In this SciArt profile, we meet Yoshinari Yoshida, a philosopher of science focusing on the conceptual and historical issues in developmental biology. Yoshinari enjoys drawing animals and plants, and have recently got into drawing primates, such as gibbons and orangutans, because of his research into in vitro models in comparative biology.
Can you tell us about your background and what you work on now?
I was born in Milton Keynes, UK, and grew up in Japan. I did my undergrad and Master’s in Philosophy and History of Science at Kyoto University, Japan, and Ph.D. in Philosophy at the University of Minnesota, USA. I am currently a postdoctoral fellow at the University of Exeter, UK. Throughout this academic career, I have studied philosophy of science, with a special focus on conceptual and historical issues in developmental biology. My central philosophical interest is in how various models and representations (e.g., “living models” such as model organisms and cell culture systems, and visual models such as diagrams and illustrations) play their roles in the production of knowledge about generality and diversity in developmental processes. My current project focuses on the prospects and limitations of in vitro models in comparative biology. I try to clarify how in vitro systems, such as organoids, play their roles as models in the context of cross-species comparison and reconstruction of evolutionary history. I examine experimental and inferential practices as well as interdisciplinary interactions among experts to tackle this philosophical question.
Catalina the Cat – digital illustration.
Were you always going to be a philosopher of science?
When I was younger, I was rather going to be a scientist. I was a kid who loved insects and extinct animals, and in my teenage era, I enjoyed learning about evolution and embryonic development. But I also liked the philosophical discussions about conceptual questions. When I was in the second year of my undergrad, I took the courses “philosophy of science” and “history of science.” I enjoyed these courses so much, and started thinking that studying these fields would allow me to fulfill both my interest in science and my love of philosophical discussions. I decided to major in philosophy of science, and since then, I’ve been in this field.
Brachiating gibbon – digital illustration. Gibbons are my favorite primates. I’m impressed by how efficient their locomotion is! I used a photo by shilmar in Pixabay as a reference.
And what about art – have you always enjoyed it?
Almost yes. I was already into art when I was very little. I was a kid who kept drawing during lunch break in elementary school as well as after school. My favorite objects were monsters, robots, and manga characters. There were periods in my life when I was a bit away from doing art, such as during high school. But I’ve maintained my interest in art. Several years ago, when I was in my Ph.D., I bought a tablet and started drawing digitally. Until then, drawing had been a private hobby just for myself. But I began posting my artwork on social media and also drawing more constantly.
Sitting gibbon – digital illustration. I used a photo by Kadisha in Pixabay as a reference.
What or who are your most important artistic influences?
It’s not easy to name one specific artist. (I still lack systematic knowledge of art history.) But I’m often inspired by realistic oil paintings from the modern and early modern periods. My favorite is those paintings that are so realistic that they look as if they are photographs from distance, but consist of explicit strokes when seen closely. Those paintings make me think about how we see the world.
Orangutan – digital illustration. It was really fun to draw the unique three-dimensional shape of the face. I used a photo by Hollasue in Pixabay as a reference.
How do you make your art?
Currently I do everything using a painting app called Procreate in my tablet. When I see an object or scene whose shapes, colors, textures, or patterns I find interesting, I take pictures, which I may use as a reference later. Or, sometimes I become interested in a certain animal or plant, and search for images of the animal or plant and then start drawing it.
Radishes – digital illustration.
Does your research influence your art at all (or vice versa), or are they separate worlds?
Art is my major hobby that is a source of joy distinct from research in my life. But I think there are some connections between the two. For instance, I am interested in the role of images in science. I have some articles (one published, one currently under review) about how the use of specific types of diagrammatic representations contribute to knowledge production in science. I am also working on a side project with my colleagues about the role of speculation in evolutionary thinking, in which we discuss the power of illustrations. I think this philosophical interest of mine in images in science has a common root with my artistic interest in drawing and painting. My art is also sometimes influenced by my academic interests. For example, I’ve recently been into drawing primates, such as gibbons and orangutans. This was triggered by my current research project on in vitro models in comparative biology. I’ve read studies that apply advanced in vitro technologies to primates to elucidate human evolution, which made me interested in primates themselves.
Puffin – digital illustration. I used a photo by mystraysoul in Pixabay as a reference.
What are you thinking of working on next?
There are a few ideas. I want to keep working on primates and drawing as many primate species as possible. That would become an interesting series! I’m also interested in making art that is related to developmental biology. Even though my primary philosophical focus has always been on developmental biology, I’ve not made art about this field. It would be fun to make drawings inspired by the normal developmental stages of chick embryos, mechanisms of collective cell migration, or tissue movements in gastrulation. Finally, I’m interested in trying oil painting. While I’ve drawn only digitally over the last several years, I love seeing oil paintings at museums. That would be an interesting new step.
In our recent paper published in Developmental Biology entitled “Localization and origins of juvenile skeletogenic cells in the sea urchin Lytechinus pictus”, we studied the intriguing and unique late larval development of sea urchins with a focus on skeletogenic cells, which deposit the biomineral skeleton. Here, I discuss how this project came about, why we were excited by our findings, some of the challenges faced, and what’s next for the project.
Project beginnings
In 2021, I joined Deirdre Lyons’ lab at Scripps Institution of Oceanography (UC San Diego) to explore my fascination for invertebrate evolution and development. I was excited to develop a project on skeletogenesis and biomineralization in sea urchins, a topic in which Deirdre and I shared interest. As I was new to the field, I dove into the literature and realized that although I was interested in embryonic development, I was most fascinated by the development of the adult body plan, which occurs throughout the late larval stage. This study was also motivated by the development of the sea urchin Lytechinus pictus as a better model species [1-3], which has been an ongoing collaboration between the Lyons lab and the Hamdoun lab, also at UC San Diego. Since L. pictus is a faster developing and more transparent species than other commonly studied sea urchins, we could study and image late larval development in higher detail.
Most sea urchins are indirect developers and undergo a complete switch in body plan during metamorphosis from a bilaterally symmetric swimming larva to a pentaradially symmetric benthic juvenile. Prior to metamorphosis, much of the adult body plan develops on the left side of the larva in a structure called the rudiment, while other smaller adult structures develop in other locations (Fig. 1). I wondered how two drastically different body plans could be made from the same set of genetic information, and how the development of a second body plan could occur outside of a classic embryonic context. I was specifically inspired by a study from 2007 by Mamiko Yajima in which she demonstrated that the juvenile skeletogenic cells arise not from the larval skeletogenic lineage, but from mesodermal cells that had a non-skeletogenic origin in the larva [4], and I found it fascinating that cells with one fate in the larva can be completely reprogrammed to make a new cell type in the adult. I therefore decided to revisit this topic using recent technical advances in the field.
Prior to this study, rudiment development had been described in detail at the tissue level and some immunostaining had been performed [5-9], however mRNA localization via in situ hybridization was challenging due to the thickness and complexity of the late larval tissue. By leveraging HCR RNA-FISH, we were able to conduct some of the first mRNA in situ hybridizations in these late stages as the small probes used in this technique are capable of penetrating into thick late larval tissue. I chose to focus on skeletogenic cells as they have been well-studied during embryonic development of sea urchins for gene regulatory networks and biomineralization [10,11] and had previously been studied in some detail in the late larva [7,8], although not in the newer model species L. pictus. We therefore asked three main questions: where are skeletogenic cells and biomineral located during late larval development in L. pictus within the complex rudiment morphology, what are the most likely origins of the juvenile skeletogenic cells, and are gene expression patterns across skeletogenic cells similar in embryonic and juvenile skeletal development?
Figure 1: Development of the sea urchin Lytechinus pictus. Most of the juvenile body plan develops prior to metamorphosis in the rudiment on the left side of the larva, which begins developing at 8 dpf. Metamorphosis occurs when rudiment is fully developed at 18-21 dpf.
What we learned
We first described in detail the localization of presumptive juvenile skeletogenic cells prior to biomineralization of juvenile skeleton, and at later stages, the localization of biomineral and juvenile skeletogenic cells both within and outside of the rudiment in L. pictus (Fig. 2A-B). We were excited to find that prior to the start of juvenile skeletogenesis in the rudiment, we could identify populations of skeletogenic cells using known biomineral marker genes that were not part of larval rods. Additionally, in some of these presumptive juvenile skeletogenic cells, we found co-expression of our skeletogenic cell marker and a marker of blastocoelar cells, which in the larva act as migratory immune cells (Fig. 2C-D). We therefore proposed that since mesodermal cells of non-skeletogenic origin contribute to juvenile skeletogenic cells [4], that blastocoelar cells may at least in part be the cell type that switches to a skeletogenic fate. We then sampled various biomineralization genes from different gene families and found that mRNA expression patterns throughout juvenile skeletogenesis are similar to the patterns during embryonic development (Fig. 2E-F).
Overall, our work gives insight into how indirect developers, like the sea urchin, can reuse cells and developmental mechanisms to make a new body plan from another. Additionally, it is thought that since all echinoderms have adult skeleton but not all have larval skeleton, that the larval skeleton in sea urchins may be a more recent innovation, while the adult skeletogenic cells could arise from a common origin [12]. Since other echinoderms have blastocoelar-like lineages in the larva [13-14], it is possible that this cell type is the ancestral adult skeletogenic cell lineage that expresses an ancestral skeletogenic gene regulatory network, although this hypothesis needs to be clarified with further work.
Figure 2: A) Late larva at 18 dpf in the left view with a box highlighting the location of the rudiment. B) Close-up of the rudiment at 18 dpf with HCR RNA-FISH for a biomineralization gene (sm37) and WGA stain to highlight biomineral. C-D) Co-expression of a blastocoelar (ron) and skeletogenic marker (sm37) in some cells around juvenile structures. E-F) Examples of skeletogenic gene expression patterns during embryogenesis at 32 hpf (E) and during adult body plan development in the rudiment at 18 dpf (F).
Unexpected challenges
One of the most challenging aspects of this project was identifying a consistent staging scheme during late larval development, which was an important part of the project to help establish L. pictus as a model sea urchin. Interestingly, the larval body plan and parts of the juvenile body plan, like the rudiment, often develop asynchronously, and so similar looking larvae may not have a rudiment at the same developmental stage [5-9]. Additionally, the extent of rudiment development was often different when metamorphosis occurred, leading to post-metamorphic juveniles in different developmental stages. Although frustrating when trying to stage the animals, this helped me think about development in new ways since in indirect developers, adult body plan development may not be as clear-cut as in embryogenesis.
I was also personally challenged to learn about all aspects of the scientific process, from asking clear scientific questions, thinking hard about the best ways to answer them, and learning to tell a compelling story through publication. As with any scientific project, there were many challenges and failed experiments along the way, particularly as I was learning many techniques for the first time. For instance, learning how to mount, orient, and image these large samples added a lot of time to the project, and I often had to retake very long acquisitions when images did not turn out as expected. This really challenged my ability to persevere when experiments were not working, but I felt especially honored and reinvigorated when one of our images was featured on the cover of Developmental Biology. Overall, I was very proud to have finished this work within the relatively short timeline of my master’s degree, and I am greatly looking forward to applying this newfound knowledge in future work.
What’s next with the sea urchins?
With this paper, we highlighted that sea urchin adult body plan development is fascinating, yet understudied, and how it is important to think of body plan development outside of an embryonic context. However, there are still many remaining questions to be answered. For instance, only skeletogenic cells have been studied in some detail during adult body plan development, and HCR RNA-FISH provides the opportunity to understand whole body patterning by investigating other cell types. However, more complex questions, such as mapping where adult cells are originating, would require more complex techniques. With the development of L. pictus as a better system where mature adults can be raised from egg in 4-6 months and with which transgenic lines can be created [1-3], an abundance of new questions could be studied. I am greatly looking forward to continuing work with this amazing animal in the future to answer innovative questions in adult body plan development and evolution. Finally, I am very thankful for my mentors, particularly Dr. Lyons, for the mentorship throughout this project, as well as other collaborators and colleagues who have supported and guided me through past and present research.
Figure 3: Video of a sea urchin mid-metamorphosis, with the juvenile body beneath the slowly metamorphosing larval body.
References
Nesbit KT, Fleming T, Batzel G, Pouv A, Rosenblatt HD, Pace DA, Hamdoun A, Lyons DC. 2019. The painted sea urchin, Lytechinus pictus, as a genetically-enabled developmental model. Methods in Cell Biology. 150: 105-123.
Jackson EW, Romero E, Kling S, Lee Y, Tjeerdema E, Hamdoun A. 2024. Stable germline transgenesis using the Minos Tc1/mariner element in the sea urchin Lytechinus pictus. Development. 151(20).
Vyas H, Schrankel CS, Espinoza JA, Mitchell KL, Nesbit KT, Jackson E, Chang N, Lee Y, Warner J, Reitzel A, Lyons DC, Hamdoun A. 2022. Generation of a homozygous mutant drug transporter (ABCB1) knockout line in the sea urchin Lytechinus pictus. Development. 149(11).
Yajima M. 2007. A switch in the cellular basis of skeletogenesis in late-stage sea urchin larvae. Developmental Biology. 307(2): 272-281.
Cameron RA, Hinegardner RT. 1978. Early events in sea urchin metamorphosis, description, and analysis. Journal of Morphology. 157(1): 21-31.
Heyland A, Hodin J. 2014. A detailed staging scheme for late larval development in Strongylocentrotus purpuratus focused on readily-visible juvenile structures within the rudiment. BMC Developmental Biology. 14(22): 1-14.
Yajima M, Kiyomoto M. 2006. Study of larval and adult skeletogenic cells in developing sea urchin larvae. The Biological Bulletin. 211(2): 183-192.
Smith MM, Smith LC, Cameron RA, Urry LA. 2008. The larval stages of the sea urchin, Strongylocentrotus purpuratus. Journal of Morphology. 269(6): 713-733.
Formery L, Wakefield A, Gesson M, Toisoul L, Lhomond G, Gilletta L, Lasbleiz R, Schubert M, Croce JC. 2022. Developmental atlas of the indirect-developing sea urchin Paracentrotus lividus: From fertilization to juvenile stages. Frontiers in Cell and Developmental Biology. 10.
Davidson EH, Rast JP, Oliveri P, Ransick A, Calestani C, Yuh C-H, Minokawa T, Amore G, Hinman V, Arenas-Mena C. 2002. A Provisional Regulatory Gene Network for Specification of Endomesoderm in the Sea Urchin Embryo. Developmental Biology. 246(1): 162-190.
Wilt FH. 2002. Biomineralization of the Spicules of Sea Urchin Embryos. Zoological Science. 19(3): 253-261.
Koga H, Morino Y, Wada H. 2014. The echinoderm larval skeleton as a possible model system for experimental evolutionary biology. Genesis. 52(3): 186-192.
Tamboline CR, Burke RD. 1992. Secondary mesenchyme of the sea urchin embryo: Ontogeny of blastocoelar cells. Journal of Experimental Biology. 262(1): 51-60.
Metchnikoff E. 1893. Lectures on the Comparative Physiology of Inflammation: Delivered at the Pasteur Institute in 1891.
The definition of outreach is “to reach further than”, however, I have found that when it comes to science outreach initiatives, we are only reaching those already in the loop. Although I personally applaud all these events and ideas and have been part of them for many years – either recruiting to my graduate program or showcasing my institution – it always seems like I am speaking to people who are already familiar with what a PhD program is or what academic research entails, and they typically seem to know which career or degree they want to pursue. I believe the key is to approach and interact with those who are not part of the scientific community.
As an international student, I thought that if I wanted to pursue a career in any way related to healthcare, the only road was medical school. It was not until pretty far into high school that I learned of alternate careers and graduate school. Maybe I am the anomaly, but I would bet that many students in similar positions do not know the many opportunities that are available by pursuing a graduate degree in biomedical sciences. Even though I have now moved on from my graduate training, I wish to remain involved in outreach initiatives. However, I want to do so a little differently, and I hope I can encourage others to do the same.
My idea of outreach will now not be limited to going to a local college to speak about my graduate program and such. I want “to reach further than” I have previously and introduce this amazing career path to people even before they reach high school, to truly go out on a limb and pitch this life to those that are not aware of it,rather than simply preaching to the choir. If we were to ask the average 3rd grader to describe a scientist, I’m sure they would all describe the typical Albert Einstein-esque look – messy hair, old and a little unhinged. And (although we all know someone like this in academia) I want to be part of outreach initiatives that challenge this idea, and instead pitch a lifestyle of endless curiosity and non-stop learning to kids that do nothing but wonder and ask questions themselves. If you had told me when I was a kid myself that I would be working with the technology used in Jurassic Park (CRISPR, gene editing, in-vitro cultures), I would have thought that it was the perfect job. I believe I can sell this same idea to kids now: kids that do not know what a PhD is, that do not think being a scientist is something that is feasible for them, or that have not met someone who is as passionate for learning as they are even later in life. There is a reason why younger kids are better at learning new languages; they are just ready to absorb all the knowledge you throw at them. So, this is the time to go and show them a science experiment, hook them in, and get them to ask “why?”.
I’m going to end my rant here, but I just think there is more we could do, there is more I want to do. Institutions around the world are starting initiatives specifically aimed at primary school children such as The Crick’s annual Discovery Day, or the Vanderbilt Institute for Infection, Immunology and Inflammation ‘MEGAMicrobe’ events which target students ages 5 to 14. This is a great starting point, and I hope that more initiatives like these start to take off, and more people are encouraged to get involved with them. Outreach should not be exclusive to the people already in the loop, the point of it all is to go beyond, and “to reach further than”.
What is one outreach event you have been involved in recently? What ideas do you have or have seen that could be used as science outreach? Comment below!
This article is co-written by Eliza Hirsch and Paul Bump.
Who are we?
Hi, my name is Eliza Hirsch, and I am an undergraduate in the Srivastava Lab at Harvard University. And my name is Paul Bump, and I am a postdoctoral fellow at the Srivastava Lab who works with Eliza. Our lab studies the highly regenerative acoel, Hofsteniamiamia. This Hofstenia species originally was collected in Bermuda and now lives in Cambridge, Massachusetts where we study stem cell biology and the evolution of regeneration across animals.
Who is Hofstenia?
Hofstenia miamia is an acoel worm capable of whole-body regeneration, meaning that if you were to bisect one, both halves would regenerate, leaving you with two worms instead of one. Hofstenia maintain a population of adult pluripotent stem cells (aPSCs) that are responsible for regeneration. The regenerative ability of Hofstenia is quite impressive but they are hardly the only systems in which such regenerative ability exists. So why study them? Well, two other key traits of Hofstenia are central to answering this question.
Hofstenia lay embryos (A) in the lab in Tupperware (B) which develop into highly regenerative worms (C) that, upon amputation (D), can generate new heads and new tails in less than ten days (E) (white arrows). Hofstenia belongs to a group of animals called acoels (F), one of the many groups of animals with adult pluripotent stem cells.
Hofstenia have experimentally accessible embryos, something that is very central to the work we do on the development of the aPSCs. They lay their embryos when they are zygotes, allowing us to study their development from the single cell stage all the way up through hatching and beyond. Hofstenia embryos are also easily accessible due to their abundance. The worms we care for lay zygotes frequently enough and at a high enough volume that we can collect almost every day of the week and on most days, we get a substantial number of them. Thus, as a system Hofstenia allow us to study the development of a highly regenerative organism as well as its adult regenerative ability.
How to work with Hofstenia
To understand what it is like to work daily on Hofstenia we thought it would be best to give a perspective from Eliza who is completing her undergraduate thesis research in the Srivastava Lab:
Hofstenia are relatively easy to care for. In the lab, we keep a large portion of our worm colony in plastic Tupperwares of various sizes with up to sixty worms being stored in any given large Tupperware box. When not being cleaned or collected from or used for any other experimental processes, these boxes sit in incubators. The worms themselves live in artificial sea water that is made in the lab, something which perhaps requires the most time and effort in the caretaking of these animals. Adult worms are fed recently hatched brine shrimp as Hofstenia require live food. Hatchlings and sick worms or worms that may be left unattended over a long weekend without cleaning are fed rotifers as they pose a far smaller risk to the pH of the water and by extension the health of the worms in the event of their death.
To clean the worms and avoid problems with ammonia build up in the water and the like, twice a week we replace the water and wipe down the inside of the container. An important element of worm care is the collection of embryos. The animals lay their embryos on the sides and bottom of the container, and I gently scrape at the walls with a glass pipette to dislodge them and then collect them with the same pipette and deposit them in a dish full of sea water. On top of the wild type worms, the lab also has various lines of transgenic worms that are more sensitive than the wild type worms and much harder to replace and therefore require even more careful care.
Recently the lab has started using a water system for many of the wild type worms that significantly reduces the amount of time spent cleaning the worms as they have circulating water and are no longer in boxes but rather are in tanks. However, since my work depends on very early embryos, my worms are still in boxes so that I have access to those embryos which are more difficult to collect in the water system.
Paul and Eliza discuss care of Hofstenia in their slightly less tropical home of Cambridge, Massachusetts
How to crack an egg, starting development in Hofstenia
For my project, I have been collecting embryos every day. Hofstenia embryos are surrounded with a transparent chorion (their eggshell) that must be removed for much of the work that I do with them. Nearly daily I perform a chemical dechorionation on the single-cell zygotes I’ve sorted from the embryos I collected that morning. For this process I use a combination of chemicals and then mouth pipette embryos one by one into twenty-four well plates filled with a combination of artificial sea water and a small amount of antibiotics. Antibiotics are an essential addition as removing the chorion strips the embryos of a key defense against infection. I then raise these one-cell embryos up without a chorion so that I can do experiments at specific developmental stages that would be too sensitive to the dechorionation process.
Eliza works on removing the chorion of the Hofstenia embryo before beginning her experiments
The future for Hofstenia
Since Hofstenia is still a relatively new research organism, there are many possible questions about them to try to answer in one’s own research. In the future, hopefully many labs will continue to increase our overall understanding of Hofstenia and use that information to evaluate evolutionary and mechanistic questions of how the stem cell lineage develops and allows the regeneration of any missing body part. While one drawback of such a new model system is that many methods for working on the animals have yet to be developed, the future is bright as we will continue developing technologies with which to study Hofstenia development and regeneration.
This post is co-authored by Beatrice L. Milnes and Mansi Srivastava, who participated in SciCommConnect organised by the Node, preLights and FocalPlane.
A frequent source of lightheaded acknowledgment at the end of many talks is often not just human collaborators, but a thank you to the model organisms themselves, which are of phenomenal importance for scientific research. To many who work with them, Model Organism Databases (MODs) are indispensable, so much so that imagining one day in a lab without access to them is horrifying. MODs curate information generated from years of experimental research, providing a scaffold for sharing data in a consistent and structured way, thereby enhancing our understanding of both the organisms and the work they are being used for. With modern technologies like nucleic acid sequencing, gene editing, and structural protein biology, the quantum of data is increasing exponentially. MODs categorise information, annotate the quirks of gene naming, and compile references that capture the growth curve of the field. Databases assemble the available informational pieces of the jigsaw puzzle and at the same time highlight the gaps in our understanding — they often serve as handbooks for researchers to delve into new aspects of their system. As biology utilises increasingly ‘omic’ data, integrating big data across species is more important than ever. Modern biology has placed a large emphasis on addressing fundamental questions and assessing the translatability of their findings to human welfare. This often requires relating data not only across scientific disciplines but also between the various model systems employed. Groups like the Alliance of Genome Resources have already begun some of this work by building a cross-species consortium. The utility of integrating data across species has resulted in a call for awareness among scientists to assist in this process by including information in publications that help with indexing in MODs.
What does it take to build a model organism database?
As active experimentalists, we rarely get a peek into the process of database consolidation despite near-daily usage of the end product. Many scientists do not interface with the management that puts great effort into intentionally curating these MODs. It is important to acknowledge that the level of data organisation and layering that databases achieve is in itself as important as the experimentation they inform. The web design contributes greatly to the utility of the sites and is responsible for visualising the available tools, which differ notably between species. MODs also facilitate the exchange of information between two researchers from different corners of the globe without the need for direct communication. In this regard, databases are directly responsible for the accelerated pace of research in the last few decades. Experimentalists, as the primary consumers and beneficiaries of MODs, should be aware and supportive of the resources needed to build the databases they rely so heavily on.
Managing and integrating scientific data has become an essential skill that needs to be inculcated in the next generation of researchers. To this end, consortia like the National Institute of Health (NIH), European Molecular Biology Laboratory (EMBL), and DNA Databank of Japan (DDBJ) can be used as benchmark examples of highly structured databases. Whether a new database is created by a lab, within an institute, in a community space, or available through open access, it should have core structural components that accommodate its growth in the future. Reporting detailed data accurately and including experimental commonalities that could benefit the larger community (eg. plasmid names or standardised phenotyping) should lead to a generation of a database seamlessly. Much of this data could already be published and locally available through alternative resources but many larger trends can only be validated once multiple sources have been compiled by curators. Perhaps one of the largest barriers to this work is that as end-users, we do not know much about the generation of MODs.
Funding support for MODs
Generating large-scale databases is a skill and time-intensive task. For example, the National Center for Biotechnology Information – Sequence Read Archive (NCBI) is curating a central repository for genome/ transcriptome sequencing datasets across model organisms. Unfortunately, such endeavours have limited funding and grant opportunities. For example, the NCBI is supported by the US government alone despite MODs being well utilised as a global resource. Several MODs that serve a smaller research community, for example, Axobase, do not have long-term sustenance funding. Model organisms that are evolutionarily closer to humans such as rodents, their disease-causing pathogens, and food crops are heavily researched. On the other hand, some model organisms are used by a smaller research community aiming to crack open a new area of biology. Intuitively, the nature and quantum of information available for each model organism is very diverse. Databases are crucial for both novices entering a field or experts looking for the next big question. For upcoming MODs, the lack of seed funding limits their conception in the first place. Securing the future of MODs must be prioritised by the scientific community, perhaps through diversification of funding sources.
What’s the future for MODs?
There is an open question of what measures need to be taken to ensure the sustenance and growth of all common and upcoming MODs. As more emerging model systems come into common use, new areas of comparative biology can be catapulted by the presence of a MOD. Perhaps we can support the generation of databases for new species by building off an existing MOD template to generate another, for example, Echinobase has been built using Xenbase as a reference. The first and foremost step would be to have ample funding opportunities for data curation. The funding bodies of existing MODs can begin by allocating annual funds for database development in addition to maintenance of current databases. To ensure revenue generation, the users of databases may be charged a nominal amount for storage and curation of their data. The databases of model organisms that are of national importance should be supported by multiple government schemes. To ensure its sustainability, database building can become an integral component of scientific training and can be developed as a career opportunity. More and more early career researchers investing their creativity and skill into science communication platforms such as MODs would ensure their growth. In the present scenario, scientific information is a commodity of high value, and its true potential can be harnessed only after compilation into these databases.
The progress of research is directly correlated to the development of databases. MODs are not just scientific repositories; they are now a direct measure of our scientific prowess. On a longer timescale, they are also the knowledge that we will pass on to the next generation of researchers. The responsibility of supporting MODs lies on the scientific community as a whole. All of us as stakeholders should prioritise, strategise, and contribute towards both old and new MODs.
Maps are vital tools for any exploration, guiding us through the unknown and helping us make sense of the world. For some developmental biologists, a map refers to a fate map. During embryonic development, a single fertilized egg divides and differentiates into various cell types. Thus, determining cell lineages over time and space in small embryos is a critical step in understanding how our body is built. One of the earliest experimental embryologists, Vogt’s seminal work with ‘vital dye’ to trace cell lineages and migration paths during amphibian embryo gastrulation remains valuable even today, despite the technological limitations of his time [Vogt, 1929]. With the more sophisticated techniques we have now, what kind of maps might we be able to create?
In our recent paper [Kuroda et al., 2024], we combined modern techniques to elucidate the complex developmental origins of the pectoral girdle in zebrafish, labeling the cells that potentially contribute to the pectoral girdle from the early developmental stage long before the formation of skeletons. By comparing this cell fate map of the fish pectoral girdle with the preexisting map of the amniote shoulder girdle, we were able to infer how the shoulder/pectoral skeletons were rearranged during the transition of vertebrates from water to land. Below, I would like to share the background scene of our research.
How I started this project
After getting my Ph.D. degree in Japan, I was fortunate enough to be hired as a postdoc in the Tetsuya Nakamura lab. Tetsuya has been researching the key morphological evolution involved in the water-to-land transition, mainly from embryological and genomic perspectives. After revealing the hidden and surprising commonality of developmental origins between fins and hands [Nakamura et al., 2016], he established his own lab at Rutgers University in the U.S. The Nakamura lab was also expanding its research scope to the skeletal structure that supports the pectoral appendages, specifically the pectoral girdle, when I moved to his lab.
The ancestry of our shoulder skeleton seems to have already existed in the pectoral girdles of the fish-like body plan before the vertebrate transition from water to land. Phylogenetic evidence for this assumption can be observed in the presence of the scapula and clavicle in extinct lobe-finned fish, such as Eusthenopteron and in extant lobe-finned fish, such as lungfish and coelacanth [Jarvik, 1980]. Their pectoral skeletons had been transformed over generations of bony vertebrates, eventually helping them adapt to terrestrial life by supporting their increased body weight after the transition to land [Romer & Parsons, 1986].
Pectoral girdle in a salmon fish (Image credit: Shunya Kuroda)
Although the scapula and clavicle were cherished and used over long geological periods, some bones were reduced or completely lost during and/or after the water-to-land transition. Among them, the cleithrum is one of the most mysterious bones. Originally, the cleithrum in aquatic fish was referred to as the clavicle. However, Gegenbaur discovered the true clavicle in fish and thus renamed the bone originally called the clavicle as the cleithrum [Gegenbaur, 1895]. The relative size of the cleithrum gradually decreased after the transition to land and disappeared multiple times independently in tetrapod lineages [Gess & Ahlberg, 2018; Matsuoka et al., 2005].
When I joined the Nakamura lab, some members had already created a mutant zebrafish with gli3 gene and discovered that this mutant exhibited an interesting phenotype: an enlarged scapulocoracoid (a cartilaginous precursor for the scapula and coracoid) and cleithrum reduction. It was as if these changes mimicked the pectoral girdle morphological changes that occurred during the water-to-land transition in bony vertebrates! They were beginning to uncover that the ratio of scapulocoracoid to cleithrum changes depending on the magnitude of the Hedgehog-Gli signaling and its downstream pathways [Wei et al., 2023]. To better understand what was happening in this mutant fish and, possibly, the actual evolutionary process, I started my project to determine 1) whether the embryonic sources of the fish scapulocoracoid and cleithrum are shared, and 2) whether there are other cell populations involved, including potential contributions from outside the pectoral fin precursors.
How I chose methods for cell lineage tracing
In animals possessing cleithra, the bone forms at the boundary between the head and trunk. So, I narrowed down the candidate cell populations that could contribute to the cleithrum to four groups: two from head mesenchymal populations (cranial neural crest cells and cardiopharyngeal mesoderm (CPM)) and two from trunk mesenchymal populations (anterior somites and fin-field lateral plate mesoderm (LPM)). Once I refined the candidates, all that remained was to investigate whether each of these cell populations contributes to the cleithrum.
There is no perfect method for cell lineage analysis, and the applicability of a particular method is limited to certain occasions or animal species. Thus, several methods should be combined for consistent and reliable conclusions. Fortunately, many tools for cell lineage analysis have been developed in zebrafish, allowing us to test cell lineages of the pectoral girdle with different methodologies. Initially, I considered tracking cell lineages through tissue transplantation, as has been done in zebrafish and medaka in previous studies [Cole et al., 2011; Shimada et al., 2013]. This involves preparing fluorescently labeled zebrafish and unlabeled zebrafish embryos and surgically exchanging tissues between them at the same embryonic stage. The advantage of this method is that, since the fluorescent protein is encoded in the donor’s genome, the label remains stable and doesn’t dilute with cell division in the host embryo, as is the case with vital dyes. This makes it suitable for long-term tracking, such as investigating the developmental origins of the musculoskeletal system. The downside of this method is that a fine surgical skill is required. Imagine precisely cutting out an approximately 100 mm square region from an almost spherical donor embryo, and transplanting it into the target region in a host embryo! Even worse, this procedure has to be performed at the developmental stage before our four target cell populations mingled with each other, i.e., late at night on the day of fertilization. I soon realized that I couldn’t perform such a precise operation with trembling hands coming from sleep deprivation, so I decided to explore other methods. (I have deep respect for the predecessors who managed to pull off such experiments in the past!)
A photoconverted zebrafish embryo at somitogenesis stage Left lateral view of a whole embryo (left) and a confocal section in the same embryo (right). A photoconverted Kaede region pseudocolored in magenta labels the anterior three somites and the adjacent neural tube.
Next, I tried a tracking method using a fluorescent protein called Kaede, which changes color from green to red upon exposure to UV light. I placed zebrafish embryos that express Kaede throughout the body on a confocal microscope stage, determined the target area with the computer monitor, and illuminated the UV laser on the target cells, converting the cell color from green to red. Although working late at night was still necessary, handling the microscope and clicking a computer mouse with trembling hands was much more feasible. This method worked nicely, and I finally succeeded in labeling the cranial neural crest cells, CPM, anterior somites, and fin-field LPM individually!
The downside of manual labeling of the spatially restricted area such as vital dye injection, surgical transplantation, and Kaede-based photoconversion is that the experimental precision depends on the experimenter’s technique. So, we decided to deploy another complementary and more reproducible method, genetic cell lineage analysis. Genetic cell lineage analysis is a technique that utilizes the tissue-specific activity of a cis-regulatory element with an artificial gene induction system, such as Cre/loxp system that permanently labels the target cell population. Of course, the activity of a cis-regulatory element is more or less pleiotropic, so one shouldn’t expect the existence of a perfect ‘marker’ enhancer/promotor. However, genetic cell lineage analysis was still an excellent tool that compensates for the weaknesses of Kaede-based photoconversion. In collaboration with Christian Mosimann and Robert Lalonde at the University of Colorado and Gage Crump and Claire Arata at the University of Southern California, we were able to collect transgenic (Tg) fishes to track progeny cells that experience the following ‘marker’ gene expressions: sox10 and crestin (as markers for neural crest cells), tbx1 (for CPM), draculin (for LPM), and tbx6 (for paraxial mesoderm including anterior somites).
Multiple lineages converge to form a single bone
By combining manual cell labeling by Kaede photoconversion and genetic cell lineage analyses by several transgenic fishes, we eventually found that the cranial neural crest cells, CPM, anterior somites, and fin-field LPM all converge to form the cleithrum. In other words, the cell populations that form the boundary between the head and trunk in vertebrate embryos all converge into the cleithrum.
Fate mapping of the zebrafish pectoral girdle Four distinct embryonic cell populations collectively give rise to the cleithrum. Each color represents a clonal descendant of each cell population as annotated in the embryo at the somitogenesis stage.
We have now successfully mapped the four distinct cell populations onto the cleithrum, from somitogenesis embryo to early larva. Let’s take another look at the development and evolution of the pectoral/shoulder girdle with this map in hand. First, the cleithrum indeed shared a developmental origin with the fin-field LPM, which differentiates into the scapulocoracoid. Perhaps the phenotype reported in the gli3 mutant mentioned above is related to the signal responsiveness of the embryonic resources shared by the cleithrum and scapulocoracoid, such as the LPM. If changes in Hedgehog-Gli signaling were also involved in the tetrapod evolution, the cleithrum may have degenerated and eventually disappeared due to losing the “resource competition” with the scapulocoracoid.
Indeed, a hypothesis has been proposed that not just a part of the LPM-derived cleithrum, but the entire cleithrum, was incorporated into the mammalian scapula through evolution [Matsuoka et al., 2005]. However, our results did not perfectly support this hypothesis. This is because recent results of genetic cell lineage analysis using mice could not confirm the contribution of neural crest cells and CPM (collectively referred as head mesenchyme) to the scapula [Adachi et al., 2020; Heude et al., 2018], while these head mesenchyme contributes to the cleithrum in zebrafish. Given this mismatch of embryonic origins of mammalian shoulder and fish pectoral girdle, our view is that the head mesenchyme which would have formed the cleithrum in ancestral tetrapods, no longer participates in the formation of the shoulder girdle skeleton in derived amniotes. This rearrangement of cell populations at the head/trunk interface may be due to the evolution of a specialized LPM region, which should be called the “neck LPM”, required for the formation of the long neck characteristic of the modern amniotes [Hirasawa et al., 2016; Lours & Dietrich, 2005]. This novel LPM population may have spatially separated the cranial mesenchyme that would have formed the cleithrum in ancestral animals from the trunk mesenchyme, leading to a cleithrum loss in multiple lineages.
Remaining questions
We propose that if we assume the complex lineages that make up the cleithrum is mechanistically indispensable for its formation, we can reasonably explain the evolutional acquisition of the functional neck and the concurrent disappearance of the cleithrum in amniotes. However, it is not yet clear what role each cell lineages plays in the formation of the cleithrum. If one or two of the four cell populations that make up the cleithrum are missing, can the other cell populations compensate for the absence of the missing cell populations and still form the cleithrum? If so, are the developmental origins of animals with the cleithra diverse? Furthermore, we emphasize that the evolution of the cleithrum and the neck cannot be discussed separately. So, then, what exactly is the neck LPM in amniotes? When and how did it evolve through changes in the ancestral developmental system? Some of these questions are now being actively pursued in the Nakamura lab, and of course, are open questions for all researchers interested in the evolution of the shoulder and neck as well.
References
Adachi, N., Bilio, M., Baldini, A., & Kelly, R. G. (2020). Cardiopharyngeal mesoderm origins of musculoskeletal and connective tissues in the mammalian pharynx. Development, 147(3), dev185256. https://doi.org/10.1242/dev.185256
Cole, N. J., Hall, T. E., Don, E. K., Berger, S., Boisvert, C. A., Neyt, C., Ericsson, R., Joss, J., Gurevich, D. B., & Currie, P. D. (2011). Development and evolution of the muscles of the pelvic fin. PLoS Biol, 9(10), e1001168. https://doi.org/10.1371/journal.pbio.1001168
Gegenbaur, C. (1895). Clavicula und Cleithrum. Morphologisches Jahrbuch, 23, 1-20.
Gess, R., & Ahlberg, P. E. (2018). A tetrapod fauna from within the Devonian Antarctic Circle. Science, 360(6393), 1120-1124. https://doi.org/10.1126/science.aaq1645
Heude, E., Tesarova, M., Sefton, E. M., Jullian, E., Adachi, N., Grimaldi, A., Zikmund, T., Kaiser, J., Kardon, G., Kelly, R. G., & Tajbakhsh, S. (2018). Unique morphogenetic signatures define mammalian neck muscles and associated connective tissues. Elife, 7, e40179. https://doi.org/10.7554/eLife.40179
Hirasawa, T., Fujimoto, S., & Kuratani, S. (2016). Expansion of the neck reconstituted the shoulder-diaphragm in amniote evolution. Development, Growth & Differentiation, 58(1), 143-153. https://doi.org/10.1111/dgd.12243
Kuroda, S., Lalonde, R. L., Mansour, T. A., Mosimann, C., & Nakamura, T. (2024). Multiple embryonic sources converge to form the pectoral girdle skeleton in zebrafish. Nature Communications, 15(1), 6313. https://doi.org/10.1038/s41467-024-50734-x
Lours, C., & Dietrich, S. (2005). The dissociation of the Fgf-feedback loop controls the limbless state of the neck. Development, 132(24), 5553-5564. https://doi.org/10.1242/dev.02164
Matsuoka, T., Ahlberg, P. E., Kessaris, N., Iannarelli, P., Dennehy, U., Richardson, W. D., McMahon, A. P., & Koentges, G. (2005). Neural crest origins of the neck and shoulder. Nature, 436(7049), 347-355. https://doi.org/10.1038/nature03837
Nakamura, T., Gehrke, A. R., Lemberg, J., Szymaszek, J., & Shubin, N. H. (2016). Digits and fin rays share common developmental histories. Nature, 537(7619), 225-228. https://doi.org/10.1038/nature19322
Romer, A. S., & Parsons, T. S. (1986). The vertebrate body (6th ed.). Saunders College.
Shimada, A., Kawanishi, T., Kaneko, T., Yoshihara, H., Yano, T., Inohaya, K., Kinoshita, M., Kamei, Y., Tamura, K., & Takeda, H. (2013). Trunk exoskeleton in teleosts is mesodermal in origin. Nature Communications, 4(1), 1639. https://doi.org/10.1038/ncomms2643
Vogt, W. (1929). Gestaltungsanalyse am Amphibienkeim mit örtlicher Vitalfärbung.II. Teil Gestaltungsanalyse am Amphibienkeim mit Örtlicher Vitalfärbung. Wilhelm Roux’ Archiv für Entwicklungsmechanik der Organismen, 120, 384-706. https://doi.org/10.1007/BF02109667
Wei, J., Wood, T. W. P., Flaherty, K., Enny, A., Andrescavage, A., Brazer, D., Navon, D., Stewart, T. A., Cohen, H., Shanabag, A., Kuroda, S., Braasch, I., & Nakamura, T. (2023). Distinct ossification trade-offs illuminate the shoulder girdle reconfiguration at the water-to-land transition. bioRxiv, 2023.2007.2017.547998. https://doi.org/10.1101/2023.07.17.547998
Fluorescence images of some organoids I have grown in the lab. In the organoid on the left, we can see how different cell fates emerge (red and yellow), and on the right we can see the some of the cellular cytoarchitecture (green) in the organoid.
At university, I am also part of the Ambassadors for a Better Research Culture (ABRC), where we aim to improve the research environment on the medical school campus for postgraduate students and staff. Here, I am part of the ‘LGBTQIA+ Inclusion’ subgroup where we run monthly events to foster a community of LGBTQIA+ researchers at the medical school campus. We have also established a larger series called ‘Pride in STEM’, where we invite external speakers to discuss their experiences of being queer in different STEM career environments. I would like to carry this into my internship and compile some LGBTQIA+ voices for a post in the Honest Conversations blog series here on the Node. If anyone is interested in sharing their experiences of being queer in academia, please feel free to get in touch at ryan.harrison@biologists.com or thenode@biologists.com.
This year, 2024, marks the 10th anniversary of the first Development ‘From Stem Cells to Human Development’ meeting, and today is the beginning of the sixth meeting at Wotton House in the UK. The influence the meeting has had on the field is discussed in a recent article by science historian Nick Hopwood (Hopwood, 2024a), who suggests that human developmental biology has experienced peaks of attention and periods of neglect, fuelled by the productivity of technical innovations. In the current issue of Development, we have published a complementary Perspective article by Nick highlighting key aspects of the history of the field for an audience of stem cell and developmental biologists (Hopwood, 2024b). In addition, Development invited researchers from eight countries around the world to respond to these ideas and comment on how human development is perceived in their country of work, discussing how they believe their local legal, political, regulatory, societal and technological frameworks are influencing the field’s trajectory (Clark et al., 2024). The authors and some highlights from the Perspective are shown in the image below, and you can click the image to read the whole article.
Recognising that this article only manages to capture a small sample of the breadth of human development and stem cell research worldwide, we encourage you, readers of the Node, to share your opinion on human developmental biology in your country of work. Do you believe that interest in human developmental biology is cyclical, as suggested by Hopwood? If so, what lies ahead? Are we experiencing a boom or bust in support of human development research? How long might this trajectory lead before turning on its head? What societal undercurrents might contribute to maintaining or changing the field’s course? The floor is yours…
References
Clark, A.T., Goolam, M., Hanna, J.H., Long, K., Nicol, D., Petropoulos, S., Saitou, M., Tam, P.L., Wang, H. Human developmental biology – a global perspective. Development. 151(17). https://doi.org/10.1242/dev.203092
Hopwood, N. (2024a). Species Choice and Model Use: Reviving Research on Human Development. In Journal of the History of Biology. Springer Science and Business Media LLC. https://doi.org/10.1007/s10739-024-09775-7
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Observing a cluster of migrating cells or a developing embryo through the lens of a microscope can be a visceral experience; one is struck by the ephemeral beauty, layered complexity, and alien intelligence displayed by such specimens. For those who seek a scientific understanding of these striking phenomena, it is also a humbling experience. There are so many moving parts here, so many subsystems within subsystems, so much noise, so much nonlinearity, so much contingency… how could we possibly hope to capture this in the simple yet powerful models that make scientific explanations so satisfying and useful?
I’ve been grappling with this question ever since my undergrad, and as anyone who does so, I have found plenty of reasons to be pessimistic about it.
Neural crest cells swarming through a zebrafish embryo are just one of countless phenomena in cell and developmental biology that are truly spectacular to behold. [Main panel: live-imaged AiryScan volume; by author. Bottom-right inset: fixed lightsheet volume for spatial reference; by Zimeng Wu, UCL.]
Though we have extensive knowledge of the molecular machines that form the building blocks of biological systems, putting this giant puzzle together from the bottom up seems an impossibly complicated task. Instead, the field’s still-dominant approach is to link particular perturbations to particular outcomes, usually by lifting out a handful of mechanisms or genes from the broader system, drawing arrows between them, and calling the result a pathway. But whilst the models this produces are of an appealing simplicity, they lack power; they often fail to explain or predict anything outside the narrow set of conditions and observations that were considered in the original study. At least we are indisputably making progress in developing new tools to collect more and better data, ever more quickly, ever more precisely… but alas, this progress is closely shadowed by the realization that it can only take us so far; more data does not yield more understanding if we don’t know how to ask the right questions.
With these problems permeating the field, it comes as no surprise that there is a measure of discontent in the community. Some argue that we have an attitude problem [1]; perhaps young researchers spend too much time on twitter and not enough time in the library? Others contend that we have an image problem [2]; perhaps we should be spending more time on twitter, reassuring each other and the wider public that our field remains essential – or even that it has recently entered, as some would have it [3], a “new golden age”? Like so many developmental biology papers, these viewpoints may not be entirely wrong, but they’re also not particularly compelling.
I’d like for us to entertain the possibility that we are in fact facing a science problem. That our progress is not bottlenecked by modern attitudes or public misperceptions, but by the profound intellectual challenge of finding new and better ways of thinking about the spectacles that play out under our microscopes. I’d like to take seriously the above reasons for pessimism and treat them as real scientific challenges for us to tackle and overcome. If the molecular details are intractable, we should search for new and better systems-level abstractions to subsume them. If the current standard of mechanistic explanation is inadequate, we should look to build new and better conceptual frameworks that set a higher standard. If it is hard to distill meaning from the deluge of high-throughput data, we should aim to develop new and better models that yield strong inductive priors for big-data analysis.
This is much easier said than done, of course, but in grappling with these issues I have also come across a few reasons for optimism!
Looking back in history, the challenge faced by Darwin and his contemporaries in seeking to unify the diversity of living organisms must have seemed no less daunting than our current predicament, yet they persevered and emerged with an entirely new understanding of life. Returning to modern times, a new theory of cell types established about a decade ago shows brilliantly that deep conceptual progress is possible even today [4]. And not only that; it also shows that such progress really does have the impact we would hope to see! For one, it has inspired new ways of analyzing and interpreting transcriptomics data (see e.g. [5]). For another, I have personally witnessed how much more productive the discourse on cell types can be within a group of researchers who know this theory (even if they don’t all fully endorse it) compared to a group who do not. These and other inspirational observations are always in the back of my mind as I explore my own ideas for tackling the field’s fundamental problems.
The C&P idea originated from discussions between first author Elisa Gallo and me on the prospects of discovering principles that generalizewell across different biological systems and phenomena. It is often implicitly assumed that the diversity of cellular and multi-cellular behaviors results from the contingent combination of various modular parts or subprocesses, much like sequence diversity on the molecular level. This would leave us with limited avenues to pursue explanations that generalize over many such contingent assemblies.
Mulling over this in search for alternative perspectives eventually led us to an almost metaphysical argument: if there do exist principles that can explain a diverse set of biological phenomena in a unified manner, then they must be generative principles, that is to say they must comprise a mechanism by which the explained diversity is generated. But are there any such mechanisms in cellular and developmental systems, or does contingency reign supreme?
As we started looking with fresh eyes, it turned out that many of the biological phenomena we are interested in (including cytoskeletal dynamics, reaction-diffusion patterning, different aspects of multicellular morphogenesis, and even embryo-scale processes like gastrulation) can indeed be decomposed into what we have come to call a versatile core and a function-specifying periphery. A versatile core is a mechanism that implements a generative principle and hence is capable of producing a wide range of different behaviors or outputs. The periphery, then, is what configures such a core to produce one particular function out of the many in its large behavior inventory.
A medley of examples of C&P architectures compiled from our recent paper. The same cores (orange disks) are reused with different peripheries (blue leaves) to generate different functional behaviors or outputs. [The exquisite illustrations in the paper were created by first author Elisa Gallo, UZH.]
Intriguingly, we expect systems with a C&P architecture to be highly evolvable because the core’s large behavioral space is readily accessible through modifications in the periphery. As a consequence, cores will tend to spread widely and become deeply conserved in evolution, even as their peripheries diversify to exploit the full range of the core’s versatility. If follows that a generative principle that describes how a core works will generalize across the many different systems and phenomena wherein that core is reused. In other words, the C&P decomposition helps us separate the generalizable (the core) from the contingent (the periphery).
A more systematic introduction and comprehensive discussion of what the C&P hypothesis proposes is of course found in the paper. For my ramblings here, what matters most is that working on this project has greatly increased my optimism, to the point where I now believe that it really is possible to discover human-interpretable yet powerful theories that capture the essence of complex living systems. It’s just that the structure of such theories may need to differ considerably from that of the classical mechanistic accounts we are accustomed to, which is what makes it so hard (and so exciting) to pursue them.
This pursuit requires conceptual work, which means reading widely, thinking deeply, and engaging in intense and interdisciplinary discussion. As it turns out, this is surprisingly difficult and time-consuming; it is real scientific work. Unfortunately, our current research ecosystem does very little to incentivize and support such efforts. Young researchers in particular feel the pressure to pipette and/or code as fast as we can, just to stay in place in an ever-accelerating academic rat race. Taking time to think outside established lines seems wasteful, let alone taking time to pursue an explicitly conceptual project. In my case, it was only through a combination of luck, privilege, and the generosity of a few individuals that I was able to take a sabbatical year and invest the time necessary to arrive at the C&P hypothesis as it now stands. If we want the pace of conceptual innovation to pick up, this will need to change. Fortunately, there are positive signals here, too, as some leading institutes are now building up new theory-focused research programs.
In conclusion, I see many serious obstacles that we must face on our quest to better understand the complexity, intelligence, and beauty of cells and embryos. But if we take these obstacles seriously, I dare hope that we can overcome them, and that the dawn of a new golden age is indeed on the horizon.
Many thanks to Elisa Gallo and Matyas Bubna-Litic for their feedback on a draft version of this post.
[1] C.D. Stern, Reflections on the past, present and future of developmental biology, Developmental Biology 488 (2022) 30–34. https://doi.org/10.1016/j.ydbio.2022.05.001. [2] J.B. Wallingford, We Are All Developmental Biologists, Developmental Cell 50 (2019) 132–137. https://doi.org/10.1016/j.devcel.2019.07.006. [3] P. Liberali, A.F. Schier, The evolution of developmental biology through conceptual and technological revolutions, Cell 187 (2024) 3461–3495. https://doi.org/10.1016/j.cell.2024.05.053. [4] D. Arendt, J.M. Musser, C.V.H. Baker, A. Bergman, C. Cepko, D.H. Erwin, M. Pavlicev, G. Schlosser, S. Widder, M.D. Laubichler, G.P. Wagner, The origin and evolution of cell types, Nat Rev Genet 17 (2016) 744–757. https://doi.org/10.1038/nrg.2016.127. [5] A.J. Tarashansky, J.M. Musser, M. Khariton, P. Li, D. Arendt, S.R. Quake, B. Wang, Mapping single-cell atlases throughout Metazoa unravels cell type evolution, eLife 10 (2021) e66747. https://doi.org/10.7554/eLife.66747. [6] E. Gallo, S. De Renzis, J. Sharpe, R. Mayor, J. Hartmann, Versatile system cores as a conceptual basis for generality in cell and developmental biology, Cell Systems (2024). https://doi.org/10.1016/j.cels.2024.08.001.
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