No such thing as a standard career path – an interview with Bill Hinchen

Bill Hinchen is currently a freelance science writer, but he never wanted to leave academia in the first place. Following the devastating loss of his PhD data while thesis writing, he ended up falling into the world of science writing. A few years ago, he was offered a second chance to do a PhD. What made him decide to turn away from his dream of an academic career? What advice does he have for early career researchers? We chatted to Bill to find out more.

Let’s start from the beginning. Have you always been interested in science?

I watched lots of David Attenborough and wildlife programmes growing up. I love the natural world and I wanted to be a vet. At secondary school, I chose biology, chemistry and art as my A levels subjects. Then I started to learn about research and decided I would do either toxicology, marine biology or biochemistry at university. At the last possible minute, I decided I wanted to do fine art, but my art teacher told me I should do science, because there’s no money in art. That swayed me, so I chose to do marine biology in Plymouth. (I want to go back and tell my art teacher that there’s no money in science either…)

How did you end up doing a PhD at the University of Cambridge?

After my undergrad, I did a Master of Research in marine biology at Plymouth, focussing on ecotoxicology – specifically I looked at the neurotoxic effects of dietary copper on catfish. On the side, I was also reading a lot about ecophysiology work, looking at how environmental conditions affect early embryogenesis. And in no time at all I just fell in love with research. As I was wrapping up my Master’s, I applied for PhDs at several places. An opportunity at Cambridge popped up. The project was on the early development of the marine crustacean Parhyale hawaiensis. That sounded interesting, but I didn’t know how I could end up getting a PhD in Cambridge. I grew up in a rough part of East London and went to secondary school and college in Tower Hamlets. I applied anyway, and I got the interview. At the time, I had a clean-shaven head, so I tried to grow my hair as fast as I could and took my piercings out. Superficial, I know, but the thought of Cambridge made me panic! At the panel interview, they fired all kinds of questions at me. My molecular biology knowledge was very lacking, but my biochemistry knowledge was good. One of the questions was “What’s your favourite experiment?” I immediately went back to my time in Plymouth at the Marine Biological Association, where Hodgkin and Huxley conducted the experiments on ion channels in giant squid axons. You can still see the giant squid axons that they used to throw up to the ceiling after an experiment. I told the interviewers that was my favourite experiment and one of them said, “That’s my favourite too!” To this day, I still think that’s the only reason I got the PhD. Then, Cassandra Extavour, my supervisor, told me she’s got an associate professorship at Harvard and asked if I’d like to go there for a year. I was a bit shell shocked – I just landed a PhD at Cambridge and Harvard! It was great, but hard. It was a big transition, going from Plymouth, feeling like a big fish in a small pond, to Cambridge, where I felt like a very small fish in a very big, scary pond.

What did you work on during your PhD?

I was using 4D microscopy to figure out cell migrations patterns during the very first few cleavage stages before gastrulation. Once we’d modelled how the cells migrate, we did single cell ablation of individual blastomeres to see if their neighbours carried on going where they need to go, or whether cells needed each other to figure out where they were in the embryo. Interestingly, it turns out that there’s plasticity and compensation at the early stages of development, where you can just do the horrible things the embryo, and it just carries on developing.

What happened towards the end of your PhD as you were thesis writing?

My PhD was based on 4D microscopy, where I did multiple z-plane time-lapse recordings. I accumulated about 300GB of data. This is a long time ago, now. The computer was rubbish, and there was no cloud storage. I went to Harvard for a year and came back to the UK to write my thesis. Things were going really well. I was writing at home one day, and I went out to do a few errands. When I came back to my house, the window was ajar. I looked in and it was just ransacked – the TV, DVD player, my laptop, external hard drives and USB sticks – literally everything on my desk had been swiped off. So that was all my PhD data gone. The only bits of my PhD left were the few drafts I’d emailed to my supervisor and advisor. I needed at least six months to re-do all my key experiments, but there was no funding available. I was already working part time to cover rent. I rewrote the thesis but there was no data to support anything I wrote. Cambridge told me they simply couldn’t examine me on data I didn’t have. I was told there wasn’t enough to submit as a PhD, so I had to submit it as an MPhil. I breezed through the viva examination, but I didn’t bother going to the graduation at the end of it all. I didn’t want anything to do with it.

Following the devastating loss of your PhD data, how did you end up getting a job in medical writing?

At that time, I never wanted to leave academia. I loved being at the bench. After the MPhil, we had to leave Cambridge because it was too expensive to live there. My wife got a job in Peterborough, and so we moved there. Work was hard to find because I was constantly told I was over-qualified. So, I worked as a cleaner in a dental surgery and as an Apple reseller at a local shop. Whatever it took. Finally, I was hired as a Research Associate in a biophysics lab at King College London. They were developing a technique to do controlled light exposure microscopy in C. elegans embryos. They were all physicists and needed someone who knew how to work with embryos. I was there for four months until they ran out of funding. It was possibly the most fun four months I’ve ever had. After that, someone mentioned medical writing to me. I ended up getting a job in an agency as a medical writer, where I produced publications and marketing materials for pharma companies. I didn’t really like it. It was very much about whatever the client says, you do. After working at a few agencies as a medical writer, I moved to Abcam as a science writer, and it was a complete change of pace. I was writing marketing materials, blogs, and guides on how to run IHC or ELISA. I eventually became the senior writer. I moved away from writing lengthy technical stuff, to doing more creative writing, like a lovely full-page advert in Nature about ELISA kits. But I decided I wanted to do something more wholesome, so I joined the charity Kidney Research UK as their Research Communications Manager. My job was to take the research they fund and turn it into something the public can understand. That was good fun but hectic.

You were offered another chance to do a PhD in 2020. How did that come about, and how did you make the difficult decision of turning down the offer?

I was getting tired of writing for people and I longed to be back at the bench doing experiments. A friend of mine mentioned that her old boss, Grant Wheeler at the University of East Anglia, was looking for a PhD student in ecotoxicology. I thought this could my opportunity to get back into academia. At the interview, they were lovely. They offered me the PhD and it became very real. I spoke to a lot of people in academia, and they all mentioned the lack of funding, lack of job security, and the huge competition – stuff I knew deep down, but needed to hear. It would’ve meant moving my wife and son to Norwich, taking a massive pay cut, and working all the hours required for a PhD. After a lot of consideration, I decided to turn down the offer. I felt bad for messing Grant around, but I think it was the right thing to do. Part of me will always long for the lab, but I think at that point, having had the chance to go back, I could close that chapter, and move on.

You’re currently a freelance science writer, specialising in copywriting. What does your job entail?

Copywriting used to mean writing short copy, but it’s since come to mean anyone who writes anything salesy. I call myself a science copywriter, as I focus on short ads, but I also still write long copy like blogs, web pages and white papers. I do creative directing and consulting as well. I made a copywriting 101 video a while ago. That was for my sister initially, who runs her own business, but I thought I should make it available online for anyone who doesn’t know where to start. I’ve also run some training workshops. And I use LinkedIn a lot as a platform to not only attract clients but put the word out there that science writing doesn’t have to and shouldn’t be boring and dry – it can be interesting and fun!

How are you finding freelancing compared to working for an organisation?

I went freelance nearly five years ago. Going freelance has been the best thing ever and the scariest thing all at once. On one hand you have complete freedom. I take off whatever days I like. I set my own breaks. And I’m lucky enough to be established now and so I can choose my clients. Freelancing works out very well for me, because I get to push back a lot more on my clients. I attract a certain type of clients who don’t just want a word monkey. Quite often they want me to show them how to do things differently, so sometimes they become more like collaborators. But the other hand, I have absolutely zero security. If I take a day off, I earn no money. If I get sick, I earn no money. If my clients decide I’m off, I’m unemployed. But the freedom and the control of being freelance is something I don’t think I could give up.

How did your experience in all the different organisations you’ve worked in help you as a freelancer?

My previous experiences have been instrumental. There was no way I could have hit the ground running quite as fast as I did, without all that experience. I’m now acutely aware of what companies need from a content marketing perspective having worked with a variety of clients. People tend to want the similar sort of things, even if they’re from different industries. Because I’ve seen such a broad spectrum of content types and strategies, I can easily come up with ways to make something stand out.

I really thought I’d like the public sector, but it wasn’t that different from working in a big private company, except the budgets are smaller and people’s roles are less defined. In the public sector, we’re communicating this wonderful work and funding researchers who’re doing brilliant science. But the reality is, most of this research will never be heard about. It’s more interesting to us (with a science background) than it will be to most people, but the goal is to get more donations for the charity. At the end of the day, whether it’s a company or a charity, there is always the drive to make more money.

Do you have any advice for people interested in getting into science writing?

The first thing is to think about the types of writing you like. Do you like writing short copy, or long, detailed pieces? There are so many styles of writing. Don’t feel like you need to pick one branch. Be open to trying different things, and then you’ll figure out which types of writing you like. I never expected I’d end up writing short copy.

Back to my point about private versus public sector: if you’re considering a job in science writing, I would think less about the overall cause of the organisation and think more about whether the science you’re writing about is interesting, because that’s what will help you write engaging pieces. I would also tell people to steer clear of recruiting agencies, if possible. Some of them are fine, but most of the ones I’ve encountered are trying to get you into almost any position. I think you’ll be more rewarded by finding people who write the things you’re interested in, and then either look for jobs with them or just message them. People are way more receptive to random questions than you think, especially on LinkedIn.

One last point I want to make is that your ambition doesn’t always need to mean becoming senior writer, creative director, or head of copy. Ambition doesn’t have to mean moving up the corporate ladder. Your ambition can be to become really good at writing this one thing. You don’t always need to be climbing some corporate ladder.

Do you think you’ll stay in science writing?

I’ve been doing science copywriting for 13 years. I don’t know if anyone would pay me to do anything else. I would like to move away from writing words for people and move more towards the consulting side, like helping people figure out the tone of voice, coming up with a marketing or communications plan, and helping people get better at writing.

Apart from science writing, you said you almost did fine art at university. Did you ever consider any other careers?

All the time! I did some steel engineering work at building sites. I thought maybe I could do an apprenticeship. I also thought about doing a graphic design course. I love drawing. My wife and I started a small T-Shirt company called Old and Board, because we like to skate and surf and we’re in our 40s now. If I could somehow turn that into a job, that would be lovely.

What do you like to do in your spare time?

I surf a lot. We moved from the middle of England down to Cornwall, so we can live by the sea and surf on demand. If I’m not swimming, surfing, or writing, I’m probably in the gym.

Thank you for sharing your story! Do you have one final piece of career advice for the Node readers?

Do not ever think you need to have everything figured out. No one has it figured out. Everyone is winging it. If you feel like you don’t know what you’re doing, or you’ve got imposter syndrome, that’s totally normal. Everyone feels like that. Don’t worry about it. Just keep doing what you’re doing!

(2 votes)

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The 20 November 2024 Development presents… webinar was chaired by BSDB Chair Marysia Placzek (University of Sheffield) and featured four talks from the prize winners of the 2024 BSDB Spring meeting. Catch up on the talks below.

Tamina Lebek (The University of Edinburgh)

Callum Bucklow (University of Oxford)

Hannah Bruce (University of Liege)

Stanley Strawbridge (University of Cambridge)

(2 votes)

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The final webinar of 2024 features two early-career researchers working on gene regulation and will be chaired by Development’s Senior Editor, Alex Eve.

Wednesday 4 December – 15:00 GMT

At the speakers’ discretion, the webinar will be recorded for viewing on demand. To see the other webinars scheduled in our series, and to catch up on previous talks, please visit: thenode.biologists.com/devpres

(3 votes)

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Queer people, trans individuals in particular, remain significantly underrepresented in STEM and academia. In August 2023, Nick wrote an Honest Conversations post on the Node entitled ‘Coming Out of my Cage and I’ve Been Doing Really, Really Good’, discussing his experience of being a transgender scientist, the importance of the support he received from his lab, and the freedom he found in living authentically.

In this Voices piece, we hear from two PhD students who identify as trans. They discuss their experiences navigating academia, issues prevalent in academia that trans people still face, and the support systems they have found that have empowered them on their journeys.

Thank you to both Aflah (author of another ‘Honest Conversations’ article Moving Forward on Diversity, Equity, and Inclusion in STEM) and James for sharing their experiences here.

Of being a trans immigrant – an uphill journey through science

by Aflah Hanafiah

As an 8^th year PhD student, my journey to climb this career ladder consisted of numerous hurdles, setbacks, and emotional and mental rollercoasters. I was lucky enough to navigate myself out of one of the most queerphobic countries in the world. The UCLA Williams Institute ranks Malaysia 115^th of 175 countries based on social acceptance. The Human Rights Watch (HRW) reported on certain Malaysian laws criminalizing same-sex sexual acts and transgender people’s gender expression and sentencing those who found guilty with jail time, fines, and whipping. These laws and the generally conservative culture that is hegemonic in the country easily subject queer people to discriminations and violence, especially towards trans femme people. I grew up learning very early on that expressing myself outside of the heteronormative traits would make my life difficult, so I learned to conform the best I could.

I spent my high school years throwing myself into schoolwork and getting my grades up so I could qualify for a government’s scholarship that would later take me to the USA where I eventually completed my bachelor’s degree in molecular biology. This opportunity allowed me to not only pursue my career goals, but it had also provided me with the space to start addressing my queer identity that I had long suppressed. During my time at Rochester Institute of Technology (RIT), I met many people, student body and faculty included, who were accepting and affirming of queer identities in general. They essentially created a safe space for people like me to feel comfortable in my own skin. However, there was still lingering stigma behind being openly queer and pursuing post-graduate education. I was reminded of this as I applied to several graduate programs. During my interviews, I pivoted strongly to presenting as the gender that appeared on my legal documents so I could avoid the possible awkwardness and questions that could arise from my queer identity.

As I went through the process and started my PhD, I felt like I was given another opportunity to further explore my queer identity now that I was in a totally new environment. This was where I started to feel comfortable to use my preferred pronouns, dressed the way that affirmed my gender identity, and explored gender affirming care. By this time, I was already 27 years old and well past my junior PhD years. My decision to undergo hormone replacement therapy (HRT) that depends on my school’s health insurance while at the same time working on my PhD was a difficult one to make. The PhD already came with its own sets of challenges, and I was unsure if I should add to this chaos by physiologically jumbling my hormonal level. However, the persistent gender dysphoria that is always occupying my mind would later drive me to embark on this next phase of my transition. I am fortunate because my student’s health insurance covers gender-affirming care, so I knew that this was an opportunity that I could not pass on.

Though I have not faced much explicit transphobia in my graduate school, which I largely attribute to me being passable enough, my other trans friends on the other hand, have a much different experience. Despite universities improving the workplace environment for queer people and other minorities; prejudice, micro- and macro-aggressions are still prevalent. I have no doubt that if I did not pass as what society deems as a woman, I would have had a very different experience going through life and specifically, working in academia. I am not “out” per se, in graduate school because it never became a question. I do make it a point that I am transgender around other queer colleagues and in queer spaces because I think that it’s important to let people know that they are not alone and that they are safe with me. As I am at the tail end of my PhD, I can’t help but be worried for my future. A slew of anti-trans laws is being passed in almost every state in the country and more companies are reportedly moving away from investing in LGBTQ+ oriented diversity, equity, and inclusion (DEI) efforts. Coupled with my F1 visa status, the career choice that is viable to me are ever narrowing. However, it is times like these that I rely on my chosen family, loved ones, and community in navigating these challenges. I believe that with a supporting community behind you, you can overcome any obstacles.

Searching for others like me: navigating academia as a trans person

By James Lythall

As a queer and trans person in STEM, I’m acutely aware of how few LGBTQIA+ people there are in STEM. There are plenty of heterosexual and/ or cisgender people who I enjoyed working and socializing with, the vast majority of whom have been very supportive. At the same time, I can count the number of queer academics I know in the field of life sciences without running out of fingers, and the number of trans academics in any scientific field on one hand. There are probably many more out there, but the number of visible, openly trans and/or queer academics is vanishingly small. Of course, representation will not solve all the problems facing queer and trans researchers, but it can help us fight the feelings of isolation that are often common amongst under-represented groups. To know that someone like you has managed to succeed, despite the odds, can both be comforting and motivating. On a more practical level, it also means there are people you can ask for advice who are familiar with the problems you may be facing and may have already found solutions to them.

I can’t help but feel that I am having to forge my own path all the time, and whilst that is sometimes exciting, it is often exhausting. There are many people who I feel I can ask for scientific guidance, but almost none who I feel comfortable asking for support on issues I face from being trans. This is not because I believe those around me to be trans- or homophobic, but simply because they are often unaware of specific problems that trans and queer researchers face.

As a researcher, I am acutely aware that my personal experience is not necessarily representative of others- an n of 1 is not much! Frustratingly, there is precious little data available on the experiences of the queer – and particularly trans – people in academia. Much of the current data focuses on the experiences of undergraduate students, often in the US, and often not stratified beyond science and humanities. Both this data and surveys conducted by scientific organizations rarely collect data on the trans status of participants, and group everyone who doesn’t identify as a woman or a man as ‘other’. Nonetheless, the little data that there is suggests that queer and trans people are often underrepresented in STEM compared to in the general population, with one US survey finding LGBTQIA+ people were ~20% less prevalent in STEM fields compared to the general population (1). The same study also reported 70% of academics felt uncomfortable being out at work. Focusing on undergraduates, another study found that LGBTQIA+ undergraduates were 9.4% less likely to remain in a STEM major (2), with this rising to 10% for trans undergraduates (3). Another study reported 45.67% of natural sciences students compared to 14.96% of social sciences students reported being misgendered (4). This is particularly alarming in the light of a new study that has found an association of higher levels of microaggressions (including misgendering) and worse mental health outcomes in trans adults in the UK (5).

Despite these gloomy statistics, I am optimistic. I do believe science is slowly becoming a more welcoming place for queer and trans people. I have had some very positive experiences and moments of connection as a trans person in STEM, and in academia. I have had lecturers who have gone above and beyond to create a welcoming teaching and learning environment for trans and queer students, as well as offering considerable personal support to me and other queer students. I have also been encouraged by the acceptance and support for trans and queer people that other students have offered, such as using and advocating for more inclusive language to challenging the heteronormative and cisnormative narratives that often pervade medical sciences. More recently when I was applying for PhDs, one potential supervisor went out of their way to ensure that only my preferred name would be used throughout the application process, and another offered to correct a colleague when they noticed they had got my pronouns wrong.

I would like to finish by suggesting a few things that I think allies can do to help improve LGBTQIA+ experiences in the academic world. Firstly, if you have teaching responsibilities alongside your research, include queer, trans and intersex people whenever possible. On a more individual level, ask and listen to what your LGBTQIA+ students and colleagues need and try to avoid making assumptions. Another important thing you can do is look into how your institution collects data on students and staff and whether this includes appropriate gender and sexuality choices, including options to not disclose. This makes institutional data much more helpful for researchers trying to understand the experiences of queer and trans people in STEM.

These are just a few suggestions, but there are numerous excellent articles out there on how to support queer and trans students and colleagues that I would encourage you to read. Equally, I would also encourage you to think about what you can do outside of the academic sphere to support LGBTQIA+ people. Visible and meaningful support for LGBTQIA+ people has never been more important, particularly in the UK where hate crime rates continue to rise and transphobic rhetoric has become increasingly commonplace in media and politics. Building a better academia also means building a better society in large.

References:

1: Freeman, J. B. (2020). Measuring and Resolving LGBTQ Disparities in STEM. Policy Insights from the Behavioral and Brain Sciences, 7(2), 141-148. doi:10.1177/2372732220943232

2: Hughes, B. E. (2018). Coming out in STEM: Factors affecting retention of sexual minority STEM students. Science Advances, 4(3), eaao6373. doi:doi:10.1126/sciadv.aao6373

3: Maloy, J., Kwapisz, M. B., & Hughes, B. E. (2022). Factors Influencing Retention of Transgender and Gender Nonconforming Students in Undergraduate STEM Majors. CBE—Life Sciences Education, 21(1), ar13. doi:10.1187/cbe.21-05-0136

4: Whitley, C.T., Nordmarken, S., Kolysh, S. and Goldstein-Kral, J. (2022), I’ve Been Misgendered So Many Times: Comparing the Experiences of Chronic Misgendering among Transgender Graduate Students in the Social and Natural Sciences. Sociol Inq, 92: 1001-1028. https://doi.org/10.1111/soin.12482

5: Wright, T., Lewis, G., Greene, T. et al. The association between microaggressions and mental health among UK trans people: a cross-sectional study. Soc Psychiatry Psychiatr Epidemiol (2024). https://doi.org/10.1007/s00127-024-02775-2

(4 votes)

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from Irene Karapidaki, Béryl Laplace-Builhé and Michalis Averof

What is this?

These are crustacean embryos injected with mRNA encoding a red fluorescent protein bound to membranes. On the left, the fluorescent protein is localised on the plasma membrane, on the right it is trapped in the endoplasmic reticulum and/or Golgi.

How was this image made?

These images were made while testing different membrane localisation tags in the marine crustacean Parhyale hawaiensis. One-cell stage embryos were injected with mRNAs encoding mScarlet3 fused to a Lyn tag, directing protein myristoylation and palmitoylation (on the left), or a signal peptide and the CD8 transmembrane domain (on the right). The embryos were allowed to grow for a day and then imaged live on a confocal microscope.

Why should people care about this?

Targeting fluorescent proteins to cell membranes allows us to visualise the shape and behaviours of cells in living embryos, as they build the body. See for example this amazing movie, showing the choreography of cells as they build sensory organs in the fish embryo: https://thenode.biologists.com/ready-steady-cooooooonga/research/

Can I do this in my favourite research organism?

The problem is that existing membrane-localising tags do not work equally well in all species. The SP-CD8 tag for example (on the right) gives good plasma membrane localisation in Drosophila, but gets stuck in the secretory pathway in our crustacean (Parhyale) embryos. In non-conventional model organisms, one needs to test several tags to find a good one.

To facilitate this process we generated a toolkit of 11 membrane-localising tags, which can be screened rapidly by microinjecting mRNA in your species of interest. Comparing results obtained in different species will help to identify tags that work well in a wide range of eukaryotes. If you are interested in trying the toolkit and joining our comparative screen, please get in touch.

Where can I find more about it?

Have a look at our preprint: https://www.biorxiv.org/content/10.1101/2024.11.12.623055v1

(2 votes)

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Hi everyone!

My name is Katie Pickup and I wanted to introduce myself as I’m a new Reviews Editor at The Company of Biologists. I am going to be working with Development and the Node, as well as with three of the Company’s other journals (Journal of Cell Science, Disease Models & Mechanisms and Journal of Experimental Biology). I’m really looking forward to being exposed to a broad range of bioscience topics in this role.

My research background is mainly in stem cell biology. I did my PhD at the MRC Human Genetics Unit at the University of Edinburgh investigating the role of DNA methylation in pluripotency and differentiation of mouse embryonic stem cells in Richard Meehan’s lab. I used 3D models of differentiation including gastruloids and embryoid bodies to understand the impact of DNA hypomethylation on cell lineage trajectories and exit from pluripotency. I’m particularly interested to see where stem cell-based embryo model research goes over the next few years, both scientifically and from the regulatory side. I’m also excited for the opportunity to branch out in my new role as an editor and learn more about other areas of developmental biology across the spectrum of model organisms.

I’m really looking forward to getting to know the wider community better through working with authors on Review articles and other front-section journal content like interviews and poster articles. I also can’t wait to travel to lots of different conferences and workshops across the world, so hopefully I’ll get to meet some of you there! In the meantime, feel free to get in touch via email, LinkedIn or X. 

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When I joined the Zon lab in June 2021, my mentor, Leonard Zon, shared an insightful piece of advice: “A good project always has two questions, one you can answer and one you dream of answering.” In this post, I’ll focus on that dream.

In brief, the question we managed to answer – at least a little bit – is how to instruct the expression of  the “eat-me” signal driven by Calreticulin (CALR) and its complementary “don’t-eat-me” signal, driven  by beta-2-microglobulin (B2M). In our study (https://www.science.org/doi/10.1126/science.adn1629) , we showed that high levels of reactive oxygen species (ROS) leads to high surface presentation of Calr, which, in turn, leads to high levels of interaction with a macrophage, and clearance of the stressed hematopoietic stem and progenitor cell (HSPC). On the flip side, TLR3 can modulate the expression of CALR together with B2M. Here, the balance between these molecules leads to a scenario where a macrophage interacts with the HSPCs, but does not “eat” them. This intricate signaling impacts clonal diversity, revealing a potential avenue for future immunotherapies targeting mutant or cancerous stem-cell populations while sparing healthy ones.

Our uncharted territory lies in harnessing macrophages to selectively target malignant clones. We found higher B2M expression in HSPCs from acute myeloid leukemia (AML) patients with malignant stratification, suggesting that malignant clones may exploit B2M to evade macrophage clearance. This paves the way for drug development aimed at eliminating pre-leukemic and leukemic cells via macrophage-mediated clearance. This idea may also be further explored in aging studies, in which one could teach the macrophage to eliminate aged progenitor cells.

Another aspect of our study that could be further explored relies on a key finding that repetitive elements (RE), including Ltr, are the endogenous ligand of the Tlr3 and triggers b2m expression via the tlr3/irf3 pathway. We observed that these endogenous REs promoted high levels of ISG15, a gene linked to the type I interferon response.

Given the evolutionary conservation of RE and B2M, we explored the significance of this mechanism in both fish and humans, focusing on pathogen infections that are a common threat to both species. Specifically, we examined the role of TLR3 signaling in inducing “emergency granulopoiesis,” a protective process that accelerates neutrophil production during severe infection. Upon poly I:C stimulation, neutrophil populations increased.

Although further studies are needed to strengthen the relevance of this phenomenon, our results suggest that viral stimulation may confer a better fit against opportunistic pathogens by promoting granulocyte differentiation. This observation gets more fascinating if one considers that this increase of type I response could not only alter the emergency granulopoiesis, but also contribute to innate immune training. Seminal studies have shown that type I IFN signaling mediates neutrophil trained innate immunity, mainly in the context of solid cancer. This therefore suggests that RE-triggered type I interferon may play a role in trained immunity—a concept previously explored in cancer but now potentially relevant in other systems.

(3 votes)

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Over the summer, I had the opportunity to conduct research in Vivian Li’s Lab, focusing on the role of WNT signalling in the response of intestinal stem cells to injury, under the expert guidance of Dr. James Wilmouth Jr. As a medical student, I am deeply appreciative of the opportunity to gain hands-on experience in fundamental research through undertaking a project over the course of two months. I am truly inspired by the continuous innovation at the Francis Crick Institute, driven by a diverse community of committed scientists who embrace collaboration and interdisciplinary approaches.

One research axis within the Li Lab focuses on how canonical WNT signalling maintains intestinal stem cells (ISCs) and influences cell fate decision. The gut epithelium can be organised into an architecture of crypts and villi (Fig 1A). Crypts are found at the base, extending into the villi towards the gut lumen. ISCs are located within the crypt and responsible for driving renewal of the gut epithelium every 3-5 days during homeostasis. High WNT signalling in the crypts maintains ISC homeostasis before decreasing along a gradient towards the villi. Publications have demonstrated that whilst inhibiting WNT signals causes degeneration, WNT overactivation induces adenoma formation. Therefore, fine-tuned WNT signalling is crucial for maintaining ISC homeostasis.

For this project, I examined the role of WNT signalling in ISCs during injury-induced regeneration. We utilized whole-body irradiation to simulate ISC injury-induced regeneration in mice. This model results in crypt degeneration at 1-day post-irradiation (dpi), followed by regeneration at 3 dpi, and recovery by 7 dpi (Fig 1B). Intestinal tissues were harvested for crypt isolation at four time points: 0 dpi (pre-irradiation control), 1 dpi, 3 dpi, and 7 dpi. These samples were then used to investigate three transcriptional signatures throughout the regenerative process: Classical Intestinal Stem Cell (ISC), Revival Stem Cell (RevSC), and WNT target genes.

I performed quantitative PCR (qPCR) to analyse the temporal changes in gene expression during the regenerative process (Fig 2). Results indicated that classic ISC markers were downregulated at 1 dpi following injury and recovered to near homeostatic levels by 7 dpi. RevSC markers showed an induction at 1 dpi, followed by a decline toward baseline levels by 7 dpi. Interestingly, WNT target gene expression remained relatively stable throughout the 7-day period.

These initial results suggest that both Yap-driven RevSC signature and certain WNT targets are expressed during injury-induced regeneration. This contradicts the current understanding, which proposed an antagonistic relationship between YAP and WNT during ISC regeneration up on injury. To further investigate the co-expression of RevSC markers and WNT in ISCs, we utilised immunohistochemistry (IHC) and flow cytometry of WNT reporter mice in the irradiation induced regeneration model (Fig 3).

To spatially characterise WNT-high cells in the crypts co-expressing the Revival Stem Cell (RevSC) signature, I conducted IHC using a TCF/Lef:H2B;mCherry reporter system. The reporter has Tcf/Lef binding sites which drive the expression of the H2B:mCherry fluorescent protein, enabling visualisation of active WNT signalling. I observed colocalisation of mCherry and Clu (RevSC marker) at 1dpi, which was more pronounced at 3dpi (Fig 3A). These results suggest that WNT-high ISCs express RevSC markers during regeneration. In order to quantify how often this happens during regeneration, I utilised flow cytometry. By gating for mCherry+ ISCs (WNT-high ISCs), I found there was a significant increase in the percentage of mCherry+ ISCs expressing the RevSC marker Sca1 at 3dpi (~20%) compared to 0 dpi (~3%) (Fig3B).

In conclusion, my project demonstrated that a proportion of WNT-high ISCs co-express RevSC markers during injury-induced regeneration. Although preliminary, these results highlight that it is necessary to further investigate the role of YAP in the interplay between WNT signalling and the RevSC signature in ISCs during regeneration. This work would provide clarity into which signals dictate ISC survival during regeneration.

This project has provided me with invaluable insight into the scientific process. I have learned advanced techniques at the Li lab, including organoid culture and maintenance. I would like to thank my supervisor, James, for his exceptional mentorship in building my critical thinking, guiding my experiments, and supporting my data analysis and interpretation. I would also like to extend my thanks to the Francis Crick Institute and the Medical Research Foundation Rosa Beddington Fund for their generous support, which has enabled me to contribute to this exciting field of research.

(2 votes)

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Brown algae are a group of complex multicellular eukaryotes, unrelated to animals, plants and fungi. It follows that brown algae evolved the process of multicellular development independently, offering a unique opportunity to investigate shared principles underlying developmental evolution across the tree of life. One such principle is the hourglass model of embryo evolution. The hourglass model describes a pattern of evolutionary conservation and divergence during embryogenesis, where the divergent earlier and later stages are bridged by a conserved mid-embryonic period (Duboule 1994). Such hourglass patterns have been observed in animal, plant and fungal development (Drost et al. 2017). But what about brown algae?

In our recent paper, “A transcriptomic hourglass in brown algae” (Lotharukpong et al. 2024), we asked a simple question: does brown algal development follow the hourglass model? By profiling the developmental transcriptome in two Fucus species, we observe an hourglass pattern in brown algal embryogenesis (Fig 1). The conserved mid-embryonic period is underpinned by the reduced expression of evolutionarily younger genes and the presence of more broadly expressed, potentially pleiotropic genes. We also explored the transcriptome across life cycle stages in brown algae with differing levels of morphological complexity. Crucially, in morphologically simple Ectocarpus species without canonical embryos, multicellular development itself appeared to constrain transcriptome evolution, suggesting how such embryo hourglass patterns may have emerged in the first place (at least in brown algae). Overall, this work gives evidence for the hourglass model as a general principle underlying developmental evolution across the tree of life.

But as we all know; a lot went on behind the paper.

Sampling and growing brown algal species:

To test the hourglass model in brown algae, we first had to literally find morphologically complex brown algae that undergo embryogenesis (Fig 2). Between France and Germany, Rémy Luthringer (co-author) had to go collect reproductively mature adults to produce embryos and cultivate them in the lab. It was a challenge to culture Fucus embryos beyond the earliest embryonic stages, since they require a lot of care to ensure healthy growth. This was all the more difficult for species such as F. distichus, which required up to half a year to reach the latest embryonic stage used in the study.

Bioinformatics in the spotlight:

We then faced several hurdles on the bioinformatics side when piecing this study together, which required a sustained push on software development. In particular, we wanted to infer the evolutionary age of each gene, which is needed for computing the transcriptome age index (a key metric for evolutionary transcriptomics). Existing approaches were not suitable nor computationally scalable to current large databases such as the National Center for Biotechnology Information (NCBI) non-redundant (nr) database and did not account for potential database contaminations among other confounding factors in gene age inference. We therefore teamed up with Josué Barrera-Redondo to create GenEra (Barrera-Redondo et al. 2023), a wrapper around the fast and sensitive pairwise sequence aligner DIAMOND v2 (Buchfink et al. 2021), which brought down the search time from months to days. This finally allowed us to infer the gene age in a timely manner for any eukaryotic genome, including the species we used in the hourglass study (Fucus serratus, Fucus distichus, Ectocarpus sp., Laminaria digitata and Saccorhiza polyschides).

On top of this, we extended the functionalities of R packages for evolutionary transcriptomics, such as myTAI (Drost et al. 2018), to accommodate our analyses. New and existing functions in myTAI enabled us to distinguish evolutionary signals from random noise. We hope these efforts will be useful for the wider community interested in asking evo-devo questions using transcriptomic data.

What’s next for the story?

It is an exciting time for brown algal research. A recent study has provided several dozen genome assemblies across major groups of brown algae (Denoeud et al. 2024). Furthermore, functional genetics is now a possibility for multiple brown algal species, fuelling recent findings such the independent evolution of HMG domain genes as a male sex-determining factor (Luthringer et al. 2024). There is also a drive to generate transcriptomic data to understand cell-type and tissue evolution in brown algae, which also evolved cell-types and tissues independently from other complex multicellular eukaryotes. There is still much more to come!

References

Barrera-Redondo J, Lotharukpong JS, Drost H-G, Coelho SM. 2023. Uncovering gene-family founder events during major evolutionary transitions in animals, plants and fungi using GenEra. Genome Biol. 24:54.

Buchfink B, Reuter K, Drost H-G. 2021. Sensitive protein alignments at tree-of-life scale using DIAMOND. Nat. Methods 18:366–368.

Denoeud F, Godfroy O, Cruaud C, Heesch S, Nehr Z, Tadrent N, Couloux A, Brillet-Guéguen L, Delage L, Mckeown D, et al. 2024. Evolutionary genomics of the emergence of brown algae as key components of coastal ecosystems. :2024.02.19.579948. Available from: https://www.biorxiv.org/content/10.1101/2024.02.19.579948v2

Drost H-G, Gabel A, Liu J, Quint M, Grosse I. 2018. myTAI: evolutionary transcriptomics with R. Bioinformatics 34:1589–1590.

Drost H-G, Janitza P, Grosse I, Quint M. 2017. Cross-kingdom comparison of the developmental hourglass. Curr. Opin. Genet. Dev. 45:69–75.

Duboule D. 1994. Temporal colinearity and the phylotypic progression: a basis for the stability of a vertebrate Bauplan and the evolution of morphologies through heterochrony. Development 1994:135–142.

Lotharukpong JS, Zheng M, Luthringer R, Liesner D, Drost H-G, Coelho SM. 2024. A transcriptomic hourglass in brown algae. Nature 635:129–135.

Luthringer R, Raphalen M, Guerra C, Colin S, Martinho C, Zheng M, Hoshino M, Badis Y, Lipinska AP, Haas FB, et al. 2024. Repeated co-option of HMG-box genes for sex determination in brown algae and animals. Science 383:eadk5466.

(3 votes)

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It’s now been 13 months since I started my lab, marking the end of my ‘New PI Diaries’ series here on the Node. The journey has so far been both overwhelming and rewarding, and I’ve enjoyed the chance to reflect and share my experiences in this blog. Overall, it’s been a lot—but mostly a good lot. My time gets split between a lot more responsibilities and I have less time to be in the lab. Both mentoring and teaching now take up much more time than during my postdoc, but luckily, I already know I enjoy both.

However, one aspect that was almost completely new to me was managing lab finances. In this blog, I want to share some examples of situations I encountered and the lessons I learned, along with a few key takeaways. To provide some context, my Independent Junior Group Leader position comes with support that includes a PhD student position, a technician, a yearly consumables budget, and some startup funds. Comparing lab resources across universities and countries is difficult. For instance, my startup budget is considerably smaller than those typically offered at US universities but potentially bigger than that available at other institutes or universities. However, I also benefit from funded positions and an equipped lab. In addition, many larger pieces of equipment and facilities are shared within the institute and can be used free of charge or at a low rate, reducing my need to purchase new equipment.

But let’s talk people first. In addition to support from the ZMBP, I was able to secure an Emmy Noether grant from the DFG. This grant covers my salary for six years, along with funding four years of two PhD students and a postdoc, allowing for steady growth and stability in the coming years. However, I quickly ran into an unexpected issue: the PhD student position from the University is paid a lower salary compared to the positions provided by the DFG. Different enough to feel unfair but unfortunately it is common. Similarly, PhD positions in different disciplines get compensated at different rates. Now, I cannot change decisions of the University or the state of Baden-Württemberg, but I figured there must be a workaround.  Once I started asking around, I learned that people have come up with a variety of solutions. Talking with fellow group leaders and our Head of Central Services I learned that we could reassign the unused % of the technician position together with some flexible lab budget to equalize the PhD salaries. So, it’s important not to hesitate in discussing challenges; I certainly wasn’t the first to face this problem, and people had already identified potential solutions.

Apart from people, we’re spending money on consumables and equipment. The ZMBP account, which includes a startup and a yearly budget, allows me flexibility in spending. Additionally, last year I received one time support from a collaborative project. This account had its own constraints, while flexible, the funds must be used within two months, adding some pressure. Finally, the Emmy Noether provides consumables funding, albeit with more limited flexibility since it is there to support the group and project and any equipment should be provided by the University. As a result, I got a crash course into which account to use for what purchase. In short: for me it’s best to save the ZMBP account for computer and equipment purchases as those cannot be made from all other accounts.

Most of the necessary equipment was actually already there, but I found several items that could significantly make our lab’s work easier and more efficient. Before purchasing these I first spent some time looking around, checking what is available already, what our need really is, and what options we have for financing the things we need.  And although I still don’t have a precise overview of our total finances, we’re in a fortunate position where I don’t have to stress excessively about money. I do feel it’s important for everyone in the lab to know the price of some of our reagents and equipment. Investing in reagents, such as 2x mixes for genotyping and colony PCR, is worth the costs right now for the time they save as long as people are aware of their cost. We’re in a good position, but I want to avoid wasting funds that could be better spent elsewhere to make our days easier. Eventually using lab funds we purchased two new stereomicroscopes to dissect Arabidopsis embryos, additional pipettes, and computers. Each piece of equipment or expensive kit is an investment that I think will pay off and that we can afford in our current situation. However, I remain careful as, well, I lack experience, and you never know what’s up ahead.

Here are my early-stage financial takeaways:

• People are expensive. Value the positions you have and hire carefully. In addition, sometimes spending more on consumables and equipment is worth the time saved for your team.
• Keep track of your accounts. Understand what’s in each account, what you can spend it on, and where your money is going. Is it what you expected?
• Use your funds. Once you have a clear overview, consider what tools could make lab operations smoother. I initially waited to determine which investments would be beneficial for everyone in the lab but then decided to make some investments.

And my personal goals:

• Have a more complete overview of the lab finances. I have a rough idea of what we’re spending and what’s available but I still have a long way to go. Luckily I have plenty of people to ask for advice.
• Get experience. While enthusiasm is important, it doesn’t replace experience. I’m learning a lot and I already feel a lot more confident in making these decisions.

While the lab’s immediate future is secure, I also need to plan for what comes next. To be honest, at this point, anytime I feel like I’m in control of things I realize I just have been forgetting or ignoring something important. I guess that’s life. In general, I think I should spend more time thinking of grants. Next year will be my final opportunity to apply for the ERC Starting Grant, so my focus will be on that. Additionally, in a few years, I’ll need to start searching for a professor position, as my ZMBP Junior Group Leader position and Emmy Noether funding will end in about five years, and securing a professorship in Germany can take some time.

Wish me luck!

First investment: new stereomicroscope for doing embryo dissection and the beautiful images it takes of GUS-stained seedlings.

(5 votes)

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