{"id":63997,"date":"2023-11-15T10:00:00","date_gmt":"2023-11-15T09:00:00","guid":{"rendered":"https:\/\/www.embl.org\/news\/?post_type=embletc&p=63997"},"modified":"2023-11-21T15:01:40","modified_gmt":"2023-11-21T14:01:40","slug":"the-secret-of-molecular-promiscuity","status":"publish","type":"embletc","link":"https:\/\/www.embl.org\/news\/embletc\/issue-101\/the-secret-of-molecular-promiscuity\/","title":{"rendered":"The secret of molecular promiscuity"},"content":{"rendered":"\n

How do cells eat? This question lies at the focus of research undertaken by the L\u00f6w Group<\/a> at EMBL Hamburg<\/a> and Centre for Structural Systems Biology (CSSB)<\/a>. Using structural biology methods, they explore how \u2018promiscuous\u2019 proteins enable cells to absorb nutrients, and how this could be used to make drug uptake more efficient in the future.<\/p>\n\n\n\n

Promiscuity has more to do with nutrition than you think<\/strong><\/h2>\n\n\n\n

To survive, living cells absorb nutrients from their environment. Their menu includes various delicacies, such as sugars, fats, and peptides, which are tiny pieces of digested proteins that cells use to build their own proteins. To capture and pull these nutrients inside, cells use dedicated transporter molecules that sit in the cell membrane.<\/p>\n\n\n\n

Many molecular transporters are highly specialised, e.g. they only transport one type of sugar. But it\u2019s different for peptides \u2013 and that\u2019s where promiscuity comes into play.<\/p>\n\n\n\n

Peptide transporters known as POTs (proton-coupled oligopeptide transporters) are not picky at all. In fact, they\u2019ll grab almost any peptide they find in their way, regardless of its composition and shape. This ability is described by structural biologists as \u2018promiscuity\u2019.<\/p>\n\n\n\n

\u201cHow promiscuity works has been one of the main questions in structural biology,\u201d said Christian L\u00f6w, Group Leader at EMBL Hamburg<\/a> and Centre for Structural Systems Biology (CSSB)<\/a>. \u201cPOTs are especially fascinating, because they are much more promiscuous than most other transporters. You could compare them to a lock that can be opened by many different keys. I wanted to learn how this works.\u201d<\/p>\n\n\n\n

The L\u00f6w Group are experts in structural biology of membrane proteins, in particular promiscuous nutrient transporters. Their work on different POTs, ranging from those in bacteria to those in humans, has yielded many insights that may help solve the mystery.<\/p>\n\n\n\n

A vehicle that wraps itself around the passenger<\/strong><\/h2>\n\n\n\n

The L\u00f6w Group explored this further in their recent work in collaboration with the Marquez Team<\/a> at EMBL Grenoble and the Steyaert Lab<\/a> at the Vrije Universiteit Brussel. They determined and compared the X-ray structures of a bacterial POT called DtpB while it was bound to 14 dietary peptides<\/a> of different sizes, shapes, and chemical properties. They were surprised to see that during the transport, DtpB undergoes major structural changes to adapt itself to each peptide, while the structure of the peptides themselves remains largely unchanged.<\/p>\n\n\n\n

\u201cYou could compare it to a vehicle that wraps itself around the passenger to transport them. In the world of molecular biology, this is very counterintuitive,\u201d said L\u00f6w.<\/p>\n\n\n\n

Further experiments brought more surprises as they showed that the peptides that most strongly bind to DtpB are poorly transported. The peptides transported most efficiently were actually the ones with moderate binding strength.<\/p>\n\n\n\n

\u201cStrong binding is like superglue that gets the peptides stuck inside DtpB and block the passage for other peptides,\u201d said Katharina Jungnickel, postdoc in the L\u00f6w Group.<\/p>\n\n\n\n

This pattern most likely also applies to POTs in humans and other species, such as those that transport dietary peptides from the gut into the bloodstream \u2013 which the L\u00f6w Group studied as well<\/a>. In fact, the scientists expect that \u2018moderate binders are best\u2019 could be a more general feature of promiscuous transporters across organisms.<\/p>\n\n\n\n

POTs can be found in different organisms and cell types. For example, in the human gut, the POT called Peptide Transporter 1 (PepT1) enables the uptake of dietary peptides as well as many drugs, including antibiotics and antivirals. The structure of PepT1 in the image is based on the PDB entries: 7PMW<\/a>, 7PMX<\/a>, 7PMY<\/a> and 7PN1<\/a>. Credit: Isabel Romero Calvo\/EMBL<\/figcaption><\/figure>\n\n\n\n

Promiscuity informs drug design<\/strong><\/h2>\n\n\n\n

Understanding POTs\u2019 promiscuity may be key for improving drug design.<\/p>\n\n\n\n

POTs transport many peptide-like drugs. For example, in the human gut, POTs are responsible for the uptake of various drug molecules, e.g. some drugs for hypertension, while in bacteria, they may serve as an entry point for certain antibiotics.<\/p>\n\n\n\n

However, this transport is often inefficient, so high drug doses are needed. This in turn may cause more side effects. Many potentially effective drugs might not even get transported to the right places in the body. This is one among several reasons why drugs fail in clinical trials.<\/p>\n\n\n\n

\u201cIf we could predict which drugs will be transported at early stages of drug development, this would save a lot of time and money,\u201d said Vadim Kotov, former postdoc in the L\u00f6w Group, now working in industry. \u201cThat\u2019s why we tried to crack the code that determines which peptides gets transported.\u201d<\/p>\n\n\n\n

To pursue this, the scientists combined experiments with machine learning. To their surprise, the analysis revealed that DtpB is much less promiscuous than thought before \u2013 out of the 8400 possible di- and tripeptides, it is likely to bind only a few hundred. They also identified a few factors, such as peptide size, charge and chemical properties, that are key for peptide recognition.<\/p>\n\n\n\n

Using this information, the scientists have built a bioinformatics pipeline that could be used for other POTs to predict which peptides might potentially get transported and which definitely not. Eventually, this could help the pharmaceutical industry exclude poorly absorbed drugs at earlier stages of drug development. However, for more precise predictions, more research is necessary.<\/p>\n\n\n\n

\u201cIt\u2019s still a mystery what exactly the peptides need in order to be transported,\u201d said Jungnickel. \u201cAlthough it\u2019s a relatively simple system, it\u2019s harder to figure out than we thought.\u201d<\/p>\n\n\n\n

\u201cArguably, an even larger dataset would be necessary to train next-generation predictive models,\u201d added Kotov.<\/p>\n\n\n\n

A 2-in-1 molecule<\/strong><\/h2>\n\n\n\n

Another recent study by the L\u00f6w Group in collaboration with colleagues from Boehringer Ingelheim dives into the function of another POT, called PHT1 (peptide\/histidine transporter 1). It is found in the membrane of lysosomes, cell organelles involved in \u2018digesting\u2019 defective and worn-out cellular components, among other functions. PHT1 is quite peculiar because besides transporting peptides, it can also detect signals and trigger molecular reactions inside the cell. Proteins with this ability are called receptors.<\/p>\n\n\n\n

\u201cWe never expected that PHT1 could function as a receptor,\u201d said T\u00e2nia Cust\u00f3dio, postdoc in the L\u00f6w Group. \u201cPOTs are predicted to have similar transport mechanisms and having a dual transport-receptor function was unheard of. I was really curious to understand the function of this peptide transporter in our immune system.\u201d<\/p>\n\n\n\n

While PHT1 is important for our immunity, overactivity of its receptor function may lead to autoimmune diseases, such as systemic lupus erythematosus, as well as to inflammatory bowel diseases and type 2 diabetes. Blocking PHT1 receptor function might, therefore, help treat systemic lupus erythematosus.<\/p>\n\n\n\n

Designing such blocker molecules requires knowing the detailed structure of PHT1. To enable this, the L\u00f6w Group determined the molecular structure of PHT1 and mapped its interaction surface with another protein that helps PHT1 to trigger the molecular response to signals.<\/p>\n\n\n\n

This model can serve as a guide for other researchers to develop molecules that would either block peptide transport or the receptor function of PHT1.<\/p>\n\n\n\n

<\/a>\u201cTen years of POT research at EMBL \u2013 from bacteria to humans and back \u2013 during which we obtained fantastic molecular insights into the structure and mechanisms of this important transporter family,\u201d said L\u00f6w. \u201cThe research opens up new avenues in academic settings and pharmaceutical industry. Our findings can be used to modify existing and future drugs for improved uptake or to develop small molecules to inhibit the PHT1\u2019s receptor function. The future looks bright for transporter research.\u201d<\/p>\n","protected":false},"excerpt":{"rendered":"

Promiscuity is critical for nourishment. How? This question lies at the focus of research by the L\u00f6w Group at EMBL Hamburg. Using structural biology methods, they explore how specialised molecules located in the cell membrane allow cells absorb nutrients from their environment.<\/p>\n","protected":false},"author":96,"featured_media":64035,"parent":0,"menu_order":0,"template":"","tags":[775,981,579,53,461,601,616,5752,35],"class_list":["post-63997","embletc","type-embletc","status-publish","has-post-thumbnail","hentry","tag-cssb","tag-drug","tag-gut","tag-hamburg","tag-low","tag-nutrition","tag-protein","tag-protein-structure","tag-structural-biology"],"acf":{"featured":true,"show_featured_image":false,"field_target_display":"embl","field_article_language":{"value":"english","label":"English"},"article_intro":"

The L\u00f6w Group at EMBL Hamburg explores the structures of promiscuous molecules critical for nourishment and drug absorption<\/p>\n","related_links":[{"link_description":"Structure of a promiscuous protein will help scientists design better drugs ","link_url":"https:\/\/www.embl.org\/news\/science\/structure-of-promiscuous-protein-will-help-scientists-design-better-drugs\/"}],"source_article":[{"publication_title":"Plasticity of the binding pocket in peptide transporters underpins promiscuous substrate recognition.","publication_link":{"title":"","url":"https:\/\/www.cell.com\/cell-reports\/fulltext\/S2211-1247(23)00842-2 ","target":""},"publication_authors":"Kotov V., Killer M., Jungnickel K. E. J., Lei J., et al. ","publication_source":"Cell Reports","publication_date":"18 July 2023","publication_doi":"10.1016\/j.celrep.2023.112831 "},{"publication_title":"Molecular basis of TASL recruitment by the peptide\/histidine transporter 1, PHT1.","publication_link":{"title":"","url":"https:\/\/www.nature.com\/articles\/s41467-023-41420-5 ","target":""},"publication_authors":"Cust\u00f3dio, T.F., Killer, M., Yu, D. et al. ","publication_source":"Nature Communications","publication_date":"14 September 2023","publication_doi":"10.1038\/s41467-023-41420-5"}],"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":64001,"post_author":"77","post_date":"2023-11-15 10:00:00","post_date_gmt":"2023-11-15 09:00:00","post_content":"\n

In a world inundated with data, curating valuable information has never been more challenging, or more important. From academic papers to scientific databases, the deluge of new information can be overwhelming, leaving researchers in a constant struggle to keep up. However, a groundbreaking innovation in artificial intelligence is helping to transform the data curation landscape: large language models (LLMs) such as those behind ChatGPT. Powered by sophisticated deep-learning algorithms, these models are revolutionising how we streamline and curate massive volumes of data.<\/p>\n\n\n\n

Here we look at some of the ways researchers at EMBL\u2019s European Bioinformatics Institute (EMBL-EBI) are taking advantage of LLMs to aid their data curation processes. From automating the summary and annotation of academic papers to assisting with ontology mapping, LLMs are not just aiding human curators but also have the potential to enhance the quality of the data EMBL-EBI provides to its users. <\/p>\n\n\n\n\n\n

Transforming data curation <\/strong><\/h2>\n\n\n\n

Academic papers are currently being published at an unprecedented pace, and the challenge of pulling out relevant information has never been greater. Andrew Green, ARISE Fellow at EMBL-EBI<\/a> has been using LLMs to streamline the data curation for EMBL-EBI\u2019s database for non-coding RNAs, RNAcentral<\/a>. <\/p>\n\n\n\n

To do this, Green has successfully developed a tool to scrape scientific articles that mention specific RNA identifiers. These sentences are then fed into GPT-3.5, which generates concise, coherent summaries about the RNA of interest. These summaries describe key details such as the RNA's functions, its involvement in diseases, and the organisms in which it has been studied.<\/p>\n\n\n\n

\"One of the intriguing features of using LLMs is the accuracy and contextual understanding they bring into the summarisation process,\" said Green. \"We've seen the model accurately decipher acronyms in a given context and even self-correct its errors when asked to fact-check its summaries.\"<\/p>\n\n\n\n

To ensure the summaries generated are robust, they go through multiple rounds of validation, and are then rated for quality before appearing in the RNAcentral database. The summaries serve as quick references for scientists to better understand a particular RNA, and also include clickable citations to the original articles on Europe PMC<\/a>.<\/p>\n\n\n\n

\"It's crucial to remember that LLMs don't inherently know the difference between what's real and what's fabricated,\u201d added Green. \u201cIn the scientific community, where factual accuracy is paramount, this could be a major concern. Models can sometimes 'hallucinate' details that aren't in the original text. To mitigate this, we have put multiple validation rounds in place. This, combined with constant human oversight, ensures that the information presented is both accurate and reliable.\"<\/p>\n\n\n\n

At the heart of this approach is an automated method for extracting and summarising valuable information from a multitude of academic articles. This means that this work can also be applied to many other EMBL-EBI resources. Once fully developed and implemented, this automated process for curation serves to aid the work of many of EMBL-EBI\u2019s curators, acting as a first filter in the lengthy process of data collection and interpretation. <\/p>\n\n\n\n

Accelerating annotation <\/strong><\/h2>\n\n\n\n

Another aspect of the EMBL-EBI database pipelines that can benefit from LLMs is data annotation. Melanie Vollmar is an ARISE Fellow at EMBL-EBI<\/a> with a strong background in structural biology and a growing expertise in machine learning. As part of her fellowship, she is looking at how to fully automate the extraction of functional information about proteins from academic papers using LLMs. <\/p>\n\n\n\n

Her project focuses on gathering structural information from the Protein Data Bank in Europe (PDBe) and supplementing it with related academic publications from Europe PMC. This curated information is then mined for specific functional details, which are mapped back onto the protein sequences listed in UniProt<\/a>. <\/p>\n\n\n\n

Until now, curating literature for functional annotations followed a purely manual approach supplemented by traditional text mining methods. LLMs, designed to grasp the intricacies of human language, can parse through vast amounts of scientific literature, weigh contrasting opinions, and generate complex text-based outputs. <\/p>\n\n\n\n

This capability can bring in a new era of data enrichment, as these models help to extract more detailed and contextually rich information from existing biological literature at an accelerated pace. At no point is such a model intended to replace the human biocurator who is required to provide a critical view on the produced output.<\/p>\n\n\n\n

\u201cWith automation, not only do we increase the pace at which we can annotate data, but we also enrich the quality of that data, offering a more comprehensive resource for our users,\u201d said Vollmar. \u201cOur focus now is on protein structures, but the beauty of our approach is its adaptability: the methods we're developing could easily be transplanted onto other types of biological data, elevating the annotation process across the board.\"<\/p>\n\n\n\n

Fine-tuning existing LLMs <\/strong><\/h2>\n\n\n\n

Europe PMC is EMBL-EBI\u2019s home of scientific literature, and after many years of serving the scientific community, the resource remains an intuitive and powerful search tool to help users stay on the cutting edge of science. Many of the database's functionalities rely on literature curation, which involves scanning through dense academic material to extract essential information. <\/p>\n\n\n\n

Santosh Tirunagari, Senior Machine Learning Developer<\/a> at EMBL-EBI is leveraging the capabilities of LLMs to accelerate the curation of scientific literature within Europe PMC. He and others in the team have developed specialised named entity recognition models, which are fine-tuned versions of existing LLMs. These sophisticated tools are designed to automatically identify critical scientific entities such as genes, proteins, diseases, and chemicals in research papers and patents.<\/p>\n\n\n\n

Using this approach helps to side-step the high computational costs of developing a language model from scratch, which could require dozens of GPUs and extensive training time. By concentrating on the fine-tuning phase, Tirunagari has been able to adapt these powerful language models to specific tasks relevant to scientific curation. This maximises efficiency while achieving high levels of accuracy.<\/p>\n\n\n\n

In one of his models, Tirunagari also uses an innovative \u2018human-in-the-loop' methodology for model training. Beginning with a limited dataset, the fine-tuned models undergo further adjustments using additional scientific papers. Human curators then verify the model's findings, enabling an iterative feedback loop that continually improves the model\u2019s accuracy.<\/p>\n\n\n\n

\"Large language models have been a game-changer in our efforts to automate the complex task of scientific curation. By fine-tuning these models, we've been able to develop highly specialised tools that can sift through vast amounts of scientific literature and patents to identify key entities such as genes, organisms, proteins, and diseases with impressive accuracy,\u201d said Tirunagari. \u201cThis not only accelerates our work but also opens up new possibilities for collaborations, like our ongoing partnership with Open Targets to use these models to aid drug discovery.\"<\/p>\n\n\n\n

A novel approach to ontology mapping <\/strong><\/h2>\n\n\n\n

Ontologies are structured, hierarchical classifications that are widely used for standardising diseases. Current practices for ontology mapping rely heavily on manual curation, making it a time-consuming and error-prone task. To address these issues, Kirill Tsukanov, Senior Bioinformatician at EMBL-EBI<\/a>, has developed a new method for ontology mapping using openly-available, GPT-based language models. <\/p>\n\n\n\n\n\n

The new method integrates EMBL-EBI\u2019s Ontology Lookup Service (OLS)<\/a> with GPT-3.5 to evaluate the relevancy of ontology terms provided by OLS. Rather than generating ontology identifiers from scratch, the GPT model is tasked with grading existing mappings. This new workflow enables the system to map about 20% more terms compared to existing methods while retaining the same accuracy.<\/p>\n\n\n\n

\"Our prototype already shows immense promise,\u201d said Tsukanov. \u201cThe integration of GPT models helps us overcome the limitations of existing systems, increasing the speed of ontology mapping. The application of LLMs in our research is not just innovative; it's transformative. These models are helping us bridge the gap between raw, unstructured information and actionable, standardised data.\"<\/p>\n\n\n\n

\"While LLMs like GPT-3.5 have proven to be invaluable in tasks like ontology mapping, they present an intriguing challenge,\u201d continues Tsukanov. \u201cThese models don't inherently know the difference between fact and fiction. Recognising this, we've been careful to integrate additional layers of validation and are exploring the use of open-source, stable models that can be fine-tuned specifically for our ontological needs. The goal is to have a tool that not only understands human language but aligns that understanding with the precise, standardised terms in our ontologies.\"<\/p>\n\n\n\n

The project is currently in its developmental phase but Tsukanov plans to test the stability of other LLMs to further improve this new system. The ultimate goal is to create a universally applicable library, serving as a foundation for ontology mapping for different EMBL-EBI initiatives.<\/p>\n\n\n\n

Large language models: a catalyst for change<\/strong><\/h2>\n\n\n\n

The advent of LLMs such as GPT represents a pivotal moment not only in the field of artificial intelligence but also in how we handle, curate, and understand enormous volumes of data. The success stories above show that, while not without their challenges, LLMs hold immense promise for making our data-rich world more understandable, accessible, and usable.<\/p>\n\n\n\n

There are obstacles to overcome, one of the foremost concerns is data integrity and trustworthiness: as LLMs are trained on massive datasets, there's a risk of perpetuating inaccuracies or biases present in the source data. This is particularly critical in scientific applications where incorrect or biased information could have far-reaching implications. Additionally, the automated nature of LLMs could lead to unintended consequences, such as the omission of nuanced insights that human experts might catch, thereby impacting the quality and reliability of curated data. <\/p>\n\n\n\n

Given these complexities, it's crucial to integrate ethical considerations into the design, implementation, and ongoing management of LLMs in scientific data curation.To address these challenges, our researchers discuss how they have implemented multi-layered verification frameworks for data curated by LLMs. Regular updates to the LLMs themselves, coupled with continuous feedback loops with human curators, allow for ongoing refinement of the models, reducing the likelihood of errors over time.<\/p>\n\n\n\n

As LLMs become an increasingly integral part of scientific research, vigilance in maintaining data quality remains a top priority. As the technology matures and as we get better at integrating human expertise with machine capabilities, these challenges are likely to diminish. Ultimately, LLMs have the potential to act as powerful catalysts in the evolution of data curation and scientific research, propelling us into an era where data can not only inform but also enhance our pursuit of understanding.<\/p>\n","post_title":"Deciphering the data deluge: how large language models are transforming scientific data curation","post_excerpt":"Large language models are changing the way we carry out scientific data curation, annotation, and research, setting the stage for a more efficient understanding of scientific literature\n","post_status":"publish","comment_status":"closed","ping_status":"closed","post_password":"","post_name":"deciphering-the-data-deluge-how-large-language-models-are-transforming-scientific-data-curation","to_ping":"","pinged":"","post_modified":"2023-11-15 10:09:02","post_modified_gmt":"2023-11-15 09:09:02","post_content_filtered":"","post_parent":0,"guid":"https:\/\/www.embl.org\/news\/?post_type=embletc&p=64001","menu_order":0,"post_type":"embletc","post_mime_type":"","comment_count":"0","filter":"raw"},{"ID":64003,"post_author":"124","post_date":"2023-11-15 10:00:00","post_date_gmt":"2023-11-15 09:00:00","post_content":"\n

The Kristineberg Center for Marine Research and Innovation sits near the mouth of the Gullmar fjord in Sweden. One day in early August this year, a large truck rolled up the narrow streets of the small settlement, coming to a halt only a few meters from the water. One of those most eagerly awaiting the truck\u2019s safe arrival was biologist Niko Leisch.  <\/p>\n\n\n\n

\u201cThere were a couple of areas where I was not sure if the truck will actually manage to make the narrow turns,\u201d said Leisch, who is currently the Operational Manager of EMBL\u2019s mobile services. \u201cI was very relieved when it finally made it.\u201d <\/p>\n\n\n\n

With a sturdy frame, expandable walls, and scientific equipment worth several million euros, the truck that arrived at Kristineberg \u2013 the EMBL Advanced Mobile Laboratory (AML) \u2013 is a unique undertaking in the history of European life science research. The AML brings cutting-edge technology directly to the field, helping researchers process biological samples immediately after collecting them, using a variety of advanced methodologies.<\/p>\n\n\n\n\n\n

Exploring symbiosis in the wild<\/strong><\/h2>\n\n\n\n

One of the first users of the AML at Kristineberg was Flora Vincent, Group Leader at EMBL Heidelberg. Vincent, a marine biologist and no stranger to fieldwork, is interested in exploring the complex interactions within microbial communities, especially those involving symbiosis in single-celled microorganisms. <\/p>\n\n\n\n

As part of the Traversing European Coastlines (TREC expedition) \u2013 a flagship project of EMBL\u2019s Planetary Biology Transversal Theme \u2013 Vincent has been collecting species across land-water interfaces along the European coast. A particular point of interest for Vincent\u2019s group is diatoms, small microscopic organisms that live in the ocean and produce a large proportion of the planet\u2019s oxygen supply. <\/p>\n\n\n\n

\u201cI use a lot of single-cell approaches, particularly single-cell sequencing,\u201d said Vincent. \u201cIn the past, I have sometimes needed to collect water samples and then drive two hours to a hospital with a flow cytometry unit to do my single-cell sorting. Here, with the cell sorter in the AML, it makes it much easier to begin the process on the spot, with a much lower risk of sample damage.\u201d<\/p>\n\n\n\n\n\n

Also interested in symbiosis is Johan Decelle, Group Leader at CNRS in the Cell and Plant Physiology Laboratory, Grenoble and one of the collaborators for TREC. \u201cMy experience with the AML was like a scientific dream coming true,\u201d he said. \u201cNot only was it a unique scientific experience with cutting-edge instruments on the field, but also a memorable human adventure with experts and colleagues in the field.\u201d<\/p>\n\n\n\n

\"An
The AML arriving in Kristineberg, Sweden. Credit: EMBL<\/figcaption><\/figure>\n\n\n\n

Decelle\u2019s team also participated in previous TREC pilot expeditions in Iceland, France, and Italy, and this work was significant in helping shape the current version of the AML.<\/p>\n\n\n\n

\u201cWe know little about the structural organisation of these systems, or how the host cell integrates with the photosynthesising cell or machinery at the subcellular level,\u201d said Decelle, \u201cThese organisms can\u2019t be easily cultured in the lab, and we wanted to explore these symbiotic relationships in their natural environment and physiological state, freezing them for 3D electron microscopy \u2013 which we can now do with some of the instruments in the AML.\u201d<\/p>\n\n\n\n

Decelle\u2019s team is also studying symbiosis in plankton \u2013 small unicellular ocean-living organisms, especially focusing on known symbiotic associations between photosynthetic and non-photosynthetic eukaryotic cells. Similar symbiotic interactions are believed to have taken place several times during evolution, leading to the acquisition of chloroplast \u2013 a key cell organelle responsible for photosynthesis \u2013 in lineages of plants and photosynthetic algae. <\/p>\n\n\n\n

\"\"
The AML at Kristineberg. Credit: Tina Wiegand\/EMBL<\/figcaption><\/figure>\n\n\n\n

According to Vincent, the AML also provides researchers an opportunity to think creatively, with tools now being available on the field that were never possible before. \u201cIt's pushing us to think about a field sampling in a different way,\u201d she said. \u201cIt really enables me to draw new paths in my brain, ones that I could have never thought of as possible in the natural environment. It also gives us the opportunity to combine the best of two worlds by using the AML tools on samples collected by the Tara schooner. In a single day, we can get a full picture of the marine microbiome thanks to the Tara holistic sampling strategy, and then leverage the AML to conduct state-of-the-art molecular and cellular analyses on targeted species\u201d<\/p>\n\n\n\n

This is particularly suited to Vincent\u2019s team, who use an adaptive sampling approach where the research strategy is tailored to the collection of living organisms that each sample contains, rather than vice versa.  <\/p>\n\n\n\n

\u201cThe challenge is that we are really building the plane as we fly it,\u201d said Vincent. \u201cA lot of the machines are on the field for the first time. Each of those machines can be used in a standalone manner, but where I have a lot of fun is building connections between those tools.\u201d<\/p>\n\n\n\n

Using these tools and creating such new symbiotic relationships between methodologies and scientific approaches, the researchers hope to arrive at new insights that could help address some of the most pressing global challenges we face today \u2013 climate change, environmental degradation, and biodiversity loss. <\/p>\n\n\n\n\n\n

Peering deeper inside plankton<\/strong><\/h2>\n\n\n\n

Another researcher interested in exploring plankton communities is Omaya Dudin, group leader at the Swiss Federal Institute of Technology Lausanne (EPFL). Dudin\u2019s lab explores the evolutionary origins of animal development and is part of the expansion microscopy (PlanExM) team that, as part of TREC, is trying to create an atlas of plankton biodiversity along European coasts. They hope to create a snapshot that would be crucial in assessing the impact of climate change on these populations in the future. <\/p>\n\n\n\n

\u201cThe biggest problem that happens in environmental sampling is that the moment you go beyond an hour or two from the time of sampling, you\u2019re not really sure what you\u2019re looking at any more,\u201d said Dudin. <\/p>\n\n\n\n

This is because many of the plankton living in coastal waters tend to die quickly when taken out of their native environment, greatly altering the species composition of the sample depending on how much time has passed since collection.<\/p>\n\n\n\n

The ability of the AML to travel very close to sampling locations allows Dudin and his team to expedite these crucial sample preservation steps and image plankton at the sub-cellular resolution using expansion and electron microscopy. It is also critical for the second part of the team\u2019s work, which focuses on culturing some of the species collected from the environment in order to potentially bring them back to the lab to study.<\/p>\n\n\n\n

\u201cEMBL is very well known for having high-end techniques in microscopy and molecular biology, and to bring them here, to a place where the samples are fresh, is something very unique,\u201d said Rainer Pepperkok, Director of Scientific Core Facilities and Services at EMBL. \u201cThis is something that I think will set the basis, for many decades, of functional and mechanistic research that integrates these different domains \u2013 the sea and the land \u2013 and to understand how these molecular ecosystems are functioning.\u201d<\/p>\n\n\n\n

\"A
The AML at Kristineberg, Sweden. Credit: EMBL<\/figcaption><\/figure>\n\n\n\n

Arriving in Kristineberg just a day or two after the AML, Dudin was excited to be able to finally use the mobile laboratories. \u201cIt's almost like an extension of my own lab,\u201d he said. \u201cThe quality of the equipment is beyond imagining and it\u2019s so well-organised, it just feels like home.\u201d<\/p>\n\n\n\n

With the help of the AML, the PlanExM team can collect samples using specially designed \u2018plankton nets\u2019, bring them to the laboratory on wheels, and \u2018fix\u2019 them in three different ways in less than an hour. These methods include using chemical fixatives, high-pressure freezing, and plunge freezing, the latter two allowing researchers to use these samples for electron microscopy. Similarly, for culturing new species, the team is going to be able to combine the speed at which the samples are brought to the mobile lab with the single-cell sorter present on board to potentially get single-cell cultures, something still uncommon in plankton research.<\/p>\n\n\n\n

\u201cI think it\u2019s going to change the perspective on how we do certain kinds of research,\u201d said Dudin. \u201cRight now, almost everyone wants to work on model systems because there are clear protocols, images, and tools. And for many of these wild species, no one\u2019s been working on them simply because they are so difficult to catch \u2013 by the time they reach the lab, they are dead. With the AML and with this mission, we are going to keep getting better at collecting data on these understudied organisms and potentially give hope to researchers who want to work on these. In that sense, I think it\u2019s going to be a game changer.\u201d<\/p>\n\n\n\n

Zooming in on species<\/strong><\/h2>\n\n\n\n

One of the key challenges in working with environmental samples when compared with model organisms in the laboratory is the sheer heterogeneity \u2013 samples can contain thousands of diverse species and finding the ones you are particularly interested in can be a herculean task. <\/p>\n\n\n\n

The TREC team led by Yannick Schwab, Team Leader and Head of the Electron Microscopy Core Facility at EMBL, is trying to solve this problem. \u201cMy team is interested in developing methods that enable researchers to target electron microscope imaging to specific cells in complex and highly heterogenous specimens,\u201d said Schwab. <\/p>\n\n\n\n

One of the projects Schwab is leading focuses on dinoflagellates, a very rich and diverse group of plankton. When trying to zoom in on specific dinoflagellate groups in environmental samples, researchers need to perform multimodal correlative imaging \u2013 where the same sample is studied via different advanced imaging methods and the results are combined to yield a \u2018big picture\u2019 view. However, to preserve the ultrastructure of these organisms, state-of-the-art cryo-fixation methods are needed, and these sample preparation steps can only be performed with dedicated machines like a high-pressure freezer or a plunge freezer. As Dudin also noted, it\u2019s very unusual for such machines to be available at or near field locations.<\/p>\n\n\n\n

\u201cWhen we are collecting non-cultivable dinoflagellates in the field, we need to rush to fix them before they start being denatured. Therefore, we must deploy those instruments for cryo-fixation as close as possible to the sampling; by doing so, we literally freeze our samples on the beach,\u201d said Schwab. \u201cThis would simply not be possible without the AML.\u201d<\/p>\n\n\n\n

\"A
The new vCLEM method reveals ultrastructural details of the phytoplankton Ensiculifera tyrrhenica<\/em>. Shown are the theca (metallic purple), mitochondria (green), chloroplasts (red), nucleus (blue), Golgi complex (yellow), mucocysts (orange) and trichocysts (pink and magenta). Credit: Karel Mocaer and Isabel Romero Calvo\/EMBL<\/figcaption><\/figure>\n\n\n\n

In a recent publication<\/a>, a team led by Schwab and Paolo Ronchi from EMBL Heidelberg demonstrates a new method<\/a> that uses correlative light and electron microscopy to help us accurately identify plankton species collected in the field. The researchers plan to apply this technique to samples from the TREC expedition, with the help of the AML. <\/p>\n\n\n\n

Bringing technologies to the field<\/strong><\/h2>\n\n\n\n\n\n

However, as Schwab points out, it is not only the advanced instruments that are important here, but also the dedicated team that enables their use by offering their expertise. In addition to Leisch, the EMBL mobile services team currently includes Michael Bonadonna \u2013 specialist in flow cytometry and cell sorting, Tina Wiegand \u2013 specialist in fluorescence microscopy, and Paulina Cherek \u2013 specialist in electron microscopy sample preparation. <\/p>\n\n\n\n

Along with the AML, the mobile services team also helped outfit vehicles that can access different terrains of the sampling sites to support on-site sample collection and a sampling van equipped for sample processing and storage.<\/p>\n\n\n\n

Leisch, along with Schwab, Pepperkok, and Paola Bertucci (Head of EMBL Scientific Expeditions), has spent over a year helping develop and deploy the advanced mobile lab, working with the Toutenkamion Group, a French industrial mobility company. \u201cThe process was surprisingly smooth,\u201d said Leisch. \u201cFor every single machine, we came up with a way of making sure we can install it in the truck in such a way that it can be used to its full potential on site, but can also be easily secured during moving. This ensures we can quickly get to work once we arrive at a site. We also brainstormed potential challenges that may arise once on the road and tried to find solutions.\u201d<\/p>\n\n\n\n

The process involved many custom-made setups and coordination with multiple scientific instrumentation providers. However, the effort paid off and in August 2023, the AML saw its first full deployment in Kristineberg. <\/p>\n\n\n\n

\u201cOn a personal note, it was a great pleasure to work with Franck Neveu and Melanie Asselin from the Toutenkamion Group,\u201d added Leisch. \u201cThe two of them were our contacts on the industry side and halfway through the project, they became as invested as we were in seeing the unit delivered in the best possible way.\"<\/p>\n\n\n\n\n\n

The TREC expedition is going to continue till mid-2024, but AML\u2019s story does not end there. \u201cWe are right now working on making the AML available as a service unit,\u201d said Leisch. \u201cEveryone from individual researchers to consortia or even nations can then ask for and request the services, and then we together with the team would come to provide those on site.\u201d<\/p>\n\n\n\n

Researchers from EMBL member states agree. \u201cBringing a truck like this on the international scene will allow us to go to places that no one has gone before,\u201d said Dudin. \u201cAnd that opens up possibilities that never existed before.\u201d<\/p>\n\n\n\n

In the meantime, the AML will make its way to the next few TREC supersites, where it will continue to inspire intellectual curiosity and collaboration. <\/p>\n\n\n\n

\u201c<\/strong>One evening, we observed the unicellular organism Noctiluca<\/em> in our samples. Like its name suggests (\u2018Noctiluca\u2019 translates to \u2018light at night\u2019) it is often responsible for the well-known phenomenon of bioluminescence.\u201d<\/em> recalled Leisch. \u201c<\/strong>Everyone got excited and we set up an impromptu midnight sampling in order to collect more of these microbes in the night. It was past midnight and the whole place was buzzing with enthusiasm and excitement and scientific curiosity. And it was just so beautiful to see that and be able to experience that with my colleagues.\u201d<\/p>\n\n\n","post_title":"Taking science on the road","post_excerpt":"With the new advanced mobile laboratory, EMBL is taking its service offerings to new heights, bringing cutting-edge life science technologies to the field in a way never seen before. ","post_status":"publish","comment_status":"closed","ping_status":"closed","post_password":"","post_name":"taking-science-on-the-road","to_ping":"","pinged":"","post_modified":"2023-11-15 10:02:50","post_modified_gmt":"2023-11-15 09:02:50","post_content_filtered":"","post_parent":0,"guid":"https:\/\/www.embl.org\/news\/?post_type=embletc&p=64003","menu_order":0,"post_type":"embletc","post_mime_type":"","comment_count":"0","filter":"raw"}]},"yoast_head":"\nThe secret of molecular promiscuity | EMBL<\/title>\n<meta name=\"description\" content=\"Promiscuity plays a critical role in nourishment. 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