{"id":64009,"date":"2023-11-15T10:00:00","date_gmt":"2023-11-15T09:00:00","guid":{"rendered":"https:\/\/www.embl.org\/news\/?post_type=embletc&p=64009"},"modified":"2023-11-15T10:17:17","modified_gmt":"2023-11-15T09:17:17","slug":"impact-of-access-to-imaging-technologies-on-scientific-achievements","status":"publish","type":"embletc","link":"https:\/\/www.embl.org\/news\/embletc\/issue-101\/impact-of-access-to-imaging-technologies-on-scientific-achievements\/","title":{"rendered":"Impact of access to imaging technologies on scientific achievements"},"content":{"rendered":"\n

Baubak Bajoghli\u2019s interest in microscopy began at an early age and helped him keep expanding his horizons in biological research. In a career spanning both fundamental and translational research, Bajoghli has kept his passion for imaging alive and has recently taken up a role as the Director of Austrian Bioimaging\/CMI, where he works to improve access to advanced microscopy infrastructure for researchers working across the country. <\/p>\n\n\n\n

We caught up with Bajoghli about his research on cancer-linked immune cells, his key takeaways from his time at EMBL, and the importance of improving access to research infrastructures across Europe.<\/p>\n\n\n\n

What triggered the start of your journey in science?<\/strong><\/h3>\n\n\n\n

Well, my interest in microscopy began when I was 14 and I visited a medical laboratory for diagnostics for a high school project. My father bought me a microscope, and I had a lot of fun counting all types of white blood cells, including neutrophils and lymphocytes, in patients’ blood smears and comparing my results with those of the laboratory staff. One thing led to another, and my endless curiosity developed into a passion for science.<\/p>\n\n\n\n

Can you tell us about your work at EMBL, and how it has influenced your journey as a researcher?<\/strong><\/h3>\n\n\n\n

It has consistently influenced my path over the last 20 years. It began when I did an internship during my undergraduate years at Jochen Wittbrodt’s lab in the Developmental Biology Unit, where I learned about using medaka fish as a model organism and transgenesis methods. After a month, I returned to Vienna with 300 medaka eggs in my baggage and, with help from Jochen, my former supervisor, Thomas Czerny, we set up Austria’s first medaka research facility in 2002. <\/p>\n\n\n\n

After my post-doctoral fellowship at the Max-Planck Institute of Immunobiology, I became fascinated by the development of T-cells, which belong to our adaptive immune system. The process involves two migratory journeys. First, T-cell progenitors originating from the hematopoietic tissue in the bone marrow must migrate through the body and find the thymus organ. Second, within the thymus, these progenitors have to follow a precise migratory path within different microenvironments, to develop as naive T-cells before they leave the organ. <\/p>\n\n\n\n

\"Microscopy
Transgenic medaka larvae can be utilised to investigate T-cell trafficking within the thymus (marked in yellow) and throughout the entire body. Credit: Baubak Bajoghli<\/figcaption><\/figure>\n\n\n\n

At that time, our knowledge relied mostly on histological sections, and how developing T-cells sense different environments and control their migratory behaviour was less understood. Being skilled in generating transgenic medaka fish, I decided to employ live imaging of the thymus in this species, because imaging of the mouse thymus is technically not possible<\/a>.<\/p>\n\n\n\n

From my time as an intern, I knew that EMBL’s Advanced Light Microscopy Facility (ALMF) was the right place to test this feasibility. In 2012, I joined Maria Leptin’s lab as an EIPOD fellow to pursue my scientific dream and visualised the migratory behaviour of all developing T-cells within an organism using different imaging technologies. The data we generated over five years at EMBL became the foundation of many studies when I became a principal investigator (PI) at the University Hospital T\u00fcbingen. <\/p>\n\n\n\n

Can you tell us a bit more about your research on immune cells and cancer at the University Hospital T\u00fcbingen?<\/strong><\/h3>\n\n\n\n

My team focused on two different research topics. First, we continued our work on the T-cell development that began at EMBL. We extracted quantitative data from our in vivo<\/em> imaging experiments and, for the first time, developed a virtual thymus organ in collaboration with Erika Tsingos. By combining cell-based computer modelling and in vivo<\/em> manipulation of the thymic niche, we uncovered how the interaction between cell location, signals from the thymic niche, and the timing of gene expression affects the fate decision of progenitor cells in the thymus. <\/p>\n\n\n\n

\"Computer
The ‘virtual thymus’ is a cell-based computational model created to assess the impact of parameters for cell migration (top-left), cell division (top-right), and various signals from the niche (bottom) on both normal and malignant T-cell development. This model, for the first time, allows scientists to predict the results of a scenario before conducting an animal experiment. Credit: Baubak Bajoghli. <\/figcaption><\/figure>\n\n\n\n

Furthermore, we enhanced our virtual thymus model to investigate the causes of T-cell lymphoblastic leukaemia (T-ALL), which is still a long-standing mystery. Through computational simulations of over 300 scenarios, we pinpointed the minimum requirements for the clonal expansion of a single developing T-cell \u2013 a process wherein immune cells divide quickly to give rise to many clones \u2013 which we confirmed experimentally. The strategy that we have developed not only provided us with a rapid and comprehensive overview of the outcomes in all scenarios but also helped in reducing the need for animal experiments, thus implementing the principles of the 3Rs (reduce, reuse, recycle) in science. Currently, we are finalising the data analysis and preparing to draft a research manuscript outlining our findings.<\/p>\n\n\n\n

\"Microscopy
Malignant T-cell progenitor cells (green) proliferate within the thymus and also exert an impact on the growth of the thymic niche cells (blue). Credit: Baubak Bajoghli. <\/figcaption><\/figure>\n\n\n\n

The focus of the translational oncology division, where I was hosted, was to find new ways to treat congenital neutropenia, a rare blood disorder that affects patients, mostly young children, causing extremely low levels of neutrophils (a type of white blood cell) in their blood. Consequently, these patients are highly susceptible to bacterial infections, and today, their only treatment option is a daily injection of a cytokine for their entire lives, which unfortunately increases their risk of developing leukaemia by 20%. Therefore, my team strongly contributed to collaborative projects which helped to better understand the underlying mechanisms. We developed various zebrafish models for congenital neutropenia. Also, we established new patient-derived xenotransplantation models (systems where patients\u2019 samples are implanted into a model organism like zebrafish or mice) to test the effectiveness of various small molecules against the proliferation of leukemic cells.<\/p>\n\n\n\n

Your work has spanned both basic and translational aspects. Could you tell us a bit about the connections between the two and your experience working across both worlds?<\/strong><\/h3>\n\n\n\n

After 15 years of working in basic research, moving to translational research was a big transition in my scientific career. You need to adjust your mindset because, as you said, these are two different worlds. Before, I was used to asking fundamental questions about how biological processes work. When I became a PI in the translational oncology division, my main focus shifted towards developing new tools for preventing or treating diseases. <\/p>\n\n\n\n

I quickly realised that success in applied research relies heavily on a solid foundation of basic research. Even something as seemingly distant as understanding the evolution of genes can be incredibly helpful in designing new tools for fighting human diseases. <\/p>\n\n\n\n

Take the gene called ELANE<\/em>, for example. About 45% of patients with congenital neutropenia have missense mutations in this gene. When I explored the evolution of this gene and used the ENSEMBL database, I noticed that ELANE<\/em> is a product of tandem gene duplication that occurred in the mammalian lineage, and lower vertebrates don\u2019t have this gene. <\/p>\n\n\n\n

Because I knew from previous studies published by other colleagues that the development of neutrophils is evolutionarily conserved across vertebrates, I made the case to medical scientists that if fish can develop neutrophils without ELANE<\/em>, then maybe this gene isn’t as crucial for human neutrophil development as we once thought. And it turned out to be true. When they knocked out the dysfunctional ELANE<\/em> gene in induced-pluripotent stem (iPS) cells derived from patients, they were able to develop as neutrophils normally. <\/p>\n\n\n\n

Now, ongoing work at the University Hospital T\u00fcbingen is focused on establishing this as a new therapeutic approach for these patients. It’s a great example of how basic research can lead to practical solutions in the field of medicine. Unfortunately, basic research often doesn’t get the recognition it deserves from funding bodies and the public, but it needs to be properly appreciated.<\/p>\n\n\n\n

You are currently the Director of Austrian Bioimaging\/CMI. Can you tell us what motivated this transition?<\/strong><\/h3>\n\n\n\n

Again, my passion for imaging and my personal experiences as a researcher played a significant role in my decision to make a huge transition in my career path, this time from a researcher to a research infrastructure provider. When I started my own lab, my host institute had promised me access to the necessary microscopes for my fully funded thymus project. However, the reality didn’t match the promise, and I had to invest a lot of time into figuring out which institutes had the right microscopes and whether my team could use them. <\/p>\n\n\n\n

It was frustrating because we could not use the imaging facilities of other institutes due to legal policies. In the end, with Maria Leptin\u2019s support, we could fortunately use the Advanced Light Microscopy Facility (ALMF) at EMBL. For almost two years, multiple times a month, I drove 180 kilometres from T\u00fcbingen to Heidelberg in the morning, performed imaging at the ALMF, and then drove back home in the afternoon. <\/p>\n\n\n\n

It was challenging, but I was grateful because, without access to the right microscope, we could not have answered a 30-year-old question about how some species, despite using the same molecular mechanism and the same progenitor cells, develop a higher frequency<\/a> of certain T-cell sublineages compared to others. In the long term, this discovery might help in the development of new therapeutic applications, as some T-cell sublineages have antitumour functions, yet their proportion in the human body is less than 1%.<\/p>\n\n\n\n

My own experiences have made me acutely aware that many scientists have outstanding research projects but struggle to conduct experiments properly due to a lack of equipment, expertise, or resources at their host institutions. On the other hand, I understand that it’s not economically feasible for institutions to invest in every expensive instrument their employees might temporarily need. In my opinion, the most effective solution to this problem is taking advantage of pan-European consortia of research infrastructures that offer access to cutting-edge technologies for all researchers, regardless of their institutional affiliations. <\/p>\n\n\n\n

Can you tell us a bit more about Austrian BioImaging\/CMI and how consortia like these can help researchers?<\/strong><\/h3>\n\n\n\n

Austrian BioImaging\/CMI is one such consortium at the national level, consisting of eight Austrian universities and leading research institutions. We enable researchers to access over 40 imaging technologies for biological and preclinical research, and as a node, we strongly cooperate with Euro-BioImaging, which is a European Research Infrastructure Consortium (ERIC) member. <\/p>\n\n\n\n

\"\"
Baubak Bajoghli at the EMBL Imaging Centre, Heidelberg. Credit: Massimo del Prete\/EMBL<\/figcaption><\/figure>\n\n\n\n

During my 18 months in office, I’ve been committed to ensuring that researchers don’t face the same challenges I did. To me, open access to research infrastructures should be a pillar of open science in European policy. I don\u2019t tire of communicating with researchers, heads of universities and funding bodies, and Austrian policymakers to raise their awareness about the key role of state-of-the-art research infrastructures in generating knowledge breakthroughs and new discoveries, and why their sustainability is so important. I’m appears that the European Commission also recognises their importance. <\/p>\n\n\n\n

Currently, there are several Horizon Europe programs that financially support researchers\u2019 access to high-quality resources, including biological and biomedical imaging technologies. I really recommend that researchers always keep themselves well-informed so that they can make the maximum use of the available resources for their projects. Since there are numerous options available, Austrian Bioimaging\/CMI and Euro-Bioimaging also provide consulting services for researchers. <\/p>\n\n\n\n

In your opinion, how do initiatives like Euro-Bioimaging and Austrian Bioimaging influence the way biological research is done in European countries (and globally)?<\/strong><\/h3>\n\n\n\n

To strengthen our competitiveness in global research, specific attention should be given to national and European research infrastructures consortia. To me, their socio-economic impact is unquestionably high. In today’s rapidly evolving technological landscape, access to cutting-edge technologies and services is crucial for performing outstanding research. However, building and maintaining cutting-edge research infrastructures can be expensive and by sharing these costs, individual institutes and countries can reduce the financial burden, making research more economically sustainable in Europe. <\/p>\n\n\n\n

Additionally, European research infrastructure consortia such as Euro-BioImaging have the potential to act as incubators for innovation and technology transfer. In Austrian BioImaging\/CMI, 40% of our technology units consist of research groups specialising in various imaging modalities, and developing tools for biological research or medical diagnostics. <\/p>\n\n\n\n

It’s important to note that we are just one of 35 nodes within Euro-BioImaging. So, there is a huge potential for cooperation between 173 imaging facilities and research groups from 16 countries and EMBL associated with Euro-BioImaging, as well as with the private sector, to drive innovation and address future research needs. Solutions for open bioimaging data, common standards and best practices for biological and medical imaging can only be achieved at the pan-European level. <\/p>\n\n\n\n

Last but not least, research infrastructure consortia must cooperate to enhance their visibility because we can only attract top talent when we can provide access to cutting-edge research infrastructures in Europe, which in the long run, will also bring financial benefits.<\/p>\n\n\n\n

What is one piece of advice you would give to young researchers just starting their scientific journeys?<\/strong><\/h3>\n\n\n\n

Find something that is your passion and dedicate your life to it.<\/p>\n","protected":false},"excerpt":{"rendered":"

Baubak Bajoghli, Director of Austrian Bioimaging\/CMI, discusses his passion for imaging and his work straddling basic and applied research in biology.<\/p>\n","protected":false},"author":124,"featured_media":64075,"parent":0,"menu_order":0,"template":"","tags":[80,38,939,598,9986,79],"class_list":["post-64009","embletc","type-embletc","status-publish","has-post-thumbnail","hentry","tag-alumni","tag-cancer","tag-euro-bioimaging","tag-imaging","tag-immune-system","tag-microscopy"],"acf":{"featured":true,"show_featured_image":false,"field_target_display":"embl","field_article_language":{"value":"english","label":"English"},"article_intro":"

Baubak Bajoghli, who did his postdoc at EMBL Heidelberg between 2012-2017 and is currently the Director of Austrian Bioimaging\/CMI, discusses his passion for imaging and his work straddling basic and applied research in biology<\/p>\n","related_links":[{"link_description":"Alumni Relations at EMBL","link_url":"https:\/\/www.embl.org\/about\/info\/alumni\/"}],"source_article":false,"in_this_article":false,"press_contact":"None","article_translations":false,"languages":"","embletc_issue":[{"ID":63969,"post_author":"72","post_date":"2023-11-15 10:00:00","post_date_gmt":"2023-11-15 09:00:00","post_content":"","post_title":"Issue 101","post_excerpt":"","post_status":"publish","comment_status":"closed","ping_status":"closed","post_password":"","post_name":"issue-101","to_ping":"","pinged":"","post_modified":"2024-05-29 12:02:08","post_modified_gmt":"2024-05-29 10:02:08","post_content_filtered":"","post_parent":0,"guid":"https:\/\/www.embl.org\/news\/?post_type=embletc-issue&p=63969","menu_order":0,"post_type":"embletc-issue","post_mime_type":"","comment_count":"0","filter":"raw"}],"embletc_in_this_issue":[{"ID":64007,"post_author":"16","post_date":"2023-11-15 13:00:00","post_date_gmt":"2023-11-15 12:00:00","post_content":"\n

By Sara Fahs,<\/em> Associate Director, BioNTech<\/em> SE<\/em><\/p>\n\n\n\n

My curiosity about the origins of everyday things, like how medicines are made or why some cultures are extremely different from others, can be traced back to my childhood. My early years were also marked by diverse interests, including acting, interior architecture, philosophy, sociology, and understanding human connections. My journey in science has thus been remarkable, transitioning from a high school background in literature and philosophy to the natural sciences in college. My ambitions led me to a career in academia and industry, which I now reflect upon with pride.<\/p>\n\n\n\n

Towards the start of this career, my initial decision to pursue a medical career in Lebanon gradually evolved into a fascination with drug design and medicinal chemistry. I narrowed down my research interests to medicinal chemistry during my MSc in the UK. My journey took a unique turn with a PhD fellowship at EMBL, a special but challenging experience given my background in organic chemistry.<\/p>\n\n\n\n

My move to EMBL posed a multitude of new layers to adapt to, including completely new cultures; new technologies, scientific disciplines, and concepts; and working in a field where generating extensive data quickly was impossible. Despite the challenges, I learned to focus on my learning path and avoid comparisons, even when surrounded by the \"buzz of abundance\", all the while expanding my technical and theoretical knowledge.<\/p>\n\n\n\n

\"\"
Sara Fahs during her time at EMBL. Credit: Photolab\/EMBL<\/figcaption><\/figure>\n\n\n\n

During my time at EMBL, I had the privilege of working with key mentors. I was lucky to work with Maja K\u00f6hn, who introduced me to the power of interdisciplinarity. Prof. K\u00f6hn's brilliant science and leadership skills, along with her determination and ambition, inspired me to seek answers using many tools. Additionally, I was mentored by David Will, who then headed the medicinal chemistry lab at the chemical biology core facility in EMBL. David's deep intellect, wide insights, and rich experience in both academia and industry, in addition to the inspiring industry-standard MedChem Lab he helped build at EMBL, provided me with valuable insights into the bigger picture.<\/p>\n\n\n\n

In light of this \u201ccriss-cross\u201d approach to growing knowledge and skills in scientific theory, practice, and ideas, my journey was distinguished by an absence of long-term, strict, and explicit goals, but a deep appreciation for, and delight in, the short-term ones. At the same time, I kept crafting a specialisation in the field I was passionate about \u2013 medicinal chemistry.<\/p>\n\n\n\n

Why the world needs generalists<\/strong><\/h2>\n\n\n\n

Originally specialised as a chemist, I found fulfilment in embracing a generalist approach to science. I strongly believe being spontaneous and open to different subjects has expanded my creativity. While specialisation is essential, building a range of skills and knowledge areas enhances problem-solving abilities. For instance, in my career, whenever a research problem needed to be addressed via a different discipline, I would not hesitate to research that discipline and then contact the right people. <\/p>\n\n\n\n

Some problems need generalists, some problems need specialists, and we must be open to both and know when to assign which of the two for a task. This way, I think we could avoid a lot of time and resources being wasted. In fact,\u00a0in today's highly complex world, developing a palette of assorted experience across many fields is perhaps more pertinent than (hyper)specialisation. The perpetually troublesome challenges\u00a0of today (be it financial, geological, computational etc.) necessitate associating skills and expertise from various domains to promote solutions.<\/p>\n\n\n\n

Research careers in industry: myths and opportunities<\/strong><\/h2>\n\n\n\n

I joined the company BioNTech after my PhD, a move motivated not only by my desire to apply my skills in a translational medicinal chemistry role but also by the need to be quick in finding a new position. Back then, I was still on a limited visa and did not have time to find the perfect academic position (or roam the world for a gap year). I was also unsure whether I wished to remain in academia. Within a few months, I wrote my research paper, wrote my thesis, defended it, applied for jobs, all the while taking care of bureaucratic chores. Hence, I didn\u2019t have much time or mind space for the common fears that some may have about switching to industry.<\/p>\n\n\n\n

The most common fear I heard about during that time is permanent project instability. Projects in industry do change, which is sometimes sad, especially when one has developed an attachment to it. But the charming thing about changing projects is the transferability of skills and experiences into the next. And this is beneficial in the long term, as one only gets better and more efficient with time. Also, projects do not change that<\/em> fast. The lifetime of a project can be prolonged as long as its efficacy remains promising.\u00a0And this makes sense.
On the positive side, the possibility of bringing an academic flair to industry while enjoying a different setting and staying scientifically curious can really act in one\u2019s best interest. Not to mention the amount of space that regular\/flexible working hours can make so one can grow other interests and\/or work on extracurricular projects. This especially benefits me who, as a generalist, constantly needs time and energy for pursuing multiple avenues, especially in an increasingly complex and intersected world.<\/p>\n\n\n\n

I would stress, however, the challenges of finding a position that combines translational medicinal chemistry with an academic touch and emphasise the need for improved job positions and networks in this context.<\/p>\n\n\n\n

During my time at BioNTech, I have transitioned from postdoc to staff scientist, to team leader, to Associate Director in medicinal chemistry, while witnessing the company\u2019s own transition from private to public. While participating in multiple projects across departments and sites, I could see first-hand how it had to grow its own structural foundations to match its rapid growth. I am lucky to have had this medium to mature.<\/p>\n\n\n\n

Pushing the frontiers of medicinal chemistry<\/strong><\/h2>\n\n\n\n

\u201cI have been involved in multiple research projects over the last several years, which illustrate both the interdisciplinary and generalist approaches to science I like to advocate for. The first of these was a discovery project, which aimed, in the long run, to make cancer cells more sensitive to the immune system, and eventually less resistant to therapy. This discovery project grew by\u00a0imbuing a classical medicinal chemistry project with interdisciplinarity (using technologies like proteomics, sequencing, novel in vitro assays, and others). From a small local project, this grew into to a larger collaborative one, and I have found that diverse perspectives always make more impact.<\/p>\n\n\n\n

A second project aimed to make delivery of anticancer drugs and immunomodulators more specific. It involved various fields of chemistry and life sciences. Due to my experience, I could serve, in the words of a colleague, as \u201cthe glue that bound together scientists\u201d from different fields. As a \u201cscientific translator\u201d in this project, who brought together experimental biologists and computational scientists, I grew a lot, learned about many techniques, and could contribute better.<\/p>\n\n\n\n

Afterwards, I worked on lipid carrier systems for mRNA delivery in vaccines, a project that required further use of my adaptability and expanding specialisation and helped me contribute to scientific improvements. Now I am creating my own project, combining years of varied experience and knowledge as a driving force. This is very exciting, especially as it also pursues a long-standing research interest.<\/p>\n\n\n\n

Chemistry was a driver in all those projects and endeavours, and I saw chemistry being tailored to apply differently to each problem, with subfields such as peptide chemistry, small molecule chemistry, lipid chemistry, probes, dyes, etc. coming into play in various ways. It is very interesting to study the therapeutic potential of small molecules.  After all, to quote a friend, chemistry can also help \u201cmake therapeutic molecules that have never been made in the history of the universe\u201d. In the light of this, I am happy to push chemistry further in today\u2019s biotech environments.<\/p>\n\n\n\n

I have also grown people management skills in science throughout this whole journey and would love to grow them even further. It is the soft skill which most enhances meaningful conversations and learning from one another. And throughout the journey, my EMBL heritage and curiosity has helped me embrace new challenges and come up with new perspectives and ways of approaching scientific problems.<\/p>\n\n\n\n

Art, science, and beyond<\/strong><\/h2>\n\n\n\n

My passion for connecting art and science is evident in my involvement in music production, theatre, DJ'ing, writing, and science communication, even during my days at EMBL. I have always highlighted the importance of keeping my inner artist alive, as creativity can be a valuable outlet for both emotions and innovative thinking. Also, I never knew this was a \u201cpassion\u201d, until I observed my patterns and decisions retrospectively after almost fifteen years of working in science. My point is that a passion, or whatever you would like to call it, doesn\u2019t have to be pre-determined; it can be discovered, and at one\u2019s own rhythm.<\/p>\n\n\n\n

Finally, <\/strong>I would like to emphasise the importance of regular drive, courage, and perseverance in the scientific journey. I advise future scientists to reclaim their attention spans (it has been stolen from us in this world of hyper information and exposure) and advocate for diversity of backgrounds, personalities, and thinking patterns. I advise making general interest a habit when listening to a peer, instead of competition. It teaches us much more. And I believe that genuine openness to different ideas and perspectives, coupled with trusting one\u2019s process of development (background, experiences, lessons, hardship etc.) but at the same time questioning one\u2019s own narratives, is crucial for growth and success.<\/p>\n","post_title":"Advocating for a generalist approach to science and life","post_excerpt":"Sara Fahs, who did her PhD from EMBL Heidelberg and is one of the newest members of the EMBL alumni association board, writes about key insights from her journey in science and her work on medicinal chemistry, during a career spanning academia and industry.","post_status":"publish","comment_status":"closed","ping_status":"closed","post_password":"","post_name":"advocating-for-a-generalist-approach-to-science-and-life","to_ping":"","pinged":"","post_modified":"2023-11-16 10:26:34","post_modified_gmt":"2023-11-16 09:26:34","post_content_filtered":"","post_parent":0,"guid":"https:\/\/www.embl.org\/news\/?post_type=embletc&p=64007","menu_order":0,"post_type":"embletc","post_mime_type":"","comment_count":"0","filter":"raw"},{"ID":63993,"post_author":"100","post_date":"2023-11-15 10:00:00","post_date_gmt":"2023-11-15 09:00:00","post_content":"\n

A bassoon\u2019s rich timbre breaks the silence of a darkened auditorium, followed closely by flutes, violins, French horns, and a variety of percussion instruments. Singers enter the stage in costume, following precisely choreographed movements, their voices blending in perfect symphony. A spectacular operatic piece is underway.<\/p>\n\n\n\n

At the heart of this performance is a network of dynamical systems \u2013 systems that evolve over time according to precise rules. Unseen cues from the conductor and interactions between instruments and performers combine to create a magical performance that could have easily devolved into chaotic noise. And the key elements that govern this system are: time, timing, and transitions.<\/p>\n\n\n\n

The same three principles hold true for living systems, where even at a molecular level, thousands of processes happen at once \u2013 millions of tiny unseen operas. Developmental biologists in particular have long appreciated the critical importance of when things happen, at what pace, and how they correlate with the major transitional events of development.<\/p>\n\n\n\n

In living systems, there is an arrow of time \u2013 a history.  For decades, scientists have recognised the importance of this notion of time, timing, and transitions in living systems. The difference these days is that technology can now not only make this \u2018time and timing\u2019 visible by revealing oscillations and rhythms, but scientists can also manipulate and therefore study these concepts in developing organisms.<\/p>\n\n\n\n

For example, a snapshot of a living system is unable to reveal \u2018timing\u2019. Instead, one must observe the systems over a long time. Over the past 10 to 20 years, this is why EMBL and other research institutes have been investing in finding ways to make timing visible, with microscopy and other tools that help us see the rhythms and associated dynamics within cells and within organisms.<\/p>\n\n\n\n

The progress in theory, imaging technology, and techniques like microfluidics, have given scientists ways to study developing systems in a much more dynamic manner \u2013 yielding findings that could even be drivers for preventing and treating developmental diseases and disorders. However, this research is fundamental, with the central goal of gaining a clearer understanding of living systems and the varied internal and external cues that provoke changes in form, function, and behaviour. <\/p>\n\n\n\n

Where physics meets sea anemones<\/strong><\/h2>\n\n\n\n
\"Male
Soham Basu's interest in the theoretical physics related to dynamical systems has found its place in developmental biology. Credit: Ivy Kupec\/EMBL<\/figcaption><\/figure>\n\n\n\n

Dynamical systems are not new to Soham Basu, a PhD student who moved to EMBL from Kolkata, India, transitioning from studying astronomy and theoretical physics to doing hands-on experimental biology in Aissam Ikmi\u2019s research group.<\/p>\n\n\n\n

Physicists have long applied dynamical systems to studying particles, or ensembles of particles, whose states vary over time, and this was the part of theoretical physics that most captivated Basu.  <\/p>\n\n\n\n

From his undergraduate days of coding, running simulations, and debugging theoretical suppositions, Basu moved on to observing the early morphogenesis of the starlet sea anemone Nematostella vectensis<\/em> in the lab. Nematostella<\/em>, an evolutionarily ancient, simple, yet distinctive genus, doesn\u2019t exhibit signs of ageing and has regenerative capabilities. <\/p>\n\n\n\n

\"A
The mouth of a young Nematostella<\/em> larva becoming a polyp. The four projections will later form the tentacles that it would use to grab food. In blue is the endoskeleton (Collagen IV), essentially their bones to support their body structure. In orange are the nuclei that contain the genetic information. Credit: Soham Basu\/EMBL<\/figcaption><\/figure>\n\n\n\n

Nematostella<\/em> constantly expand and contract while water is pumped through their body cavity. Basu wanted to understand how the anemones\u2019 very flexible skeletons couple with surrounding tissue and how the combination dictates the organism's tube-like shape. On small time scales, such as seconds, the continuous pumping of water doesn\u2019t have much impact on Nematostella\u2019s <\/em>size, but it underlies their flexibility.  However, on a longer time scale, the anemones keep growing incrementally, while also becoming less flexible. Basu refers to this phenomenon as a \u2018bridging of the scales\u2019. <\/p>\n\n\n\n

With support from EMBL\u2019s Advanced Light Microscopy Facility team and its microscopes, Basu follows the growth trajectory of Nematostella <\/em>larvae over a 36-hour period, finding ways to zero in on specific points in the growth process and at key locations of their developing bodies and explain the incremental biophysical process that stabilises the shape of the sea anemone at each step. <\/p>\n\n\n\n

\u201cAt this point, we have a beautiful story of how interactions are happening,\u201d Basu said. \u201cAnd, in a way, I\u2019m coming full circle, now collaborating with a theoretical biophysicist, who is well known for his work in morphogenesis.\u201d<\/p>\n\n\n\n

Synchronicity and the rhythm of cells<\/strong><\/h2>\n\n\n\n

Each of us begins life as a single cell, which then divides into a mass of undifferentiated cells. Bit by bit, these undifferentiated cells get assigned functions and positions, and take these up to give rise to a specific shape per a body plan. This basic understanding is at the crux of the work of several researchers in Alexander Aulehla's research group, including Simona Gio\u00e8 and Sarkis Tafnakaji, both PhD students; and Simon Knoblich, a trainee who came to EMBL from medical school. <\/p>\n\n\n\n

\"Three
(Left to right) Simona Gio\u00e8, Simon Knoblich, and Sarkis Tafnakaji, from the Aulehla group, are particularly interested in the synchronicity of events that occur just as undifferentiated cells get assigned functions per the body plan. Credit: Kinga Lebowiecka\/EMBL<\/figcaption><\/figure>\n\n\n\n

During development, each cell needs to know what to do and when to do it in coordination with everything that is going on. Gio\u00e8, Tafnakaji, and Knoblich are studying these timing cues and the larger impact they have on an organism\u2019s development.  <\/p>\n\n\n\n

\u201cIn my research, I am looking at the timing of somite formation (the precursors to vertebrae) and trying to figure out what else is being controlled by this timing \u2013 is it just the time when things form, or does it influence the shape they will have?\u201d said Gio\u00e8, who comes to EMBL from Italy. <\/p>\n\n\n\n

Gio\u00e8 uses a technique called microfluidic entrainment to manipulate the tempo of a \u2018segmentation clock\u2019 that dictates the rate of skeletal formation in mice embryos.  Microfluidics involves the precise control and manipulation of flows with miniaturised devices. Using such a system, she periodically flushes the embryo with drugs that slow down or speed up development and then observes developmental consequences, such as changes in shape in the developing mice. In her current work, she looks specifically at signalling via the Notch pathway that not only is central to normal development but has been connected to tumour development.<\/p>\n\n\n\n

Gio\u00e8 follows skeletal development over 24 hours, taking images every 10 minutes. She then uses these images to reconstruct the time series and better understand the interconnectedness of the dynamics occurring at any given point. With this method, she is able to observe something not visible normally because it happens inside the uterus. The microfluidics bring it \u2018ex vivo\u2019 so she can capture a \u2018sweet spot\u2019 of imagery to see otherwise unknown nuances and analyse the dynamics in a manageable way.  <\/p>\n\n\n\n

Likewise, Knoblich, who comes to EMBL from Austria, is applying this same microfluidics approach to Japanese rice fish (medaka) for his research. He hopes to better understand the segmentation clock in a non-mammal vertebrate model. <\/p>\n\n\n\n

Medaka embryos usually develop in the brackish water of rice fields in Japan. While the average water temperature is 28\u00b0C, embryos can experience seasonal and daily temperature fluctuations ranging from 10\u00b0C to 35\u00b0C. Despite these drastic conditions, medaka embryonic development has been shown to be remarkably robust. Knoblich is trying to gain an understanding of the segmentation clock, which is typically set to produce a new segment or somite every 80 minutes at 27\u00b0C. This is a faster model organism than the mouse, and comes with a wide array of genetic tools that offer Knoblich a variety of options for manipulating and viewing the transparent fish embryos.<\/p>\n\n\n\n

\"A
Simon Knoblich is expanding his research to include Nothobranchius furzeri <\/em>killifish embryos that are able to enter diapause, which allows them to survive annual dry periods and environments hostile to other fish species, much like in this petri dish that contains killifish embryos for his research. He is interested in connecting his observations in medaka with the related species to gain an understanding of developmental timing in these unique species. Credit: Ivy Kupec\/EMBL<\/figcaption><\/figure>\n\n\n\n

In another project, Knoblich looks specifically at the very first stages of embryo development when medaka and other teleost (related ray-finned fish) embryos spread over their yolk in a fairly short span of time, undergoing significant morphogenetic and developmental changes. Knoblich is particularly interested in the collective calcium signalling that occurs in waves and that traverses throughout entire embryos at this stage. <\/p>\n\n\n\n

\u201cWhat I\u2019ve found interesting is the comparative nature of this research,\u201d Knoblich said. \u201cIt\u2019s why I\u2019m looking at doing similar experiments with killifish that experience diapause, a condition which suspends development and allows them to survive annual dry periods and environments hostile to other fish species. Despite being closely related to medaka, killifish go through very different early developmental stages that can span days to months (as opposed to hours in medaka), for reasons, and with biological mechanisms, not entirely understood yet.\u201d<\/p>\n\n\n\n

Tafnakaji\u2019s work also is connected to Knoblich and Gio\u00e8\u2019s research projects in that he wants to know how the dynamic signalling involved in somite formation instructs the developmental progress and subsequent differentiation.<\/p>\n\n\n\n

Tafnakaji, who grew up in Armenia and Syria and came to EMBL after R&D research at AstraZeneca in Sweden, was also inspired by the segmentation clock.  Wave-like signals across the developing tissue provide many cues for the cells. His work explores which of these cues are most relevant for the cells to synchronously and precisely form somite structures. Working with Gio\u00e8, Tafnakaji explores also how the change of timing in cellular communication can instruct the patterning of a developing embryo body. <\/p>\n\n\n\n

Understanding these aspects of cell communication helps inform basic questions like, \u2018If you have a group of identical cells, what are the different ways we might instruct them to create new, different types of tissues or structures?\u2019<\/p>\n\n\n\n

\u201cThis is curiosity-driven fundamental information that will help us later in realising our full potential in any sort of field in which cells are the building blocks, such as tissue engineering or cellular therapeutics,\u201d Tafnakaji said. \u201cThis can be foundational work for anything we want to do that is cell-based.\u201d<\/p>\n\n\n\n

Studying key transitional moments in development<\/strong><\/h2>\n\n\n\n

Just as Knoblich looks specifically at the very first stages of embryo development and the collective waves there, so do the researchers in Nicoletta Petridou\u2019s group at EMBL Heidelberg. <\/p>\n\n\n\n

The survival of the embryo is critically dependent on certain key transitions that occur early in development. Lena Schindler and Camilla Autorino, PhD students in the Petridou group, are focusing on a very short transitional window in zebrafish embryo development that may provide important clues to the biophysical interactions that shape this process. <\/p>\n\n\n\n

Schindler and Autorino are exploring the biological functions of tissue transitions in development \u2013 work inspired by Petridou\u2019s postdoc research at the Institute of Science and Technology, Austria. Petridou joined EMBL in 2020 and is originally from Cyprus. While observing the very first movement that embryonic tissue undergoes during development, she noticed a rapid transition where the tissue goes essentially from a solid to fluid state, and the cells\u2019 collective resistance to flow abruptly drops. <\/p>\n\n\n\n

\"Two
Lena Schindler and Camilla Autorino may be looking at adult zebrafish here, but their research focuses on key transitional moments in zebrafish embryonic development in EMBL's Petridou group. Credit: Stuart Ingham\/EMBL<\/figcaption><\/figure>\n\n\n\n

The scientists describe this as a fluid state because the material state is measured based on its viscosity. Initially, when pipetted, the tissue shows high resistance and doesn't quite \"flow\" up the pipette (like honey). Once the transition has happened, it is much more deformable and moves up the pipette quickly (more like water). Later, it changes back to a less deformable state.<\/p>\n\n\n\n

Petridou\u2019s work brought her in contact with Bernat Corominas-Murtra, a physicist at the University of Graz, Austria, who was also studying phase transitions, albeit not in biological systems. Petridou applied a mathematical framework from 1864 that used the concept of networks to understand real material properties of embryonic tissues. This subsequently helped shape her research direction.<\/p>\n\n\n\n

\u201cImagine an iron bridge composed of lots of bars. You don\u2019t have to remove all the bars for the bridge to collapse; it may only require a few bars being removed,\u201d Petridou explained. \u201cSo, then, instead imagine this breach is happening in a network of cells and links between cells. As links are removed, the whole network becomes unstable, vulnerable to breaking.\u201d<\/p>\n\n\n\n

Petridou soon found that the minimum number of connections required to break a network, as predicted in the mathematical theory from 1864, matched what she found to be true in tissues as well. And rather than activity just within <\/em>the cell, a cell\u2019s connections to other cells determined the key solid-to-fluid transition of the tissue. <\/p>\n\n\n\n

This approach has informed a lot of the Petridou group\u2019s work on critical transitional moments in embryo development, where tiny cellular manipulations can have a tissue-scale effect, simply by disrupting the synchronicity between biological processes. As connections between cells change, transitions occur because collective tissue properties are changing too. The group is still investigating if and how cells respond to their environment and its changes.<\/p>\n\n\n\n

\u201cI think this is what is so interesting;  you don't have a steady state,\u201d said Autorino, who joined Petridou\u2019s group in 2020 and is originally from Italy. \u201cThe system keeps changing. In 10, 15, or 20 minutes, you create a new normal. And then it changes again.\u201d <\/p>\n\n\n\n

In that 10-minute period when zebrafish embryos are just beginning to set up their body plan, the tissue of the future embryo spreads and starts to cover the yolk while the yolk \u2018domes\u2019 upward into it to assist the process, as seen in the video here.  Schindler, who came to EMBL from Austria, wants to better understand how cells work together to form tissues, and uses this key transition to understand how the synchronisation between cell divisions in the embryo (or lack thereof) can help regulate this process. <\/p>\n\n\n\n