The case for long reads, the benefits of cell atlases, spatial transcriptomics, and genomics at the intersection of microbial communities were among the key themes from the 2024 Norwich Single-Cell Symposium, held at the Earlham Institute.
Speakers and delegates working on a range of systems, species, and approaches came together to explore the latest trends in single-cell science.
“The breadth of topics is probably unique among similar events and is enormously valuable for such a dynamic field,” said Dr Iain Macaulay, Technical Development Group Leader at the Earlham Institute and co-chair of the symposium.
Jointly organised with the University of East Anglia (UEA), the seventh incarnation of the symposium also featured complex tissues, dynamic systems, and spatial approaches, offering plenty of food for thought for attendees.
“There’s so much we can learn from others who are applying single-cell approaches to very different questions,” added Dr Macaulay
“And, thanks to the range of technologies and biological systems being studied at the Earlham Institute, this is an ideal place to bring the diverse single-cell community together.”
Dr Tanja Woyke, Deputy of User Programs at the Joint Genome Institute, is predicting a new renaissance for microbiome single cell sequencing.
It has traditionally been a more niche area of single cell science, partly due to challenges in sample-to-sample variation, sample preparation, genome amplification biases, and low genome completeness.
For those with an interest, metagenomics has been the go-to approach for studying microbiomes. But one of the key issues with, for example, metagenome assembled genomes (MAGs) is the tendency to overlook less abundant species or strains.
The attraction of single-cell approaches has always been the ability to find these underrepresented microorganisms, also known as “microbial dark matter” - a term popularised by Dr Woyke.
Thanks to a number of recent improvements in microbial single-cell whole genome amplification, alongside scalable approaches, Dr Woyke used her keynote address to set the scene for a resurgence of microbial single-cell sequencing.
“In order to understand the microbiome in greater detail, it’s important to study it at both bulk and single-cell level to unlock that extra layer of microbial resolution.” says Yash Bancil, a PhD student at the Earlham Institute.
“Microbiomes are complex communities and their inferred dynamics can be significantly influenced by underrepresented species - for instance, keystone species that are pivotal for community structure and behaviour.
“Microbial single-cell research will add further insights into the cellular heterogeneity we know exists within microbiomes and help us understand how spatial microbial organisation is influenced by different microenvironments.”
His project is exploring the genomic and functional complexities of different microbiomes, including the human gut. Based in the Macaulay Group, single-cell approaches are key tools at his disposal.
“I don’t think it’s a question of one approach over the other - they are complementary,” he concludes.
It is an area that bridges the Earlham Institute’s strategic research programmes, Cellular Genomics and Decoding Biodiversity; the former is using single-cell approaches to understand genome variation and regulation while the latter is exploring biodiversity, including complex microbiomes.
During her keynote speech, Professor Ana Conesa from the Institute for Integrative Systems Biology in Spain, pointed to recent research suggesting readouts from short read datasets miss around 80 per cent of the biology.
Her views were echoed by many others, with a range of talks and discussions about the importance of the information captured in long reads - including isoform switching, protein coding regions, and alternative splicing events. For Dr Conesa, this means she may not see potential disease targets.
Long read sequencing enables the capture of full-length transcripts and is helping to profile transcriptome diversity and isoform use. But it is still an emerging field, particularly in the context of single cells.
Over time, the technology platforms, chemistry, and approaches will all improve to reduce bias and error. And, as with metagenomics, short read data will complement - rather than compete with - long reads.
One of the future avenues proposed by Professor Adam Cribbs from the Nuffield Department of Orthopaedics at the University of Oxford was the application of AI or machine learning approaches to make the wealth of data manageable.
A lot of that data comes from building reference maps, providing the baselines we need for describing healthy systems.
Millions of years of evolution have led to the diverse cellular functions we can observe today. Some of these divergences are ancient and others more recent.
While this differentiation exists, there are clear trends across the tree of life. Most of the organs and basic tissue types are similar. This is where cell atlases can help.
Cell atlases are comprehensive maps of cell types and states within a tissue or organism, such as the human cell atlas. These atlases enable you to, for example, look across patient cohorts for pathogenic or disease-related differences.
They can be whole body, organ specific, condition/disease specific, species atlases, and even developed for mapping inputs or across dynamic processes. Understandably, cellular cartographers require a huge amount of computational resource to build and manage them.
Professor Irene Papatheodorou, the Earlham Institute’s Head of Data Science, discussed the emergence of multi-layer atlases with more modalities for single cell data.
The aim is to use them as tools to better understand cellular diversity and function, whether that’s between healthy or unhealthy patients - mapping pathogenic cell types to disease phenotypes - or across anatomical functions between species.
This sort of insight is one of the ambitions of the Institute’s Cellular Genomics strategic research programme.
For those looking for an existing knowledge base of single cell expression, Iris Yu from EMBL-EBI pointed delegates to the Single Cell Expression Atlas.
From L-R: Dr Tanja Woyke from the JGI, Yash Bancil, PhD Researcher at EI, and Irene Papatheodorou, Head of Data Science at EI
As the fundamental unit of biology, single cells are the great leveller across the biological sciences.
From wheat spikelets to human ovaries, common challenges and potential solutions exist - often in spite of the evolutionary distance between species.
The Earlham Institute hosts Transformative Genomics, a BBSRC-supported National Bioscience Research Infrastructure. This offers access to a range of platforms and expertise in single-cell and spatial analysis - as well as next-generation sequencing.
The Institute’s Advanced Scientific Training team also offers opportunities to develop your single-cell knowledge and discover spatial technologies, generating breathtaking visualisations of where gene expression is happening.
“Assumptions about the costs and scale of single-cell approaches can put people off them, even in cases where the data would be invaluable,” said Dr Iain Macaulay.
“But the field is moving fast, and things are constantly improving, so now is definitely the time to engage with these technologies - the Earlham Institute is definitely well-placed to help with this.”
The Norwich Single-Cell Symposium 2024 was organised by the Earlham Institute and UEA, and was co-chaired by David Monk, Professor of Developmental Epigenetics at UEA.
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