outside of the lab, I really enjoy going for walks—especially in parks or outside the city, where I can reconnect with nature. Living in Milan, I also like going to the theater and meeting friends for an aperitivo.

BN: Outside the lab, I enjoy spending time reading, as it offers a break from continuous scientific reflection while still keeping my mind engaged in a pleasant way. I also like to take advantage of the many cultural and recreational initiatives that Milan has to offer, often in the company of my friends.

EM: I usually try to spend time in nature and clean air when I am not in the lab. Milano is really close to beautiful mountains and lake,s and those are my favorite spots for the weekend. I also enjoy food, art and history.

AG: In my free time, I enjoy reading and spending time in the mountains outside of Milan, whether it’s hiking, skiing or horseback riding. Skiing, in particular, is a great way to unwind on the weekends and enjoy the outdoors. Being able to combine outdoor activities with some quiet time to read makes my free time really enjoyable.

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I am Saanjbati and I am beyond thrilled to announce that I have joined Development as a new Reviews Editor. A big part of my job involves travelling to conferences – both in the UK and internationally – to represent the journal, meet Development and the Node’s communities (which I absolutely love doing!), learn about emerging trends in developmental and stem cell biology as well as commission review-type articles that would be of interest to our broad readership. I also coordinate peer review and developmentally edit our review-type articles, compose accessible ‘Research Highlights’ on selected primary research papers and interview researchers for our variety of interview series – including the ‘People behind the paper’ series, Transitions in development and the PI fellow series.

I originally joined The Company of Biologists in March 2024 as a Cross-title Features Editor, working across the portfolio of our five leading peer-reviewed journals to create front-section content celebrating the Company’s 100-year anniversary in 2025. You can read some of the articles that my amazing colleagues and I have authored for the 100-year anniversary subject collection here: https://journals.biologists.com/dev/collection/10745/The-Company-of-Biologists-celebrating-100-years.

Earlier this year, I successfully defended my PhD thesis (at Queen Mary University of London, UK) on the molecular characterisation of Astrin, a mitotic protein with crucial roles in bridging kinetochore-microtubule attachments during mammalian cell cycle. Shortly after that, I joined Development as the Reviews Editor, initially part-time and now full-time since November. Coming from essentially a cell biology and biochemistry background, exploring the world of developmental biology over the past 5(ish) months has been genuinely fascinating (and obviously challenging!).

Looking forward, I am excited to continue expanding my knowledge across developmental and stem cell biology concepts, including but not limited to early development and plant and invertebrate biology, as well as to network with more of our community in a meaningful manner. If you’d like to chat, share ideas for front-section content, or just say hello, please feel free to get in touch with me at saanjbati.adhikari@biologists.com.

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Before diving into the science and the path we took to reach our most recent publication in Development¹, let me (Anne Schmidt, senior CNRS scientist, France) take a few lines to introduce the people behind the work.

The first author, Léa Torcq, studied mathematics and developmental biology. Léa began her PhD in October 2019, just a few months before the COVID pandemic. Our second key contributor is Catherine Vivier, our invaluable technician. The third and fourth members of our team are highly dedicated engineers from our platforms, Sandrine Schmutz and Yann Loe-Mie, who brought their excellent expertise in FACS-mediated cell sorting and bioinformatics, respectively. All three of them are staff members of the Pasteur Institute in Paris, France.

Léa and I will take turns sharing our exciting and fruitful collaboration aimed at tracking emerging and newly born hematopoietic stem cells to their implantation sites in developmental niches, using the zebrafish embryo and larva.

Anne: Our project began when — with my background in cellular and bio-membrane dynamics — I decided to investigate fundamental aspects of the cell biology of pre-hematopoietic stem cell emergence. This intriguing and unusual process, first visualized by Karima Kissa and Philippe Herbomel 15 years ago in the zebrafish embryo, is referred to as the Endothelial-to-Hematopoietic Transition or EHT². To our knowledge, this unusual way of emerging from a flat tissue, where the cell bends outwardly from the aortic plane toward the sub-aortic space, appears to be specific to zebrafish (until it is observed in another tissue or species!).

While we began to unveil some fundamental aspects of these intriguing mechanics in 2018³ (see our previous ‘Behind the Paper’ story), we questioned how the luminal membrane of these emerging cells is maintained throughout emergence and how it evolves after completion — with the key feature being the control of apico-basal polarity. Importantly, the evolution of this luminal membrane after release may influence the cell’s behavior, including its migration capacity (for example, if used as a membrane reservoir for cell locomotion), its signaling features (if recycled and/or degraded), and ultimately, its fate.

To tackle these ideas, I developed transgenic lines expressing a well-characterized apical marker, podocalyxin-l2, fused with eGFP (eGFP-podxl). Interestingly, using this line, EHT-undergoing cells imaged with confocal microscopy exhibited obvious asymmetric eGFP-podxl localization, with enrichment at the luminal membrane⁴. Astonishingly, the apical/luminal membrane is extremely dynamic (see Fig. 1) and eventually collapses into a pseudo-endocytic compartment after chasing engulfed intra-aortic fluid, which persists for several hours after release from the aortic floor (a post-EHT signature). This showed that apico-basal polarity is a key feature of EHT cells, maintaining a large apical domain until release, which is unconventional for a cell extruding from a tissue⁵. Perhaps this is the only way a cell can extrude from a flat tissue under strong mechanical tension (the tension exerted on the aortic wall by blood flow and its associated forces⁶), but in fact, it is not! Another outcome from our eGFP-podxl line unambiguously revealed another type of emergence dynamics, which showed no obvious apico-basal polarity. These emerging cells maintain a round shape (not resulting from recent mitosis), with endothelial neighbors crawling on their membrane facing the aortic fluid⁴. These two types of emerging cells, which we called EHT pol+ and EHT pol- cells (for polarized and unpolarized cells, based on podocalyxin localization), suggested that they may have different fates.

Figure 1: Series of z planes showing the dynamics of the EHT cell apical/luminal membrane labelled with eGFP-podocalyxinL2. Spinning disk confocal images obtained with Tg(kdrl:Gal4;UAS:RFP;4xNR:eGPF-podxl2) 50-55 hpf embryos (green: cellular membranes; red: cytosolic RFP). A, single z plane of a longitudinal section of the dorsal aorta (aortic lumen) showing one pre-hematopoietic stem or progenitor cell undergoing EHT (white delimited area on the right). Note the inward bending of the cell, toward the sub-aortic space. B, cropped views of single z planes extracted from a time-lapse sequence starting with the timing point visualized in the field delimited in (A). Images were acquired with 7 minutes intervals, from t=00.00 to t=04.47 hours as indicated in panels 1 and 42, respectively. Numbers 1 to 42 correspond to the progression of the time-lapse sequence throughout time. Note the enrichment of eGFP-podxl2 in the apical/luminal membrane as well as its remarkable dynamics (ex: compare panel 1 with panels 4, 9-12, 14-18). Note also the apparent regression of the apical/luminal membrane in panel 42, indicating that the cell has completed emergence from the aortic floor (we make the interpretation that the cell has detached from the floor in panel 30). Scale bar: 12 µm.

Besides characterizing junctional dynamics at the interface between EHT cells and endothelial neighbors, Léa’s aim was to tackle the question: are EHT pol+ and EHT pol- cells leading to different progenies? The idea was to set up single-cell photoconversion of EHT-undergoing cells, exploring the niches into which progenies establish throughout early larvae (an invaluable advantage of zebrafish, which develops quickly yet remains small) and characterizing their molecular signatures using single-cell RNAseq (sc-RNAseq).

Léa: I joined the lab as a Master’s student to work on this project in January 2019. I had previously studied EHT in Thierry Jaffredo’s lab, conducting work on self-organizing quail embryo explants in vitro. Although such models are fundamental to scientific discovery, I wanted to move toward more physiological, in vivo approaches. When I met Anne and she showed me the movies generated through live imaging of transgenic zebrafish embryos, I was instantly fascinated by this beautiful – both scientifically and aesthetically – approach. I also quickly discovered that Anne was a unique kind of senior researcher. She remains actively involved in performing and analyzing experiments at length with a combination of youthful drive for science with wise meticulousness, which convinced me to follow my initial internship with a PhD, with Anne as my advisor.

I was also drawn to this project because it gave me the opportunity to learn many different techniques, ranging from live imaging to scRNAseq and transgenesis. It came with challenges in optimizing and analyzing these diverse experiments, compounded by the COVID lockdown during most of 2020. Nevertheless, we persevered, and I was fortunate to receive invaluable help from several people, particularly our co-authors. Catherine taught me how to perform in situ hybridization and set up single molecule fluorescence in situ hybridization (smFISH), using RNAScope. Sandrine, from our institute’s cytometry platform, spent around 100 hours sorting cells for subsequent scRNAseq experiments. As for Yann, he originally helped set up the analysis pipeline for MARS-seq and provided guidance when I began training myself in scRNA-seq analysis.

Overall, we used nearly 400 embryos for photoconversion of single cells based on their morphology as they emerged from the aorta. Subsequently, larvae were used to track migration patterns and build precise lineage trees. We also index-sorted the progenies of 2,036 photoconverted cells and generated MARS-seq libraries from them. Separately, we used gata2b and cd41 reporter lines and 10X Chromium to generate a complementary scRNA-seq dataset of more than 30,000 cells, encompassing the whole hematopoietic lineage sorted by their niche of origin. Our main discovery was the differential fate of EHT pol+ and EHT pol- cells, with a bias regarding the lymphoid lineage. We identified different propensities to seed the thymus as well as different abilities to differentiate into T-lymphocytes. Moreover, our work contributes to the characterization of zebrafish hematopoietic cell types with new insights on the origin of some populations, like the ILC2-like and ILC3-like cells, never before observed at such early developmental stages.

Anne: Léa’s hard experimental and bioinformatic work has been extremely fruitful. From our single cell pipelines and their integration, we retrieved informative signatures of Hematopoietic Stem and Progenitor Cell (HSPC) populations. These included the transcription factor gata2b⁷ (which is upstream of runx1, a transcription factor essential for hematopoiesis⁸) and podocalyxin/cd34. Intriguingly, we found that in addition to embryonic HSPCs (eHSPCs) and other multipotent progenitors, gata2b is also expressed in sub-populations of ILC2-like cells enriched in the anterior/trunk region of the larvae, and of young eosinophils. We discovered that eosinophils possess the unique property of differentially expressing genes related to extracellular niche/matrix functions, including serine protease inhibitors of the spink2 family, timp4.2 (an inhibitor of metalloproteases), as well as one specific member of the MFAP4 locus. We then used these markers to investigate the localization of hematopoietic populations through whole-mount in situ hybridization. With Catherine’s expertise, we developed RNAscope applied to zebrafish. While whole-mount RNAscope had rarely been used for zebrafish embryos and larvae at that time – essentially because chromogenic and/or fluorescent in situ hybridization using long antisense nucleotide probes were routinely used and at relatively low cost –, it proved to be a great decision. Because it provided a high signal-to-noise ratio and sensitivity, RNAscope allowed us to investigate cells implanted in niches throughout the entire early larval body, including the pronephros region, which is challenging because it requires deep penetration of probes and low background (see our recent technical paper ⁹).

With the timp4.2 marker highly expressed in eosinophils, we found an intriguing accumulation of cells almost exclusively in the most anterior region of the pronephros, in the 5 dpf larva. These cells, with a maximum of 15 per animal in that region (on average more than in the trunk and the Caudal Hematopoietic Tissue (CHT)), also faintly express eGFP driven by an enhancer of the hematopoietic transcription factor runx1, confirming their hematopoietic origin (see Fig. 2 and Movie 1). This pointed to sub-compartmentation of the pronephros niche. Currently, we do not know if these cells, presumably eosinophils (or progenitors), home there for maturation and/or if they contribute to building a sub-niche hosting specific hematopoietic cell subtypes. Anyhow, these results highlight the functional complexity of the developing pronephros niche and point to the importance of investigating micro-environmental properties supporting the differentiation and/or maintenance of specific hematopoietic populations.

Figure 2: Whole-mount in situ hybridization revealing timp4.2 mRNA expression in hematopoietic and vascular cells using RNAscope. A, C, D, Representative images (Imaris 3D-rendering) of RNAscope ISH for timp4.2 (magenta spots) in 5 dpf Tg(runx1+23:eGFP) larvae. Images show the pronephros region (A, see also Movie 1), the posterior trunk region (C, above the elongated yolk) and the CHT (D). a’, c’, d’ are magnifications of regions outlined with white dashed boxes in (A, C, D), respectively. eGFP positive hematopoietic cells were segmented (green contours). White arrows point at timp4.2 positive hematopoietic cells. The sub-aortic clusters are delimited by yellow dashed lines and the gut by magenta dashed lines. B, Relative position of eGFP positive cells along the antero-posterior axis of the pronephros (n=681 timp4.2– cells, n=46 timp4.2+ cells). E, Percentage of eGFP positive hematopoietic cells expressing timp4.2, n=6 larvae for pronephros, n=3 for trunk and CHT regions. (B, E) Two-sided Wilcoxon tests. NC: notochord. Scale bars: 10 µm.

Movie 1: 3D visualization of RNAscope in situ hybridizations for timp4.2. Timp4.2 (in magenta) in the pronephros region of Tg(runx1+23:eGFP) 5 dpf larvae, 3 representative replicates are shown. Bottom row shows magnifications of the top row. Hematopoietic cells in the pronephros are delineated (green contours). Scale bars: 10 µm.

Finally, the most unexpected results came when using the gata2b probe. We detected strong expression of this transcription factor in endothelial cells of the supra-intestinal artery (SIA), a small vessel located just above the intestinal tract and beneath the posterior cardinal vein (for detailed anatomy, see Isogai et al¹⁰). We obtained these results in March 2023, more than 2 years ago and about a year and a half before submitting our paper to Development. Importantly, our images unambiguously showed that not only do SIA endothelial cells express gata2b, but so do other cells in their direct vicinity, even contacting the SIA wall. These cells also express eGFP driven by the vascular kdrl promoter, and it appeared that many of them express eGFP at levels comparable to SIA endothelial cells.

Léa: When we realized this, we considered that the SIA region might not only be a niche for hematopoietic stem and progenitor cells and more differentiated cells whose ancestors emerged from the dorsal aorta days before (e.g., ILC-like cells with immune functions in the gut¹¹), but that these cells might also derive directly from the SIA wall itself! To reinforce our results, I quantified the number of gata2b-positive cells in the direct surroundings of the SIA as well as near the dorsal aorta, showing that the SIA region is significantly enriched in gata2b cells compared to the dorsal aorta. After 3D segmentation of the cells with Imaris, I quantified their eGFP signals (driven by the kdrl promoter) and found that gata2b-positive cells near the SIA express comparable levels of eGFP to SIA endothelial cells (with no such cells around the dorsal aorta). This suggests they are relatively newly born cells whose eGFPcontent has not been diluted by division cycles, reinforcing the idea that they may originate from the SIA endothelium.

Anne: All this evidence supports the hypothesis that the SIA may be hemogenic. Due to the constant movement of the gut beneath the SIA, we struggled to provide high quality time-lapse sequences for our paper in Development (even acquiring a single complete z-stack was difficult). However, we obtained discontinuous images over relatively short periods of up to 2 hours that strongly suggest emergence from the SIA wall (see Fig. 3). Importantly, cells undergoing apparent emergence remained very ‘sticky’ to the SIA wall, making it difficult to confirm they fully completed EHT. Our results clearly demonstrate that the SIA region is at least a niche hosting HSPCs and suggest that these may be born from this small artery. Hence, the SIA may be hemogenic, a potential novel finding requiring further validation. As discussed in our Development paper¹, this validation will require characterizing the SIA hemogenic endothelium and the fate of the derived EHT cells at the single-cell level.

Figure 3: Evidence of emergence from the SIA endothelium. Top panel: schematic representation of a 5 dpf larva (reproduced with modifications from Schmidt, 2022, doi:10.7554/eLife.64835); red line = aorta, blue line = vein, magenta line = SIA. (a – d’), spinning disk confocal microscopy of a 5 dpf Tg(kdrl:eGFP) zebrafish larva, in the upper part of the trunk region (delimited in the cyan box of the upper cartoon). Panel a (z projection), the upper part of the trunk region encompassing the dorsal aorta, the posterior cardinal vein, and the SIA with the latter passing beneath the swim bladder (SB, on the left side of the image). White and magenta asterisks indicate cells expressing eGFP at apparently comparable level than SIA endothelial cells and that are contacting the SIA wall (note that no such cells are in contact with the ventral floor of the dorsal aorta). (b – d’), single z planes extracted from the z stack projected in (a), with images magnified from the region in (a) delimited by the white rectangle and showing the cell surrounded by the green rectangle in (a) and undergoing emergence between 0 min (b, b’), 10 min (c, c’), and 20 min (d, d’). Panels (b, b’), (c, c’), and (d, d’) are images separated by 1 mm depth in z. Green arrows point at the connection of the emerging cell with the aortic lumen; magenta arrows point at the disappearance of this connection, which suggests completion of the emergence. Scale bar: 20 µm.

This story behind our paper in Development summarizes an exciting research journey that led to several previously undescribed findings. This was made possible by assembling a team of passionate and efficient people and pushing forward the resolution of our analyses, including technically demanding single cell photoconversion, multiple single-cell RNAseq approaches, and powerful smFISH technology using a new generation of small, highly specific probes (we’ve significantly contributed to increasing the number of zebrafish hematopoietic probes in the ACD catalogue!).

Finally, we are convinced that our work opens new avenues for exciting future discoveries in the fields of hematopoietic stem cells and vascular biology.

References

1.   Torcq, L., Vivier, C., Schmutz, S., Loe-Mie, Y., and Schmidt, A.A. (2025). Single-cell and in situ spatial analyses reveal the diversity of newly born hematopoietic stem cells and of their niches. Development 152, dev204454. https://doi.org/10.1242/dev.204454.

2.   Kissa, K., and Herbomel, P. (2010). Blood stem cells emerge from aortic endothelium by a novel type of cell transition. Nature 464, 112–115. https://doi.org/10.1038/nature08761.

3.   Lancino, M., Majello, S., Herbert, S., De Chaumont, F., Tinevez, J.-Y., Olivo-Marin, J.-C., Herbomel, P., and Schmidt, A. (2018). Anisotropic organization of circumferential actomyosin characterizes hematopoietic stem cells emergence in the zebrafish. Elife 7, e37355. https://doi.org/10.7554/eLife.37355.

4.   Torcq, L., Majello, S., Vivier, C., and Schmidt, A.A. (2024). Tuning apicobasal polarity and junctional recycling in the hemogenic endothelium orchestrates the morphodynamic complexity of emerging pre-hematopoietic stem cells. Elife 12, RP91429. https://doi.org/10.7554/eLife.91429.

5.   Staneva, R., and Levayer, R. (2023). Cell polarity and extrusion: How to polarize extrusion and extrude misspolarized cells? Curr Top Dev Biol 154, 131–167. https://doi.org/10.1016/bs.ctdb.2023.02.010.

6.   Campinho, P., Vilfan, A., and Vermot, J. (2020). Blood Flow Forces in Shaping the Vascular System: A Focus on Endothelial Cell Behavior. Front Physiol 11, 552. https://doi.org/10.3389/fphys.2020.00552.

7.   Butko, E., Distel, M., Pouget, C., Weijts, B., Kobayashi, I., Ng, K., Mosimann, C., Poulain, F.E., McPherson, A., Ni, C.-W., et al. (2015). Gata2b is a restricted early regulator of hemogenic endothelium in the zebrafish embryo. Development 142, 1050–1061. https://doi.org/10.1242/dev.119180.

8.   Gao, L., Tober, J., Gao, P., Chen, C., Tan, K., and Speck, N.A. (2018). RUNX1 and the endothelial origin of blood. Exp. Hematol. 68, 2–9. https://doi.org/10.1016/j.exphem.2018.10.009.

9.   Torcq, L., and Schmidt, A. (2025). Single Molecule Fluorescence In Situ Hybridization Using RNAscope to Study Hematopoietic and Vascular Interactions in the Zebrafish Embryo and Larva. BIO-PROTOCOL 15. https://doi.org/10.21769/BioProtoc.5269.

10. Isogai, S., Horiguchi, M., and Weinstein, B.M. (2001). The Vascular Anatomy of the Developing Zebrafish: An Atlas of Embryonic and Early Larval Development. Developmental Biology 230, 278–301. https://doi.org/10.1006/dbio.2000.9995.

11. Hernández, P.P., Strzelecka, P.M., Athanasiadis, E.I., Hall, D., Robalo, A.F., Collins, C.M., Boudinot, P., Levraud, J.-P., and Cvejic, A. (2018). Single-cell transcriptional analysis reveals ILC-like cells in zebrafish. Sci Immunol 3. https://doi.org/10.1126/sciimmunol.aau5265.

The post Delving into the complexity of hematopoietic stem cell genesis, fate, and developmental niches: novel insights from the zebrafish embryo and larva appeared first on the Node.

What is this?

A high magnification video of a zebrafish embryo demonstrates sensory neurogenesis in the developing nose (olfactory epithelium), with newly forming neurons labeled in orange and blue cells indicating high Notch signaling activity. The developing eye is also visible nearby. The olfactory epithelium houses remarkable levels of neuroregeneration, including in humans, and is a robust model for investigating the molecular pathways that drive continuous neuronal renewal.

Where can this be found?

Zebrafish are ray-finned fish that are native to freshwater habitats in South Asia and are widely used as vertebrate model systems due to their high degree of genetic similarity to humans. We use a suite of tools to genetically manipulate the organisms, and the optically transparent embryos are amenable to high-resolution microscopy.

How was this taken?

We performed live confocal microscopy of transgenic zebrafish embryos at 2 days post-fertilization (dpf). The embryos expressed red fluorescent protein (orange) in olfactory sensory neurons and destabilized green fluorescent protein (blue) in cells with active Notch signaling. Images were acquired at regularly spaced time intervals for 15 hours using a Zeiss LSM 800 confocal microscope and stitched together to make this timelapse video.

What happens during olfactory sensory neuron (OSN) development?

We discovered that during olfactory sensory neuron (OSN) development, discrete groups of progenitor/stem cells communicate with each other via a unique Notch/Insm1a signaling module to form neighborhoods of cells that act as hot spots of neurogenesis (generation of new neurons). Retinoic acid signaling from the nearby eye influences this intricate process of new OSN formation, and BDNF (brain-derived neurotrophic factor) signaling helps guide new neurons to their final destinations.  

Why should people care about this?

Neurodegenerative disorders are strongly associated with the depletion of neurons across the nervous system. Interestingly, while olfactory sensory neurons (OSNs) are known to be highly regenerative, the loss of smell is often an early indicator of potential neurodegeneration. As a first step to understanding this apparent paradox, we aimed to uncover how new OSNs are generated. Additionally, we hope to discover conserved pathways that might aid neuroregeneration in other organ systems. Finally, our observations of the close coordination and exchange of signals between the nose and the eye shed light on the importance of inter-organ communication for neurogenesis.  

How would you explain this to an 8-year-old?

Our noses have tiny nerve cells that detect different kinds of smells that help you enjoy pizza or not enjoy medicine. While zebrafish don’t eat pizza (as far as we know), they have those types of cells, too. Because you can see through zebrafish pretty well, we can put them under a fancy microscope, watch those nerve cells get made, and learn how that happens. What we learn then allows us to think of ways to make new nerve cells that could help people and keep them healthy.

Where can people find out more about it?

You can read our recent paper in Stem Cell Reports https://www.cell.com/stem-cell-reports/fulltext/S2213-6711(25)00179-1; read a short news story about it https://www.uab.edu/news/research-innovation/sniffing-out-how-neurons-are-made; and check out the fun journal cover image https://www.cell.com/stem-cell-reports/issue?pii=S2213-6711(24)X0010-7#fullCover

To follow other research projects from the Saxena lab, go to www.saxenalab.com

The post Sniffing out olfactory neurogenesis appeared first on the Node.

The question

You may know the axolotl (Ambystoma mexicanum), its funny face and gills floating around its head.

What you may not know is that it is also a model organism for organ regeneration thanks to its ability to regenerate many body parts, including its limbs. This is possible because cells know and remember where they are and can use this knowledge to inform the regeneration process. Cells found at the front of the limb possess so-called anterior identity, while those at the back hold posterior identity information. After amputation, cells from the anterior and posterior parts of the stub meet and trigger correct limb regeneration.

But how do cells know to produce a new limb after limb amputation, and not a tail or head instead?

The molecular bit

A recent study by Otsuki and colleagues¹, highlighted in a News & Views article², investigates the process of limb regeneration in axolotl through transgenic lines, transcriptomics and grafting experiments.

Otsuki and colleagues found that posterior identity in axolotl is established and maintained by a positive feedback loop that involves Hand2, a protein that controls the expression of other genes, and Shh (Sonic hedgehog), a signalling protein involved in limb growth. During development, Hand2 is expressed in posterior cells, and it is present at a steady state in adults. During regeneration, Hand2 is necessary and sufficient to induce the expression of Shh, which in turn activates Hand2 expression in nearby cells, sustaining the establishment of posterior identity in the new limb. After regeneration, Shh expression stops but residual Hand2 ensures lasting positional memory.

The unexpected discovery and why it matters

Interestingly, Otsuki and colleagues were able to rewire anterior-posterior memory, but only during regeneration and in one direction: anterior cells can stably acquire posterior identity when placed in posterior zones (or upon transient Shh signalling), but the opposite leads to defective limb regeneration.

The results presented by Otsuki and colleagues represent an important step forward in the understanding and manipulation of organ regeneration, and future studies into therapeutic applications in humans will benefit from this important work.

References

1. Otsuki, L., Plattner, S. A., Taniguchi-Sugiura, Y., Falcon, F. & Tanaka, E. M. Molecular basis of positional memory in limb regeneration. Nature 1–9 (2025) doi:10.1038/s41586-025-09036-5.

2. Wu, S. Y. C. & Whited, J. L. How axolotl cells ‘remember’ development to rebuild a lost limb. Nature d41586-025-01447–8 (2025) doi:10.1038/d41586-025-01447-8.

The post Limb regeneration guide for axolotls appeared first on the Node.

We are all stepping into a story where evolution, development, and regeneration converge in the eye of a snail.

Throughout their lives, organisms encounter injuries and stresses that threaten the integrity of their bodies and have evolved remarkable ways to restore lost or damaged tissues. This ability to replace body parts, which can range from reorganizing existing structures to generating entirely new ones—is known as regeneration.

Among many forms of regeneration, the ability to rebuild eyes is especially striking. Eyes are among the most intricate organs, requiring precise anatomical organization and highly ordered neural wiring to restore function. Across the animal kingdom, eyes vary widely, reflecting adaptation to different ecological demands. While regeneration of simpler structures, such as planarian pigmented eye cups, and partial regeneration of camera-type eyes in vertebrates has been described, the idea that complete adult camera-type eyes could regenerate has long seemed improbable. These highly specialized organs, capable of high-resolution vision, present unique challenges that extend beyond conventional models.

In a recent groundbreaking Nature Communications study, Alice Accorsi, Alejandro Sánchez Alvarado, and colleagues demonstrate that the apple snail, Pomacea canaliculata can completely regenerate its camera-type eyes. By coupling this discovery with CRISPR–Cas9 genome editing, they establish a new genetically tractable model to probe regeneration of complex sensory organs. Here are behind the scene stories from the corresponding authors – Dr. Alice Accorsi and Dr. Alejandro Sánchez Alvarado.

First we have behind the science stories from Dr Alice Accorsi !

How did you first get introduced to apple snails, and what drew you to them? Tell us about your PhD work.

Throughout my career I have worked with several invertebrate species, such as snails, leeches and planarians. These apple snails are originally from South America, particularly Brazil and Argentina, but have now spread to parts of Asia, Europe, and North America, where they pose a serious threat to local ecosystems. The same traits that make them invasive, such as resilience, rapid growth and prolific reproduction, also make them easy to care for. And it turns out this also makes them excellent laboratory models. My PhD mentor, Dr. Enzo Ottaviani, once purchased some apple snails from a pet shop and had them in his office. It was during one of our meetings that we wondered if we could use them as another invertebrate in my research! During my graduate studies, I was interested in studying their immune system to understand what makes them so resilient and to explore ways to affect their survival without using environmentally harmful compounds. I was also intrigued by the possibility that their immune and nervous systems might communicate with each other, as we see in vertebrates. My research uncovered evidence of this crosstalk, offering a new evolutionary perspective on neuroimmune interactions.

What convinced you to keep working with snails in your research – even during post doc and now in your independent research program as a faculty? What led you to the Sánchez Alvarado lab?

This journey began with a conversation between Dr. Alejandro Sánchez Alvarado (Stowers Institute for Medical research, Kansas City, MO) and me at the Marine Biological Laboratory in Woods Hole, MA. I was still a graduate student at the time, studying the immune system of apple snails, while Alejandro’s laboratory was focused on regeneration in planarians. Although snails have been known for their regenerative abilities since the 1700s, no one had explored their biology using modern molecular tools. That conversation sparked my interest in applying these approaches to snails to see what we could uncover.
We already have several model systems that excel at regenerating different body parts, such as planarians, hydras, and axolotls. I began to wonder whether these snails could regenerate an organ that the others could not, making them unique and even more relevant to study. That is when I discovered that apple snails possess complex camera-type eyes, the same kind of eyes found in humans. This opened up a unique opportunity to explore regenerative biology in a new way, with potential implications for human health. That is what convinced me to continue working with snails, even as I transitioned into postdoctoral and now independent research.

How was your transition from Italy to US for postdoctoral work?

Moving abroad for my postdoctoral studies was a major life change. I left my family behind and immersed myself in a new culture and scientific environment. I moved from a small lab with limited resources where I was the most senior member to the Stowers Institute for Medical Research, a place with nearly unlimited possibilities and a large, diverse team of scientists, including many senior researchers.
Despite the challenges, I never regretted the move. I learned more than I ever imagined and had the chance to connect with scientists across the country and the world. The Technology Centers at Stowers supported my work and introduced me to techniques I had only read about before. I am deeply grateful for the preparation I received through the Italian educational system, which gave me the foundation to take this leap.

What was it like to take on eye regeneration in snails – a phenomenon that hadn’t really been studied in them before?

Taking on a project about complete eye regeneration in snails was both exciting and challenging. Since this phenomenon had not been studied before and this was a relatively novel model system, we had to start from scratch. We began by characterizing the morphology of apple snail eyes using microscopy and histological techniques to understand their structure and cellular composition. Then, we performed genomic and transcriptomic analyses to identify the genes involved in eye development and regeneration. Finally, we developed techniques to manipulate their genome to test gene function.
This multi-approach research allowed us to build a comprehensive picture of apple snail eye anatomy, gene expression and regeneration, laying the groundwork for deeper investigations into the molecular mechanisms behind this process.

Your genomic analyses revealed genes shared between apple snails, humans, and Drosophila, particularly related to eye development and photoreceptor formation. What does this shared genetic toolkit tell us about the evolution of complex eyes across distant lineages?

Our molecular studies revealed that many genes are involved in forming both snail and human eyes, even though these eyes evolved independently. This suggests that, while there may be many ways to build an eye, the fundamental genetic building blocks are conserved between very different species (humans and snails). These findings have important implications for evolutionary biology. By comparing the development of camera-type eyes in snails, cephalopods, and humans we can shed light on how these complex structures evolved multiple times independently. This helps us identify both conserved mechanisms and evolutionary novelties across species.

Can you describe the moment you first saw a regenerated camera type eye?

Seeing the regenerated eye for the first time was exciting, but in that moment, I was not even close to fully grasp the importance of that one piece of data. It was later on, reading literature and looking through old papers and I started appreciating how this unconventional system could reveal something truly profound about regeneration. That realization was the real turning point that deepened my commitment to this research.

Your experiments showed eye regeneration unfolded in defined stages—wound healing, blastema formation, tissue emergence, and maturation. Did any of these phases surprise you ?

One of the most remarkable aspects of apple snail eye regeneration is how fast, precise, and reproducible it is. After complete eye removal, early signs of regrowth appear in less than two weeks, and a fully reconstructed eye, with all its components, is restored in under a month.
What surprised me most was the efficiency and consistency of this process. The speed at which regeneration unfolds, and the minimal variability between individuals, suggest a tightly regulated mechanism. Just as striking was the discovery that many of the genes active during regeneration are also involved in vertebrate eye development. This points to a shared genetic toolkit and opens exciting possibilities for comparative studies that could inform regenerative medicine.

Your pax6 studies reaffirmed its conserved function, do you think the role of pax 6 is binary ?

In our system, pax6 appears to play a binary role. When pax6 is knocked out, eye development is completely abolished. We did not observe any eye-related structures or any intermediate phenotypes, which underscores how essential this gene is. It is astonishing to see such a conserved function across species.

Do you plan to test the behavioral capabilities of regenerated eyes?

Absolutely. One of our main goals moving forward is to study the behavior and visual capabilities of apple snails. We are planning to collaborate with labs that specialize in behavioral neuroscience and vision to explore what snails can see in their environment and how well regenerated eyes can function.

What challenges did you face developing CRISPR lines?

Establishing stable CRISPR/Cas9 mutant lines in snails was a major technical challenge. A few steps were quite difficult. The first was collecting and injecting the zygotes, as they are very small! The next difficult step was ensuring their survival to adulthood after we removed them from the eggs. It took a lot of trial and error. Each step required patience and precision, but eventually, we developed a reliable workflow that allowed us to generate reproducible mutant phenotypes.

How do snails complement fly eye development in other model systems like Drosophila?

While Drosophila has been a powerhouse for studying eye development, its compound eyes are anatomically different from human eyes. Moreover, adult fruit flies do not regenerate their eyes after injury. Apple snails, on the other hand, have camera-type eyes, just like us, and can regenerate them completely.
This makes apple snails a powerful complementary model. Their regenerative abilities, combined with shared genetic pathways, offer a unique window into how complex organs can be rebuilt. Studying molecular pathways involved in eye formation and function across such diverse species helps us identify conserved mechanisms and evolutionary innovations, expanding our understanding of how regeneration evolved.

What was your most validating moment in this project?

The most emotional moment of this project was when I obtained pax6 homozygous mutants. I looked in the microscope without daring to hope for anything special. But after getting the embryos in focus, I saw that some of them did not develop eyes. That was the moment I knew CRISPR/Cas9 was working and the function of the gene pax6 was conserved in apple snails. It was incredibly validating and empowering. That was the moment when I truly felt I could start thinking about “the rest of my scientific career” as the leader of a lab using apple snails to study eye regeneration.

Can you share some challenging moments from the project. What were your ways to reset/unwind ?

One of the biggest challenges of this research was figuring out how to collect, inject and raise snail embryos to adults. This was a long, slow and meticulous process. I spent hours carefully observing embryos trying to pinpoint what was not working and letting the biology guide the adjustments. I for sure learnt patience and resilience through this process.
Outside the lab, I love to do yoga, listen to audiobooks and spend time with the people I love. These moments help me recharge and return to the lab with fresh energy.

Were there any quirky moments that shaped the trajectory of the study?

A quirky moment that shaped not just this study but of my entire career happened during graduate school. I was so excited about regeneration after attending the MBL Embryology Course in Woods Hole that I immediately wanted to test if the apple snails I was working on were able to survive injuries and regenerate. I got dissection scissors and… well, luckily for me and for them, they regenerated!

How did your team coordinate such a complex study?

At Stowers, I had incredible support from the Technology Centers, which helped optimize protocols, run experiments and maintain the snails. At UC Davis, we also have excellent core facilities for imaging and sequencing, but the members of my lab play a central role in all the work that we do. I encourage everybody on my team to learn all aspects of research, from animal husbandry, to sample processing and data analysis. Through this approach I aim to foster collaboration and independence.

What big questions are you excited to explore next?

Some of the key questions I hope to answer about apple snail eye regeneration revolve around uncovering the fundamental biological mechanisms behind this remarkable process. One major area of interest is identifying the specific cell types responsible for regenerating all the eye components: the retina, lens, and cornea. Understanding whether these structures arise from a shared pool of cells or from distinct cell populations is essential to understanding how such complex tissues are rebuilt.
Equally important is exploring the genes involved in the regeneration process and how they are regulated. Dissecting these molecular circuits could reveal conserved pathways and highlight potential targets for biomedical applications.
Another critical question is how neural connections between the regenerated eye and the brain are re-established. While regenerating the physical structure of the eye is impressive, full functional recovery requires precise reintegration into the central nervous system. Studying how apple snails accomplish this could provide valuable insights into nervous system regeneration.
Finally, one of the most exciting prospects is the potential to identify specific genes or regulatory elements that can be tested in species lacking natural regenerative capacity. By comparing regenerative and non-regenerative systems, we may uncover key factors that could one day be harnessed to promote regeneration in humans.

Anything you’d like to highlight about your lab?

We are always interested in hearing from people who are excited about development, regeneration and snails and who would be interested in joining our team or collaborate with us! We highly value basic science, curiosity, creativity and community.

Now we have behind the science stories from Dr Alejandro Sánchez Alvarado !

You’ve pioneered much of what we know about planarian regeneration. What motivated you to pivot toward the apple snail? What were your initial plans when you and Alice started the project?

Curiosity has always driven my research. After years delving into planarian regeneration, I wanted to take the lessons learned and test their validity in other systems. I knew from the work of Charles Bonnet (Observations sur la Physique, sur l’ Histoire Naturelle et sur les Arts, vol. 10, Paris, 1777, in Tracts on the Natural History of Animals and Vegetables, 2nd, ed., vol. II, Edinburgh, 1803, plate 8, p. 360) that some snails could regenerate their heads after decapitation. Given that such a head included complex sensory organs such as camera type eyes, I was intrigued to see how much regeneration was possible in snails and thought of it as a great opportunity to test how far fundamental principles of regeneration extend beyond our favorite models. When Alice and I initiated the project, we aimed to develop the apple snail into a powerful system, one where we could explore not only eye regeneration but new rules for organ complexity and repair.

Having studied planarians extensively, what similarities and differences strike you most between their eye regeneration and what you observed in Pomacea canaliculata?

In planarians, eye regeneration is fairly direct, that is, the structure is simple, and the set of participating cells is relatively constrained. Apple snail eyes, in contrast, are much more anatomically elaborate: they possess a lens, cornea, and a retina. Despite these differences, we observed the employment of a surprisingly conserved genetic toolkit, yet the deployment is tailored to the organism’s needs and eye architecture. While planarians offer lessons in simplicity and robustness, snails challenge us to understand regeneration in complex, multi-tissue architectures.

As you said, snail eyes are highly organized with a lens, cornea, and retina. How did you approach regeneration of a complex organ? What were your reactions when Alice and the team showed you the eye regeneration phenotype? How did you celebrate?

We approached snail eye regeneration with a mix of excitement and humility. Knowing the added complexity, our first step was to characterize the anatomy and developmental processes in exquisite detail, as we’d done in planarians. When Alice showed me the early phenotypes (eyes regrowing with partial or complete restoration of layers) it was exhilarating. There was a sense of witnessing something extraordinary, something no one had seriously documented in this way before. We asked ourselves: if this is the wild type (eye regeneration) imagine what phenotypes will we get once we can begin to genetically perturb this process? We celebrated in true lab fashion: with data, good coffee, and a shared sense of purpose.

For the broader scientific community, how important it is to move beyond conventional systems towards models which are more “problem suited”?

I believe science advances most meaningfully when we select models tailored to address questions, not just because they’re easy or fashionable. Apple snails forced us to reconsider mechanisms dogmatically ascribed to “higher” animals. For example, we unexpectedly found developmental modules acting outside canonical developmental windows, hinting at a flexibility in the animal’s response to injury or loss. Integrating these observations required both developmental and regenerative frameworks to be more plastic and open to revision. In essence, exploring unconventional systems not only expands our sense of what is possible in biology, but also reminds us, quite humbly, that we have yet to discover the full scope of what biology is already capable of achieving.

Across planarians, snails, and vertebrates, pax6 seems to act as a unifying thread in eye development. How do you see your work helping to connect these very different models into a broader evolutionary framework?

Pax6 is a beautiful example of deep homology: one gene at the crux of eye development in organisms as disparate as worms, snails, and humans. Our work allows us to chart the variations on a theme: the “melody” played by pax6, for example, shifts based on the “instrument.” This comparative approach helps trace evolutionary logic in how complex traits are built, lost, or re-invented, and fosters a more unified evolutionary understanding.

Was there a moment in this project that reminded you of your early planarian work—perhaps seeing the first signs of tissue re-emergence or recognizing a familiar gene playing a role in an unexpected context?

Absolutely. Seeing the initial re-emergence of eye tissue in snails, especially with familiar candidates like pax6 lighting up, evoked the earliest days in our planaria research. There’s a special thrill in spotting a familiar genetic face performing in a new “play.” These moments reinforce just how interconnected biology’s solutions really are. Perhaps more importantly, it presses us to recognize that, among countless possible outcomes, biology did not have to unfold in precisely this way, yet it did. The question, then, is why? What fundamental principles have shaped these solutions over evolutionary time, and might there be yet-undiscovered rules underlying these phenomena that the study of regeneration could help us uncover?

Do you imagine a comparative roadmap, linking regeneration in planarians, snails, and vertebrates, that might one day illuminate how regenerative capacity has been gained or lost across the tree of life?

One of my greatest hopes is for the field to embrace genuine comparative biology across multiple scales and levels of resolution—a comprehensive roadmap that interweaves regeneration in planarians, snails, vertebrates, and beyond. By charting where regenerative capacity is retained or lost, and probing the underlying reasons, we may finally decode the molecular signatures and constraints that shape these outcomes. This is an ambitious, long-term vision that traces its roots back to my earliest work (BioEssays, 22:578–590, 2000).

How do you look at processes of regeneration and development – where do they overlap, and where do they diverge?

Regeneration recapitulates development, sometimes literally, often figuratively. There are clear overlaps in gene regulatory networks and cell behaviors, but crucial divergences arise: injury response, aged tissue, functional integration of new tissues with old, and organismal context all shape outcomes. Examining both processes in parallel ensures our interpretations remain grounded and discerning, fostering an appreciation for both their commonalities and their distinctions.

You’ve mentored so many students and postdocs who have gone on to start their own labs and do incredible science. What is your mentoring philosophy?

Mentoring is, without question, the most rewarding aspect of this work. Science is inherently a human pursuit, and watching students and postdocs mature into independent thinkers is the ultimate measure of success. My approach centers on fostering autonomy, intellectual rigor, and genuine kindness. My greatest hope is that everyone who passes through my lab carries forward a deep sense of curiosity, confidence, and thoughtful skepticism wherever their careers take them. To me, choosing to mentor means embracing the responsibility to help cultivate scientists who will one day surpass us and, in doing so, move the field forward in ways we have yet to imagine.

Experiments don’t always work, and science can be frustrating. How do you help your students and trainees stay curious, motivated, and resilient during unfavorable circumstances?

I frequently remind my lab that failed experiments are the tuition we pay for discovery. I encourage tenacity by fostering a culture in which failures are shared, analyzed, and celebrated as learning opportunities. Curiosity is self-sustaining if it’s nurtured, and joy in small wins (finding a new phenotype, seeing cells behave unexpectedly) is kept front and center. It is important to emphasize that both true innovation and robust, lasting knowledge are built bit by bit, through careful testing, iterative refinement and the willingness to work patiently in the face of complexity, particularly when the prevailing winds conspire against such efforts. Our job as scientists is to contribute and continue to build a legacy of discovery that is as relevant tomorrow as it is today.

What do you find most awe-inspiring about nature’s capacity to regenerate, and how does that influence the way you think about biology?

To witness a fragment of an animal regenerate into a complex, living structure is to brush up against the truly profound. These moments evoke a sense of philosophical awe, as life reasserts itself with ancient, elegantly orchestrated mechanisms. Nature’s answers to damage and loss inspire both humility and an unshakable urge to understand how such feats are possible. In this light, every act of regeneration becomes a fresh retelling of an ancient narrative, one that has unfolded, again and again, across the history of life on Earth.

What continues to drive your curiosity and excitement about regeneration after all these years?

It’s the interplay of questions, the unexpected twists, and the pure delight in discovering something genuinely new. Regeneration is a frontier: every answer spawns new mysteries, and the joy of discovery, whether majestic or subtle, never fades.

A note from Shefali : I came across this beautiful research paper by Accorsi et al on bluesky and it literally blew my mind. It’s one of the rare times in the year when you stumble upon a piece of science that reminds you why you chose this path in the first place. As a grad student who is in the last leg of their PhD, it’s easy to to lose sight of the bigger picture – this paper brought it all back. I urge you all to read it—it’s rare and remarkable. Check out the Accorsi lab webpage and reach out if you’re interested in studying development and regeneration in snails.

The post In the apple eye of evolution: Camera-type eye regeneration appeared first on the Node.

Hi there,

I’m Ingrid and I’m very happy to be introducing myself as the new Reviews Editor for Development. I will mainly be working behind-the-scenes with authors to commission and produce our six (!!) different kinds of review-type content. You may also hear from me about research highlights, interviews and other such matters.

I have just moved to Cambridge from Copenhagen, Denmark (swapping one cycling city for another) where I did a PhD on Wnt signalling and tissue dynamics in intestinal stem cell homeostases (yes, that is meant to be plural). As part of my PhD, I also carried out research with the Medical Museion on science communication and the social science of stem cell and developmental biology research.

Prior to my doctoral adventures, I studied (predominantly zebrafish) blood and cardiovascular development before moving on to projects on tissue injury and repair more generally. I’m excited to be returning to my roots in developmental biology and putting my broad interdisciplinary perspective to good use in creating thought-provoking and timely review articles for the community to read.

I’m very much looking forward to getting to know the developmental biology and stem cell research community better, and am especially keen to expand my horizons in the plant biology and evo-devo fields. Please feel free to get in touch if you have any questions, suggestions for what you’d like to read about, or just want to say hi!

The post Introducing Ingrid – the New Reviews Editor for Development appeared first on the Node.

Toshi Yamada (University of California San Francisco)

Daniel Medina-Cano (MSKCC)

The post Catch up on Development presents… webinar on stem cells and organoids appeared first on the Node.

Join us to hear three early-career researchers speaking on the topic of stem cells and organoids, chaired by Yuchuan Miao. One of Development’s first PI fellows, Yuchuan is an Assistant Professor in the Department of Cell Biology at Johns Hopkins School of Medicine. Yuchuan’s lab uses stem cells to study human vertebral column development.

Wednesday 13 August – 16:00 BST

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 post Development presents… stem cells and organoids appeared first on the Node.

Emerging perspectives in metabolism

This week we’ll meet Anna-Lena Vigil, who is a PhD candidate in the Crocker Group, EMBL. From her postbac days in Seattle to her graduate research in Heidelberg, metabolism has remained her throughline: a dynamic system that powers cells, guides their fate, and adapts across contexts, from cancer to development. What drives her is the vastness of unanswered questions — the sense that even well-mapped pathways hold surprises when viewed through the lens of adaptation, evolution, or cell identity. Her first spark came in a college biochemistry class, where she realized metabolism wasn’t just “organic chemistry with a purpose,” but a living system at the heart of biology. That curiosity led her from studying gene regulation in plants to investigating how metabolism drives cancer cell proliferation at the Fred Hutchinson Cancer Center, Seattle. Along the way, she discovered how mentorship and the freedom to explore questions could transform a research career. Now, as a graduate student at EMBL in Heidelberg, Anna explores how metabolic signals guide cell fate decisions during development — and how these processes can adapt and evolve. In this first part of our conversation, Anna reflects on her scientific journey, the questions that drew her in, and why metabolism remains her lens for exploring life’s complexity using Drosophila as a model. In this first part of our conversation, Anna reflects on her scientific journey, the questions that drew her in, and why metabolism remains her lens for exploring life’s complexity. Check out all her work here.

Anna’s interview is a two part conversation, while you’re currently reading part 1 where she discusses her scientific journey, do check out the part 2 Between Molecules and Milestones, where she describes in detail – her journey to grad school, her continued interests in the field of metabolism, why she values curiosity and mentorship, and what keeps her motivated to continue moving forward.

What was your first introduction to the field of metabolism – what’s your first memory?

Outside of learning that the mitochondria is the “pOwErHoUsE” of the cell in high school biology class, my first introduction to metabolism started in my first biochemistry class at the University of Nevada, Las Vegas during my bachelor studies. My professor jokingly described the subject material of his class one day as: “organic chemistry but with a purpose.” During my time in this class, I was fascinated to learn how biological systems have figured out these extremely intricate ways of sustaining life through various different metabolic processes. It was after this class that I knew I wanted to learn more about how biochemical processes that make up metabolism can be the driving force of life on Earth.

Could you share your journey into studying metabolism and what inspired you to specialize in metabolic studies using two incredibly unique systems – mammals/cell lines and flies?

After my undergraduate studies, I was really interested in diversifying my research experiences in the early stages of my career. After studying gene regulation and stress tolerance in plants, and hibernation in a peculiar hibernator during my undergraduate research journey, I was really interested in understanding how metabolism can shape phenotypes, and how it may provide insight to help broaden our knowledge of disease mechanisms. So, with this in mind, and of course a stroke of good luck, I joined Lucas Sullivan’s lab as a research technician at the Fred Hutch Cancer Center in Seattle, where the lab’s main area of focus was understanding metabolic determinants of cancer cell proliferation. It was there where I learned of mechanistic details of how metabolism occurs in real systems, and how it can go wrong to lead to disease phenotypes, such as cancer. I think my drive for understanding metabolic systems really flourished in Lucas’s lab, as he was a great mentor and allowed me the resources and flexibility to pursue my own interests and curiosity. His passion for metabolism was infectious and he had a special way of promoting this same passion within his own lab members. Having a good mentor can really determine the rest of your research career! And after gaining a more informed mechanistic understanding about cancer metabolism, I wanted to learn more about physiological metabolic programs throughout development, so naturally using Drosophila as a model to learn more about this was a good way to transition from cancer metabolism to developmental metabolism.

Tell us about your undergrad/postbac work – particularly about the role of mitochondrial redox adaptations in regulating cellular fitness in the context of both normal and tumor cells.

The work on mitochondrial redox adaptations was an amazing project that was led by Dr. Madeleine Hart, a very talented graduate student in the Sullivan Lab at the time. She was primarily interested in understanding how certain subtypes of cancers, in particular, succinate dehydrogenase (SDH)-deficient cancers, were able to sustain intracellular aspartate when a major mitochondrial protein responsible for generating aspartate, was defective. SDH is also known for its role as complex II in the electron transport chain (ETC) in the mitochondria, and is responsible for the oxidation of succinate to fumarate. Fumarate is then later converted into malate and finally oxaloacetate, which is used to generate aspartate, a key amino acid that is required for cell proliferation. So, understanding how cancers with abnormal ETC activity sustained intracellular aspartate levels gave us an opportunity to learn more about the basic biology driving these types of cancers. In a glimpse into Madeleine’s work, she discovered that SDH-deficient cells were able to adapt to limiting environments by also adapting to downregulate the activity of complex I in the ETC. This downregulation resulted in restoring the NAD+/NADH balance to support further cancer cell proliferation. While we did not investigate this phenomenon in normal cells, the aspects we learned about how cell proliferation can be sustained in these scenarios helped provide insights into the broader theme of cellular adaptation to varying environments, in both normal and disease contexts.

The project I primarily worked on during my time as a technician included discovering novel metabolic fates in NRF2-activated cancers. As we all know that key metabolites and the components of metabolic pathways of cells have been known for decades, there are likely still metabolites, and entire metabolic pathways that are yet to be discovered. This is especially important when we think about how alterations in metabolism can lead to various human diseases. So to tackle the goal of trying to identify novel metabolites, we were interested in finding a system in which unknown metabolites likely existed, and so we decided to turn our attention to NRF2-activated cancers. NRF2 is a main transcription factor that regulates the production of various different antioxidants and detoxification programs. In the process of upregulating these detox mechanisms, one key target gene of NRF2 includes the xCT/SLC7a11 antiporter system, that is responsible for the uptake of extracellular cystine, and the excretion of glutamate. So with this in mind, and with the help of a clever isotope tracing method, we were able to uncover and validate ~9 novel metabolic fates, some of which can be detected in tumors. Also in this work, we learned very interesting aspects of intracellular cystine/cysteine that may help broaden our knowledge of cell proliferation mechanisms and metabolic phenotypes in cancer. I was very grateful to have been able to work on this project with such an amazing team, and hopefully you can read all about it soon!

Tell us how you got interested in cancer/immune metabolism for your post-bac work and how did you transition into Drosophila to study metabolic control of cell fate decisions?

For me, many aspects and fields of scientific research are extremely fascinating, but I decided to pursue metabolic research because I felt as though it viewed biology at the most molecular level in order to understand how life occurs. Many foundational concepts of metabolic programs that we know today were discovered using cancer model systems and in the context of cancer biology, so I felt as though joining a lab that studied cancer metabolism was a great way to enter the field. Although I greatly enjoyed my time working on how metabolism can be rewired to drive diseases, I wanted to learn about metabolic systems more from a normal physiological perspective, for example, in the context of developmental programs. In other words, I wanted to change from understanding how metabolism can go wrong (for a patient) and lead to disease, to learning about all the ways that metabolism can go right and facilitate the development of a whole organism from one single cell.

Metabolism is generally viewed as the sum of biochemical reactions that occur within cells and organisms to provide energy in the form of ATP, with the production of anabolic precursors and maintenance of NAD(P)+/NAD(P)H co-factor pools. A less appreciated view of metabolism is that metabolites themselves can act as signaling molecules to facilitate the up- or downregulation of other cellular processes. As certain cell types become more differentiated, so do their biological roles and needs, which at the root is driven by the utilization of alternative metabolic pathways. As someone who appreciates just how nuanced and complex biology can be, it was reassuring to learn that metabolism is also something that is extremely multifaceted, with new metabolites, roles of metabolites, and metabolic systems that are emerging everyday.

Tell us about your current work and how are you using flies as a model to study physiological consequences of metabolic signaling and its impacts cellular status and development?

My current work is about understanding how mutations in the genome can lead to altered metabolic states, and how these altered metabolic states can be inherited through generations. Mutations are thought to be the driving force of evolution; as mutations in coding regions are thought to affect mature RNAs or protein, noncoding mutations, or cis-regulatory mutations, are thought to affect the levels of transcription, acting as a knob to fine-tune expression programs throughout development. For my PhD work, I am interested in understanding how these mutations can lead to altered metabolic phenotypes, and in particular, how metabolism can be rewired to accommodate adaptive phenotypes, and how these adaptations can persist and lead to evolutionary novelties. These broad questions are especially important when considering natural Drosophila populations that are exposed to various different agrochemicals that are used in modern-day agricultural practices. I am interested in understanding how mutations in regions that are associated with detoxification programs affect adaptive phenotypes in the form of agrochemical resistance. These types of questions can hopefully assist us with understanding resistance mechanisms in natural populations, and how we can potentially use this knowledge to better design more targeted approaches when trying to combat agricultural pest species. Although this specific aim is not super relevant to human disease, learning about resistance mechanisms in general can provide insights into how certain aspects of this mechanism can potentially be conserved to humans and may help provide orthogonal evidence to understanding these mechanisms in general.

Your work intersects metabolism, development and cell biology. How do these fields overlap and how do you integrate these disciplines in your research, and what unique insights have emerged from this approach?

In my view, the field of metabolism is so deeply connected with every aspect of biology that when you think of any phenomenon in a biological system, there is a  metabolic contribution to it. This is especially interesting when considering a developing organism, and how it has figured out methods to perfectly coordinate its metabolic needs in order to facilitate the existence of multiple cell types at once. As every cell type emerges throughout a given developmental program, the metabolic needs of each one of those cell types changes to then carry out more specialized functions. For example, mutations that affect metabolic systems which arise in the germline of a fly may or may not have an immediate impact on certain processes early in development, but then those changes are more apparent when certain cell types become more differentiated and specialized. As my work focuses on how mutations can impact metabolic phenotypes, understanding how these impacts manifest in different developmental stages will provide a more complete picture of the physiological mechanisms at play.

You have worked with both in-vivo and in-vitro systems. Tell us about their roles and how important it is to study both in the context of both normal development and diseases?

In vitro and in vivo systems both have their pros and cons. In my experience, working with in vitro cell culture was an easy way to get a generalized picture of how basic cell biology occurs and what aspects of metabolism are altered in the face of perturbation in the most basic biological level. Also, cell culture is actually very easy, as you just have to split your cells before confluence, switch out media, and freeze the cells when you don’t need them. In vitro systems do allow you to interrogate a disease space without the ethical constraints associated with testing ideas in actual patients, so it is still a very powerful method to test hypotheses about disease mechanisms.

In vivo systems, such as Drosophila, are a bit more difficult to maintain, but also more interesting in the context of multicellularity and development. Flies have longer generation times than cells in a dish, so it could be a few months before you have your transgenic line needed for your experiments. However, Drosophila do provide a very testable platform to study inheritance patterns, the developmental context of specific phenotypes, and metabolic aspects in the context of a whole organism.

Tell us about the experimental approach/techniques you are using for your project.

Luckily for me, Dr. Xueying Li, a previous postdoc in the lab, developed a method which involves fusing transcription factors with a cytosine deaminase domain that induces mutations in proximal regions of specific transcription factor binding sites. This method, termed TF-HighEvolutionary, can be used to induce targeted mutations within networks of interest and can potentially lead to new phenotypic outcomes. My approach involves using this tool in combination with a lab evolution setup, so the hard part will be having to wait a while for cool results to emerge!

Tell us about how you see the future of metabolism evolve with the new upcoming tools.

In my work, I have extensively used various isotope tracing techniques measured by targeted and untargeted liquid chromatography-mass spectrometry (LC-MS), but I think newer techniques that allow you to visualize different metabolites, such as metabolic biosensors or combined spatial assays with cell- or tissue-level resolution, are going to be very useful for the future of metabolic studies.

What are your upcoming plans? What metabolic pathways or signals you aim to investigate further to understand their role in cell fate/cancer progression?

As I worked on the NRF2/antioxidant pathway during my time at the Hutch, I am really interested in investigating this orthologous pathway in Drosophila as well. I am excited to see what physiological aspects of this pathway are conserved, and how it can operate in a non-oncogenic developmental context.

What changes have you seen in the scientific community in regard to studying unique aspects of metabolic signaling in flies?

I think there are many great groups studying many fascinating aspects of metabolic signaling. I really appreciate how the field is moving toward investigating not only specific pathways, but how these pathways are integrated as a system rather than considering them in isolation. I do believe we are moving toward a more nuanced understanding when we consider them on a systems-level and I can’t wait to see what the future holds for the field.

What role does curiosity play in your life, both within and outside of science? What motivates you to be a basic science researcher?

Curiosity is the fuel that keeps all scientists going! Curiosity is crucial to make it through difficult periods that are inherent to science, and I am grateful to have new curiosities to pursue everyday. I think basic science research is the diesel that fuels our societal understanding of the natural world around us. I find it a great honor and privilege to be able to contribute my career to help broaden our collective understanding of how nature works. Knowing that something I observe in the lab may be the first time it has ever been observed is literally the most exciting thing you could experience. To me, there is no better way to spend the day! I believe that basic science questions lay the foundation for the rest of the scientific community to build upon, and aid in advancing our collective health as a society. Without basic science research, the realm of health advances that we have achieved would eventually collapse. Understanding basic principles of how biology occurs in a general sense is the only way we can progress in the fields of health sciences as well, as many basic science and clinical questions overlap. Moreover, I am a huge plant lover and have many plants in my house. I find having plants in my home and seeing all the crazy developmental stages and cell-type changes that occur when you propagate them brings me back to why I find biology so cool!

In the second part of our conversation – Between Molecules and Milestones, Anna reflects on how her training shaped her scientific independence, shares her journey from research in the U.S. to graduate studies in Germany, and discusses how she transitioned — all while holding on to her fascination with the many roles metabolism plays across biology.

Previously we learnt about the role of metabolism in developmental patterning and embryogenesis. Check out – Metabolic Origins: Steering of early developmental fate featuring Kristina Stapornwongkul. Krisitina will be starting her lab at her own lab at IMBA, Vienna and will be hiring soon. Check out her lab page here !

Check out the article All the world’s a metabolic dance, and how early career scientists are leading the way !!

The post Currents of Change: Metabolism shaping cell fate and evolution #MetabolismMondays appeared first on the Node.

Emerging perspectives in metabolism

This week we’ll meet Dr Kristina Stapornwongkul, a new incoming faculty at IMBA, Vienna where her lab will focus on how metabolism influences the dynamic process of embryonic development. Kristina’s journey into the world of biology began with a simple school experiment involving potatoes, iodine, and saliva—an early lesson in the unseen chemical choreography that drives life. Today, she is at the forefront of a rapidly evolving field that explores how metabolism shapes embryonic development. With a background in developmental biology and a growing toolkit of synthetic and molecular approaches, Kristina investigates how cellular metabolism influences stem cell fate decisions during the earliest stages of life. Her recent work using gastruloids – a stem cell-based model of early embryos, reveals how metabolic pathways like glycolysis do more than supply energy; they act as key regulators of signaling and pattern formation. She often refers to metabolites and metabolic enzymes as “moonlighting” agents, highlighting their unexpected and influential roles in directing cellular behaviour. As she prepares to launch her own lab at IMBA in Vienna, Kristina is driven by a deep curiosity about how cells make decisions under changing nutritional conditions, and how robust development is maintained despite metabolic challenges. Through her interdisciplinary lens, she brings fresh insights into how environmental and cellular metabolism shape the blueprint of life. Check out her Lab page here and give her a follow over Twitter and Bluesky. She will be hiring soon at all levels so please reach out to her if you’re interested !

What was your first introduction to the field of metabolism, what’s your first memory?

It was actually the first experiment I ever did in school: an iodine starch test with potatoes. We took a potato slice and applied saliva to one half before adding the iodine solution, which normally turns black in the presence of starch. The half without saliva turned black as expected, while the other half didn’t—showing that something in the saliva had already broken down the starch into simpler sugars. That clear, visual result was such a striking demonstration of how our bodies are built to break down food, and I think that’s why it made such a lasting impression on me.

Tell us how you got interested in the field of nutritional and metabolic aspects of animal development from a cell cycle/cell fate perspective?

I did my Master thesis in the Aulehla lab which did some pioneering work in the field of developmental metabolism at that time. It was a completely new and fascinating concept for me. So even though I didn’t work on a metabolism-related project myself at that time, it really got me interested in that topic.

Your work intersects metabolism, development and cell biology. How do you integrate these disciplines in your research, and what unique insights have emerged from this approach?

To understand how metabolism shapes development, I believe we need to uncover molecular mechanisms at the cellular level and understand how they influence tissue-level behaviour and function. So far, my work has been mainly based on developmental and synthetic biology approaches. Looking ahead, I would like to incorporate mass spec-based readouts and develop new tools to manipulate metabolism in a targeted manner.

Introduce us to the field of embryonic development and how does cellular metabolism influence stem cell behavior and fate decisions during embryonic development. Tell us about your recent work on the relationship between glucose metabolism and signaling pathways during cell fate determination during embryonic development?

In the last decade, it has become increasingly clear that metabolic pathways do more than meet the bioenergetic needs of cells—they also play an active role in regulating differentiation. The underlying mechanisms include metabolite-driven post-translational modifications, metabolite-protein interactions, and moonlighting functions of metabolic enzymes, which can influence the epigenetic and signalling state of cells. Based on this, I set out to investigate whether the metabolic state can significantly impact cell fate decisions during the exit from pluripotency.

Using an in vitro model for gastrulation based on mouse embryonic stem cells (gastruloids), we found that inhibiting glycolysis promotes ectodermal differentiation at the expense of mesoderm and endoderm lineages. This effect is dose-dependent, indicating that germ layer proportions can be modulated by adjusting exogenous glucose levels. We further showed that glycolysis acts upstream of key developmental signalling pathways, including Nodal and Wnt, and that its influence on cell fate can be separated from its effects on growth. DOI: 10.1016/j.stem.2025.03.011.

What evidence supports the idea that glycolytic activity acts as a signaling regulator rather than merely an energy source during gastruloid development and what are the broader implications of glycolysis functioning as an activator of morphogen signaling pathways in early development?

The inhibition of glycolysis resulted in the clear downregulation of Nodal and Wnt signalling targets, which are absolutely required for mesoderm and endoderm specification. This suggested that glycolytic activity might be upstream of morphogen signalling. To test this we tried to rescue the phenotype by activating Nodal or Wnt signalling while inhibiting glycolysis. To my surprise, this restored normal germ layer patterning, even though glycolytic activity and overall growth were not recovered. That indicates that glycolysis is not merely fueling signalling but rather functions as an upstream activator!

Tell us about gastruloids as a model. In your view, what advantages do gastruloids offer for understanding early development and metabolism?

The original work establishing gastruloids as a model is here – https://doi.org/10.1242/dev.113001. For me, stem cell-based model systems are an exciting and versatile tool for studying specific processes during development. Pluripotent stem cells are easy to genetically engineer, which opens the door to powerful synthetic and (opto)genetic tools for controlling metabolism in space and time. Their accessibility makes it possible to observe metabolic and signalling dynamics in real time, and the controlled culture conditions allow us to explore how different nutritional environments influence cell behaviour.

How challenging were the experiments in the paper—both in terms of building or standardizing the model, and in the day-to-day logistics?

Mouse gastruloids are a well-established and robust model system, and they were already up and running in the Trivedi Lab when I joined. Thanks to that, it was quite straightforward for me to start working with them. But I did get great help from others in the lab, especially during revisions. So, it was really a team effort.

What are your upcoming plans – what questions are you excited to pursue in future?

I am currently trying to put together an enthusiastic team and tackle some of the questions I am really excited about: How does metabolism influence cell fate decisions? What is the energetic cost of morphogenesis, and do cells adapt their metabolism to overcome energetic constraints? How robust are developmental processes, such as patterning and morphogenesis, to changes in the nutritional environment? We’ll definitely keep an eye on glycolysis, but I’m also really keen to explore other metabolic pathways and see what else we can discover.

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?

I would say that being curious is one of my most important character trait, and I really cherish it. It’s what drives me to explore new people, cultures, places, and ideas. When it comes to basic science questions, I think curiosity is absolutely essential, since you can’t always rely on other motivations, such as direct applications to human health. For me, basic science questions are usually the most exciting ones, and I wouldn’t want to work on anything that doesn’t truly fascinate me. I guess it comes from the longing to understand how life works. How can that not be exciting J?

How can insights from understanding basic science aspects of early development help us understand the impact of maternal nutrition and metabolic microenvironment on embryonic health and the risk of congenital/metabolic disorders in humans?

I think understanding basic science aspects of early development is absolutely crucial to understand the impact of the nutritional environment on embryonic development on a molecular level. We know since a long time that the maternal nutrition impacts even early stages of embryonic development. What we often don’t understand are the phenotypes and their underlying mechanisms. So, it’s important to support basic science on early development to better understand what goes wrong in suboptimal nutritional environments or during metabolic disorders.

Tell us about how you see the future of developmental metabolism and cell fate evolve with the new upcoming tools.

Development happens in time and space, so I believe that visualizing metabolic dynamics is essential for better understanding the role of metabolism during development. Techniques like spatial metabolomics and the use of biosensors will be incredibly valuable for this purpose.

I’m also really excited about the development of new tools that allow us to manipulate metabolic pathways in a spatiotemporal manner. In my recent work, I developed a genetic tool to restrict glucose availability by leveraging a sucrose-cleaving enzyme from yeast, and I’m eager to further refine and expand this approach in the future.

Were there any pivotal moments that shaped your career path? What’s an unexpected place you’ve found inspiration for your work? What advice would you offer to students and early-career scientists interested in exploring the intersections of metabolism and cell fate regulation?

One pivotal moment was seeing a zebrafish embryo develop during an undergraduate course (thank you, @Gerrit Begemann!). It was so beautiful and fascinating that I immediately wanted to understand how something like that works.

Not sure, whether there is an unexpected place but I like to think about things I don’t understand (including science) when I am moving between places, especially while cycling. Maybe it’s something about being in motion.

For students early-career scientists and actually everyone interested in the intersection of metabolism and cell fate regulation, my advice is to seek as much feedback as possible on your ideas and work. This is a complex and rapidly evolving field, and most of us were trained primarily in either developmental biology or metabolism, but rarely both. Engaging with experts from different backgrounds can really broaden your perspective and strengthen your research.

How do you maintain a balance between your rigorous research activities and personal life?

I really like to do outdoor sports, such as rock climbing and beach volleyball. It helps me to clear my head. 

If you hadn’t embarked on a career in biological research, what other profession might you have pursued, and why?

That’s a tough question—I really love what I do! But if I hadn’t gone into biological research, I think I’d still want a career where I’m surrounded by smart, creative people and constantly learning new things. Whether it was in education, technology, or even the arts, the most important thing for me would be working in an environment that challenges me intellectually and encourages curiosity.

Anything you’d want to highlight for the future !

Yes, I actually will be starting my lab at IMBA Vienna in September! We’ll be looking at environmental and metabolic regulators of embryonic development. There is more info on our website (https://www.oeaw.ac.at/imba/groups/kristina-stapornwongkul). So please reach out if you feel enthusiastic to join the team!

Previously we learnt about the role of metabolism in seasonal adaptations and phenotypic plasticity using two unique insect models – butterflies and budworms. Check out – The season’s script: Tales of Metabolic adaptation (Karin Van Der Burg).

Check out the article All the world’s a metabolic dance, and how early career scientists are leading the way !!

The post Metabolic Origins: Steering of early developmental fate #MetabolismMondays appeared first on the Node.

Behind the Paper Story of “CLAVATA signalling shapes barley inflorescence by controlling activity and determinacy of shoot meristem and rachilla”.

Grasses play a crucial role in human food production and are primarily cultivated for their edible grains. The quantity of grain a grass species can produce is closely linked to the architecture of its inflorescence. Over the course of evolution, grasses have developed a wide variety of inflorescence architectures. From the complex branched inflorescences of the Oryzae tribe (e.g. rice), where multiple grains develop on primary and secondary branches, to the simple spike-type inflorescence of the Triticeae tribe (e.g barley and wheat), where single grains develop on short vestigial axes called rachillae¹ (Fig.1 A).

These architectural differences are established during the early stages of the plant’s development by the activity of meristems, specialised structures leading organ growth. The size, position, and lifespan of these meristems determine the eventual shape of the inflorescence². An example of how small differences in meristem activity can significantly impact the final inflorescence architecture is found within the Triticeae tribe. In barley, the rachilla primordium grows just enough to form a single floret and grain. In contrast, in wheat, its prolonged activity allows for the formation of multiple florets per spikelet, ultimately resulting in its characteristic multi-grain spikelet¹ (Fig.1 B,C).

Figure 1: (A) Schematic representation of different grass inflorescence architectures. Main stem and branches in dark green, grains in light green and rachillae in red. (B,C) Scanning electron microscope images of barley and wheat inflorescences at early stages of development. Different organs comprising a spikelet are coloured (rachilla primordium in red, floret meristem in yellow and lemma primordium in green). Each spikelet develops into a single grain in barley and multiple grains in wheat.

When I joined Rüdiger Simon’s lab to begin my PhD, the group was primarily focused on understanding the role of CLE signalling pathways in regulating shape, size, and maintenance of shoot and root apical meristems in Arabidopsis thaliana. At that time, they had begun extending their research to the cereal plant barley. Gwendolyn Kirschner, a former PhD student in the lab, had started investigating the role of CLE-peptide signalling in barley by generating fluorescent reporter lines, including the barley orthologs of the Arabidopsis CLE40 peptide (HvFCP1) and CLV1 receptor (HvCLV1), which had previously been shown to regulate stem cell fate in Arabidopsis meristems^3,4. While Gwendolyn primarily analysed barley roots, my project focused more on shoot apical meristem and inflorescence development.

In comparison to the simple inflorescence of Arabidopsis, grasses evolved a more complex organisation, with different meristem types leading to the formation of various organs comprising the spikelet, the basic unit responsible for the development of grains in cereals. This observation led us to the questions: “How is the shape and activity of all these different meristems regulated and coordinated to generate specific inflorescences in grasses? Did barley evolve specific CLE/CLAVATA signalling pathways to regulate the activity of different meristem types?”

HvCLV1 regulates meristem activity along the vertical and lateral axes of the barley inflorescence.

I began by mutating the closest ortholog of CLV1 in barley (HvCLV1) as well as other closely related receptors, which we are still investigating. In maize, as in Arabidopsis, mutation of CLV1 or its ortholog leads to a drastically enlarged inflorescence meristem, resulting in the disorganised formation of additional primordia^4,5. In the barley Hvclv1 mutant, I initially observed occasional formation of extra grains within the inflorescence. However, detailed analysis by scanning electron microscopy revealed that an enlarged inflorescence meristem generated an additional row of spikelet primordia, organised in a spiral phyllotaxis rather than in a disorganised manner (Fig. 2A, B).

Moreover, I noticed that Hvclv1 inflorescences developed an elongated rachilla primordium, which produced additional florets per spikelet, an effect previously observed in barley mutants as multiflorus2.b and INTERMEDIUM-m^6,7. These results led me to conclude that the ectopic grains generated by the Hvclv1 mutant were due to increased activity of the inflorescence meristem along the vertical axis and of the rachilla primordium along the lateral axis. To further support this, I imaged mature rachillae from WT and Hvclv1 plants and observed the formation of a meristem-like structure at the tip of the Hvclv1 rachilla, which developed into an actively growing small branch instead of the vestigial hairy structure seen in WT (Fig. 2C, D).

Figure 2: (A,B) Scanning electron microscope images displaying spikelet phyllotaxis (dashed lines) in WT (A) and Hvclv1 (B) early inflorescence tips, combined with photos of the respective final inflorescences. (C,D) Scanning electron microscope images of WT and Hvclv1 early inflorescences. Colours were used to highlight different meristems and primordia (inflorescence meristem in blue, spikelet meristem in violet, rachilla primordium in red, floret meristem in yellow, anther and carpel primordia in brown and pink). Red dashed lines indicate the mature rachilla, combined with zoom-in images where the white arrow indicates the meristem-like structure identified in Hvclv1. Figure modified from Vardanega et. al 2025.

The CLE peptide HvFCP1 acts with HvCLV1 to restrict rachilla primordium activity to the formation of a single floret.

Once the function of the HvCLV1 receptor was characterised, I wondered whether the regulation of rachilla growth was determined by the binding of a specific CLE peptide. Barley possesses 28 different CLE peptides, but I was specifically seeking one that is strongly conserved among grasses and may have contributed to the drastic reduction of branch size in Triticeae. Upon reviewing the literature, I realised that only one peptide retained the same protein sequence across all studied grass species: FCP1⁸. HvFCP1 is the closest ortholog to the Arabidopsis CLE40, for which we already had a fluorescent reporter line. When I examined the expression of HvFCP1 during barley inflorescence development, I noticed that it was not only co-expressed with HvCLV1 but also specifically expressed in the rachilla primordium (Fig. 3 A,B). The insensitivity of the Hvclv1 shoot apical meristem to HvFCP1 peptide treatment, along with the formation of an elongated rachilla producing additional florets even in Hvfcp1 mutants (Fig. 3 C), ultimately demonstrated that HvFCP1 interacts with HvCLV1 to regulate rachilla activity in barley, thereby determining its specific inflorescence architecture.

Figure 3: (A,B) Confocal microscope pictures of barley spikelets displaying HvCLV1 protein localisation (green) and HvFCP1 promoter activity (magenta). The white arrow indicates the rachilla primordium. (C) Hvfcp1 inflorescence displaying double florets (white arrow). (D) RNA seq results. The heatmap shows the z-score of median Transcripts Per Million (TPM) values for each of the Differently Expressed Genes (DEG) in Hvclv1 vs WT and Hvfcp1 vs WT. Black rectangles indicate similarly differentially expressed genes between Hvclv1 vs WT and Hvfcp1 vs WT, with the affected biological processes on the side. Figure modified from Vardanega et. al 2025.

I then investigated which genes are directly or indirectly regulated by HvFCP1/HvCLV1 by performing RNA sequencing on mutant inflorescences compared to wild type (WT). The transcriptome analysis revealed several similarly differentially expressed genes (DEG) between Hvclv1 vs WT and Hvfcp1 vs WT, involved in processes such as cell division, auxin signalling, and trehalose-6-phosphate signalling, providing possible target genes that we are currently investigating (Fig.3 D).

Translating knowledge and techniques from model plants to crops.

In addition to its biological novelty, this paper represents a successful example of translational research, bridging techniques and knowledge from model species to agronomically significant crops. We applied various microscopy techniques more commonly used in model plants, such as Arabidopsis thaliana, but less frequently employed in cereal biology. We developed reporter and complementation lines and quantified receptor cytoplasmic internalisation in rachilla and floret meristems. Furthermore, we utilised methods such as 3D reconstruction and smRNA-FISH for detailed phenotypic analysis of the inflorescence meristem and its expression patterns.

To build on this approach, we generated BARVISTA (http://purl.org/barvista/home), a dataset providing transcriptional information for each cell within the barley inflorescence by integrating single-cell RNA sequencing data with spatial transcriptomics results. Using this resource, we identified transcription factors involved in establishing the specific patterns of meristem ontogenesis necessary to shape the characteristic morphology of the barley spike⁹.

In conclusion, our work shed light on the signalling pathways that regulate the shape and behaviour of individual meristem types within the inflorescence, paving the way for future efforts to engineer inflorescence architecture through targeted regulation of distinct meristem activities.

REFERENCES:

1. Koppolu, R. & Schnurbusch, T. Developmental pathways for shaping spike inflorescence architecture in barley and wheat. Journal of Integrative Plant Biology 61, 278–295 (2019).
   
2. Kyozuka, J., Tokunaga, H. & Yoshida, A. Control of grass inflorescence form by the fine-tuning of meristem phase change. Current Opinion in Plant Biology 17, 110–115 (2014).
   
3. Berckmans, B., Kirschner, G., Gerlitz, N., Stadler, R. & Simon, R. CLE40 Signaling Regulates Root Stem Cell Fate. Plant Physiol 182, 1776–1792 (2020).
   
4. Schlegel, J. et al. Control of Arabidopsis shoot stem cell homeostasis by two antagonistic CLE peptide signalling pathways. eLife 10, e70934 (2021).
   
5. Bommert, P. et al. thick tassel dwarf1 encodes a putative maize ortholog of the Arabidopsis CLAVATA1 leucine-rich repeat receptor-like kinase. Development 132, 1235–1245 (2005).
   
6. Koppolu, R. et al. The barley mutant multiflorus2.b reveals quantitative genetic variation for new spikelet architecture. Theor Appl Genet 135, 571–590 (2022).
   
7. Zhong, J. et al. INTERMEDIUM-M encodes an HvAP2L-H5 ortholog and is required for inflorescence indeterminacy and spikelet determinacy in barley. Proceedings of the National Academy of Sciences 118, e2011779118 (2021).
   
8. Goad, D. M., Zhu, C. & Kellogg, E. A. Comprehensive identification and clustering of CLV3/ESR-related (CLE) genes in plants finds groups with potentially shared function. New Phytologist 216, 605–616 (2017).
   
9. Demesa-Arevalo, E. et al. Imputation integrates single-cell and spatial gene expression data to resolve transcriptional networks in barley shoot meristem development. 2025.05.09.653223 Preprint at Biorxiv https://doi.org/10.1101/2025.05.09.653223 (2025).

The post From Tip to Grain: Sculpting Barley Inflorescence Through the Regulation of Meristem Activity appeared first on the Node.

Chimpanzees are our closest relatives, and closer than most of us would probably like to think about. We share some 98.8% of our DNA with chimps.¹ This means only about 1.2% of our DNA accounts for the uncanny power of our species to build cities, write symphonies, split atoms, and do all the other things we alone do so well. We know that much of this uncanny power resides in our brain, which is massive compared to a chimp’s brain,² and has a much larger wrinkled region at its front³ that does most of our complex “higher” thinking. This wrinkled region at the front of our brains takes almost twice as long to finish developing in us as it does in chimps,⁴ and scientists have long thought that its slow development in humans helps to explain our subtle and adaptable “higher” thinking abilities.⁴ What we do not know is how that meager 1.2% of our DNA goes about making our wrinkly-fronted brains develop so slowly.

For the last two years, a young scientist named Reem Abu-Shamma has been trying to change that. Since graduating summa cum laude from UCLA, Reem has made a career of mutating genes, creating artificial 3D clusters of human intestinal cells (delightfully called “organoids”), and using computer programs to study vast amounts of DNA. These endeavors might sound eerily sci-fi, but have in fact taught us a lot about public health and disease. Her work mutating genes in parasites could shed light, down the line, on how we treat some particularly nasty strands of malaria,⁵ and her work with human intestinal organoids promises to tell us more about the cellular basis for inflammatory bowel disease. Now, as a PhD student at Yale University, Reem has set her sights on what makes our brains human.

” Slower development means more time to make a big brain…So where in the genetic code is it telling our brains to develop slower? “

To investigate what makes our brains unique, Reem has created something like a hybrid “half-human, half-chimp brain.” This phrase baffled me as much as it’s probably baffling you, so I sat down with Reem to ask her more about what inspired this research. And, as I listened to Reem’s enthusiastic, down-to-Earth explanation for her project, it began to seem less like mad science and more like vital research. “Large brains allowed us to dominate the world for better or for worse,” Reem explains. She wants to find “the underlying code in our cells that has allowed us to do that.” In searching for this code, Reem has focused on the speed at which that wrinkly portion at the front of our brains develops. “Slower development means more time to make a big brain…and we know that the human brain takes a really long time to develop.” This slow pace of human brain development manifests at the cellular level⁶—individual human brain cells take years to branch out and mature, whereas those of chimps develop much faster. Reem’s research question is simple, then: “Where in the genetic code is it telling our brain cells to develop slower?” 

To answer this question, Reem recently joined the Noonan Lab at Yale University, which has a long history of using the best-available gene-editing technology to study human brains. One particular focus of the Noonan Lab has been to find particular bits of DNA that distinguish humans from chimps and other animals. What exactly are these bits of human specific DNA? Well, as Reem explains, “they’re parts of the genome that are not genes,” but “dials” for genes, which make various brain-building genes more or less active as the brain develops.⁷ These bits of DNA are part of that 1.2% of our genetic code separating us from chimpanzees, and could tell us a lot about how that huge wrinkly portion at the front of our brains develops so slowly, gets so big and complex,⁵ and makes us so clever. Each one of these bits, once found, “gives us a hint that maybe this part of the genome helped us evolve big brains.” However, that hint alone doesn’t prove the bit’s role in making our brains bigger or tell us how it did. In order to actually verify what these human bits of DNA do, scientists have to mutate them, and see how those mutations affect the development and interaction of different human and chimp brain cells over time. Obviously, no one at any credible research institution wants to mess with the brain of an actual living human—institutional and federal guidelines fortunately forbid that kind of work. But scientists dowant to understand what these human-specific bits of DNA are doing. So how do you mutate realistic human brains without using actual real human brains?

Well, remember those “organoids” I mentioned before? Reem uses those. And they’re a lot less scary than they sound. “We’re not using real animals, or growing real brains” Reem assures me with a laugh. Instead, she’s using what amounts to just a few cells: To create brain “organoids”—again, 3D clusters of living brain cells—she uses cells that other labs have collected from human or chimp skin. These labs treated those skin cells with various molecules to “reprogram” them into stem cells, which can turn into almost any other kind of cell if given the right molecular cues. “In our case,” Reem explains, “we make them turn into neurons.”⁸ Reem uses this approach to create human and chimp brain cells, and then grows each reprogrammed brain cell into a different 3D cell cluster or “organoid.” The result in each case is a separate ball of brain cells⁹ for each species that develops much like they would in a real brain. 

A human brain organoid, 30 days old, made by combining two different human cell lines. Cells are labeled with two overlain molecular markers——a blue one marking all cell nuclei and a violet one that marks “forebrain cortical neuron progenitors” (the kind of cells that end up forming the wrinkly front of our brains). The cells in this organoid have spontaneously arranged themselves into “rosettes”, much like brain cells do in an embryonic brain. Image courtesy of Reem Abu-Shamma.

With each brain organoid, Reem plans to test what our human-specific bits of DNA are doing to make our brains grow slower and larger. She will do this by tweaking or changing¹⁰ various human-specific bits of DNA to make them act more like the corresponding regions of chimp DNA, and vice versa. Then she’ll see how these modifications affect the activity levels of various brain cell genes and the “speed” at which those brain cells ultimately develop. “By ‘speed’, we don’t mean absolute time; rather, we have the technology to look at a single cell and figure out how mature it is based on the molecules we observe in it,” Reem clarifies. Then, for each bit of human-specific DNA, she’ll see whether the humanized chimp cells appear to develop more slowly, while the “chimpanized” human cells develop more quickly. Then we would know that this specific bit of our 1.2% unique genetic code is partly responsible for making our brains so weirdly human. 

Reem finds the sheer size of this mystery fascinating. “The genome is a really big place,” she explains. “It’s so vast and we don’t know what most of it does. It kind of feels like detective work, because you’re trying to see where in this really big space it’s telling us to be human.” By tweaking little bits of human and chimp DNA so they behave more like their counterparts—a sort of genetic Freaky Friday—Reem can do just that, finding which bits of human-specific DNA tell our brain cells to grow in a human way. This in itself is the stuff of science fiction. However, Reem and her PhD advisor, Dr. James Noonan, are taking this approach one step further.

They aren’t just growing human brain-cell colonies and chimp brain-cell colonies. They’re mixing them together, to make something like a miniature hybrid brain. Despite their different origins, these cells branch out and interconnect much like the cells in our own brains, possibly creating a cellular communication network unseen in nature. “Why would you make a half-human, half-chimp brain?” Reem jokes that her mother and even her colleagues have often asked her this question. But Dr. Noonan initially suggested this approach, and Reem has pursued it, because we can learn a lot from it. 

” It kind of feels like detective work, because you’re trying to see where in this really big space it’s telling us to be human. “

Brain cells don’t usually grow on their own. They grow in response to cues from neighboring cells, and these hybrid brains can show us the extent to which human brain cell development is genetically encoded. How much of how our brain cells behave is written in their DNA, and how much is determined by interaction with their cellular neighbors? Specifically, Reem is curious whether the sum of brain cell interactions, and the presence of similar brain cells from other species, together affect how fast that wrinkly portion at the front of the brain develops. Previous studies have found that these external cues (the “cellular environment”) don’t matter much for the development speed of human brain cells.^11,12 However, few if any studies have used hybrid chimp-human brain organoids to study that big wrinkly-fronted part of the human brain. By creating hybrid chimp-human organoids with this specific type of brain cell, Reem will finally test whether environmental cues help it grow slower in humans. Reem gives me an example to help me wrap my head around this. So, suppose you “take a human cell and transplant it into a chimp brain organoid,” Reem explains. And then suppose you collect molecular data from human brain cells inside a purely human organoid and then do the same to human brain cells inside a human-chimp hybrid organoid. “If they’re exactly the same, then the environment the cell is in isn’t as important!”

Making and mutating hybrid brains is intense work. To do it right, Reem has to set up hundreds of different brain organoids, each in its own plastic well, and from a variety of different human and chimp donors. She goes into the lab every day. “I check on my cells immediately…first thing. I make sure they’re still alive.” She recounts instances where some of her organoids became cancerous, and others spontaneously collapsed and started dying—both unplanned events that threatened to skew her work and required hours of manual labor to remedy. “So many things can go wrong…it’s a lot of manual labor to make sure they’re alive and happy.” On a daily or weekly basis, she has to feed her many hundreds of brain organoids, and look at each one under a powerful microscope to make sure nothing has gone horribly wrong. She has to modify them all at just the right time, in just the right way. And then, when all of that is done, within the next few months, she’ll have to extract specific molecules from these organoids and analyze the resulting vast amounts of data to see how her mutations changed the approximate speed of brain cell development in her human brain, chimp brain, and hybrid brain organoids. 

Reem is eager to find “what inferences we can make about the speed of development using these models”—at what rate the brain cells are likely growing, dividing, branching out, and developing their various special functions. With this approach, Reem wants to pinpoint some of the intrinsic genetic factors responsible for speeding up and slowing down the “molecular rate” of human brain cell development.

A hybrid human-chimp brain organoid from Reem’s first experiment on this project. Molecular markers tag chimp brain cells red and human ones green. This hybrid chunk of brain is 17 days old. Image courtesy of Reem Abu-Shamma.

When I asked Reem about the benefits of this research, her answer surprised me. Of course, her work does have implications for treating and understanding psychiatric or developmental conditions—autism spectrum disorder, schizophrenia, and other cognitive differences that often relate to brain development. That was the answer I expected. But Reem went on to highlight something else. “This is a very exploratory study,” she explained. “It’s hypothesis-generating,” and “in the history of science, doing fundamental research can sometimes lead you down unexpected paths, just because you’re exploring your curiosity.” This “fundamental research” is done not for its direct societal benefits, but to better understand ourselves and our world, and often has unexpected humanitarian value. For example, Reem points out, CRISPR was discovered by fundamental research projects on a few seemingly random repetitive patterns in microbe DNA. And yet, CRISPR now forms the most promising avenue for therapeutic gene editing and has a variety of other applications for human health and disease worldwide.^13,14

Reem’s work on hybrid brains is fundamental research in the same way. Yes, it has biomedical implications. But its potential value is so much broader. It can shed light on the parts of our genetic code that separate us from chimps and other animals. As Dr. Noonan told her when he first suggested making human-chimp hybrids, “no one’s done it before,” and we can hardly begin to predict what it might tell us about what makes us human. 

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Caleb Gordon is a Postdoctoral Associate at Yale University, where he studies the evolution of reptiles during the time of the dinosaurs. Check out his website to follow his research and popular science writing.

Note from the author: This piece was written as part of a workshop series taught by Carl Zimmer, and organized by Yale’s Graduate Writing Lab, on science reporting intended for a general audience. This workshop challenged us to write a popular science article without any scientific jargon. However, for any scientists missing this jargon, I’ve included more scientific terminology in the References Cited below. This article benefited greatly from feedback by Lauren Gonzalez and Joseph Lee at the Graduate Writing Lab.

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References Cited

• [1] The figure of 98.8% is given in Smith, Shelley L. “Connecting with Our Ancestors: Human Evolution Museum Experiences.” Interdisciplinary Evolution Research 9, 1–528. https://doi.org/10.1007/978-3-031-69429-5. It is also often shown online: American Museum of Natural History, Hall of Human Origins. “DNA: Comparing Humans and Chimps.” Accessed online April 25, 2025. https://www.amnh.org/exhibitions/permanent/human-origins/understanding-our-past/dna-comparing-humans-and-chimps.

• [2] For more information about the evolution of human brain size, you can check out this research paper: Smaers, J. B., R. S. Rothman, D. R. Hudson, A. M. Balanoff, B. Beatty, D. K. N. Dechmann, D. De Vries, et al. “The Evolution of Mammalian Brain Size.” Science Advances 7, no. 18 (April 30, 2021): eabe2101. https://doi.org/10.1126/sciadv.abe2101.

• [3] This wrinkled region at the front of the brain is called the “prefrontal cortex.” For more information about this remarkable brain region and its implications for our higher executive functioning abilities, you can check out this research paper: Preuss, Todd M., and Steven P. Wise. “Evolution of Prefrontal Cortex.” Neuropsychopharmacology 47, no. 1 (January 2022): 3–19. https://doi.org/10.1038/s41386-021-01076-5.

• [4] Additional information on the prefrontal cortex is provided in this research paper from the same journal: Kolk, Sharon M., and Pasko Rakic. “Development of Prefrontal Cortex.” Neuropsychopharmacology 47, no. 1 (January 2022): 41–57. https://doi.org/10.1038/s41386-021-01137-9.

• [5] The following research paper summarizes the results from Reem’s collaborative gene-editing work with malarial disease vectors: Subudhi, Amit Kumar, Anne-Lise Bienvenu, Guillaume Bonnot, Reem Abu-Shamma, Faryal Khamis, Hussain Ali Abdulhussain Al Lawati, Stephane Picot, Eskild Petersen, and Arnab Pain. “The First Case of Artemisinin Treatment Failure of Plasmodium Falciparum Imported to Oman from Tanzania.” Journal of Travel Medicine 30, no. 3 (May 18, 2023): taac092. https://doi.org/10.1093/jtm/taac092.

• [6] The human brain matures more slowly in part because individual human brain cells take longer to develop. For a great review highlighting the uniquely protracted nature of human brain cell development, check out this recent paper: Lindhout, Feline W., Fenna M. Krienen, Katherine S. Pollard, and Madeline A. Lancaster. “A molecular and cellular perspective on human brain evolution and tempo.” Nature 630 (19 June 2024): 596–608. https://doi.org/10.1038/s41586-024-07521-x. 

• [7] For more information on what these human-specific bits of DNA are and what they do, check out this recent paper from the Noonan Lab: Pal, Atreyo, Mark A. Noble, Matheo Morales, Richik Pal, Marybeth Baumgartner, Je Won Yang, Kristina M. Yim, Severin Uebbing, and James P. Noonan. “Resolving the Three-Dimensional Interactome of Human Accelerated Regions during Human and Chimpanzee Neurodevelopment.” Cell 188, no. 6 (March 2025): 1504-1523.e27. https://doi.org/10.1016/j.cell.2025.01.007.

• [8] For additional information about how these scientists create brain cells from stem cells, check out the following paper: Mariani, Jessica, Maria Vittoria Simonini, Dean Palejev, Livia Tomasini, Gianfilippo Coppola, Anna M. Szekely, Tamas L. Horvath, and Flora M. Vaccarino. “Modeling Human Cortical Development in Vitro Using Induced Pluripotent Stem Cells.” Proceedings of the National Academy of Sciences 109, no. 31 (July 31, 2012): 12770–75. https://doi.org/10.1073/pnas.1202944109.

• [9] These colonies of brain cells are called “cortical organoids.” For more information about these remarkable 3D brain cultures, check out the following paper: Pollen, Alex A., Aparna Bhaduri, Madeline G. Andrews, Tomasz J. Nowakowski, Olivia S. Meyerson, Mohammed A. Mostajo-Radji, Elizabeth Di Lullo, et al. “Establishing Cerebral Organoids as Models of Human-Specific Brain Evolution.” Cell 176, no. 4 (February 2019): 743-756.e17. https://doi.org/10.1016/j.cell.2019.01.017.

• [10] Reem mutates brain cell colonies using “arrayed CRISPR screens,” which are described in more detail in the following research paper: Bock, Christoph, Paul Datlinger, Florence Chardon, Matthew A. Coelho, Matthew B. Dong, Keith A. Lawson, Tian Lu, et al. “High-Content CRISPR Screening.” Nature Reviews Methods Primers 2, no. 1 (February 10, 2022): 8. https://doi.org/10.1038/s43586-021-00093-4.

• [11] This research paper studied pure human and pure chimp brain cell organoids: Otani, Tomoki, Maria C. Marchetto, Fred H. Gage, Benjamin D. Simons, and Frederick J. Livesey. “2D and 3D Stem Cell Models of Primate Cortical Development Identify Species-Specific Differences in Progenitor Behavior Contributing to Brain Size.” Cell Stem Cell 18 (April 7, 2016): 467–480. http://dx.doi.org/10.1016/j.stem.2016.03.003. 

• [12] This research paper took human brain cells from that wrinkly region at the front of the brain and transplanted them into a live mouse brain: Linaro, Daniele, Ben Vermaercke, Ryohei Iwata, Arjun Ramaswamy, Baptise Libé-Philippot, Leila Boubakar, Brittany A. Davis, Keimpe Wierda, Kristofer Davie, Suresh Poovathingal, Pier-Andrée Penttila, Angéline Bilheu, Lore De Bruyne, David Gall, Karl-Klaus Conzelmann, and Vincent Bonin. Neuron 104 (December 4, 2019): 972–986. https://doi.org/10.1016/j.neuron.2019.10.002. 

• [13] Doudna, Jennifer A., and Emmanuelle Charpentier. “The New Frontier of Genome Engineering with CRISPR-Cas9.” Science 346, no. 6213 (November 28, 2014): 1258096. https://doi.org/10.1126/science.1258096.

• [14] Barrangou, Rodolphe, and Jennifer A Doudna. “Applications of CRISPR Technologies in Research and Beyond.” Nature Biotechnology 34, no. 9 (September 2016): 933–941. https://doi.org/10.1038/nbt.3659. 

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Emerging perspectives in metabolism

This week, we delve into the story of Dr. Lianna W. Watt, a Leading Edge fellow and a postdoctoral researcher at Stanford University, who is passionate about unraveling the intricacies of metabolism and sex differences—one fly and mouse at a time. Driven by curiosity and a deep respect for basic science, Lianna has explored how diet can rewire the way male and female bodies store and break down fat. She’s worked across model systems—from Drosophila to mammals—always with an eye toward understanding how sex-specific metabolic regulation shapes health and disease. Keep reading to discover how mentorship, curiosity, and a few bags of mini eggs helped shape Lianna’s career—and why she believes that studying both sexes is fundamental biology, essential not only for understanding disease
and metabolism, but also for uncovering evolutionary principles. Check out all her work here .

What was your first introduction to the field of metabolism – what’s is your first memory?

It was actually a conversation with my future undergraduate thesis supervisor, Dr. Ian Dworkin at McMaster University. I was interviewing to join his lab as a summer research student and that was when I learned that changing the diet of flies can reduce how different male and female wing shape and size are. The idea that changing the diet could have such drastic effects on metabolism to the point that organ shape and size are altered is what first drew me into metabolic research.

Could you share your journey into studying metabolism and what inspired you to specialize in metabolic studies using Drosophila melanogaster?

My research journey in metabolism began in flies, and it was truly just luck. I was in a joint-major undergraduate program and part of the requirement was an undergraduate thesis project. I had always planned on going into medical school, so I was late to the game looking for a lab. But a new professor had just joined McMaster’s biology department (Ian), and he took a chance on me. I worked with Ian on understanding how the ratio of macronutrients, or nutritional geometry, affected how different male and female shape and size are using Drosophila wings as a model system. This summer research projected turned into an undergraduate thesis and is what made me fall in love with research. I ended up forgoing applying to medical schools and instead applied for graduate research programs.
From my time with Ian, I knew I wanted to do research in sex differences, continue using Drosophila as my model, and transition to a more biomedical research question. At the time, very few labs focused on investigating sex differences but there was a new lab at the University of British Columbia (UBC) that studied sex differences in metabolism and physiology in Drosophila. This was Dr. Elizabeth Rideout’s lab, and it was the perfect fit for what I wanted to do and is ultimately where I completed my PhD.

How has your transition from working in Drosophila to working in the mammalian system been?

After my PhD, my career goal was to open my own lab that used multiple model systems to bridge the gap between basic science and clinical research. This motivation was why I transitioned to a mammalian lab for my postdoc. The transition for me was fairly smooth as I had ~1yr experience with the Kieffer and Clee labs at UBC using mice. The main differences between using flies and mice for me was how you plan experiments. In flies, you can decide to do an experiment and have the flies ready to go in 1-2 weeks and you can simply do one experiment per cohort. However, with the mice, I would need to have experiments planned over a month in advance (quarantine, breeding, weaning etc) and because it took so much time to have the correct mice for an experiment, you had to maximize what experiments you would perform on each cohort. However, after joining a mouse lab, I quickly realized that I much preferred working with flies to mice. It turns out, I am a geneticist at heart and many of the genetic tools I was used to having in my arsenal in a fly lab did not exist in the mouse world yet. Additionally, while vertebrate model systems are incredibly important for basic research, there is an emotional toll associated with solely using mammalian models. My time in a mammalian lab also helped me realize that I was more interested in understanding the basic science underlying the regulation of metabolism rather than the discovery of new therapeutics to treat metabolic disease. This together with the development of an anaphylactic allergy to mice is what solidified my return to a Drosophila model system.

Tell us how you got interested in the field of nutritional and metabolic aspects of sex differences? How do you think the fields of studying sex differences and metabolism overlap – tell us about your interests in these areas? How have both the sexes evolved to respond to nutrition and metabolic stresses?

One of my motivators for wanting to study metabolism is that my family has a history of type 2 diabetes and obesity – I recently found out that I have a genetic variant that predisposes me to obesity. While starting in the sex differences world was by luck, I decided to stay in this field because I realized just how widespread yet understudied sex differences are (almost every phenotype has a sex difference). Historically, females were omitted from studies because they didn’t show the same phenotypes as males and there was this belief that sex hormones just complicated the data. We can learn so much new biology if we were to include both sexes since males and females form naturally dichotomous groups.
In the case of metabolism, sex differences can be found everywhere from the risk and prevalence of metabolic disease, the response to therapeutics, basal metabolic phenotypes (ie. fat accumulation, blood glucose levels), and the regulation of major metabolic signaling pathways such as insulin and GLP1 (Glucagon-Like Peptide-1). In the metabolism field, is it widely accepted that males and females are phenotypically very different but many studies still only investigate males because females tend to have much weaker responses to metabolic challenges such as high fat diet. To me, this is actually an extremely exciting phenotype. Why are females more protected from developing metabolic dysfunction in response to metabolic challenges? If we could figure out the mechanisms that allow females to be protected, these may be promising avenues for new therapeutics to reverse or alleviate metabolic disease.

Why do you find the basic science aspects exciting ?

I find basic science so exciting because it is the foundation of discovery. We first need to understand normal regulatory processes to understand how these processes become dysfunctional and lead to disease. By investigating how metabolism is regulated in healthy individuals and how these processes can go wrong form the foundation for the development of novel therapeutics to treat metabolic disease. Without basic science, the development of new therapeutics would be significantly hampered.

Why do you think understanding both males and female systems from a metabolic perspective is important? How is it relevant in today’s human health dynamic? Your work is focused on uncovering mechanisms explaining how sex differences in fat metabolism arise, identifying novel functions for metabolic genes and pathways that contribute to how males and females store and break down fat differently. Could you elaborate on the key findings and their implications for the field?

For many years, the metabolism field has known that males and females store and distribute fat differently, and that many metabolic diseases associated with abnormal fat storage hare a male-biased risk and prevalence. While there is a beautiful body of work investigating how sex determination factors (ie. sex chromosomes and sex hormones) establish these sex differences, we lack an understanding of the metabolic genes and metabolic pathways that act downstream of sex determination factors to contribute to the regulation of sex differences in fat metabolism.
My major findings during my PhD were 1) majority of lipid metabolism genes are sex-biasedly regulated, 2) the triglyceride lipase brummer (mammalian ATGL) acts in the somatic cells of the gonad and the neurons to regulate sex differences in fat storage and fat breakdown, 3) lipid droplets are normally present in the neurons (not just diseased states) and may be sex-biasedly regulated by brummer, and 4) the sex determination factor Transformer establishes sex differences in fat metabolism in flies via the sex-biased regulation of the adipokinetic hormone (Akh) signaling pathway. These findings represent novel functions of metabolic effectors and open the doors for interesting questions such as how lipid droplet dynamics in neurons are regulated and how does this impact whole-body fat metabolism, how sex determination factors regulate downstream metabolic effectors like brummer (bmm) and Akh. Also, ATGL inhibition is being investigated in mammals and humans as a potential therapeutic but my data suggests that inhibiting bmm/ATGL function will have greater effects in males than females, thus indicating that ATGL inhibition studies need to be performed in both sexes.

Your work intersects sex differences, metabolism and aging. How do you integrate these disciplines in your research, and what unique insights have emerged from this approach?

I tend to think of sex differences as a tool to understand metabolism. For example, my broad question is how does our brain respond to a high fat diet? Are there certain regions/neuronal populations that become more or less active? How are these high fat diet-induced changes different between males and females? In this way, studying sex differences sheds light on understanding the metabolic phenotype.

You work on sex specific hormonal regulation of lipid metabolism. How difficult were those experiments? Did you have to deal with midnight timepoints or require an army of undergrads/ long hours etc.?

I think the difficulty of any experiment or technique really varies from person to person. For example, molecular techniques such as colorimetric assays and qPCRs came easily to me but I always found imaging more challenging. Having more hands on deck was always a huge bonus because it meant larger or more experiments could be done. For example, if it was just me, I could maybe screen ~5 RNAi lines simultaneously. But if I had 2-3 trainees helping me, that could easily go up to 15-20 RNAi lines. Training and mentoring the next generation of scientists has always been very important to me and I’m really grateful that I had the opportunity to work with so many amazing budding scientists – many of which are recognized as authors on my publications.
As for late night timepoints – this only happened for specific experiments, namely whether circadian rhythm affected the sex difference in fat storage. For this set of experiments, I had a timepoint every 4 hours for a 24 hour period. My philosophy is that I would never have my trainees do something that I wouldn’t do myself so for these experiments, I collected all the samples. While napping on a desk wasn’t the most comfortable, I didn’t mind because I knew this data was important and it wasn’t a regularly occurring experience. I also had the added benefit of Liz (my PhD supervisor) buying me a huge bag of mini eggs to help me make it through the night haha

Building upon your findings in sex-specific fat metabolism and hormonal regulation, what are your upcoming plans? Are there particular metabolic pathways or hormonal regulators you aim to investigate further?

My plans going forward are actually to take a broader look at metabolic function. I mentioned earlier that one well-known sex difference in mammalian metabolism research is that females do not develop metabolic dysfunction to the same degree as males in response to metabolic challenges such as high fat diet. For example, in response to HFD, male mice will develop glucose intolerance and gain more body weight/fat mass than females, and male mice will also have worse cognitive defects after chronic high fat diet than female mice. This together with my previous work suggests that the brain plays a major role in regulating the sex-biased response to HFD. Thus, one major question of my postdoctoral work is what are the brain-wide effects of HFD on neuronal metabolic function? My goal is to use live, volumetric 2-photon imaging in conjunction with genetically-encoded metabolite sensors to investigate how HFD alters neuronal metabolic flux and function in male and female brains.

How are you planning to integrate insect and mammalian models to bridge basic science and therapeutic research?

My current plan for the future is to establish a lab that integrates neurobiology and molecular biology to study how the brain responds to external metabolic stressors (such as chronic diet perturbations or fasting) to regulate whole-body energy homeostasis. My primary model system will likely be Drosophila and any findings that are particularly exciting, I will also investigate in mammalian models, thus allowing me to bridge the gap between invertebrate and vertebrate systems.

What changes have you seen in the research community in regard to studying sex differences ? How do you think scientific paradigms around studying both sexes will evolve in the coming decades? Are we moving toward a more nuanced understanding, or do you see potential pitfalls?

When I started my PhD, I felt that the community acknowledged that sex differences exist but did not think they were important enough to dedicate an entire research project to. In the last decade, I have definitely seen this mentality shift to more appreciation for studies that uncover the mechanisms by which sex differences are established and controlled. We’ve also seen changes in regulations where studies need to justify why they only study one sex and more acknowledgement that what we learn from studying males may not necessarily apply to females. Studies are now also more transparent regarding which sexes are used for specific experiments. This shift towards more studies including both sexes or detailing which sex is used can only be a good thing as it provides us with more data and thus a better understanding of the normal regulatory processes of metabolism. However, even sex is a spectrum with many variations in sex chromosomes. As the field of sex differences evolve, I believe it will become increasingly nuanced until the whole spectrum of sex can be studied to the best of our ability.

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 ?

One roadblock that has hampered the discover of new signaling pathways that control metabolism is the identification of ligand-receptor pairs. With the advent of AI-assisted protein structure prediction (eg. AlphaFold, AlphaLigand), the ability to predict receptors for a known ligand or vice versa significantly speeds up our ability to identify metabolic molecular mechanisms. Recent advances have even been able to use AI to predict new drug therapies for example. I think AI will be a really strong tool in a basic scientist’s arsenal.

What role does curiosity play in your life, both within and outside of science? 

Curiosity is a huge part of being a scientist – the desire to know more can really motivate your work. There’s this misconception that scientists know all there is to know about a subject, but if you maintain a child-like sense of wonder or curiosity, you’ll see that there is so much left to learn. When I spend time with my nieces and nephews, my favorite part is hearing their questions because really, every question can lead to a research project. I recently told my niece that our hair and our nails are made of the same thing. She asked me why and I didn’t know. But that could be a budding scientist’s first foray into research.

Were there any pivotal moments that shaped your career path? What advice would you offer to students and early-career scientists interested in exploring the intersections of metabolism and inter-organ communication?

My pivotal moment was joining the Dworkin lab for my undergraduate thesis project – if I hadn’t, I very likely wouldn’t have fallen in love with research and would have gone to medical school.
For anyone interested in research, I would suggest that you think broadly and approach your research question from many angles. While my main focus is on energy metabolism, you can study this from many different points of view such as a neuroscientist or a mathematician.

How do you maintain a balance between your rigorous research activities and personal life? Are there hobbies or practices you find particularly rejuvenating?

I learned the hard way that if you don’t make time for things outside of research, you will burn out. My life outside the lab is equally as important as my time in the lab so I put more effort into planning my work week/month and experiments to maximize the likelihood that I won’t need to be in lab on the weekends or late into the night. Sometimes, that’s just impossible and I work the occasional weekend/late night. Outside the lab, I’m a huge book lover and spend a lot of time reading. I also love to cook and bake. I’ve also been an avid yogi since my undergraduate days so I try to maintain this hobby by going to yoga practice first thing in the morning – I find that waking up early is more reliable than leaving lab at the same time every day.

If you hadn’t embarked on a career in biological research, what other profession might you have pursued, and why?

I’d love to open a cozy bookstore/café hybrid! Somewhere people could get lost among the shelves with a mug of tea. Or maybe that’s just what I want to do haha !

Anything you’d want to highlight ?

I was just selected as one of 2025’s Leading Edge fellows. This is a group of women and non-binary early career scientists that support one another in obtaining R1 faculty positions and tenureship. I’m really proud to be a part of this community to elevate women and non-binary individuals in science.

Last week we learnt about how nutrient dependent signaling shapes cell fate decisions and developmental plasticity in aquatic organisms like sea anemones and planarians. Check out – Of Tor and Tide (Eudald Pascual-Carreras)

Check out the article All the world’s a metabolic dance, and how early career scientists are leading the way !!

The post The Fat of the Matter: To know a fly, To know ourselves #MetabolismMondays appeared first on the Node.

Emerging perspectives in metabolism

This week we will get to know insights from Dr. Eudald Pascual-Carreras, who is a postdoctoral researcher in the Multicellgenome lab at IBE Barcelona where he’s studying how metabolism regulates the cell cycle at the origin of animal multicellularity. Before joining IBE, he conducted postdoctoral work in the Steinmetz Group at the Michael Sars Centre, University of Bergen, Norway. Eudald has long been fascinated by how nutrient-dependent signaling influences stem cell proliferation and growth, approaching these questions using unique model systems like the planarian flatworms and the sea anemones. Keep reading to learn about his journey through the world of metabolism—and why curiosity driven basic science remains at the heart of it all. Along the way, he’s embraced the value of mentorship, stayed motivated through scientific challenges, and remained rooted in a deep curiosity for basic biology. Discover his journey through metabolism and learn about the mindset that keeps him going. Give him a follow over twitter or bluesky and check out his work here .

What was your first introduction to the field of metabolism? What inspired you to specialize in metabolic studies using two incredibly unique systems – the planaria flatworms and the sea anemones ?

I can clearly remember my first introduction to metabolism during high school biology class. My teacher explained how glucose is broken down, the Krebs cycle, how ATP is generated. I was fascinated by the intricated biochemical pathways that sustain life. Later, in university, I took an animal physiology course that provided a broader biochemical perspective.
For my PhD, I decided to study planarians due to their remarkable body plasticity. These animals can regenerate and modulate their body size depending on the nutrient availability. Initially, my research focused on regeneration, and metabolism wasn’t my main area of interest. However, over time, my focus shifted toward understanding the regulation of animal growth. This eventually led me to pursue a postdoctoral position in a Nematostella lab, where I kept exploring how nutritional changes influence organismal growth.
Classic research organisms such as Drosophila, C. elegans and mice have a predetermined, fixed body size. In contrast, the unique organisms I study can grow and shrink throughout their lifetime, a trait common among many non-bilaterian animals, including sponges, corals, sea anemones and ctenophores. This suggests that body plasticity is likely ancestral to all animals. Studying these organisms has allowed me to explore fundamental questions about the evolution of animal growth, the mechanisms that regulate it and the intricate interplay between metabolism and genetics.   

What sparked your interest in exploring nutritional and metabolic aspects of animal development through the lens of cell cycle and cell fate? Your work intersects metabolism, development and evolution. How do you integrate these disciplines in your research, and what unique insights have emerged from this approach?

Planarians and Nematostella can rapidly adjust their body size in response to nutrient availability. In both cases, cell number drives organismal growth, making the regulation of cell proliferation a crucial factor. This sparked my interest in understanding the cellular and molecular mechanisms that enable these animals to adapt. Therefore, I began studying the cell cycle, which I consider a fundamental cornerstone of this process. I found it fascinating that a such a highly conserved process as cell cycle can exhibit remarkable plasticity – pausing or adjusting its duration to accommodate different nutrient conditions.
Trained as a developmental biologist, I became increasingly interested in evolutionary questions during my PhD. Deciphering how developmental processes have evolved has always been on my interest. Integrating a metabolic perspective into this field adds a new layer of complexity that has been overlooked in evolutionary developmental biology. I believe this perspective has the potential to reshape fundamental concepts in cell biology, physiology and developmental biology.

Can you briefly summarize how you’re using Nematostella to uncover unique mechanisms by which body plasticity responds to environmental inputs, particularly how stem or progenitor cell populations driving this plasticity adapt to nutritional cues?

Nematostella vectensis has emerged as a powerful research organism for studying body plasticity in response to environmental changes, including
nutrient availability and temperature. Nematostella polyps exhibit a remarkable resilience during starvation conditions, capable of surviving over 200 days without food. In Steinmetz lab, we observed that after
prolonged starvation, these animals can be refed and return to their original body size within two weeks.
Our research demonstrated that changes in cell
number and cell proliferation directly correlated with organismal growth (doi: 10.1242/dev.202926). This led us to ask a fundamental question: which cells
contribute to this remarkable organismal growth? At
the same time, the lab was also investigating the identification and characterization of a multipotent stem/progenitor population that contributes to both germline and somatic tissues (doi: 10.1038/s41467-024-52806-4). My project naturally evolved from these findings – I studied how this multipotent stem/progenitor population behaves under starvation and refeeding conditions. Essentially, my goal was to move from the organismal level to the cellular and molecular level, dissecting how this specific population adapts to the extreme nutritional shifts (doi: 10.1101/2025.02.27.640509).

Tell us about your work on nutritional control of cellular quiescence and how Nematostella  is a unique model to answer questions about nutrient dependent quiescence. Summarize your key findings on cell cycle dynamics, the signaling pathways involved, and how these insights differ from known mechanisms in yeast and mammals.

When we began studying how starvation affects this stem/progenitor population, we considered different hypotheses based on observation in planarians and Hydra. In these organisms, stem cell populations (neoblast for planarians and i-cells for Hydra) continue dividing even under starvation. However, in Nematostella, we observed that the stem/progenitor population exhibited a low division rate, suggesting that these cells might enter a state of cellular quiescence.
We then found differences in cell cycle phase distribution depending on the duration of the starvation. The longer the starvation period, the deeper the quiescent state these cells entered! This progressive deepening of quiescence following nutrient withdrawal had only been observed in yeast and cell culture models, never in an organismal level! What is fascinating is that after refeeding, these cells are primed to re-enter the cell cycle in short-term condition while the re-entry was delayed following prolonged starvation.
Our findings position Nematostella as a unique in vivo model to study nutrient-dependent quiescence, and all it requires is subjecting animals to different starvation durations. Surprisingly simple yet incredibly powerful!
Specifically, we have found that starvation induces a G1/G0 quiescence state. During short-term starvation, some cells remain cycling, and after refeeding, quiescent cells rapidly re-enter the cell cycle. However, after long term starvation, the majority of the cells have entered a deep quiescent state, and their cell cycle re-entry is delayed upon refeeding! While we are still investigating the molecular mechanisms underlying quiescence acquisition, we have identified that TOR signalling is essential for feeding-dependent cell cycle re-entry!

Tell us about the experimental challenges you encountered during this project?

This project was a major challenge from the start. I spent my first year establishing quantitative flow cytometry analysis in Nematostella. Since the stem/progenitor population is located deep with the tissue and cannot not be imaged directly, I quickly realized that understanding cell cycle dynamics would require a tightly controlled time course experiments. This meant meticulous planning, and of course, having the support of colleagues and undergrads was essential.
To optimize time course experiments, I decided to try something slightly different. From T0 to 12 hours post feeding (hpf), I could sample continuously, which meant spending at least 14 hours in the lab. However, for the later time points (15, 18 and 21 hpf), instead of staying up all night, I strategically delayed the last feeding 3, 6 or 9 hours, allowing me to collect the samples the following morning. Naturally, I ensured that this adjustment had no circadian effects.
This approach not only made the experiment more manageable but also allowed me to generate high-resolution temporal data without requiring overnight shifts. Though long hours were certainly still part of the process!

Before this, you worked on planaria and identified a novel gene family – blitzschnell, which coordinates cell proliferation and differentiation in response to nutritional availability. Please tell us about your exciting findings.  

This was a truly unique project. Characterizing the function of a novel gene family came with significant challenges, as we had no reference to guide our understanding of the phenotype. It took time to piece everything together, but our findings were exciting!
One of our key discoveries was that the transcription of this gene family, blitzschnell, is directly regulated by nutrient intake! Moreover, its function is critical for controlling the cell number by balancing cell proliferation and cell death. In planarians, this regulation may be linked to the requirement for continuous and rapid modulation of cell numbers in response to nutrient availability (doi: 10.1242/dev.184044)

How do you think the fields of studying evolution and metabolism overlap? How do the two model systems you worked with differ in terms of nutrient-dependent regulation ?

Evolution and metabolism are deeply intertwined! Nutritional regulation is likely one of the most ancient evolutionary mechanisms. In unicellular eukaryotes, one of the earliest forms of cellular regulation is nutrient-dependent division: cells divide when food is available, and halt division when it is scarce. In multicellular organisms, this regulation has become more complex due to cell type and tissue specialization, certain tissues sense the nutrients and signal other cells to divide.
While nutrient-dependent growth regulation has been well studied in some animal tissues and cell cultures, we still lack a broader understanding from an organismal perspective. Using planarians and Nematostella as models, we can explore how stem cell populations that drive organismal growth respond to nutritional cues. One of the key differences we have observed is that in Nematostella, stem cells enter a quiescent state during starvation, whereas in planarians, this is less clear. Neoblasts continue proliferating even in the absence of food. The cell cycle dynamics of neoblasts during starvation remain poorly understood, with some results suggesting that starvation prolongs the G2 phase, allowing some neoblast to re-enter the cycle upon refeeding. However, this has not been definitively proven.
To gain a more comprehensive understanding of how nutrient-dependent regulation evolved, more organisms with body plasticity, such as ctenophores, Ciona, and sponges, should be studied. These models could provide crucial insights into the cellular mechanisms underlying metabolic control of animal growth.

How have different animals evolved to respond to nutritional and metabolic stresses? TOR signaling is conserved from yeast to humans, but are there organism specific differences in which the pathway is utilised ?

Yes, the signalling pathways are highly conserved across species. TOR signalling is required for organismal growth and cell proliferation in both Nematostella and planarians. What is particularly interesting is how these different animals utilize the same conserved pathway in distinct ways. While both rely on TOR signalling, they employ different strategies to cope with nutrient availability. As I mentioned earlier, Nematostella stem cells enter a quiescent state during starvation, while planarian neoblasts continue proliferating, even under nutrient-deprived conditions. Despite these differences, both organisms use the same fundamental molecular toolkit, illustrating the remarkable versatility of conserved signalling mechanisms across evolution.

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 human health/relevance ?

Curiosity is at the core of my scientific journey. I am deeply interested in basic science, particularly in understanding how developmental processes are regulated, how cells integrate surrounding signals, and how the metabolome interacts with the transcriptome and signalling pathways. These fundamental questions drive my research, as uncovering mechanisms not only expands our knowledge of biology but also lays the groundwork for better understanding of human biology and health.
Although my research is not explicitly focused on human biology, I believe that the questions I explore have significant implications for human health. Fundamental discoveries in model organisms often provide insights into conserved biological processes, ultimately influencing biomedical research and our understanding of disease mechanisms.

What are your upcoming plans? What metabolic pathways or signals you aim to investigate further to understand their role in stem cell regulation?

The Steinmetz group at the Michael Sars Center (UiB, Bergen, Norway), where I conducted my postdoc, remains deeply interested in studying the metabolic regulation of this stem/progenitor cell population. Our ongoing work aims to uncover the transcriptomic and epigenetic changes these cells can undergo in response to nutritional shifts. Additionally, the group is exploring metabolic changes at the organismal level.
Personally, I am about to start a new postdoctoral position, where I will investigate the metabolic regulation of the cell cycle in the context of the transition of animal multicellularity. As mentioned, nutritional regulation is likely one of the most ancient evolutionary mechanisms. I plan to leverage a facultative multicellular organism, whose life cycle includes distinct unicellular and multicellular stages. I am particularly curious to understand how metabolism influences multicellularity transition, whether nutritional gradients are generate within cell aggregates and whether shifts in metabolic state serve as prerequisites for multicellularity.

What changes have you seen in the scientific community in regard to studying these unique aspects of metabolic signaling in unconventional systems? How do you think scientific paradigms around gaining new insights from non-model organisms will evolve in the coming decades? Are we moving toward a more nuanced understanding, or do you see potential pitfalls?

The scientific community is increasingly recognizing that non-classic research organisms can provide valuable insights into the more fundamental questions. As a developmental biologist, I am well aware of the critical role that non-classic research organisms have played in advancing our understanding of core processes. For example, the discovery of cyclins in sea urchins. Similarly, I believe that studying unconventional model can unveil new and extraordinary metabolic processes that may have previously been thought to exist only in unicellular eukaryotes.
Moreover, one aspect that has often been overlooked in recent years is the metabolic state of organisms when designing experiments. As we gather more data, it will become increasingly important for each scientific community to establish standardized protocols to improve reproducibility and ensure more meaningful interpretations of results. By integrating a more nuanced understanding of metabolic context, we can refine experimental approaches and uncover deeper insights into the fundamental principles of biology.

How do you see the future of metabolism evolve with the new upcoming techniques  – what are you most excited about ?

I would love to establish metabolic sensing lines, as my work over the past few years primarily relied on fixed tissue, making it challenging to assess the dynamic nature of metabolic processes. Having live metabolic sensor lines would be a game-changer, allowing us to directly observe and analyze the metabolic state of a cell under the microscope in real time! Additionally, I believe it is crucial to move beyond relying solely on metabolomics. While metabolomic profiling provides valuable insights, integrating real-time metabolic imaging with other approaches will offer a more comprehensive understanding of cellular metabolism and its regulation. These advancements will open new avenues for studying metabolism in a more dynamic and physiologically relevant context.

Were there any pivotal moments that shaped your career path? What’s an unexpected place you’ve found inspiration for your work?

I don’t think I’ve had a single pivotal moment that shaped my career. Instead, I see my scientific journey as continuous progression. However, one thing I am certain of is that having good professors and mentors was essential in building my scientific confidence, which, in itself, is crucial for a successful career. Equally important is making time to disconnect and relax. Some of my ideas have come not while working in the lab, but while running, hiking, spending time with my family, or even having a beer with friends, often in moments when I wasn’t thinking about science at all. Stepping away from research can provide the mental space needed for creative problem-solving.

What advice would you offer to students and early career scientists interested in exploring the intersections of nutrition/metabolism and cell fate decisions ?

For early-career scientists interested in exploring the intersections of nutrition, metabolism, and cell fate, my advice would be to choose an organism with a significant body or developmental plasticity. These are the most fascinating systems, and there is still so much to learn from them!

How do you maintain a balance between your rigorous research activities and personal life? Are there hobbies or practices you find particularly rejuvenating?

Finding balance isn’t easy, and I’ve learned mostly through trial and error. I try to be as focused and productive as possible while I’m in the lab, but once I leave, I make a conscious effort to disconnect. That doesn’t mean I never check an email or skim through a paper in the evenings, but I don’t make it a habit. Setting boundaries has helped me maintain a healthier work-life balance.
I also make time to run at least once a week. It’s a great way to clear my mind, organize my thoughts, and stay active. At the end of the day, having a fulfilling life outside of academia is essential for me. It keeps me motivated and ultimately makes me a better scientist.

If you hadn’t embarked on a career in biological research, what other profession might you have pursued, and why?

I would be a high school science teacher. Over the past few years, I’ve had the opportunity to teach both high school and undergraduate students, and I’ve genuinely enjoyed the experience. Teaching allows me to share my passion for science while inspiring the next generation of students.
I also had an incredible high school biology teacher who played a significant role in shaping my path. His enthusiasm and teaching style sparked my interest in biology, and I wouldn’t be where I am today without that influence.

Check out the article All the world’s a metabolic dance, and how early career scientists are leading the way !!

The post Of TOR and Tide: Metabolism Beyond the Model #MetabolismMondays appeared first on the Node.