In their paper recently published in Evolution & Development, Vanessa Spieß, Rannyele P. Ribeiro and colleagues explore the regenerative abilities of the marine segmented worm Syllis malaquini. Their research reveals that a small piece of this tiny worm can regenerate its entire body forming a whole new individual. Now, co-first and co-corresponding author Rannyele P. Ribeiro offers insights behind this fascinating discovery.

How did the project get started?

During my PhD, supervised by Dr. M. Teresa Aguado, professor at University of Gottingen, I discovered a new species of segmented worm, Syllis malaquini, living in an aquarium. This worm has a segmented body, which means that between the head and tail there is a trunk formed by repeated body units called segments. The trunk of the worm also has a regionalized digestive tube, with foregut and gut regions. My thesis characterized morphological and cellular dynamics of S. malaquini regeneration, showing that the worm could restore the missing body part after amputation of half of its body¹. That means splitting a worm into two pieces generates two new worms that are clones of one another. This breakthrough revealed a critical research challenge: identifying the smallest body fragment that retains the potential for whole-body regeneration. To answer this question, Master’s student Vanessa Spieß conducted many experiments isolating body fragments with different segment numbers, and from different gut regions along the antero-posterior axis of the worm.  At that time, I transitioned to do my postdoctoral research with Dr. Duygu Özpolat, assistant professor at Washington University in St. Louis. However, I continued to collaborate with Vanessa Spieß and Dr. Aguado to analyze and interpret the acquired data, culminating in the recently published paper in Evolution & Development².

Why did you choose Syllis malaquini as your research organism?

Syllis malaquini was discovered serendipitously while performing experiments to investigate regeneration in segmented worms collected from an aquarium located at the University of Leipzig, Germany³. While working with what was thought to be Typosyllis antoni, I observed an unexpected ability to regenerate the anterior body, of which T. antoni is incapable^4,5. This observation led to a careful examination of the morphology and DNA sequence of my experimental worms, revealing a new species that we named S. malaquini. This species amazed me in many ways. During an experiment, I successfully cultured multiple fragments from a single individual in a Petri dish, with each fragment regenerating into a complete clone, multiplying the worm culture. This astonishing ability suggests a form of near immortality by continuous regeneration and self-cloning. I think that their regenerative mechanisms probably rely on powerful mechanisms that maintain cellular health and proliferative capacity. Therefore, this worm is an excellent model for studying not only whole-body regeneration but also fundamental mechanisms of cellular integrity maintenance.

Can you summarize the key findings of the paper in one paragraph?

Our research revealed the minimum body size for whole-body regeneration in Syllis malaquini, assessing regenerative success and failure. We not only confirmed the worm’s remarkable regenerative capacity but also demonstrated its ability to achieve whole-body regeneration from extremely small fragments of the trunk, specifically from the intestinal region. We discovered that, while a piece of trunk with just two segments (that is around 300 μm long) can initiate head and tail regeneration, it cannot restore the whole-body. However, a fragment with three segments can successfully regenerate an entire new individual (Fig. 1). The research also uncovered that regenerative capacity varies depending on the gut region, with fragments of the foregut being less regenerative than of the ones from the intestinal region. This discovery opens new avenues for understanding the influence of the gut regions in successful regeneration in segmented organisms.

Were there any other unexpected results and challenges, especially associated with working with a non-model research organism?

Working with Syllis malaquini presented unique challenges, particularly in controlling sexual reproduction, which hindered our ability to perform transgenesis and genome editing. While we successfully maintain asexual reproduction in aquariums, the lack of control over egg and embryo production limits genetic tractability in this species, as generating transgenic segmented worms typically relies on egg injection techniques. To overcome these obstacles, I’m currently developing gene knockdown systems using RNAi in segmented worms. This approach offers a promising avenue for investigating the molecular basis of S. malaquini’s regenerative ability, despite limitations in traditional genetic editing techniques. By adapting and refining these methods, we aim to unlock new insights into the mechanisms underlying whole-body regeneration in this fascinating species.

What’s next for this story?

A direction to be followed next in S. malaquini research is identifying the crucial factors that enable successful regeneration in amputated fragments with three segments but are absent in fragments with only two segments. We will keep this question in mind exploring anterior-posterior molecular patterning and specific cell-cell signaling as candidate components playing a vital role in successful regeneration. My current postdoctoral research on Platynereis dumerilii explores the systemic effects of regeneration on developmental transitions, gametogenesis, and lifespan, potentially revealing parallels with S. malaquini. Leveraging comparative research across multiple species, we aim to unravel unique regeneration mechanisms and adaptations in segmented worms.

Figure 1. Regenerative capabilities of Syllis malaquini. A body fragment containing two segments can regenerate both head and tail structures but does not exhibit further growth. Body fragments with three or more segments can regenerate into complete individuals. This demonstrates the remarkable regenerative plasticity of S. malaquini, with segment number being a critical factor in determining regenerative outcomes. Figure obtained from Spieß et al. 2024².

References

1. Ribeiro, R. P., Egger, B., Ponz-Segrelles, G. & Aguado, M. T. Cellular proliferation dynamics during regeneration in Syllis malaquini (Syllidae, Annelida). Front. Zool. 18, 27 (2021).

2. Spieß, V., Ribeiro, R. P., Helm, C. & Aguado, M. T. From two segments and beyond: Investigating the onset of regeneration in Syllis malaquini. Evol. Dev. 26, e12492 (2024).

3. Ribeiro, R. P., Ponz-Segrelles, G., Helm, C., Egger, B. & Aguado, M. T. A new species of Syllis including transcriptomic data and an updated phylogeny of Syllinae (Annelida: Syllidae). Mar. Biodivers. 50, 31 (2020).

4. Weidhase, M., Beckers, P., Bleidorn, C. & Aguado, M. T. On the role of the proventricle region in reproduction and regeneration in Typosyllis antoni (Annelida: Syllidae). BMC Evol. Biol. 16, 196 (2016).

5. Weidhase, M., Beckers, P., Bleidorn, C. & Aguado, M. T. Nervous system regeneration in Typosyllis antoni (Annelida: Syllidae). Zool. Anz. 269, 57–67 (2017).

(2 votes)
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Last year I became the mother of fraternal twins. I love being a parent, but in a profession rife with gender inequalities, I am also aware of how my transition to motherhood will affect my career. What I didn’t realise, however, was how being a scientist would help me to be a good mother to my two children.

We often hear about the difficulties facing women (and mothers) in academia. At my main university in Denmark, men still hold more than 75% of professorships, 85% of top management positions and receive 76% of the total funds paid out from Denmark’s Basic Research Fund¹. To exist in this environment, women often need to do better and work harder than their male colleagues. So how does one fit in starting a family?

Even in the most balanced relationships, women pay a higher price for their children. During pregnancy, most women experience some level of illness, sleep deprivation and pregnancy-related complications. They take time off for scans, classes, medical appointments and prescribed rest. Safety concerns for the developing foetus can interrupt or stop laboratory and field work. After birth, many women experience the “hidden” medium-term and long-term complications of pregnancy and birth, including depression (11-17%), urinary incontinence (8-31%), anal incontinence (19%) and lower back pain (32%)². When women do return to work, they may need to schedule time for pumping into their workday and often come to work exhausted from nighttime feeding. Attending and presenting at conferences as an expectant or new mother is often not possible³. Moreover, women typically carry a larger mental load than their spouse and can be unfairly criticised for this with the label “mommy brain”⁴. Sadly, many department chairs—aware of the unequal load of parenthood—do not appropriately recognise career interruptions during hiring and tenure evaluations, and seem genuinely flabbergasted when there are then fewer women candidates available for recruitment at the more senior levels⁵.

Becoming a mother undoubtedly impacts our careers as scientists. But women also receive messaging that being a scientist influences their ability to be a good mother. We can be made to believe that we have left it too late⁶, returned to work too soon and that the time demands of the job are simply incompatible with the traditional view of motherhood. What I have come to realise over the last few months, however, is that being a scientist has laid the groundwork for me to be a fantastic mother to my two children. By sharing my experiences, I hope I can help to write a new narrative and highlight to women scientists the unique strengths and abilities that will prepare them for this stage of their journey.

—

As a cell biologist, I am accustomed to repetitive tasks. Recurrent cycles of feeding, changing and putting my babies to sleep during the first few months of their lives therefore felt somewhat familiar and manageable, rather than overly burdensome and monotonous. Having spent most of my adult life formulating and testing hypotheses in the lab, my mind easily came up with new theories for why things may be going wrong or why the babies may be being fussy, and I have been able to experiment with possible solutions. Importantly, I know how to persevere with a hypothesis and not give up on a good idea too soon, a problem that many desperate and time-poor new parents can fall victim to. I am accustomed to working extremely long days, late nights and weekends. My friends are used to long stretches of time without seeing me and me turning up late to social events. Being a scientist has even helped me to develop a taste for cold coffee, which only makes me smile when I order a flat white and both babies instinctively begin crying.

I am particularly good at multi-tasking and managing my time. My many years at the bench have made me incredibly proficient at opening bottles with one hand, sterilising and labelling things, and protecting myself from spills. I can forecast, plan and mitigate risk better than most parents. I am almost always prepared and when I’m not, I learn quickly and pay attention to the serendipitous wins. I understand how drugs work, when vaccines are due and when to be worried about a fever. Contrary to the conventional view of scientists as cold, unemotional beings, most of us are extremely creative and playful, a trait that has obvious benefits when raising young children. Those of us who engage in teaching are accustomed to teach Socratically, which I believe will be helpful as my children begin to ask questions about the world around them.

—

Gender inequalities in academia are a huge problem—for all women—and this requires urgent attention from our university leaders⁵. But to those women scientists apprehensive about the kind of mothers they may be, my message is simple: your efforts in the laboratory are likely to help you in ways you may not have yet imagined.

Acknowledgements

I am supported by grants from the National Health and Medical Research Council of Australia (NHMRC, #2003832), the Novo Nordisk Foundation (#NNF20OC009705) and the International Brain Research Organization (PG24-9230796649).

References

1.         Mænd og kvinder på de danske universiteter – Danmarks talentbarometer 2019. (2020).

2.         Vogel, J. P. et al. Neglected medium-term and long-term consequences of labour and childbirth: a systematic analysis of the burden, recommended practices, and a way forward. The Lancet Global Health 12, e317–e330 (2024).

3.         Chalmers, S. B. et al. Towards inclusive and sustainable scientific meetings. Nat Cell Biol 25, 1557–1560 (2023).

4.         Callaghan, B. L., McCormack, C., Kim, P. & Pawluski, J. L. Understanding the maternal brain in the context of the mental load of motherhood. Nat. Mental Health 2, 764–772 (2024).

5.         Davis, F. M., Elias, S. & Ananthanarayanan, V. Scientists with intersecting privilege must work towards institutional inclusion. Nat Cell Biol 25, 789–792 (2023).

6.         Nowogrodzki, J. PhD parents: the pros and cons of having a child during your doctorate. Nature 637, 749–751 (2025).

(8 votes)
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Stem cell models as laboratories to study self-organization

My road from physics to developmental biology began in a journal club during my PhD in Adam Cohen’s lab at Harvard. We were discussing the first reports from Madeline Lancaster, Jürgen Knoblich, and their co-authors(Lancaster et al., 2013) describing the self-organization of cerebral organoids from stem cells. I was instantly fascinated by the images they reported: while no one would mistake these in vitro structures for a real brain, they still showed remarkably complex patterns of gene expression and tissue morphologies. In the physics community, there is longstanding interest in self-organizing systems: patterns that do not follow an external blueprint, but rather emerge from feedbacks in interactions between a system’s components. These stem cell models demonstrated the power of biological self-organization, and offered simplified ‘physics laboratories’ for decoding how multicellular programs arise from basic interactions between cells.

After completing my PhD, I moved to the Lewis-Sigler Institute (LSI) at Princeton as an independent fellow to study stem cells and organoids. The scientific community at the LSI is deeply interdisciplinary and has a long tradition of excellence in both developmental biology and biological physics. Much of this success came from leveraging the fruit fly embryo (D. melanogaster) as a quantitative system for studying fundamental principles of pattern formation. Fly embryos are highly amenable to quantitative measurement and genetic perturbation, and they can be produced at scale to achieve statistical power. I hoped that stem cell models could offer similar advantages, while opening new questions in developmental biophysics.

Choosing a problem: symmetry breaking in the gastruloid

I arrived at Princeton in January 2021 – a challenging time to start a postdoc anywhere, but my transition was made easier by the collegial and collaborative nature of the Princeton community. I was broadly interested in stem cell self-organization, and I began by searching for a self-organizing program to ‘decode’. I found a collaborator and mentor in Jared Toettcher. Jared is a bioengineer and molecular biologist whose group (together with Stas Shvartsman’s group, also at Princeton) had done pioneering work applying ideas from signal processing to the role of the Erk signaling pathway in fly development. Recently, he and his student Evan Underhill had started studying a stem cell model called the gastruloid(van den Brink et al., 2014).

The gastruloid recapitulates aspects of gastrulation: specifically, the formation and morphology elongation of an anterior-posterior axis. Evan and Jared were studying how FGF signals produced in the posterior end of the gastruloid activated downstream Erk and Akt signals to control patterning and elongation. I became interested in an earlier aspect of gastruloid formation: how does the gastruloid break symmetry to establish a posterior pole in the first place?

The mystery stems from the lack of explicit spatial cues which the gastruloid receives. In vivo, gastrulation is patterned by spatial cues provided by extra-embryonic tissues, including Wnt signaling molecules provided to the posterior epiblast. Gastruloid formation is triggered by activating Wnt signaling activity everywhere with the small molecule CHIRON-99201 (‘CHIR’). Gastruloids eventually form a polarized domain of Wnt activity in the posterior, just as the embryo does – but how does this local domain form when all cells receive the same stimulus?

Theories of self-organization and pattern formation offer candidate explanations. One possibility is that gastruloid polarization could be an example of Alan Turing’s reaction-diffusion theory of pattern formation(Turing, 1952): that is, Wnt-dependent feedback in the production of diffusing activators and inhibitors of Wnt signaling can amplify small differences and eventually spontaneously restrict activity to one local domain. Another possibility is that cells spatially rearrange to sort themselves into different domains as they change signaling levels. Discerning between these candidate models is extremely challenging: both could explain the patterns of Wnt signaling activity we observe during symmetry breaking and morphogenesis.

Recording signals to decode self-organization

Ideally, we could trace the history of signals that cells see and ask: when can we predict cell fates based on early signaling states? By measuring this kind of ‘fate information’, we could identify when the gastruloid breaks symmetry, and test predictions of mechanistic models. But this is also a very hard problem: cells communicate through many different signaling pathways, and optically tracking cells through divisions and migrations over several days of gastruloid morphogenesis would be extremely challenging.

 To trace signaling histories of cells, we turned to synthetic biology. When I was in graduate school, I had followed work from Alex Schier’s group (then at Harvard MCB) developing new technologies for recording cells’ lineage within the genome(Farrell et al., 2018; McKenna et al., 2016). I realized that if this ‘molecular recording’ strategy were adapted to record signaling states (rather than lineage), it could offer us a tool to reconstruct signaling histories without solving the live-imaging cell tracking problem. (As an aside: many other groups have shared this same insight; signal recording is now a robust area of biotechnology development!)

Fortunately, Michelle Chan had just joined the LSI and Molecular Biology Department at Princeton. Michelle is an expert in lineage tracing and had done pioneering work building molecular lineage recorders in the mouse embryo(Chan et al., 2019). With her advice and guidance, we were able to weigh tradeoffs between different design strategies.  After prototyping a few flavors, we settled on a recombinase-based strategy. Recombinases (the most famous of which is an enzyme called Cre) can make site-specific modifications at target sites: for example, excising a red fluorescent protein from the genome to permit expression of a green one. We adapted this classical lineage tracing strategy by embedding Cre within a genetic circuit that only expresses in the presence of two inputs: (1) signaling activity in a pathway of interest, and (2) a small molecule (doxycycline, or ‘dox’) used to gate a ‘listening window’ in which the circuit is queried. This logic allows us to relate the output of the Cre recording activity in a target signaling pathway within a known time window.

In many ways, this approach is quite old-school compared to other emerging technologies for signal recording. As designed, each recombinase only can record one bit of information in a single signaling pathway. But while our design sacrifices in information bandwidth, it gains exceptional sensitivity and fidelity: we could reliably resolve signaling states with high confidence within developmentally relevant temporal windows (3-6 hours). While this approach may not scale to the unbiased screening of all signaling pathways, in many developmental contexts we have a strong prior to focus on a few signals of outsized importance. We viewed this tradeoff of channel bandwidth for sensitivity and fidelity as favorable for our application.

As a practical matter, the main challenge in building these designs into cells was tuning the sensitivities of relevant components. There is a strong ‘Goldilocks principle’ at play: if signal recording is too sensitive, we may get ‘leaky’ background activity even in the absence of signaling activity or dox. But if it is not sensitive enough, then we may not be able to resolve signaling activity effectively. Ideally, the circuit sensitivities should be balanced to be just right.

One way to alter component sensitivities is via the genomic context around the integration site of our synthetic genes. We developed a cell engineering pipeline to screen libraries of randomly integrated parts and then select-out the candidates which landed in the Goldilocks zone. We ultimately identified high-performing cell lines which record each of three canonical signaling pathways that orchestrate gastrulation: Wnt, Nodal, and BMP. The latter two were crucially enabled by work from Ken Zaret’s lab, which validated a panel of pathway-specific sentinel promoters(Serup et al., 2012). This work is a wonderful resource for the community, and we are grateful that they shared constructs of for Nodal- and BMP-responsive elements (AR8 and IBRE4).

Putting theories of self-organization to the test

With our signal-recording cell lines in hand, we set out to systematically map when early Wnt, Nodal, and BMP signaling states predict future cell fates. I won’t belabor all of our results here – please read our paper for the complete story! But I will describe my favorite experiment. One surprising observation was that when we recorded Wnt activity during a ‘patchy’ state – that is, when signaling activity was locally correlated into domains, but not yet globally polarized – we could already predict future cell fates along the final A-P axis. It seemed that cell rearrangements (and *not* reaction-diffusion feedbacks) were sorting the patchy domains into a single pole. But we still weren’t completely certain of our interpretation – more complex reaction-diffusion models could in principle still be consistent with our data.

We put our model to the test by testing its predictions more explicitly. Under a strong cell-sorting model, we should be able to record Wnt states with our signal recorder, and then scramble cell positions by dissociating (with Trypsin) and then reaggregating to form new spheroids. We did the experiment, and the result was clear as day – the red and green cells managed to find each other and phase-separate into different domains! We also incidentally observed that reaggregating sometimes made smaller ‘satellite’ gastruloids that sorted into a scaled-down pattern (which we then confirmed by deliberately making smaller reaggregate gastruloids with a flow cytometer). Scaling follows nicely from a cell sorting model: as long as you have the right balance of cell types, sorting gives you scaling for free.

Our synthetic biology approach provided us with an integrated description of how the gastruloid self-organizes and allowed us to interrogate fundamental theories of pattern formation. Many interesting questions remain: for example, what are the physics of gastruloid cell sorting? Are there even earlier physical or biochemical cues which contribute to symmetry breaking? I am also excited about opportunities to use synthetic biology to control signaling states in the gastruloid, and to use this synthetic biology toolbox to decode self-organization in other organoid and embryoid models. In January 2025, I moved to Yale to start a new research group to chase these questions. Please reach out if you are interested in joining the adventure!

References

Chan, M. M., Smith, Z. D., Grosswendt, S., Kretzmer, H., Norman, T. M., Adamson, B., Jost, M., Quinn, J. J., Yang, D., Jones, M. G., et al. (2019). Molecular recording of mammalian embryogenesis. Nature 570, 77–82.

Farrell, J. A., Wang, Y., Riesenfeld, S. J., Shekhar, K., Regev, A. and Schier, A. F. (2018). Single-cell reconstruction of developmental trajectories during zebrafish embryogenesis. Science 360, eaar3131.

Lancaster, M. A., Renner, M., Martin, C.-A., Wenzel, D., Bicknell, L. S., Hurles, M. E., Homfray, T., Penninger, J. M., Jackson, A. P. and Knoblich, J. A. (2013). Cerebral organoids model human brain development and microcephaly. Nature 501, 373–379.

McKenna, A., Findlay, G. M., Gagnon, J. A., Horwitz, M. S., Schier, A. F. and Shendure, J. (2016). Whole-organism lineage tracing by combinatorial and cumulative genome editing. Science 353, aaf7907.

Serup, P., Gustavsen, C., Klein, T., Potter, L. A., Lin, R., Mullapudi, N., Wandzioch, E., Hines, A., Davis, A., Bruun, C., et al. (2012). Partial promoter substitutions generating transcriptional sentinels of diverse signaling pathways in embryonic stem cells and mice. Disease Models & Mechanisms 5, 956–966.

Turing, A. M. (1952). The Chemical Basis of Morphogenesis. Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences 237, 37–72.

van den Brink, S. C., Baillie-Johnson, P., Balayo, T., Hadjantonakis, A.-K., Nowotschin, S., Turner, D. A. and Martinez Arias, A. (2014). Symmetry breaking, germ layer specification and axial organisation in aggregates of mouse embryonic stem cells. Development 141, 4231–4242.

(1 votes)
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Where is the lab?

The lab is located at National Centre for Biological Sciences, Tata Institute for Fundamental Research, Bangalore, India.

Lab website: https://daslaboratory.weebly.com

Research summary

Soumya Das: Ischemic heart disease (IHD) is the number one killer world-wide and in India. IHD is primarily caused by coronary occlusions. Most patients are ineligible to undergo the invasive treatments (like stenting, coronary bypass surgeries) for IHD. An alternate is to create artery to artery connections called collateral arteries which can perfuse tissue downstream of an occluded artery. Our group investigates cellular mechanisms, molecular drivers and physiological triggers which facilitate the de novo formation of collaterals. Using mouse genetics, single cell RNA sequencing analyses and whole heart confocal imaging at single cell resolution, we show that young mouse artery cells can de-differentiate and proliferate in response to myocardial infarction, a phenomenon absent in older hearts. Additionally, combining genetic lineage labeling/tracing with in vivo live imaging of mouse embryos, we show that artery cells extend on pre-determined microvascular tracks to build pial collaterals in brain. Our study reveals that Vegf/VegfR2 axis facilitates pial artery-tip extensions in the developing brain, but drives coronary proliferation in injured hearts. Thus, while developmental pathways reactivate in response to injury, their mode of action may be distinct. Together, our work suggests organ-specific mechanisms drive collateral formation in the heart and brain.

Currently, we are identifying other molecules and physiological factors which tune the process of collateral making. We are also exploring the relevance of multiple (cellular) processes to create these collaterals, and what is the impact on overall organ function.

Lab roll call

Bhavnesh Bishnoi (2021-present) is a graduate student investigating the biochemical contribution of cardiac cells towards coronary artery development and collateral formation. He is the first graduate student of the young Das lab at NCBS.

Swarnadip Ghosh (2022-present) is a graduate student who is exploring the mechanisms underlying collateral development in the brain. He is also interested in the mechanobiology of vessels. He was a critical part of the recent study (Kumar et al., Cell Reports, 2024) describing the cellular and molecular regulation of pial collaterals in development and homeostasis.

Ravindra Kailasrao Zirmire (2023- present) is a postdoctoral fellow interested in uncovering the role of artery cell proliferation in coronary collateral vessel formation and its effect on cardiac regeneration. He is also interested in parsing out the details of inflammation-mediated cardiac fibrosis, and the role of vasculature in the process.

Alfia Nirguni Saini (2024- present) is a graduate student who focuses on developing tools to study Artery Reassembly in vitro. She also wants to capture ischemia-driven (and specific) artery cell behavior, which significantly contributes to collateral formation in an injured mouse heart.  

Zidhan Subair (2024- present) is a project associate interested in using microfluidics to study blood-flow induced mechanosensory pathways in cardiovascular remodeling.

JerushaEmanuel (2025- present) is a graduate student who just joined the lab and wants to explore if and how cellular interactions between vascular and non-vascular cells facilitate collateral formation in the heart and brain.

Over the past few years we also had a postdoctoral fellow, few Masters thesis students and some interns who were a delight to work with.

Favorite technique, and why?

Soumya: We like to not limit ourselves to a single technique, and develop them as and when needed. That being said, a significant amount of our work is primarily driven by mouse genetics and microscopy. We have developed ways to perform whole organ imaging at cellular and sub-cellular resolution, in fixed and live tissues. This has allowed us to capture the cellular dynamics of endothelial cells during embryogenesis, adulthood, and in diseased states. Together, we now probe deeper questions which seemed unapproachable earlier.

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

Soumya: What intrigues me most is the genetic variation that exists within the genome of a population─ how did it come to place, and how has it evolved over time. This eventually reflects on various measurable observations, and I wonder if we can predict the evolutionary trajectory learning from these changes in structures and functions.

How do you approach managing your group and all the different tasks required in your job?

Soumya: I am lucky that there is not much to be “managed”. My young team at NCBS, (though small) is extremely driven, smart and efficient. At NCBS, students and postdocs run the lab─from procurement of lab equipment/consumables to steering their projects. I meet with each member of my team individually, to discuss “raw” data, every couple of weeks, and sometimes multiple times within the same week, or even a day. This happens on a need basis. We have weekly lab meetings where one team member would present their analyzed data. This is to give everyone a bigger picture, brainstorm ideas and decide on the next logical step of experimentation. We also have weekly journal clubs where we discuss a unique discovery or novel technology. Apart from these interactions, everyone is welcome to stop by my office and have a conversation if and when needed. Additionally, everyone is encouraged to participate in meetings and conferences and science competitions. The other (significant) aspects of being a PI in academia is procuring funds, editing/reviewing manuscripts, and performing administrative duties.

What is the best thing about where you work?

Soumya: What I like most about working with my team at NCBS is the freedom to do the science I want to do and pursue the questions that intrigue me. One of the best feature of NCBS is the on-campus creche (Dolna), which is a life-saver to all parents working at NCBS. We are able to give our 100% to science because we know our little ones are happy and safe at Dolna.

Bhavnesh Bishnoi: The opportunity to explore new ideas, engage with diverse scientific fields, and discuss research with the community are some of the greatest aspects of NCBS.

Swarnadip Ghosh: The best part about NCBS is the technical support we get for our research work. The staff is very sincere, the environment is extremely supportive and student-friendly.

Ravindra Kailasrao Zirmire: The freedom to pursue an idea even if it is exploratory and seems out-of-the-box.

Alfia Nirguni Saini: The access to many instruments and devices to do experiments and of course the collaborative atmosphere.

Zidhan Subair: The best part of being at NCBS is the support and freedom to pursue projects that truly excite me. There is always an opportunity to learn, and the NCBS community is always willing to assist with both technical and academic matters.

JerushaEmanuel: I love that NCBS has a diverse scientific community, not a day goes by without us learning something new. Interacting with people who are excited about science inspires me. The campus being gorgeous and having many cafeterias is a major plus.

What’s there to do outside of the lab?

Soumya: As a team, we occasionally go out for lunches or dinners. We try to celebrate every big or small victory with chai and samosas in one of the many cafes on campus─be it an acceptance of a manuscript or a student passing their comprehensive (qualifying) exam. Most of us spend their weekends with family and friends. I like spending time with my 2 years old daughter, I am currently learning gardening skills and over the weekend, I like to gettogether and relax with close family and friends.

Bhavnesh Bishnoi: What I enjoy most outside the lab is watching movies and taking long walks in nature.

Swarnadip Ghosh: Outside the lab, in the afternoon, the lab goes for tea, spends time and discuss about science and non-science matters. We also often go for swimming and play indoor games.

Ravindra Kailasrao Zirmire: Outside of the lab, I like swimming, listening to music and learning and brainstorming about entrepreneurship ideas.

Alfia Nirguni Saini: There’s so much greenery outside the lab and many places to sit and chat with lab mates and friends. It helps me unwind after a long day.

Zidhan Subair: Outside the lab, I love reading, exploring the open road, and discovering new restaurants around town.

JerushaEmanuel: When not in the lab, I like going on long walks, playing the piano and singing. There’s a ton of extracurricular activities on campus─from movie screenings to concerts. I enjoy being a part of them occasionally.

(6 votes)
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The use of preprints in biology has thrived over the past decade. Many groups now regularly share their latest papers on a preprint server with the COVID-19 pandemic highlighting the incredible value of preprints as a mechanism to promptly disseminate the latest research findings.

To work toward our mission to make communication in the life sciences more open and transparent, ASAPbio promotes the productive use of preprints. Many researchers do not receive training in scholarly publishing or communication. Additionally, many researchers have become familiarized with preprints by hearing about them from colleagues or by finding a preprint reporting the latest work in their field. These researcher-to-researcher interactions are invaluable to raise awareness about preprints. To foster more of these conversations, ASAPbio started a Fellows program in 2020.

The ASAPbio Fellows drive engagement and adoption of preprints

The ASAPbio Fellows program provides participants with a comprehensive overview of the preprint and preprint review landscape. The program provides opportunities to explore trends, tools and the outlook for preprints in the life sciences while connecting with others interested in preprints and science communication. The program also allows Fellows to help shape and develop ASAPbio strategic initiatives, develop their own preprint based talk or to optionally take forward a project of their choice. 

Community is the heart of ASAPbio, and the Fellows program encapsulates this focus perfectly. In addition to the training that Fellows of previous years have received, in 2024, there was a greater emphasis on embedding Fellows in their local communities as preprint experts. All Fellows were asked to prepare slides and deliver a local talk on preprints. Fellows had full choice over the exact topic, with a variety of topics chosen. Nineteen Fellows successfully delivered a local preprint talk with their slide decks available to all through a Zenodo repository. 

In addition to the local talks, Fellows engaged in optional projects. One project, specifically focussed on the African region, involved a series of webinars to raise awareness of preprints for researchers based in Africa. Over 140 people registered for the webinar series with the Fellows delivering 3 of the 4 sessions. This 4-part webinar series is available on the ASAPbio YouTube channel.

Two Fellows took up the opportunity to produce three podcast episodes; one on the perspective of librarians towards preprints and two on the role of preprints in tenure and promotion. These episodes are available via the Preprints in Motion podcast, and you can listen to the librarian episode here and the tenure and promotion episodes here and here.

Continuing the more creative theme, another group of 2024 Fellows created animated YouTube videos to tackle persistent preprint myths. Despite preprints having been established for over 10 years in the Life Sciences, a number of persistent myths remain. To tackle these myths and build from previous efforts of ASAPbio Fellows, a group of 2024 Fellows produced whiteboard-style animated videos. Fellows chose to tackle myths on preprints being preliminary work and scooping. 

Institutional recognition is a vital step towards greater preprint adoption. Frequently cited as a significant barrier to preprint use by researchers, it is essential that institutions adopt policies that support and reward preprint use. Building on a previous ASAPbio funder’s toolkit, a group of Fellows developed expanded policy wording for a greater number of institutionally-focussed stakeholders. This whitepaper was preprinted and is available on Zenodo. 

These are just some of the 2024 projects that Fellows got involved in. You can learn more about the highly productive 2024 Fellows on the ASAPbio website.

Engage with preprints & open science – Become a 2025 ASAPbio Fellow

Building from the hugely successful 2024 Fellows cohort, this year we will be continuing to offer a wide range of opportunities and support. Our Culture & Community track will run from March-August and include the delivery of local talks, 1 on 1 meetings and small group meetings. The optional projects track will run until May-September and include a variety of projects that are aligned with ASAPbio’s strategic direction. 

The 2025 ASAPbio Fellows program is now open for applications, and we invite all interested in preprints and science communication to apply. There are no restrictions related to geographical location or career stage. We just ask you to bring an interest in preprints and availability to give the program a few hours per month from March to September 2025. 

Interested? Apply to the 2025 Fellows program now! You can learn more about the program in the Fellows handbook, or contact Jonny with any questions (jonny.coates@asapbio.org). Applications will close 10th Feb 2025. 

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Over the last few weeks, we asked you to vote for your favourite 2024 Development cover image. Thank you to everyone who voted. Now that the poll is closed, let’s reveal the results!

*Drumroll*

The 2024 Development cover of the year is the image of a superimposition of three stages of embryonic mouse lungs! Congratulations to Paramore et al.!

Browse the full 2024 issue collection, including our Special Issue: Uncovering Developmental Diversity.

Winner

First runner-up

Second runner-up

Honourable mention

Browse the full 2024 issue collection, including our Special Issue: Uncovering Developmental Diversity.

We look forward to seeing more amazing cover images featured in Development in the coming year!

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Happy New Year, everyone. 2025 is a big year for us at The Company of Biologists, marking 100 years since the Company was founded. We’re using this opportunity to reflect on what we do, how we got here and what lies ahead, alongside some special celebrations of this once-in-a-lifetime milestone.

Here, I highlight four projects to look out for during the year. You can help celebrate by visiting our anniversary page here, where you can register for updates, or by following #biologists100 on social media (The Company of Biologists is on BlueSky, X, Mastodon and LinkedIn).

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In plants, the vascular cambium, a bifacial stem cell niche, drives wood formation by generating the xylem on one side and the phloem on the other. In this post, Ari Pekka Mähönen, Peter Etchells and Kirsten ten Tusscher tell the story behind their paper “Identification of cambium stem cell factors and their positioning mechanism”.

Ari Pekka Mähönen:

In the autumn of 2009, I returned from my post-doctoral period in Ben Scheres’ lab, located then in Utrecht. During my postdoc I was working on the roles of PLETHORA/AINTEGUMENTA-LIKE (PLT/AIL) transcription factors in stem cell regulation in the root meristem. Moving back to Finland my idea was to study whether any of these factors are expressed in Arabidopsis root cambium, the meristem I intended to study in my newly established research group. It was exciting to see that PLT5 showed very specific expression in the dividing cambial cells (Figure), however, further studies had to wait for several years due to my focus on finalizing ongoing projects. After obtaining funding for my research group, a PhD student, Gugan Eswaran, started to work on the project, and he discovered that ANT, PLT3 and PLT7 are also expressed in the cambium, suggesting genetic redundancy in cambium development. Unfortunately, ant single mutants and plt triple mutants showed only slightly reduced secondary growth. I was expecting a stronger phenotype from putative stem cell factors of cambium. In subsequent attempts, generation of the quadruple mutant failed due to unexplained lethality, and an artificial microRNA approach did not provide stronger phenotypes either. This was disappointing and thus Gugan started to focus more on his side projects. Then, rescue for the project came a few years later from a technical innovation. Xin Wang, a PhD student in my lab, invented an inducible genome editing system (IGE) for plants (Wang et al Nature Plants 2020). This IGE system was used to generate a conditional quadruple ant/plt mutant. Finally, this mutant showed severely reduced radial growth, something one would expect from loss of stem cell factors. This was great, but of course now we had a new question to answer – what regulates CAMBIUM-EXPRESSED AINTEGUMENTA-LIKE (CAIL) (the name we gave to ANT, PLT3, PLT5 and PLT7) expression in such a narrow, specific domain? I think, this was the point where you Peter contacted me, or was it even earlier than when we got the conditional quadruple mutant results?

Peter Etchells:

I got in touch while Gugan was making the IGE construct. I had been working on putting the pieces of PXY signalling together since joining Simon Turner’s lab in Manchester in 2007, and this continued when I moved to Siobhán Brady’s lab at UC Davis in 2013. Over that whole period, through my work and that of others in Hiroo Fukuda’s lab, a series of PXY-downstream targets, WOX4, WOX14, BES1, LBD4 and TMO6 were identified (Hirakawa et al Plant Cell 2012; Etchells et al Development 2013; Kondo et al Nature Comms 2015; Smit et al Plant Cell 2020). However, I was never satisfied that all the transcriptional targets of TDIF-PXY had been uncovered. PXY is homologous to CLAVATA1, which famously regulates the shoot apical meristem via regulation of the homeodomain transcription factor WUSCHEL (WUS). WOX4 and WOX14 are homologous to WUS, so they were a natural focus for investigation, but wox4 wox14 mutants only have a mild cambium phenotype. BES1, LBD4 and TMO6 are also only responsible for regulation of a subset of the pxy phenotypes. It seemed like we were missing something. The key was a transcriptomic experiment which demonstrated that CAIL genes were differentially expressed in both pxy and TDIF over-expression lines, performed just as I was transitioning out of Siobhán’s group to start my own lab in 2015. To test for a genetic interaction between the CAILs and TDIF-PXY, we crossed the TDIF over-expression line, which is characterised by ectopic cambium, to plt357 mutants. Although the plt357 line alonedid not have a cambium phenotype, it did suppress phenotypes associated with TDIF over-expression, which, combined with the CAIL expression patterns that Ari Pekka’s group had, demonstrated that the CAIL genes did have a cambium function and were likely controlled by TDIF-PXY. It was not long after that Gugan’s IGE line came through which sealed the deal. Still, the story was incomplete because the PXY expression domain is so broad relative to that of the CAILs.    

Ari Pekka Mähönen:

So, now we knew that CAILs are regulated by the TDIF-PXY ligand-receptor pathway. However, we still did not know how come CAILs are only expressed in such a narrow region in stem cells, given that the PXY receptor expression domain spans from the stem cells into the xylem. A few researchers in my lab participated to hunt for the mechanism underlying this tight spatial control, and we indeed found a few regulatory feed-back mechanisms that could help excluding the CAILs from the xylem. On top of this, we wondered whether efficient sequestration of diffusing TDIF peptide by the PXY receptor could play a role in focusing CAIL signalling. With all the feedback regulation and a possible sequestration of TDIF, we were quite unsure which one of these mechanisms (or whether any of these mechanisms) could contribute to narrow CAIL expression in planta. Therefore, I contacted Kirsten ten Tusscher, a computational biologist, with whom I had collaborated before on addressing the role of PLT genes in root zonation (Mähönen, ten Tusscher et al. Nature 2014). I suggested that we could address these different scenarios in TDIF-PXY-CAIL signalling in a computational model.

Kirsten ten Tusscher:

As I had greatly enjoyed our previous collaboration, and questions on patterning are the bread and butter of computational biology, this was of course an offer I could not refuse. Luckily, a talented PhD student in my group, Jaap Rutten, was quite far already with the results for the main project of his PhD thesis and waiting for experimental data. Thus, it was not hard at all to convince him to broaden his horizon beyond the control of root meristem size that we were working on together with Sabrina Sabatini to the control of cambium patterning and positioning together with Ari Pekka and Peter. To investigate the importance of different feedback mechanisms as well as the potential of ligand sequestration in defining the narrow domain of CAIL cambium expression, we started building a model incorporating all the important molecular players and the regulatory interactions between them, using both new and previously published data. As a start we developed a model for a single cell and tested whether it could model xylem, phloem and cambium cells depending on the incoming signals. However, for non-modelers it often seems that if models are complex enough and you tweak parameters you can make them do anything you want. Therefore, it was important to show that the models’ capacity to simulate phloem, xylem or cambium forming cells was a very generic property of the modelled network architecture, not of precise parameter values or details. To achieve this Jaap performed a whopping 1,768,593,750 simulations to extensively test different model settings, occupying some of our computers for weeks, and show that overall model behaviour remained the same. In the process we could already confirm that some of the feedback uncovered by Ari Pekka’s team indeed limited cambium formation and promoted xylem formation. As a next step we could now move to a one-dimensional model of a strip of cells spanning from xylem to phloem and start testing the ligand-sequestration hypothesis. Key to this was to include an auxin-dependent PXY gradient starting from the xylem end of the tissue, and a TDIF gradient arising from the diffusion of TDIF from TDIF producing phloem cells into our model. With this in place, Jaap demonstrated that if binding of TDIF ligand to PXY receptors is sufficiently strong, at the tissue position where TDIF meets the first low levels of PXY receptors, TDIF is bound and effective diffusion is halted, preventing TDIF-PXY interaction further towards the xylem. Interestingly, this also explains why cambium stem cell patterning is robust under various cambium sizes: when the xylem and phloem are further apart, the TDIF will diffuse further before it reaches the first PXY receptors and until that time it diffuses freely ensuring it will still meet PXY receptors!  However, an important issue remained: the regulatory feedback mechanism uncovered earlier could to some extent limit CAIL expression. So, to test which of these potential mechanisms occurs and/or is most important in planta, we tested in silico what would happen if we decreased PXY expression or elevated TDIF levels. Next these experiments were also performed in the lab, with lab outcomes matching the predictions made by the sequestration-based model. This finally enabled us to cement the importance of sequestration for defining the CAIL expression domain.    

Ari Pekka Mähönen, Peter Etchells, Kirsten ten Tusscher:

So, now we could confidently say that sequestration of TDIF is the key to focusing the TDIF-PXY signalling and thus CAIL expression in a narrow domain to define the stem cells. The manuscript was submitted, and we got constructive comments from the reviewers, especially on providing more evidence for the sequestration mechanism. Xixi Zhang, a post doc in the Mähönen lab, had already earlier started to work on the generation of PXY reporter lines. She noticed, among other findings, that the translational reporter pPXY:PXY-YFP has a significantly sharper gradient within the cambium than the transcriptional reporter line pPXY:erYFP, indicating that the PXY-YFP fusion protein is more unstable in phloem-side cambium cells than in the cells on the xylem-side of the cambium. Since TDIF ligand originates from phloem, this suggest that the TDIF binding to PXY could make PXY-YFP unstable. Thus, regulation of TDIF-PXY stability could be the key mechanism for the sequestration, and this is what Xixi is studying now, as a follow up of the published work.     

In the end, seeing this paper published was particularly satisfying, both because of the long journey it took to finalize it and because of the enjoyable collaboration we had while working together on this project.

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Dear Colleagues,
Happy New Year!

Two years ago, we organized the inaugural symposium dedicated to Women in Tunicate Biology. It was a joyful event, celebrating women scientists from the 19th century to the present. A special issue of the journal genesis was published in November 2023, collecting the biographies and research talks from the symposium (https://onlinelibrary.wiley.com/toc/1526968x/2023/61/6).

We would like to announce that the second edition of this symposium will take place on Tuesday March 25th and Wednesday 26th, 2025 by Zoom. In this upcoming event, we will include talks by graduate students and postdocs working in the field of tunicate biology, as well as PIs.

If you are interested in participating, whether as a speaker or attendee, please let us know. All researchers are welcome to attend!

Thanks for your attention and best wishes,
Anna Di Gregorio and Marie Nydam
adg13@nyu.edu
mnydam@soka.edu
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In 2023 I was awarded a NC3Rs 20th Anniversary Public Engagement Award to develop and print a “Biological Research Trump Cards” game. I have now designed and printed 100 packs of the game, and my aim is to share them with the scientific community and educators. I hope they will prove a fun and engaging public engagement tool in a variety of different settings.

Please get in touch if you are:

• • A researcher in an academic setting who would like to use the cards in your outreach programme

• • A teacher at primary or secondary school and would be interested in having some packs / hosting a workshop (see below for an example)

• • Interested in using them but unsure if they are suitable for your audience

So what are “Trump Cards”?

There are few people who have gone through life without encountering Top Trumps in some form. First published in 1978, there are now hundreds of different varieties, from football teams to dinosaurs. The gameplay is simple, with users comparing numerical data to try and trump and win an opponent’s card. It is this simplicity, along with the easily adaptable format, that makes it ideal as a customisable public engagement tool.

Why this format?

I have always wanted to create a card game on a scientific theme that is both fun and educational, and Trump cards are an obvious choice – no complicated rules, compact, and the numerical categories offer the opportunity to convey a lot of information on a single card. The idea for the specific theme of these cards came to me after attending an NC3Rs early career researcher event, where I learnt about all the different research models and systems scientists were using for their research.

How was the game developed?

After extensive research into different research models, I came up with a full set of Top Trumps, including systems ranging from mathematical models to sea urchins. I decided to focus the game on the 3Rs message, specifically the replacement of animals in research. Each card has 5 categories, including “replacement potential”, which is based on whether the system is an animal, partial replacement, or full replacement. Together with the NC3Rs team, I fine tuned the cards, making sure it conveyed the 3Rs message in a clear and accessible way. The other categories are “genome size”, “speed”, “size”, and “popularity”, with “speed” referring to how quickly experiments can be carried out, and “popularity” based on the number of articles published in 2019. I designed the cards myself using Adobe Illustrator, and spent many evenings deciding the perfect colour scheme, fonts, and drawing cartoons of fruit flies playing cards.

What is in the pack?

Each pack contains a set of Trump cards, along with explanatory cards for each of the categories, what the NC3Rs is and their mission, and a “how to play” card.

Who are the intended audience?

Top trumps are a well-loved game by children and adults alike, and no prior knowledge of scientific research is necessary to engage with the activity. Most adults and secondary school pupils will have some understanding of how we use animals in research and may have opinions about this, but I anticipate that they will not have been introduced to the myriad other model systems that scientists use. The aim is to promote discussion around the use of animals and alternatives. Younger children will enjoy the pictures and facts about unusual animals, and hopefully it will pique their interest in scientific research.

How do you use the cards?

I have 100 packs for distribution to schools and other researchers for use in their public engagement activities and would be delighted to share them with you. Their use is not limited to playing the full game from start to finish- here are some other examples of ways they can be used:

1. 1. Short format – one card is chosen at random by each player and one turn is played. This would be most appropriate for stands at science fairs, for example, where people are passing through quickly.
   2. As illustrations – if you are focusing on one or a few different model systems, the cards can be laid out, or images of them displayed on screen, as a quick way to convey a lot of information about that system. In addition to the numerical categories, there is a description on the bottom of the card explaining what the organism or system is used for.
   3. Workshops in schools – in addition to simply playing the game, they are a useful tool to get students thinking about why scientists might use different model systems. For example, I have designed a workshop where students are given three scenarios and they have to choose what they think the best three models are for each research aim. This gets them thinking and discussing the advantages and disadvantages of different models, with support from scientists leading the workshop.

1.  

1.  

Example workshop

I have designed a workshop aimed at secondary school and sixth form students, which is available for you to download. It can easily be adapted to suit different abilities. The workshop begins with a short introduction to modelling and why we do it, followed by examples. It also touches on what to consider when choosing a model. The main activity involves the students choosing three models for each research aim. During this activity, I would allocate one volunteer per group if possible to sit with the students whilst they discuss. This is helpful because they may have technical questions about different systems that would influence their choices. Additionally, you can probe their reasoning and get them to think about less obvious choices. For example, they might not know that fruit flies can be used for exercise experiments, or consider that mathematical modelling could be used for looking at the relationship between diet and motor neuron disease.

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