Dr. Alexa Sadier is a Research Scientist in Karen Sears’ lab at UCLA. She is using bats as a model system to understand the origin and diversification of a key mammalian innovation, the tooth classes (e.g. incisors, canine, premolars and molars). From the µCT scans and two-photon microscope in the lab to the jungles and caves of Trinidad, find out more about the story behind the team’s recent paper!

What brought you to join Karen’s lab?
I joined Karen Sears’ lab in 2015 to study the evolution of sensory systems in noctilionoid bats, the family I am focusing in. As an evolutionary developmental biologist, I quickly fell in love with both the animals and the system.

How did the project get started? What was known about the origin of mammalian teeth before your work?  
I did my PhD on molar evolution in mice, in which we demonstrated that the particular shape of the mouse first molar can be explain by the complex evolution of dental patterning in this species. This training gave me a deep knowledge of tooth development and the potential of this system. After working on bat vision evolution, I decided to launch my own area of research in Karen Sears lab (I thank her SO MUCH for giving me this opportunity) because I realized that bat teeth are so diverse that they can be a good model system to study phenotypic diversification given our deep knowledge of tooth development in mice. On the contrary to mice, bats possess all tooth classes so we can study not only molars and very derived incisors, but all of them. We can investigate mechanisms that are still not known such as what makes an incisor an incisor, a canine a canine, a molar a molar, etc. Indeed, most of the developmental studies have been done in mice. We know that tooth class identity seems to be determined early during development, through a prepatterning of the jaw, but our understanding of what happens after and their respective morphogenesis is extremely limited.

What made you choose noctilionoid bats as your model organism?
For an evolutionary biologist, noctilionoid bats are a fantastic model since phyllostomids (a group of noctilionoids) underwent an adaptive radiation (like Darwin finches) and have evolved various diets. You probably know the vampire bats which eat blood but other species specialize on fruit, nectar, insects, vertebrates, fishes or even pollen. This adaptation to various diets had shaped their evolution at all levels: the shapes of their skull and teeth are adapted to their main diet, so are other systems such as vision, echolocation, etc. In the Sears’ lab, I realized that what I thought was only possible in model species, such as mice, was also doable in bats (up to a certain point). Before working with them, I would have been skeptical about the ability to perform developmental biology or even functional experiments on non-model species. Now that the genomes are available through Bat1K, and developmental material thanks to field expedition and museum specimens, we have all the tools we need to study them from genotype to phenotype. It’s a kind of an eco-evo-devo researchers’ dream.

Can you summarise your key findings?
Noctilionoid bats exhibit a huge variation in their tooth number, size and shape due to the colonization of various dietary niches in only 25 million years, making them a fantastic model to study the developmental basis of rapid morphological evolution. We used integrative approaches (morphological measurement on adults and embryos, cell proliferation labeling and modeling) to investigate the development and evolution of two tooth classes, premolars and molars.

We found that premolars and molars develop and evolve independently by two different Turing-like rules in bats, and probably other mammals, that deviate from previous models (the Inhibitory Cascade (IC) model). This important result brings new insights regarding the developmental and evolutionary differences between tooth classes – a major mammalian innovation – that remain relatively obscure and limited in their taxonomic scope. Then, by linking this variation with the variation in jaw length, we show that the interaction between Turing-like mechanisms and growth rate is sufficient to generate the observed variation. Our work demonstrates how new morphologies are reached by modulating the interaction between multiple developmental constraints during the burst of diversity that accompanies adaptive radiations. While the idea that growth rate variation is important for Turing mechanisms is not novel, our work proposes that it can facilitated the apparition of new phenotypes in teeth and potentially other ectodermal appendages that develop like teeth.

How was it like working with bats? Any memorable stories about the fieldwork?
It’s probably my favorite moment of the year even if it implies being sleep deprived, long nights, a lot of work and administrative tasks but all of this disappear when we hold a bat with its little personality. Typically, we travel to Trinidad, Dominican Republic or Puerto Rico for 2 to 3 weeks at the time. Our days and nights are organized around bats. At 2-3 pm, we generally drive to a field site to be ready with our traps at 5-6pm when the bats come out. We then catch them until 11pm and put up a triage station to decide which one we release (95% of them) before driving back with them in cotton bags. Then, the long processing night starts, sometimes often until 5-6 am. We then sleep for a few hours, eat, and repeat. Some people think we go to the beach and enjoy the Caribbean life with rum every night but the reality is that we barely have time to complete our tasks. And when we do, we try to catch some sleep. As though as it could be for the body, there is something magical when we go down into a cave with all the bats flying around us. Forests are also special places, with so many species, so are abandoned houses, sometime frozen in time. I have so many fieldwork memories, but one is particularly fun. When looking for fishing bats, we had, one day, to swim into a bat cave from a boat with our butterfly nets. As we were swimming into the cave, which was like a narrow tunnel, we started to smell them. Then the cave became wider and all the bats were there, with pup, looking at us. We couldn’t believe it was true. Finally, the best of all is probably sharing this with our local collaborators, year after year, triaging bats sitting in the back of the truck, laughing, sharing, nerding, eating the delicious Trinidad doubles, working hard but in such a special atmosphere.

Do you think that doing fieldwork change the way you perform your research?
Yes! In eco-evo-devo, it’s a new way to think about the species you work on. Seeing them in their environments can really make a difference in your research. I remember this conversation with a researcher who solely study the genomic aspects of bat evolution. From his dataset, he thought that one bat species was blind although it’s clear, when seen it in the field looking at you, following your finger, looking around, that it is not the case. Fieldwork adds another dimension to our work as evolutionary biologists. From a more personal point of view, as an outdoor person who grew up in the French Alps, I have always been skiing, climbing, hiking, etc. I love being outside and I always think of science as a way to explore, exactly like explorers who discover new territories. Fieldwork represents the ultimate fusion between geographical and intellectual exploration: we are looking for new species, new specimens, new results while we explore new areas and make link between everything.

How was your experience collaborating with people with different expertise for the paper?
It was really great, especially regarding the modeling aspect of it. Being able to find a mathematician interested in biology and vice versa was really one of these fun moments in research. Interdisciplinary research is not always easy and it’s always a special moment when everything is finally getting together. It’s also a way to push the boundaries when it works well like this.

Did you have any particular result or eureka moment that has stuck with you?
Yes! And it was so good. I was segmenting teeth at the computer and my colleague and friend Neal, who is a co-author, was in the lab. I realized that, in some bats, the premolar that disappears is the middle one (on the contrary to molars) and that it happens gradually during evolution. I was like WTF! and asked him to come next to me to tell him what was his conclusion (without telling him first). We looked at each other being like: that’s AMAZING! It really changed the study and the way I then thought about these results.

And the flipside: were there any moments of frustration or despair?
Of course, when the two-photon images were too big (1.6 Tb) to be opened and we had to start imaging everything again not knowing if the dyes would have survived in our precious samples. Or during COVID, when fieldwork was not possible despite our need to get more developmental stages or more museum specimens and thought it would delay the paper. And more than anything else, being a postdoc and then a research scientist with all the uncertainty that comes with it. While it’s exhilarating in so many ways, it’s still a temporary situation that implies a lot of sacrifices, long distance relationships, and living on grants, sometimes not knowing if everything will stop after 6 months. Delaying results can have devastating consequences on an application cycle. I knew I couldn’t abandon this project because I deeply believed in it (its significance, the science behind it and where we can go from it), but I had some close calls because I was so sick of sacrificing many things I love (including my personal life) for my career. I made these sacrifices but not anyone can do it (or even want). For me, this is the most challenging part of developing new risky research at this career stage.

Where will this story take the lab? 
This paper really showed the potential of this model to study the origin of tooth classes and is the foundation of my future research program. Next research will investigate how the variation of the dental gene network drives tooth class diversification. We will still use bats as a model system and plan to extend to other mammals, and long term, ectodermal appendages that develop the same way!

What is next for you personally after this paper?
Hopefully, the best is yet to come! I’m about to start my group using this model system to study the evolution of tooth classes, so this paper constitutes the foundation of the future, it’s a beginning. Developing this model and program (along with the other paper that came out of it) helped me to gain confidence in my science and research and establish my area of research. It will always have a special place.

Reference
Sadier, A., Anthwal, N., Krause, A.L. et al. Bat teeth illuminate the diversification of mammalian tooth classes. Nat Commun 14, 4687 (2023). https://doi.org/10.1038/s41467-023-40158-4

Pictures: Alexa Sadier, group picture: Marie Treibert

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From Procko, Radin et al., 2022. “Dynamic calcium signals mediate the feeding response of the carnivorous sundew plant.” PNAS.

More plant representatives

For this postcard, I’ve selected Ivan’s talk about calcium signaling in the sundew, but I wanted to give a shoutout to some of the conference’s other plant representatives. We’ve learned about

• how the brown algae Ectocarpus can help us answer questions about the origin and evolution of multicellular development (FUN FACT: this algae’s female gametes emit a pheromone that smells like gin)

• how the moss Physcomitrella patens teaches us about single-cell perspectives of tissue patterning

• how the wild grass Brachypodium distachyon addresses developmental questions of how form impacts function in plant stomata (FUN QUOTES: “Stomata are cellular bouncers” and “”Plants are tunneling experts, much like the Swiss”).
  
  

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On Monday we learned a bit about early branching animals, especially the cnidarians. One poster mentioned ongoing work in ctenophores.

Note: I should point out that Nematostella wasn’t the only cnidarian mentioned at the conference. We’ve had representation from Hydra showing us how cell types may have evolved, as well as from Aiptasia teaching us about intracellular host-algal symbiosis.

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Have you ever had to interview someone for an article? What are the considerations before, during and after the interview?

A group of active members of the three community sites (the Node, FocalPlane and preLights) got together to discuss their experiences of interviewing people and shared a few tips and good practices.

We created a visual summary of the discussion on preLights. Check it out: How to conduct interviews – brainstorming session with members of the Node, preLights and FocalPlane. – preLights (biologists.com)

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Help the NC3Rs fund the best new science that could replace, refine or reduce the use of animals in research.

Our panels are instrumental in supporting the development of new 3Rs models, promoting uptake and championing early career researchers and we are now inviting applications from talented senior researchers to become Panel members from January 2024. For this recruitment round, a wide range of expertise is sought after and applications are particularly welcome from individuals with industrial or interdisciplinary experience. Applications from women, those with a disability, and members of minority ethnic groups are especially encouraged.

For further information, including an application form, visit: https://nc3rs.org.uk/funding-panel-vacancies

The deadline for applications is 4pm (GMT) on Monday 20 November.

If you have any queries, or you would like further information, please email recruit@nc3rs.org.uk.

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Introducing “unconventional posts,” a miniseries celebrating the “unconventional” experimental systems presented at #DevMeeting23. Each day I’ll upload handmade postcards spotlighting the breadth of unconventional systems shared in talks or posters and post it on The Node. Here are the first couple to get us started:

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When I was a child, I loved the movie “The Fifth Element”—the people working together with living beings from other planets, the space travel while you sleep, the queer clothes, the microwave that makes a fried chicken from a pressed tablet, and the restoration of a living being from a remaining piece. Years later, I am basically working on the last one: creating tissues from cells, building models of organs, and trying to use them to model healthy and diseased conditions. The field I am working in, tissue engineering and regenerative medicine, sounds as futuristic as the film is. And I often feel that people see this field of research in that way— as a science that emerged out of nowhere, in a kind of Frankesteinish and mad scientist way. Talking with people about this area of research and my work, I have heard different reactions, starting from fascination and ending with a question I was asked by one of my friends: “Is it even legal?”. So, I started wondering where this outlandish image was coming from. Is it the lack of awareness of its origin and its goals, or maybe the ethical controversies widely covered by the media, or is it the desire to have simple answers contradicting attempts to share complicated scientific progress?

The first attempts to replace and restore damaged organs

When I started working in this field, I didn’t look too much into history; I just loved the challenge of mixing different subjects and trying to unveil the biological processes by modeling organs outside of the human body. However, talking with people and seeing a lack of trust and disbelief that I was doing something useful or feasible inspired me to investigate the history of how tissue engineering and regenerative medicine came to be. I was struck by how logical its emergence was. The gist of this field is the desire to recreate such biological processes as development and disease outside of the human body and to replace or restore failed organs with artificially created ones. The interest in replacing some lost parts of the human body is not a modern idea, though. One of the oldest mentions that I found is the ancient text on medical and surgical practices from India written somewhere between one millennium BCE to the first centuries CE, which is called “Sushruta Samhita”. The text describes an autograft skin transplantation, which we would now probably call rhinoplasty. The procedure allowed restoration of the nose, which was tightly connected with the image of dignity in India and could be lost due to punishment or in wars¹.

Another area with a long history of replacement attempts is dental implantology. Historical evidence suggests that as early as 7^th century BC, Etruscans used golden wire and artificial teeth to replace loosened incisor teeth². The first documented teeth transplantations, though, happened in Europe in the Middle Ages³. And titanium implants were discovered only in the 20^th century.

The rapidly changing world of the 20^th century

The 20^th century brought the beginning of fast scientific progress and associated with it changes in the way we see the world. The work of Swiss surgeon Theodor Kocher (late 19^th to 20^th century), who perfected thyroid gland surgery and discovered its function, shaped how we see organ transplantation. His findings led to surgeons’ and physiologists’ interest in organ replacement, extensive experiments in animals, and attempts to use animal organs to replace failed organs in humans. Then Alex Carrel figured out how to reconnect the transplanted organ to the respective blood vessels in a host body (early 20^th century). Gradually, the surgery skills reached the level when it became obvious that even when the surgery itself is done perfectly, organ transplantation does not lead to the intended results of restoring a fully functioning body. Through many theories, researchers then concluded that the main problem is probably connected with the immune system⁴. Starting around the 1950s, people gradually learned how to suppress the immune rejection of transplanted organs⁵ and how to transplant organs, first from living (kidneys) and then from deceased donors⁶.

The progress medicine and physiology saw in the 20^th century is astonishing. Apart from the obvious positive influence of improved medical care and longer life expectancy, it brought a major philosophical shift. The development of organ transplantation marks the end of an era when the prevalent belief was that the human body is a whole thing and diseases are connected with disturbances of liquid flows inside it⁴. The human body becomes an assembly of organs. Questions like “Do organs hold a part of a host soul?” or “Will transplantation affect the soul of a patient?” captivate the minds of people. We still can see the remnants of these beliefs in art. Just last year, I watched a movie where the main heroine receives a heart transplant and falls in love with a stranger, only to discover that it was the soul of the heart donor living inside her. Everything changes: the way people see themselves, the way people define death, and the way people see each other. It brings the necessity to develop ethical and legal rules for organ donation and transplantation, for experiments on human beings and animals. A lot of questions only become visible with time, like the differences in legal regulations of organ transplantation in different countries resulting in medical tourism.

In parallel with organ transplantation, techniques for growing cells outside the body were developed. First, the physiological solutions, like Ringer’s solution, which allowed keeping organs alive outside the animal body for several hours or days (late 19^th century). Then the cells are successfully cultured in vitro by Margaret Reed Lewis (early 20^th century), the standard culture medium recipe is developed, and the standardized cell lines appear⁷. Science is constantly changing people’s views on what is possible. Advances in cell culture bring the question of the possibility of recreating organs outside of the human body. And here we are, seeing the beginning of tissue engineering and regenerative medicine at the end of the 20^th century.

The role of communication in scientific progress

While reading about the history of the tissue engineering and regenerative medicine field, I noticed that there wasn’t a lot of information about how these discoveries were accepted by public. Just imagine being born and raised with the idea that your body is the vessel of a soul and then being told that, actually, it is just like a clock – a mechanism with many replaceable parts. I remember a similar experience from my childhood. In primary school, I was told that you should always subtract a smaller number from a bigger one; you can’t do it vice versa. And then, in middle school, I learned that you actually can, and then you will get a negative number. Even though that was the way everyone learned mathematics, I felt betrayed. Why was it necessary to conceal the truth about the possibility of subtracting whatever you want from whatever you want? And what else is concealed until the time to know comes?

I guess part of the answer lies in how science was communicated throughout history. For a long time, science was mainly practiced by the privileged social classes, and communication mostly happened in a kind of top-down direction, where scientists or their benefactors showcased or shared only the things they wanted to share. Only in the 20th and 21st centuries science communication started to be seen as a way to allow people to make informed decisions and even influence the research direction when it concerns the everyday life of society ⁸. Part of the answer lies in the way science is taught as a subject with straightforward results, skipping a part where scientists were not sure or had conflicting ideas. As a result, when this process is shared, and some facts scientists believe to be true turn out to be wrong, instead of natural progression, it looks like not trustworthy. But also when reading stories like “The Immortal Life of Henrietta Lacks”, documented by Rebecca Skloot, or a recent article about using the CRISPR technique for editing human embryos by Dana Goodyear⁹, the thing that bothers me is often too superficial communication between scientists themselves. Too often connections are just networking when you briefly listen to 10 minutes of results that took a couple of years to get and then congratulate each other with a newly published article without looking too much into the details. Too rarely it is a meaningful connection when you are interested in another person’s work and ready for in-depth discussions.

I feel that lately, the academic structure is pushing for faster, bigger, better. It needs simple narratives and fast results. The never-ending competition brings the over-focus on your own work; researchers are constantly searching for their own niche, something to be at least a little bit different from others. It sometimes feels that instead of solving the problem, it is important to solve it differently from others. As a result, we have so much literature in our own domain that we hardly have time to follow other fields of science; we are so focused on our own research that hardly have time to listen and understand others. We are constantly networking and collaborating, but it feels that we are as isolated from each other as we can possibly be. Lately, I started asking myself questions. How often do you read papers that are not from your field? How often do you go for an adventure and read on completely unrelated topics? When was the last time you attended an interdisciplinary conference? And I mean truly interdisciplinary, not around the topic you work on, but rather an event where different people talk about the universe, climate change, medicine, and literature in one place. We all want to be heard, but how often are we the ones listening?

I first came up with the question of why people think of tissue engineering and regenerative medicine as a strange science because I felt misunderstood, but the longer I think about it, the more I think that it is a reflection of how the academic system is currently working. And maybe this is one of the reasons I decided to try science communication – to become the one who listens.

Further reading:

1. Saraf S. Sushruta: Rhinoplasty in 600 B.C. The Internet Journal of Plastic Surgery 2006; 3.https://ispub.com/IJPS/3/2/7839 (accessed 8 Sep2023).
2. Donaldson JA. The use of gold in dentistry: An historical overview. Part I. Gold Bull 1980; 13: 117–124.
3. Pasqualini U, Pasqualini ME. THE HISTORY OF IMPLANTOLOGY. In: Treatise of Implant Dentistry: The Italian Tribute to Modern Implantology. Ariesdue, 2009https://www.ncbi.nlm.nih.gov/books/NBK409631/ (accessed 18 Aug2023).
4. Schlich T. The origins of organ transplantation. The Lancet 2011; 378: 1372–1373.
5. Allison AC. Immunosuppressive drugs: the first 50 years and a glance forward. Immunopharmacology 2000; 47: 63–83.
6. Nordham KD, Ninokawa S. The history of organ transplantation. Proc (Bayl Univ Med Cent); 35: 124–128.
7. Yao T, Asayama Y. Animal‐cell culture media: History, characteristics, and current issues. Reprod Med Biol 2017; 16: 99–117.
8. Nielsen KH. Histories of Science Communication. Histories 2022; 2: 334–340.
9. Goodyear D. The Transformative, Alarming Power of Gene Editing. The New Yorker 2023.https://www.newyorker.com/magazine/2023/09/11/the-transformative-alarming-power-of-gene-editing (accessed 7 Sep2023).

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