When I joined the Zon lab in June 2021, my mentor, Leonard Zon, shared an insightful piece of advice: “A good project always has two questions, one you can answer and one you dream of answering.” In this post, I’ll focus on that dream.
In brief, the question we managed to answer – at least a little bit – is how to instruct the expression of the “eat-me” signal driven by Calreticulin (CALR) and its complementary “don’t-eat-me” signal, driven by beta-2-microglobulin (B2M). In our study (https://www.science.org/doi/10.1126/science.adn1629) , we showed that high levels of reactive oxygen species (ROS) leads to high surface presentation of Calr, which, in turn, leads to high levels of interaction with a macrophage, and clearance of the stressed hematopoietic stem and progenitor cell (HSPC). On the flip side, TLR3 can modulate the expression of CALR together with B2M. Here, the balance between these molecules leads to a scenario where a macrophage interacts with the HSPCs, but does not “eat” them. This intricate signaling impacts clonal diversity, revealing a potential avenue for future immunotherapies targeting mutant or cancerous stem-cell populations while sparing healthy ones.
Macrophage and long-term hematopoietic stem cell (LT-HSC) interaction in mammals. Life imaging of calvarium bone marrow from Mds1GFP/+ Flt3Cre (MFG) mouse showing macrophages (F480+) in red and LT-HSCs in green.
Our uncharted territory lies in harnessing macrophages to selectively target malignant clones. We found higher B2M expression in HSPCs from acute myeloid leukemia (AML) patients with malignant stratification, suggesting that malignant clones may exploit B2M to evade macrophage clearance. This paves the way for drug development aimed at eliminating pre-leukemic and leukemic cells via macrophage-mediated clearance. This idea may also be further explored in aging studies, in which one could teach the macrophage to eliminate aged progenitor cells.
Another aspect of our study that could be further explored relies on a key finding that repetitive elements (RE), including Ltr, are the endogenous ligand of the Tlr3 and triggers b2m expression via the tlr3/irf3 pathway. We observed that these endogenous REs promoted high levels of ISG15, a gene linked to the type I interferon response.
Given the evolutionary conservation of RE and B2M, we explored the significance of this mechanism in both fish and humans, focusing on pathogen infections that are a common threat to both species. Specifically, we examined the role of TLR3 signaling in inducing “emergency granulopoiesis,” a protective process that accelerates neutrophil production during severe infection. Upon poly I:C stimulation, neutrophil populations increased.
Although further studies are needed to strengthen the relevance of this phenomenon, our results suggest that viral stimulation may confer a better fit against opportunistic pathogens by promoting granulocyte differentiation. This observation gets more fascinating if one considers that this increase of type I response could not only alter the emergency granulopoiesis, but also contribute to innate immune training. Seminal studies have shown that type I IFN signaling mediates neutrophil trained innate immunity, mainly in the context of solid cancer. This therefore suggests that RE-triggered type I interferon may play a role in trained immunity—a concept previously explored in cancer but now potentially relevant in other systems.
Over the summer, I had the opportunity to conduct research in Vivian Li’s Lab, focusing on the role of WNT signalling in the response of intestinal stem cells to injury, under the expert guidance of Dr. James Wilmouth Jr. As a medical student, I am deeply appreciative of the opportunity to gain hands-on experience in fundamental research through undertaking a project over the course of two months. I am truly inspired by the continuous innovation at the Francis Crick Institute, driven by a diverse community of committed scientists who embrace collaboration and interdisciplinary approaches.
One research axis within the Li Lab focuses on how canonical WNT signalling maintains intestinal stem cells (ISCs) and influences cell fate decision. The gut epithelium can be organised into an architecture of crypts and villi (Fig 1A). Crypts are found at the base, extending into the villi towards the gut lumen. ISCs are located within the crypt and responsible for driving renewal of the gut epithelium every 3-5 days during homeostasis. High WNT signalling in the crypts maintains ISC homeostasis before decreasing along a gradient towards the villi. Publications have demonstrated that whilst inhibiting WNT signals causes degeneration, WNT overactivation induces adenoma formation. Therefore, fine-tuned WNT signalling is crucial for maintaining ISC homeostasis.
Figure 1. A) Intestinal epithelium during homeostasis. B) Model of intestinal injury. TCF/Lef:H2B:mCherry reporter mice were exposed to 12Gy of whole body CSM radiation. Intestine or isolated crypts were collected at 0 dpi (pre-irradiation control), 1 dpi, 3 dpi, and 7 dpi.
For this project, I examined the role of WNT signalling in ISCs during injury-induced regeneration. We utilized whole-body irradiation to simulate ISC injury-induced regeneration in mice. This model results in crypt degeneration at 1-day post-irradiation (dpi), followed by regeneration at 3 dpi, and recovery by 7 dpi (Fig 1B). Intestinal tissues were harvested for crypt isolation at four time points: 0 dpi (pre-irradiation control), 1 dpi, 3 dpi, and 7 dpi. These samples were then used to investigate three transcriptional signatures throughout the regenerative process: Classical Intestinal Stem Cell (ISC), Revival Stem Cell (RevSC), and WNT target genes.
I performed quantitative PCR (qPCR) to analyse the temporal changes in gene expression during the regenerative process (Fig 2). Results indicated that classic ISC markers were downregulated at 1 dpi following injury and recovered to near homeostatic levels by 7 dpi. RevSC markers showed an induction at 1 dpi, followed by a decline toward baseline levels by 7 dpi. Interestingly, WNT target gene expression remained relatively stable throughout the 7-day period.
Figure 2. qPCR analysis of isolated crypts from 0, 1, 3 & 7 dpi. A) Classis ISC markers (Lgr5, Olfm4) decrease after injury at 1dpi, but recover close to homeostatic levels by 7 dpi. B) RevSC markers (Trop2, Anxa1, Clu, Sca1) increase after injury at 1-3dpi and 3/4 targets recover back to homeostatic levels by 7dpi. C) Most WNT target genes (3/4) remain constant over all timepoints. One target, Cd44, showed increased levels from 1-3dpi and recovered to homeostatic levels by 7 dpi. Graphs represent means ± SEM.
These initial results suggest that both Yap-driven RevSC signature and certain WNT targets are expressed during injury-induced regeneration. This contradicts the current understanding, which proposed an antagonistic relationship between YAP and WNT during ISC regeneration up on injury. To further investigate the co-expression of RevSC markers and WNT in ISCs, we utilised immunohistochemistry (IHC) and flow cytometry of WNT reporter mice in the irradiation induced regeneration model (Fig 3).
Figure 3.A) Co-expression of WNT and Clusterin upon injury. mCherry (WNT reporter) in red, Clusterin (RevSC marker) in green, DAPI in grey. mCherry and Clusterin colocalised at 1dpi, with stronger signals overlapping at 3dpi. B) Quantifying the percentage of WNT-high ISCs that are positive for Sca1 (RevSC marker) by flow cytometry. Graphs represent means ± SEM. Statistical analysis were conducted by two-way ANOVA in (B).
To spatially characterise WNT-high cells in the crypts co-expressing the Revival Stem Cell (RevSC) signature, I conducted IHC using a TCF/Lef:H2B;mCherry reporter system. The reporter has Tcf/Lef binding sites which drive the expression of the H2B:mCherry fluorescent protein, enabling visualisation of active WNT signalling. I observed colocalisation of mCherry and Clu (RevSC marker) at 1dpi, which was more pronounced at 3dpi (Fig 3A). These results suggest that WNT-high ISCs express RevSC markers during regeneration. In order to quantify how often this happens during regeneration, I utilised flow cytometry. By gating for mCherry+ ISCs (WNT-high ISCs), I found there was a significant increase in the percentage of mCherry+ ISCs expressing the RevSC marker Sca1 at 3dpi (~20%) compared to 0 dpi (~3%) (Fig3B).
In conclusion, my project demonstrated that a proportion of WNT-high ISCs co-express RevSC markers during injury-induced regeneration. Although preliminary, these results highlight that it is necessary to further investigate the role of YAP in the interplay between WNT signalling and the RevSC signature in ISCs during regeneration. This work would provide clarity into which signals dictate ISC survival during regeneration.
This project has provided me with invaluable insight into the scientific process. I have learned advanced techniques at the Li lab, including organoid culture and maintenance. I would like to thank my supervisor, James, for his exceptional mentorship in building my critical thinking, guiding my experiments, and supporting my data analysis and interpretation. I would also like to extend my thanks to the Francis Crick Institute and the Medical Research Foundation Rosa Beddington Fund for their generous support, which has enabled me to contribute to this exciting field of research.
Brown algae are a group of complex multicellular eukaryotes, unrelated to animals, plants and fungi. It follows that brown algae evolved the process of multicellular development independently, offering a unique opportunity to investigate shared principles underlying developmental evolution across the tree of life. One such principle is the hourglass model of embryo evolution. The hourglass model describes a pattern of evolutionary conservation and divergence during embryogenesis, where the divergent earlier and later stages are bridged by a conserved mid-embryonic period (Duboule 1994). Such hourglass patterns have been observed in animal, plant and fungal development (Drost et al. 2017). But what about brown algae?
In our recent paper, “A transcriptomic hourglass in brown algae” (Lotharukpong et al. 2024), we asked a simple question: does brown algal development follow the hourglass model? By profiling the developmental transcriptome in two Fucus species, we observe an hourglass pattern in brown algal embryogenesis (Fig 1). The conserved mid-embryonic period is underpinned by the reduced expression of evolutionarily younger genes and the presence of more broadly expressed, potentially pleiotropic genes. We also explored the transcriptome across life cycle stages in brown algae with differing levels of morphological complexity. Crucially, in morphologically simple Ectocarpus species without canonical embryos, multicellular development itself appeared to constrain transcriptome evolution, suggesting how such embryo hourglass patterns may have emerged in the first place (at least in brown algae). Overall, this work gives evidence for the hourglass model as a general principle underlying developmental evolution across the tree of life.
But as we all know; a lot went on behind the paper.
To test the hourglass model in brown algae, we first had to literally find morphologically complex brown algae that undergo embryogenesis (Fig 2). Between France and Germany, Rémy Luthringer (co-author) had to go collect reproductively mature adults to produce embryos and cultivate them in the lab. It was a challenge to culture Fucus embryos beyond the earliest embryonic stages, since they require a lot of care to ensure healthy growth. This was all the more difficult for species such as F. distichus, which required up to half a year to reach the latest embryonic stage used in the study.
Figure 2. Rémy (left; phycoculturalist) and Sodai (right; bioinformatician) sampling brown algae in the wild.
Bioinformatics in the spotlight:
We then faced several hurdles on the bioinformatics side when piecing this study together, which required a sustained push on software development. In particular, we wanted to infer the evolutionary age of each gene, which is needed for computing the transcriptome age index (a key metric for evolutionary transcriptomics). Existing approaches were not suitable nor computationally scalable to current large databases such as the National Center for Biotechnology Information (NCBI) non-redundant (nr) database and did not account for potential database contaminations among other confounding factors in gene age inference. We therefore teamed up with Josué Barrera-Redondo to create GenEra (Barrera-Redondo et al. 2023), a wrapper around the fast and sensitive pairwise sequence aligner DIAMOND v2 (Buchfink et al. 2021), which brought down the search time from months to days. This finally allowed us to infer the gene age in a timely manner for any eukaryotic genome, including the species we used in the hourglass study (Fucus serratus, Fucus distichus, Ectocarpus sp., Laminaria digitata and Saccorhiza polyschides).
On top of this, we extended the functionalities of R packages for evolutionary transcriptomics, such as myTAI (Drost et al. 2018), to accommodate our analyses. New and existing functions in myTAI enabled us to distinguish evolutionary signals from random noise. We hope these efforts will be useful for the wider community interested in asking evo-devo questions using transcriptomic data.
What’s next for the story?
It is an exciting time for brown algal research. A recent study has provided several dozen genome assemblies across major groups of brown algae (Denoeud et al. 2024). Furthermore, functional genetics is now a possibility for multiple brown algal species, fuelling recent findings such the independent evolution of HMG domain genes as a male sex-determining factor (Luthringer et al. 2024). There is also a drive to generate transcriptomic data to understand cell-type and tissue evolution in brown algae, which also evolved cell-types and tissues independently from other complex multicellular eukaryotes. There is still much more to come!
References
Barrera-Redondo J, Lotharukpong JS, Drost H-G, Coelho SM. 2023. Uncovering gene-family founder events during major evolutionary transitions in animals, plants and fungi using GenEra. Genome Biol. 24:54.
Buchfink B, Reuter K, Drost H-G. 2021. Sensitive protein alignments at tree-of-life scale using DIAMOND. Nat. Methods 18:366–368.
Denoeud F, Godfroy O, Cruaud C, Heesch S, Nehr Z, Tadrent N, Couloux A, Brillet-Guéguen L, Delage L, Mckeown D, et al. 2024. Evolutionary genomics of the emergence of brown algae as key components of coastal ecosystems. :2024.02.19.579948. Available from: https://www.biorxiv.org/content/10.1101/2024.02.19.579948v2
Drost H-G, Gabel A, Liu J, Quint M, Grosse I. 2018. myTAI: evolutionary transcriptomics with R. Bioinformatics 34:1589–1590.
Drost H-G, Janitza P, Grosse I, Quint M. 2017. Cross-kingdom comparison of the developmental hourglass. Curr. Opin. Genet. Dev. 45:69–75.
Duboule D. 1994. Temporal colinearity and the phylotypic progression: a basis for the stability of a vertebrate Bauplan and the evolution of morphologies through heterochrony. Development 1994:135–142.
Lotharukpong JS, Zheng M, Luthringer R, Liesner D, Drost H-G, Coelho SM. 2024. A transcriptomic hourglass in brown algae. Nature 635:129–135.
Luthringer R, Raphalen M, Guerra C, Colin S, Martinho C, Zheng M, Hoshino M, Badis Y, Lipinska AP, Haas FB, et al. 2024. Repeated co-option of HMG-box genes for sex determination in brown algae and animals. Science 383:eadk5466.
It’s now been 13 months since I started my lab, marking the end of my ‘New PI Diaries’ series here on the Node. The journey has so far been both overwhelming and rewarding, and I’ve enjoyed the chance to reflect and share my experiences in this blog. Overall, it’s been a lot—but mostly a good lot. My time gets split between a lot more responsibilities and I have less time to be in the lab. Both mentoring and teaching now take up much more time than during my postdoc, but luckily, I already know I enjoy both.
However, one aspect that was almost completely new to me was managing lab finances. In this blog, I want to share some examples of situations I encountered and the lessons I learned, along with a few key takeaways. To provide some context, my Independent Junior Group Leader position comes with support that includes a PhD student position, a technician, a yearly consumables budget, and some startup funds. Comparing lab resources across universities and countries is difficult. For instance, my startup budget is considerably smaller than those typically offered at US universities but potentially bigger than that available at other institutes or universities. However, I also benefit from funded positions and an equipped lab. In addition, many larger pieces of equipment and facilities are shared within the institute and can be used free of charge or at a low rate, reducing my need to purchase new equipment.
But let’s talk people first. In addition to support from the ZMBP, I was able to secure an Emmy Noether grant from the DFG. This grant covers my salary for six years, along with funding four years of two PhD students and a postdoc, allowing for steady growth and stability in the coming years. However, I quickly ran into an unexpected issue: the PhD student position from the University is paid a lower salary compared to the positions provided by the DFG. Different enough to feel unfair but unfortunately it is common. Similarly, PhD positions in different disciplines get compensated at different rates. Now, I cannot change decisions of the University or the state of Baden-Württemberg, but I figured there must be a workaround. Once I started asking around, I learned that people have come up with a variety of solutions. Talking with fellow group leaders and our Head of Central Services I learned that we could reassign the unused % of the technician position together with some flexible lab budget to equalize the PhD salaries. So, it’s important not to hesitate in discussing challenges; I certainly wasn’t the first to face this problem, and people had already identified potential solutions.
Apart from people, we’re spending money on consumables and equipment. The ZMBP account, which includes a startup and a yearly budget, allows me flexibility in spending. Additionally, last year I received one time support from a collaborative project. This account had its own constraints, while flexible, the funds must be used within two months, adding some pressure. Finally, the Emmy Noether provides consumables funding, albeit with more limited flexibility since it is there to support the group and project and any equipment should be provided by the University. As a result, I got a crash course into which account to use for what purchase. In short: for me it’s best to save the ZMBP account for computer and equipment purchases as those cannot be made from all other accounts.
Most of the necessary equipment was actually already there, but I found several items that could significantly make our lab’s work easier and more efficient. Before purchasing these I first spent some time looking around, checking what is available already, what our need really is, and what options we have for financing the things we need. And although I still don’t have a precise overview of our total finances, we’re in a fortunate position where I don’t have to stress excessively about money. I do feel it’s important for everyone in the lab to know the price of some of our reagents and equipment. Investing in reagents, such as 2x mixes for genotyping and colony PCR, is worth the costs right now for the time they save as long as people are aware of their cost. We’re in a good position, but I want to avoid wasting funds that could be better spent elsewhere to make our days easier. Eventually using lab funds we purchased two new stereomicroscopes to dissect Arabidopsis embryos, additional pipettes, and computers. Each piece of equipment or expensive kit is an investment that I think will pay off and that we can afford in our current situation. However, I remain careful as, well, I lack experience, and you never know what’s up ahead.
Here are my early-stage financial takeaways:
People are expensive. Value the positions you have and hire carefully. In addition, sometimes spending more on consumables and equipment is worth the time saved for your team.
Keep track of your accounts. Understand what’s in each account, what you can spend it on, and where your money is going. Is it what you expected?
Use your funds. Once you have a clear overview, consider what tools could make lab operations smoother. I initially waited to determine which investments would be beneficial for everyone in the lab but then decided to make some investments.
And my personal goals:
Have a more complete overview of the lab finances. I have a rough idea of what we’re spending and what’s available but I still have a long way to go. Luckily I have plenty of people to ask for advice.
Get experience. While enthusiasm is important, it doesn’t replace experience. I’m learning a lot and I already feel a lot more confident in making these decisions.
While the lab’s immediate future is secure, I also need to plan for what comes next. To be honest, at this point, anytime I feel like I’m in control of things I realize I just have been forgetting or ignoring something important. I guess that’s life. In general, I think I should spend more time thinking of grants. Next year will be my final opportunity to apply for the ERC Starting Grant, so my focus will be on that. Additionally, in a few years, I’ll need to start searching for a professor position, as my ZMBP Junior Group Leader position and Emmy Noether funding will end in about five years, and securing a professorship in Germany can take some time.
Wish me luck!
First investment: new stereomicroscope for doing embryo dissection and the beautiful images it takes of GUS-stained seedlings.
[Editorial from Development’s latest Special Issue ‘Uncovering Developmental Diversity’, edited by Cassandra Extavour, Liam Dolan and Karen Sears.]
Scanning through early issues of the Journal of Embryology and Experimental Biology (the previous name for this journal) reveals the diverse range of organisms that were investigated by developmental biologists in the 1950s and 1960s. However, the rise of molecular genetics in subsequent decades led to a narrowing in species choice to a small repertoire of well-characterised model organisms for which there were genetic tools for functional experimentation. In recent years, however, technological advances, including genome and transcriptome sequencing, flexible genome-editing approaches and high-resolution four-dimensional imaging, provide an opportunity to once again study developmental questions in organisms across all kingdoms of life. Given the current global challenges of climate change and biodiversity loss, it is particularly important that we turn our attention to understanding development in an unstable world.
This important topic was the basis of Development’s Journal Meeting, ‘Unconventional and Emerging Experimental Organisms in Cell and Developmental Biology’ in 2023, which you can learn more about in the Meeting Review published here (Lemke et al., 2024). Fuelled by the success of the meeting, we chose to focus this Special Issue, led by Academic Editor Cassandra Extavour, together with Liam Dolan and Karen Sears as Guest Editors, on a related topic: Uncovering Developmental Diversity. We are particularly delighted that multiple attendees from our meeting have contributed both research and review-type articles to this issue.
The 28 research papers in this Special Issue highlight 32 different organisms from across the multicellular tree of life, featuring cnidarians (Garschall et al., 2024), insects (Matsuda et al., 2024; Bai et al., 2024; Beaven et al., 2024; Pallarès-Albanell et al., 2024) and annelids (Bideau et al., 2024), as well as echinoderms (Barone et al., 2024; McDonald et al., 2024; Jackson et al., 2024; Clarke et al., 2024) and chordates (Gigante et al., 2024; Johnson et al., 2024), including vertebrates (Rees et al., 2024; Pérez-Gómez et al., 2024), many of which are various fishes (Leclercq et al., 2024; Li et al., 2024; Woronowicz et al., 2024; Peloggia et al., 2024; Jin et al., 2024). These articles demonstrate the importance of finding the best model to address a developmental question, such as making use of the curved epithelium in the sea star embryo to investigate cell organisation and packing (Barone et al., 2024) or using the regenerative capacity of annelids to learn more about cell plasticity (Bideau et al., 2024). In addition to annelids, a Perspective in this issue highlights five more ‘extraordinary’ model systems for regeneration across scales from single cells to whole organisms (Accorsi et al., 2024).
Not limited to animals, the Special Issue also embraces a wide array of studies uncovering fundamental developmental processes, such as axis formation and organogenesis in photosynthetic organisms, including brown algae (Vigneau et al., 2024; Boscq et al., 2024), liverworts (Attrill and Dolan, 2024; Attrill et al., 2024; Sakai et al., 2024), and vascular plants such as ferns (Woudenberg et al., 2024) and angiosperms (Mody et al., 2024; Spiegelhalder et al., 2024). Photosynthetic organisms feature heavily in the issue’s review-type content, too, with articles describing how brown algae can inform us about the transition to multicellularity (Batista et al., 2024), how the environment and climate change influence development through the lens of stomata (Chua and Lau, 2024) and what we can learn about the evolution of plant development through the fossil record (Hetherington, 2024).
The evo-devo field, in particular, has benefitted from the appreciation of biodiversity and increased taxonomic sampling. Reflecting this, two Reviews discuss fundamental evolutionary concepts, including how phenotypes can be maintained by different underlying genetic architecture through developmental systems drift (McColgan and DiFrisco, 2024), as well as a cautionary tale of how reports on the low-hanging fruit of simple genetic explanations of evolution should not change our perception that evolution is inherently complex (Cooper, 2024).
A broad selection of available organisms also allows the study of rare evolutionary innovations, such as the ability of Nematostella to degrow in response to food availability (Garschall et al., 2024) or of teleost fish to adapt ionocyte differentiation to regulate osmotic levels within aquatic environments (Peloggia et al., 2024). Adaptive plasticity is also the focus of a Review article describing how organisms assess environmental cues across scales and respond via phenotypic changes (Hill et al., 2024). Furthermore, capturing developmental biodiversity furthers our understanding of complex life cycles (McDonald et al., 2024; Peloggia et al., 2024) – a topic motivating a Hypothesis for unravelling cellular rejuvenation (Berger, 2024). Indeed, studying organisms with metamorphic life cycles allows us to learn about the intrinsic developmental process, such as how the rhinoceros beetle remodels its horn (Matsuda et al., 2024) or neuronal cell survival in Ciona (Gigante et al., 2024).
Importantly, research using emerging model systems relies on new tools that facilitate functional experiments. Our Techniques and Resources section features methods for the delivery of proteins and nucleic acids into oocytes in a variety of species (Clarke et al., 2024), as well as approaches for generating stable genetic lines (Jackson et al., 2024) and tools for quantifying diversity (Mody et al., 2024). However, not all species are amenable to being cultured in the lab, and a Perspective describes the importance of fieldwork for developmental biology in unconventional model systems (Brown et al., 2024). In addition, a Spotlight article describes how modern innovations in stem cell technology might be employed for species conservation (Hutchinson et al., 2024), highlighting how understanding biodiversity is the first step to its preservation, an increasingly prevalent topic in the context of climate change.
Overall, we hope that this issue demonstrates both how technological advances have made it possible to understand development and regeneration in previously intractable organisms, as well as the importance of this pursuit. We continue to ensure Development is an appropriate home for your studies in developmental biology, stem cells and regeneration using any organism. We welcome your submissions.
Maria Victoria Serrano, Stephanie Cottier, Lianzijun Wang, Sergio Moreira-Antepara, Anthony Nzessi, Zhiyu Liu, Byron Williams, Myeongwoo Lee, Roger Schneiter, Jun Liu
Aaron M. Savage, Alexandra C. Wagner, Ryan T. Kim, Paul Gilbert, Hani D. Singer, Erica Chen, Elane M. Kim, Noah Lopez, Kelly E. Dooling, Julia C. Paoli, S.Y. Celeste Wu, Sebastian Bohm, Rachna Chilambi, Tim Froitzheim, Steven J. Blair, Connor Powell, Adnan Abouelela, Anna G. Luong, Kara N. Thornton, Benjamin Tajer, Duygu Payzin-Dogru, Jessica L. Whited
Peggy P. Hsu, Ansley S. Conchola, Tristan Frum, Xiangning Dong, Lila Tudrick, Varun Ponnusamy, Michael S. Downey, Manqi Wu, Mengkun Yang, Yusoo Lee, Emma Niestroy, Yu-Hwai Tsai, Angeline Wu, Sha Huang, Ian A. Glass, Sofia D. Merajver, Jason R. Spence
Ling S. Loh, Joseph J. Hanly, Alexander Carter, Martik Chatterjee, Martina Tsimba, Donya N. Shodja, Luca Livraghi, Christopher R. Day, Robert D. Reed, W. Owen McMillan, Gregory A. Wray, Arnaud Martin
Tim Ott, Amelie Brugger, Emmanuelle Szenker-Ravi, Yvonne Kurrle, Olivia Aberle, Matthias Tisler, Martin Blum, Sandra Whalen, Patrice Bouvagnet, Bruno Reversade, Axel Schweickert
Yuchen Liu, Tianli Qin, Xin Weng, Bernice Leung, Karl Kam Hei So, Boshi Wang, Wanying Feng, Alexander Marsolais, Sheena Josselyn, Pingbo Huang, Bernd Fritzsch, Chi-Chung Hui, Mai Har Sham
Qiao Wu, Jian Zhang, Bing Long, Xiao Hu, Bruna Mafra de Faria, Stephen Maxwell Scalf, Kutay Karatepe, Wenxiang Cao, Nikolaos Tsopoulidis, Andres Binkercosen, Masaki Yagi, Aaron Weiner, Mary Kaileh, Enrique M. De La Cruz, Ananda L Roy, Konrad Hochedlinger, Shangqin Guo
Stephen Spurgin, Ange Michelle Nguimtsop, Fatima N. Chaudhry, Sylvia N. Michki, Jocelynda Salvador, M. Luisa Iruela-Arispe, Jarod A. Zepp, Saikat Mukhopadhyay, Ondine Cleaver
Sera Lotte Weevers, Alistair D. Falconer, Moritz Mercker, Hajar Sadeghi, Jaroslav Ferenc, Albrecht Ott, Dietmar B. Oelz, Anna Marciniak-Czochra, Charisios D. Tsiairis
Theopi Rados, Olivia S. Leland, Pedro Escudeiro, John Mallon, Katherine Andre, Ido Caspy, Andriko von Kügelgen, Elad Stolovicki, Sinead Nguyen, Inés Lucía Patop, Thiberio Rangel, Sebastian Kadener, Lars D. Renner, Vera Thiel, Yoav Soen, Tanmay A.M. Bharat, Vikram Alva, Alex Bisson
Nora Ditzer, Ezgi Senoglu, Theresa M. Schütze, Aikaterina Nikolaidi, Annika Kolodziejczyk, Katrin Sameith, Sevina Dietz, Razvan P. Derihaci, Cahit Birdir, Anne Eugster, Mike O. Karl, Andreas Dahl, Pauline Wimberger, Franziska Baenke, Claudia Peitzsch, Mareike Albert
Audrey J. Marsh, Sergei Pirogov, Abby J. Ruffridge, Suresh Sajwan, Tyler J. Gibson, George Hunt, Yadwinder Kaur, Melissa M. Harrison, Mattias Mannervik
Dimitris Botskaris, Ioannis K. Deligiannis, Ioanna Peraki, Haroula Kontaki, Marianna Stagaki, Matthieu D. Lavigne, Celia P. Martinez-Jimenez, Iannis Talianidis
Surbhi Sood, Aktan Alpsoy, Guanming Jiao, Alisha Dhiman, Charles Samuel King, Gabriella Grace Conjelko, Judy E. Hallett, Sagar M Utturkar, Jill E Hutchcroft, Emily C Dykhuizen
Olga M. Sigalova, Mattia Forneris, Frosina Stojanovska, Bingqing Zhao, Rebecca R. Viales, Adam Rabinowitz, Fayrouz Hamal, Benoît Ballester, Judith B Zaugg, Eileen E.M. Furlong
Yuliia Haluza, Joseph A. Zoller, Ake T. Lu, Hannah E. Walters, Martina Lachnit, Robert Lowe, Amin Haghani, Robert T. Brooke, Naomi Park, Maximina H. Yun, Steve Horvath
Rita Manco, Camilla Moliterni, Gauthier Neirynck, Maxime De Rudder, Corinne Picalausa, Leana Ducor, Montserrat Fraga, Frédéric Lemaigre, Christine Sempoux, Alexandra Dili, Isabelle A. Leclercq
Yingnan Lei, Mai Chi Duong, Nuša Krivec, Charlotte Janssens, Marius Regin, Anfien Huyghebaert, Edouard Couvreu de Deckersberg, Karen Sermon, Diana Al Delbany, Claudia Spits
Julian Weihs, Fatima Baldo, Alessandra Cardinali, Gehad Youssef, Katarzyna Ludwik, Harald Stachelscheid, Nils Haep, Peter Tang, Igor Sauer, Pavitra Kumar, Cornelius Engelmann, Susanna Quach, Philip Bufler, Namshik Han, Milad Rezvani
Milad Rezvani, Kyle Lewis, Susanna Quach, Kentaro Iwasawa, Julian Weihs, Hasan Al Reza, Yuqi Cai, Masaki Kimura, RanRan Zhang, Yuka Milton, Praneet Chaturvedi, Konrad Thorner, Ramesh C. Nayak, Jorge Munera, Phillip Kramer, Brian R. Davis, Appakalai N. Balamurugan, Yeni Ait Ahmed, Marcel Finke, Rose Yinghan Behncke, Adrien Guillot, René Hägerling, Julia K. Polansky, Philip Bufler, Jose A Cancelas, James M. Wells, Momoko Yoshimoto, Takanori Takebe
B. Pardo-Rodríguez, A.M. Baraibar, I. Manero-Roig, J. Luzuriaga, J. Salvador-Moya, Y. Polo, R. Basanta-Torres, F. Unda, S. Mato, G. Ibarretxe, J.R. Pineda
Sara Cannavò, Chiara Paleni, Alma Costarelli, Maria Cristina Valeri, Martina Cerri, Antonietta Saccomanno, Veronica Gregis, Graziella Chini Zittelli, Petre I. Dobrev, Lara Reale, Martin M. Kater, Francesco Paolocci
Alicia Tovar, Scott Monahan, Trevor Mugoya, Adrian Kristan, Walker Welch, Ryan Dettmers, Camila Arce, Theresa Buck, Michele Ruben, Alexander Rothenberg, Roxane Saisho, Ryan Cartmill, Timothy Skaggs, Robert Reyes, MJ Lee, John Obrycki, William Kristan, Arun Sethuraman
Haidong Yan, John P. Mendieta, Xuan Zhang, Alexandre P. Marand, Yan Liang, Ziliang Luo, Mark A.A. Minow, Hosung Jang, Xiang Li, Thomas Roulé, Doris Wagner, Xiaoyu Tu, Yonghong Wang, Daiquan Jiang, Silin Zhong, Linkai Huang, Susan R. Wessler, Robert J. Schmitz
Magdalena Schindler, Christian Feregrino, Silvia Aldrovandi, Bai-Wei Lo, Anna A. Monaco, Alessa R. Ringel, Ariadna Morales, Tobias Zehnder, Rose Yinghan Behncke, Juliane Glaser, Alexander Barclay, Guillaume Andrey, Bjørt K. Kragesteen, René Hägerling, Stefan Haas, Martin Vingron, Igor Ulitsky, Marc Marti-Renom, Julio Hechavarria, Nicolas Fasel, Michael Hiller, Darío Lupiáñez, Stefan Mundlos, Francisca M. Real
Cristofer Calvo, Casey O. Swoboda, Fabian Montecino Morales, Siddhant Nagar, Michael J. Petrany, Chengyi Sun, Hima Bindu Durumutla, Mattia Quattrocelli, Douglas P. Millay
Ismael Moreno-Sanchez, Luis Hernandez-Huertas, Daniel Nahon-Cano, Carlos Gomez-Marin, Pedro Manuel Martinez-García, Anthony J. Treichel, Laura Tomas-Gallardo, Gabriel da Silva Pescador, Gopal Kushawah, Alejandro Díaz-Moscoso, Alejandra Cano-Ruiz, John A. Walker II, Manuel J. Muñoz, Kevin Holden, Joan Galcerán, María Ángela Nieto, Ariel Bazzini, Miguel A. Moreno-Mateos
Sara Di Carlo, Adrian Salas-Bastos, Mariela Castelblanco Castelblanco, Muriel Auberson, Marie Rumpler, Malaury Tournier, Lukas Sommer, Olaia Naveiras, Edith Hummler
Ália dos Santos, Oliver Knowles, Tom Dendooven, Thomas Hale, Alister Burt, Piotr Kolata, Giuseppe Cannone, Dom Bellini, David Barford, Matteo Allegretti
Daniel Medina-Cano, Mohammed T. Islam, Veronika Petrova, Sanjana Dixit, Zerina Balic, Marty G. Yang, Matthias Stadtfeld, Emily S. Wong, Thomas Vierbuchen
Brian Ho Ching Chan, Holly Hardy, Teresa Requena, Amy Findlay, Jason Ioannidis, Dominique Meunier, Maria Toms, Mariya Moosajee, Anna Raper, Mike McGrew, Joe Rainger
Guilherme E. Kundlatsch, Alina S. L. Rodrigues, Vitória F. B. Zocca, Laura A. S. Amorim, Gabriela B. de Paiva, Almiro P. S. Neto, Juliana A. D. B. Campos, Danielle B. Pedrolli
The 30 October 2024 Development presents… webinar was chaired by Development’s Executive Editor, Katherine Brown and featured three talks on the topic of the development of ectoderm derivatives. Catch up on the talks below.
During my time as a summer student at the Francis Crick Institute, I had the privilege of working in the Developmental Signalling Laboratory of Dr Caroline Hill. Under the mentorship of Dr Berta Font Cunill, I have gained an insight into the realities of cutting-edge scientific research and was able to contribute to experiments advancing the understanding of developmental biology.
Throughout embryonic development, as cells divide, they begin to specialise to later form diverse functional tissues. This is possible because, even though progenitor cells contain copies of the same genetic code, they express different sets of genes. These gene expression patterns are governed by various complex signalling pathways, which ultimately determine cell fate. The Hill Lab is interested in understanding how cells use specific signals to communicate with each other and their environment to drive the development of an organism and tissue specialisation. During gastrulation, this cellular communication results in the embryonic stem cells transforming into three distinct germ layers: endoderm, mesoderm, and ectoderm. As their subsequent patterning generates all future body structures, this process sets the stage for the functioning of the entire organism (Richardson et al., 2023).
In my research project, I was specifically interested in the mechanism of cell differentiation into definitive endoderm. This germ layer gives rise to the lungs, bladder, the majority of the digestive tract, as well as vital endocrine organs like the pancreas and thyroid (Fang & Li, 2022). Understanding the signalling pathways involved in endoderm differentiation is necessary to generate novel therapeutic solutions to diseases associated with endoderm-derived tissues, such as diabetes. This is possible by using human induced pluripotent stem cells (iPSCs) to generate endodermal cells, and possibly their derivatives, in vitro (Fang & Li, 2022).
To study the differentiation to endoderm, I cultured iPSCs for four days in differentiation media with addition of CHIR-99021 (5 µM) for 24h, and Activin A (20 ng/mL) for 72h, following a standard protocol (Fig. 1a). Based on previous publications (Diekmann and Naujok, 2015), I expected that throughout this process, cells would follow certain patterns of gene expression (Fig. 1b). After 72h of differentiation (Day 4), I fixed and stained the cells with antibodies recognising key markers of pluripotency (Oct4) and endoderm (Sox17). I imaged the cells (Fig. 1c), quantified the results and was able to establish that the protocol of interest results in about 80% of stem cells differentiating to endoderm cells (Fig. 1d), confirming what has been observed in published articles.
Fig. 1 Standard differentiation efficiency from iPSCs to endoderm cells in vitro. (a) Schematic of the 4-day protocol used for differentiating pluripotent stem cells to endoderm cells. CHIR99021 functions as a Wnt pathway activator. Wnt signalling is required to reduce cell pluripotency, and promote mesendodermal (TBXT, EOMES) differentiation (Zhao et al., 2019). Activin A, a member of the TGF-β superfamily, is an activation factor for the Nodal pathway. High Nodal signalling gradient leads to further differentiation into endoderm (SOX17, GSC) (Richardson et al., 2023 ; Silva et al., 2022). (b) Predicted patterns for the expression of markers (Sox17, Oct4, Brachyury) throughout the differentiation process (Diekmann and Naujok, 2015). (c) Nuclei of cells fixed after carrying out the standard protocol (a), stained with Oct4 (green) and Sox17 (red) antibodies. Imaged using confocal microscopy. (d) Quantified results (n=8) of the percentage of differentiated cells expressing Sox17 (red) vs cells remaining pluripotent and expressing Oct4 (green).
Having established the standard differentiation protocol, I wanted to understand the process itself in more detail. I set out to investigate the gene expression patterns throughout the transition of cells from pluripotency to endoderm. I collected cell samples on each day of the protocol. After extracting RNA, I synthesised cDNA to be used in quantitative polymerase chain reaction (qPCR) analysis. qPCR allows for the amplification of target DNA sequences, with simultaneous quantification of their concentration throughout the process. Thus, I was able to obtain and visualise the levels of expression of endoderm differentiation marker genes on each day of the protocol (Fig. 2). I was able to prove that cells transitioning from pluripotency to endoderm follow predicted patterns of gene expression (Fig. 1b). Pluripotency genes (POU5F1, SOX2) gradually decline as the differentiation continues (Fig. 2a), while endoderm markers (SOX17, GSC) are expressed more substantially towards the end of the process (Fig. 2c). I was also able to confirm that the cells go through an intermediate stage, with mesendoderm genes (TBXT, MIXL1) being expressed transiently on Day 2 (Fig. 2b).
Fig. 2 Relative expression of marker genes throughout differentiation of iPSCs to endoderm. (n=3) Expression levels of all genes of interest were normalised to that of a housekeeping gene GAPDH. Obtained results have been quantified and visualised using Python. (a) Relative expression levels of pluripotent marker genes POU5F1 and SOX2. (b) Relative expression levels of gene markers (TBXT and MIXL1) for the intermediate stage of mesendoderm, peaking at day 2. (c) Relative expression levels of endoderm marker genes SOX17 and GSC.
To better understand the signalling pathways involved in the process of cell differentiation to endoderm, Dr Berta Font Cunill screened a library of over 1,000 small molecules of diverse molecular structure that could possibly affect the process by interacting with proteins important for endoderm differentiation. She identified one small molecule (compound “953”) that increases the differentiation efficiency to endoderm (from 80 to 90% approximately).
As I previously mentioned, after following the standard protocol the rate of differentiation to endoderm cells reaches about 80% (Fig. 1d). This high efficiency leaves a small margin for improvement. My goal was to modify the standard differentiation protocol to achieve a lower differentiation efficiency, and therefore increase the margin for improvement upon addition of compound “953”. I seeded pluripotent cells in media with varying concentrations of CHIR-99021 and Activin A (Fig. 3) and carried out the differentiation protocol for three days. I observed that even when the amount of Activin A was lowered from 20 ng/mL to 4 ng/mL, the differentiation proceeded only with minor changes in efficiency (Fig. 3a). However, lowering the amount of CHIR-99021 in just 1 µM increments hindered the process considerably (Fig. 3b). When CHIR-99021 was not present at all, most cells didn’t survive. These results show that CHIR-99021 is vital for endoderm differentiation.
Fig. 3 The effect of Activin A and CHIR-99021 concentration on differentiation efficiency. (n=8) The differentiation efficiency was measured on Day 3 based on the levels of expression of pluripotent (Oct4, green) and endodermal (Sox 17, red) marker genes. Obtained results were quantified and visualised using Python. (a) Pluripotent cells were cultured in conditions dictated by the standard protocol but with varying concentrations of Activin A. (b) Pluripotent cells were cultured in conditions dictated by the standard protocol but with varying concentrations of CHIR-99021.
Based on the obtained results, I decided that the best condition to test the effect of compound “953” was 20 ng/mL of Activin A (48h), and 3 µM of CHIR-99021 (24h), which resulted in around 50% of differentiation efficiency, leaving a large margin for improvement. I cultured the cells for three days using these new conditions and different concentrations of compound “953”, after which I stained for Oct4 and Sox17 (Fig. 4). I observed that cells grown with 10 µM of compound “953” in the media, reached 10-15% higher differentiation efficiency than those grown without the compound (Fig. 4a). However, the final total number of cells was lower than in control groups (Fig. 4b). These results suggest that while molecule “953” pushes differentiation from pluripotency into endoderm cells, it is also possibly mildly toxic or hinders cell proliferation. The results also suggest that even if differentiation is hindered, compound “953” is not able to increase the differentiation efficiency beyond 10-15%.
Fig. 4 The effect of compound “953” on differentiation efficiency. (n=8) (a) boxplots representing quantified results of differentiation efficiency for varying concentrations of “953”. (b) Nuclei of cells fixed after carrying out the modified protocol, stained with Oct4 (green) and Sox17 (red) antibodies. Imaged using confocal microscopy. The represented samples suggest that while the amount of pluripotent cells (green) is lower when 10 µM of “953” is present in the growth media, and therefore the differentiation rates are higher, the observed total number of cells is lower than in control groups.
The future of this project will focus on identifying the protein impacted by compound “953” through extensive proteomic analysis. This will allow for a better understanding of the signalling pathways involved in cell differentiation to definitive endoderm, which is a necessary step for the successful differentiation of downstream endoderm-derived tissues and organs to develop novel solutions in regenerative medicine. I am incredibly grateful for the opportunity to contribute to such inspiring scientific advancements. It has been an honour to be supported by the Rosa Beddington Fund. This experience has been a defining moment for my academic and professional development, and I have made the decision to pursue similar research through a PhD studentship and the rest of my scientific career. I would like to thank the Hill Lab, where I had the pleasure of working with incredible scientists, for their support and for welcoming me as a valued team member. I am especially grateful for the guidance and expertise of my supervisor, Dr Berta Font Cunill.
SOURCES
Diekmann, U., Naujok, O. (2015). Generation and Purification of Definitive Endoderm Cells Generated from Pluripotent Stem Cells. Methods in Molecular Biology, 1341, 157-72. https://doi.org/10.1007/7651_2015_220
Fang, Y., Li, X. (2022). Metabolic and epigenetic regulation of endoderm differentiation. Trends in Cell Biology, 32(2), 151-164. https://doi.org/10.1016/j.tcb.2021.09.002
Richardson, L., Wilcockson, S.G., Guglielmi, L. et al. (2023). Context-dependent TGFβ family signalling in cell fate regulation. Nature Reviews Molecular Cell Biology, 24, 876–894. https://doi.org/10.1038/s41580-023-00638-3
Silva, I.B.B., Kimura, C.H., Colantoni, V.P. et al. (2022). Stem cells differentiation into insulin-producing cells: recent advances and current challenges. Stem Cell Research & Therapy, 13, 309. https://doi.org/10.1186/s13287-022-02977-y
Zhao, M., Tang, Y., Zhou, Y. et al. (2019). Deciphering Role of Wnt Signalling in Cardiac Mesoderm and Cardiomyocyte Differentiation from Human iPSCs: Four-dimensional control of Wnt pathway for hiPSC-CMs differentiation. Nature Scientific Reports, 9, 19389. https://doi.org/10.1038/s41598-019-55620-x
[This post is co-written by Joan-Josep Soto Angel and Pawel Burkhardt.]
Timelapse showing reverse development in a lobectomized individual of M. leidyi. Note the progressive reduction in size and reabsorption of lobes and auricles typical of the lobate phase (absent on Day 41), followed by a normal cydippid morphology, showing long, functional tentacles (Day 48). https://doi.org/10.1073/pnas.2411499121
What is this?
The video depicts the process of reverse development in the ctenophore Mnemiopsis leidyi over several weeks. Adult and larval M. leidyi are anatomically different: lobate adults have lobes and auricles that are not yet developed in the larval stage. Cydippid larvae have a rounded body and tentacles that get reabsorbed during the lobate adult stage. The timelapse video shows an adult comb jelly slowly transitioning to a larval form over time, with lobes and auricles disappearing, and tentacles being regained. This is a process called reverse development.
Where can this be found?
This footage was obtained in our Ctenophore Facility at the University of Bergen, under controlled laboratory conditions, and following the same individual over time. Whether or not these comb jellies are equally capable of doing this in the ocean still remains a mystery, but the potential is definitely there!
The timelapse is made out of 24 individual pictures, each taken every 2-3 days, and shows the animal in the same position for comparison purposes. We used a Canon 5D Mark IV coupled to a Canon MP-E 65mm f/2.8 1-5x Macro Photo, usually known as an extreme macro lens. As the animals are very transparent, and the details are difficult to observe, we used a black background and added an extra light source from the side using a Canon speedlite strobe.
What causes M. leidyi to reverse develop?
Reverse development in M. leidyi is triggered by improved environmental conditions after a period of stress. Stress was simulated by either removing the lobes (lobectomy) or by prolonged starvation. Mnemiopsis leidyi is able to efficiently regenerate any missing body part, as well as shrinking considerably when starved. However, when adequately fed after shrinking to a size of just a few millimetres, instead of growing back the lobes, they grew tentacles typical of the larval stage.
Why should people care about this?
So far, reverse development was thought to be restricted to a few cnidarian species and one cestode. Our study is the first to report the occurrence of this peculiar feature in ctenophores, suggesting that reverse development may be more widespread than previously thought. The occurrence of reverse development in a lineage that originated prior to cnidarians can help to better understand central aspects of life cycle plasticity and evolution in early animals. The ability to rejuvenate in harsh conditions also provides further research opportunities for ecological studies aiming to explain, among others, the high invasive success of this comb jelly. Our study highlights Mnemiopsis leidyi as a potential model species to study life cycle plasticity, aging and rejuvenation.
How would you explain this to an 8-year-old?
Aging is a one-way route for a great majority of animals. However, there are a few that seem to be able to escape the fate of getting old. An adult transforming into a baby was only known for a species of jellyfish, usually called the immortal jellyfish (its scientific name is Turritopsis dorhnii). We found this capacity in an entirely new group of animals: the comb jellies. When Mnemiopsis leidyi (also known by its common name as sea walnut) becomes an adult, it grows two lobes and four pointy finger-like structures called auricles that they use for feeding. Baby sea walnuts do not have these body parts. Instead, they use two long tentacles to trap their prey and direct it to the mouth. The tentacles are lost once these animals reach their final adult form. We discovered that adult sea walnuts can rejuvenate when they eat properly after going through a period of stress.
Joe: Our lab aims to understand how developmental mechanics regulates mammalian folliculogenesis and ovarian dynamics. We focus on three overarching themes: First, how mechanical signals such as tissue pressure and hydraulics impact folliculogenesis and oocyte growth. Second, how the mechanical environment around the follicles influence collective dynamics of follicles and ovarian functions. Third, we are interested to understand how changes in tissue mechanics and misregulated mechano-signaling impacts follicle functions and ovulation during ageing and infertility. To address these questions, we develop multidisciplinary approaches based on novel (bio)mechanics, (bio)photonics and (bio)physical tools, using ex vivo assays.
Group photo of the lab
Can you give us a lab roll call?
Arikta Biswas: I am a postdoctoral research fellow: I study how mechanical interactions are generated, controlled, and transmitted within ovarian follicles at the secondary stage of development using mice as model systems.
Kim Whye Leong: I’m a postdoctoral fellow investigating the process of antrum formation and how its mechanochemical functions shape ovarian follicle development. Using advanced 3D microscopy (my favorite technique) and cutting-edge tools for force measurement and manipulation, I’m exploring the forces and dynamics that drive this crucial stage of development.
Jake Turley: I am a postdoc in the lab and I work on the biophysics of ovulation combining advanced microscopy, biomechanical tools and machine learning.
Huan Ting Ong: I am a Postdoctoral Research Fellow co-advised by Jennifer Young and Joe, studying mechanoregulation during ovarian ageing driven by the extracellular matrix and stroma.
Boon Heng Ng: A fourth-year student, trying to study how ovarian theca cells could sense mechanical cues and contribute to ovarian follicle development.
Kosei Tomida: I am a second year PhD student in the lab and I am studying follicle-follicle interactions through mechanochemical feedback interactions.
Kelly Tan: I am an incoming first-year graduate student, hoping to investigate a cool question on how the somatic (granulosa) cells contribute mechanically to follicle growth, apart from its classical signalling pathways.
Apoorva Shivankar: I am a Research Assistant in the Chan Lab group. In addition to my administrative duties, I have the opportunity to engage in research. I’m currently investigating the functional and mechanical differences between the immune cells in young and aged ovaries.
Le Mai Tan Dat (Daniel): I’m an undergraduate student doing a semester-long research project, mentored by Jake. We are studying the biophysics of ovulation, applying machine learning to quantify tissue dynamics.
Favourite technique, and why?
Joe: I adore any new biophysical tools that allow us to gain new insights into tissue mechanobiology. One of my favourite tools is micropressure probe, which allows us to measure and manipulate fluid or cytoplasmic pressure in cells and tissues. I am excited to expands its use to study hydraulic control in development, physiology, disease and ageing.
Apart from your own research, what are you most excited about in developmental and stem cell biology?
Joe: I am a firm believer that new technology often leads to new discoveries, so any biophysical approaches to probe mechanics in living tissues excite me! I also think the application of machine learning approach will not only help us gain quantitative understanding of tissue dynamics during development, it also harbours great potential to uncover new physics regulating biological processes. I am particularly excited about ongoing work to apply these approaches to address ageing and diseases.
How do you approach managing your group and all the different tasks required in your job?
Joe: As an assistant professor, it can indeed be daunting to handle multiple tasks like teaching, research and administrative duties. I hold regular group and 1-1 meetings with lab members to stay connected with their projects and give timely feedback. Given the highly interdisciplinary nature of our research, I do my best to foster exchange amongst lab members, often teaming them up in joint projects, while maintaining autonomy in their own projects. Recently I realised that too many back-to-back meetings can negatively impact the quality of meetings, and moving on I might try to cut down non-essential meetings. I also work on annual individual development plans with my team, which is a great platform to provide mutual feedback. This also helps to keep track of what’s going on at the ground and calibrate my management style. I recently shared this in more detail in a People & Ideas article in Journal of Cell Biology.
Something I wish to do, but haven’t got a chance to, is to hold an annual lab retreat or a joint retreat with other labs – those are great opportunities to share blue-sky research ideas and learn from each other!
What is the best thing about where you work?
Joe: I am super grateful to have a family-like lab-mosphere! The various core facilities and admin team at MBI are doing an amazing job in supporting the research. Being at Singapore is unique in the sense that we can serve as a focal point in Asia pacific for scientific exchange and collaborations with people from Japan, China, Hong Kong and Australia.
Arikta: It is not often that researchers have dedicated core facilities who work tirelessly and silently ‘behind-the-scenes’ to make our science go smoother, but it is the case here and I am very appreciative of their strong yet quiet efforts. Also, I thoroughly enjoy the freedom to think and brainstorm ideas with my lab-mates without hesitation.
Jake: My labmates are very supportive and generous with their time and help. This allowed me to quickly settle in and it also makes working in the lab a more enjoyable experience.
Kim Whye: The best thing about where I work is the collaborative atmosphere. Everyone, from researchers to staff, is incredibly supportive, and it fosters a real sense of teamwork. We also have a lot of microscopes and cutting-edge biophysical tools! It’s exciting to work in a place where you’re empowered to push the boundaries of what’s possible.
Huan Ting: The multidisciplinary environment the institute has, which encourages collaborations and cross-fertilisation of new ideas!
Boon Heng: Everyone is very supportive and collaborative with the different projects! If we are unsure about anything, we never hesitate to consult anyone in the lab. We also try to have lunch together every day, like a ‘family’ daily lunch?
Kosei: I appreciate the availability of resources in core facilities, items, and people from different backgrounds. I was lucky to have been blessed with a wonderful mentor.
Kelly: I really like how the lab fosters a welcoming environment for anyone to ask all sorts of questions, and to suggest unconventional (crazy) ideas. Everyone is more-than-merely-willing to help one another, and there has been no shortage of encouragement (and laughter) to enjoy pursuing great science even amidst the most stressful and busiest of days.
Apoorva: To me the four cornerstones of our lab are the 1) freedom to explore topics, 2) supportive and friendly atmosphere, 3) access to cutting-edge techniques, and 4) guidance from supportive colleagues.
Daniel: I enjoy the conversations that spontaneously arise, especially in the weekly lab meeting. Sometimes, we just share about our projects and scientific discussions will follow. Everyone is very experienced and receptive to comments and opinions, making it a great opportunity for me to learn more about the sciences.
What’s there to do outside of the lab?
Joe: I enjoy hiking and exploring the beautiful nature reserves across the island with my family. After sending kid to school in the early morning, I cherish the quiet moments where I get to hang out at the coffee shop in the hawker center to do some personal reading. Watching sci-fi movies (even better, combined with horror elements like Alien series), is also one of my favourite hobbies.
Arikta: I love reading outside of work, mostly fiction though, and spend an incredibly large amount of my free time at the Kinokuniya bookstore. When I am not strolling through the aisles of books, I am usually watching any Southeast Asian content on the internet; and then messaging my lab members to bug them about the accuracy of the cultures being represented onscreen.
Jake: I mainly enjoy eating out at the massive variety of food places available in Singapore and watching live gigs.
Kim Whye: When I’m not deep in follicle research, I enjoy reading up on bottom-up approaches in synthetic developmental biology and staying on top of the latest biotech innovations. Singapore may not be renowned for its pub culture (though we do indulge occasionally), but what we lack in that area, we more than make up for with our incredible food scene. There’s always something new and delicious waiting to be discovered.
Huan Ting: Despite the hot and humid weather, Singapore has plenty of natural trails featuring the flora and fauna unique to the tropical regions, just around the neighbourhood. Coming from Australia, one of my favourite things to do outside the lab is to explore these hiking trails with my family.
Boon Heng: While Singapore might lack nature reserves, there are still nice hiking trails and various outdoor activities. Maybe just a little bit hot and humid. As a Singaporean, I like to explore interesting food places from different races/cultures. You can’t go wrong with nice food!
Kosei: Swimming became my routine in Singapore. I often go swimming outside throughout the year because it’s warm and sunny every day, making you feel refreshed!
Kelly: I like to stay at home… but otherwise, targeting the stereotyped marathon-running scientist, there are many scenic running routes at every corner of Singapore, so you can get your daily dose of running endorphins easily.
Apoorva: Outside of the lab, I enjoy exploring the beautiful spots in the city, such as Gardens by the Bay, Marina Bay Sands, Sentosa and Singapore Botanic Gardens. I also love to check out the charming small islands surrounding Singapore.
Daniel: I enjoy reading books, especially classic novels and biographies. I enjoy the stories that are to unfold on each page of the books, with a plethora of emotions attached to each story. Books allow me to appreciate life in another form. “When Breath Becomes Air” by Paul Kalanithi is one of my favourites.
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