Exceptional teamwork, exceptional results. In the margin of a PLoS Biology article

The image of the lone, isolated scientist may never have been true, but it certainly isn't today. It was no joke that Peter W. Higgs, the discoverer of the Higgs boson, who won the Nobel Prize in 2013 for his 1964 theory, said that if he were a scientist today, he would not have a professorship because he published so little. No publications mean no funding and no money means no research. And without teamwork, it is almost impossible to achieve results.

Gábor Nyiri's research team uses several techniques to discover which cells and processes are involved in learning and memory. And to better understand the communication network between cells, they are also building neuroscientific computer models, led by Szabolcs Káli. Based on the results published in 2019 by the Nyiri lab, the importance of hippocampal interneurons expressing somatostatin in learning and memory processes is enormous, and it seemed appropriate to better understand these cells. The group has therefore undertaken to study these cells as part of the European Union Human Brain Project, which started in 2019. 

Such accurate neuronal models, which can be used to study the role of the hippocampus in learning and memory processes realistically, have never been created before, so the work published in PLoS Biology is exceptional. It is also not common because of the collaboration that made it possible, so there is nothing special about the fact that the paper has five first authors, all outstanding in their contribution to the result. Named Virág Takács and Zsuzsanna Bardóczi postdocs, Luca Tar and Áron Orosz PhD students, and Ábel Major student research student.

Ábel joined the research group in 2017 as a first-year pharmacy student and together with Zsuzsi he immersed himself in the mysteries of the then-arrived Scanning Electron Microscope (SEM). Virág joined Zsuzsi and Ábel at this stage as an experienced anatomist. Áron joined in November 2018 and immediately started working on this project. The team will be joined by Szabolcs Káli and his PhD student Luca Tar, who will arrive at the end of 2022 at the latest, and who were asked for help by the topic leader Gábor Nyiri. 

- How long did it take for this huge work to be submitted and accepted?

Virág: It would be impossible to say, as everyone works on several projects in parallel and it varies which one is the focus at any given time. However, during the coronavirus epidemic, this was the main focus of everyone involved. Zsuzsi and I alternatively went to the scanning electron microscope to take serial pictures of the dendrites, which we all enthusiastically drew at home.

Áron: As a student, I did pretty much this in my first year, then I got involved in other projects, and again during COVID several assignments could be done at home. And once the quarantine was over, it was continuous work with it until the handover. Weekly in the beginning and daily in the run-up.

Ábel: I spent as much time as possible doing this while I was working on my TDK alongside the university. I was driven by curiosity and often worked on the project on weekends and late at night.

Zsuzsi: It involved a lot of electron microscope work. There were times when I worked on it full-time. 

Luca: Gábor approached me to complement his detailed anatomical work with modeling, demonstrating the importance and usefulness of anatomical work. With Szabolcs, we figured out how to put a biophysically simplified model under the data to show, for the two cell types studied (HS and OLM cells), the consequences for signal propagation of differences in their dendritic diameters and synaptic envelopes. I spent lots of time on my task until the paper was submitted. When we got the response from the reviewers the major extensions were requested primarily from me because they wanted to see detailed active models in addition to the biophysically simplified models. I spent the time available for revision almost exclusively on this. Much to my delight, I managed to finish what I needed to do on time.

- How did who contribute to the writing of this article? 

Virág, is the first of the first authors. She was responsible for the modeling parts, while I was responsible for the anatomical results. Áron extracted the 3d data from the models, he did the many supplementary tables and Figure 2. Ábel was mainly involved in the early setup, building, and formatting of the database and writing the material and methodology.

- Is there anything in this joint work that you think is most attributable to you?

Virág: Since I have previously investigated the synaptic properties of HS cells under the guidance of Attila Gulyás, we adopted several methodological techniques from our previous work. One of them was how to label their entire dendrite file and their local axonal file.  We could not selectively label OLM cells then, but this is now possible in the α2-nicotinic receptor-Cre transgenic mouse strain. Examining the axons was not originally part of our plan, but when I saw how well they were plated and could be labeled in HS cells, I suggested using them in the analysis, too. I should add, however, that none of the discoveries should be attributed to a single author, as everyone was involved in some step that led to the discovery!

Áron: I can only agree with that! I think the biggest achievement was the creation of the whole workflow. That's what makes the study unique. We were all individually involved in creating parts of the workflow.

Zsuzsi: But in the end, the developers, working closely with us, created a version that works well and is easy to use. I also played a major role in the electron microscope sample preparation.

Ábel: I was actively involved in the electron microscope work. I even visited the manufacturer's pilot plant. I am proud that one of my electron microscope images taken during the optimization process was so well received by the manufacturer that it is now featured on the scanning electron microscope website and in their presentation material! 

- What was your most memorable experience of this job?

Áron: This was my first project, which I started as a student. Despite being a beginner, there were parts from the very beginning where I was given full responsibility. This is very surprising for a student.

Zsuzsi: The fact that it was a real team effort is best exemplified during COVID-19 when the whole group was working on the dendrites. 

Ábel: Immediately after high school I got involved in the research team and had to learn lots of new things, techniques, and procedures. I was afraid, that the more experienced researchers would quickly get over the work and finish the task. It was a great pleasure to participate as an equal partner in the research soon, as there were many technological unknowns and novelties for them too. There was room for my ideas, too and I could do my daily work in an inspiring environment, working with colleagues towards a common goal. I will always remember this attitude and atmosphere.

Virág: If you look at the figures, I think you can understand how much fun it was to see such beautiful microscopic images, to draw the cells, to scroll through the beautifully preserved electron microscope sections, and finally to see the dendrites/axons with their synapses and mitochondria in 3 dimensions. 

- What did you think about all five of you becoming shared first authors?

Virág: I was delighted because the project required extensive expertise, years of experience, and long years of persistent work.  By drawing on everyone's experience, an article can be completed much faster. 

Áron: This is the first first-authored article for several of us, and I am satisfied with this way of authorship.

Zsuzsi: the 5 first authors also show that the article was built up from several parts, and all five of us contributed a great deal of work to these, which finally came together as a big whole. 

Ábel: It may seem strange to see so many first authors, but my years at KOKI have taught me that good and useful results can only be achieved in a team! 

Luca: At the beginning, I was supposed to be a co-author and was the last one to be one of the first authors. However, Gábor felt that the active model, which I helped to create alongside the passive model, was such a significant contribution that he said I should be a first author. This was a huge recognition for me and I was happy about it very much.

- This article is published in a flagship journal, and you are among the first authors! What could be the next step in your career?

Ábel: With this topic, I have successfully participated in several TDK and OTDK conferences, and won several National Scholarships for Higher Education, and New National Excellence Programme (NNEP) grants. I hope it will help me in my PhD studies! 

Áron: This is my first (co-) first-authored paper, which certainly played a role in my winning the New National Excellence in Research (NAP) and the NAP 3.0 travel grant last year, and thus being able to present our work in poster form at the IBRO World Congress last fall. 

Luca: It counts as one of the required publications in the doctoral school and I can use it to support a thesis in my dissertation, so it is a huge help for me in my PhD studies.

Zsuzsi: At the moment, I have neither a degree nor a proposal in the pipeline to use it for, but the experience gained and the methods set up will facilitate the implementation of future projects. 

When asked about the real significance of the work that has just been published, not surprisingly, everyone gave very similar answers, so at Virág's suggestion I will only quote the answers of Áron and Luca the modeler:

Áron: Hippocampal interneurons are being worked on by many research groups in many places. We investigated and compared two of them. The workflow we created allowed us to compare the two cell types morphologically with unprecedented accuracy. It is the most significant thing.

Luca: From my point of view, therefore, what I consider the most significant is that this work is an excellent demonstration of the importance of detailed anatomy, of the fact that without knowledge of synaptic covering, we cannot build models that describe reality well. And such anatomical differences can/have functional consequences that cannot be explained in any other way. I wish many more like it would follow!

- Is this how you imagined a research career?

Ábel: In high school, I was interested in science, I liked to do experiments, but I didn't know how research worked. I had no expectations. When I became a TDK student at KOKI, I looked forward to going to the lab every day after university with great enthusiasm. Few of my fellow TDK students in other groups could do meaningful work on an exciting, important project and put their ideas into practice. If you utilize the opportunities provided by the KOKI, you can become an internationally recognized, successful, and credible researcher.

Áron: This is not how I imagined the concrete workflow. However, the fact that we were constantly using/finding new tools to solve a problem did not surprise me.

Zsuzsi: I think this project reflected the characteristics of a research career. There were challenges and tasks to be solved, and once we had the right method, the persistent and monotonous work played a significant role.

Luca: I didn't think I would become a researcher, so I didn't imagine anything. But I would be no different!

Virág: When I was in high school, I didn't want to be a lab researcher because I thought sitting in front of a microscope all day was boring. Now I'm sitting in front of a microscope all day, and I can find it exciting even if that one cell type has more synapses and mitochondria than another.