First Steps to Launch Ambitious Quest to Chart Cellular Biodiversity

Biodiversity underpins all life support systems on Earth. The variety of animals, plants and microorganisms, including the genetic diversity within and between species, provide us with air to breathe, food to eat and medicines to consume. The present and future of humanity depends on our ability to understand and protect the diversity of life on our planet.

For years, biodiversity has been organised at three different levels: ecosystems, species and genes. However, these traditional models fail to capture how life is related at the most fundamental level – cells. Studying biodiversity at this level of hierarchy can unlock profound new insights into the evolution of living organisms and usher in a new generation of advanced therapies, technologies, and conservation strategies.

To understand biodiversity at the cellular level, researchers have to create detailed maps of all the different types of cells in many different organisms, also known as a cell atlas. This requires collecting species in their natural habitat and finding ways of sequencing all the transcripts expressed inside each of these cells. Doing this at scale is a monumental effort requiring large-scale international collaborations that rival the ambition and scope of ‘moonshot’ initiatives such as the Human Genome Project in the early 21st century, and more recently, the Earth BioGenome and Human Cell Atlas initiatives.
One of the main hurdles of creating cell atlases for many different species is that scientists have yet to agree on a standard set of methodologies they can use to make comparing cell types across different species feasible in the first place. After addressing this, the next big challenge to overcome is how to process and store the huge amounts of data generated by global efforts in the field. This data would also need to be accessible to the scientific community.

Researchers at the Centre for Genomic Regulation (CRG) in Barcelona have begun efforts to tackle these first two steps. Led by ICREA Research Professor Arnau Sebé-Pedrós, the researchers will develop, test and benchmark techniques required to chart cell types in many different species. Backed by a $3.8 million grant from the Gordon and Betty Moore Foundation, the project will lay the groundwork for the ambitious quest to chart the diversity of cell types on Earth.

"Our planet has a vast living tapestry of cells, each with specialized functions and structures and a unique evolutionary story. This funding is a bold first step towards explaining each type of cell’s journey on Earth, knowledge that can illuminate how these foundational units of life have evolved over time and provide new insights into the functional diversity and interactions between organisms” explains Dr. Sebe Pedros.

The Herculean Task Ahead

Rapid advancements in sequencing technologies such as single-cell RNA sequencing have made possible creating cell atlases at scale. Cell atlases allow researchers to interrogate what each individual cells are doing at any given moment. Every cell in our body contains the same DNA, but different cells use different parts of this DNA. Which parts a cell uses determines what type of cell it is (like a skin cell, blood cell, or nerve cell) and what job it does in the body.

RNA is the messenger that carries information from DNA for making proteins. By sequencing the RNA in a single cell, we can figure out which genes are active in that cell. This is like knowing what instructions it's following and, ultimately, uncover the identity of that cell. By using single-cell RNA sequencing, researchers can listen to the stories of many thousands of individual cells one by one. This helps them understand what each cell is doing – information then used to create detailed maps of cell types, also known as a cell atlas.

However, there is no universal solution for creating cell atlases across animal, plant, fungus or other lifeforms. Each species will have specific requirements for sample collection, preservation, processing and data analysis. Using one method can destroy the RNA in cells of another species and vice versa, leading to the creation of inaccurate maps. Another challenge is that the nature of the data collected means it is not possible to compare with other cell atlases.

To address these challenges, the researchers will use the funding to test and benchmark methodologies for profiling single-cell atlases in non-model organisms, creating a "decision tree" for approaching new species. This will be led by a team led by Dr. Sebé-Pedrós from the Centre for Genomic Regulation alongside Prof. Tom Richards (Oxford University), Dr. Heather Marlow (Chicago University), Dr. Jordi Solana (Oxford Brookes University) and Dr. Lauren Saunders (Heidelberg University).

Dr. Sebe Pedros will also work with Dr. Irene Papatheodorou (EBI/Earlham Institute) to tackle the challenge of data analysis, integration and storage/accessibility. Each research group around the world is likely to be studying different cell types in different species. Standardised pipelines ensure that everyone processes their data in the same way, so when they combine their data, it fits together and can enable accurate and meaningful comparisons between studies. The team will also create a comprehensive database for storing these cell atlases, fostering worldwide knowledge sharing and collaboration.

The Biodiversity Cell Atlas

The ultimate goal of Dr. Sebe Pedros’ efforts is to lay the groundwork for the Biodiversity Cell Atlas. This is an emerging international initiative which aims to coordinate global efforts to chart cell types across different many different species, first articulated by the scientific community at a meeting at the Centre for Genomic Regulation in Barcelona in May 2023.

Funded by the Wellcome Trust, it was organised by Arnau Sebé-Pedrós and Roderic Guigó (Centre for Genomic Regulation), Mara Lawniczak (Wellcome Sanger Institute), Detlev Arendt (European Molecular Biology Laboratory), Amos Tanay (Weizmann Institute of Science) and Irene Papatheodorou (EMBL's European Bioinformatics Institute).

The project is a joint effort of different research communities that develop and apply single-cell sequencing technology to build cell atlases of model organisms, sequence genomes of a diversity of species and compare single-cell genomics datasets. Ultimately, the single-cell transcriptomic data generated by the Biodiversity Cell Atlas will be integrated with other datasets, for example information on how accessible certain parts of DNA (chromatin) are in the cells, or the three-dimensional structure of the genome. This will provide a comprehensive understanding of how genes are regulated and how cell types emerge.

A New Voyage of Biological Discovery

The creation of a Biodiversity Cell Atlas would have profound implications for many different areas ranging from industrial applications, drug discovery, design of synthetic biological systems, and the understanding of the evolution of life. Comparing cell types across species and life stages, has already revealed important insights that the Biodiversity Cell Atlas can eventually support and expand upon.

For example, Dr. Sebé-Pedrós recently created the first cell atlases for placozoans, tiny sea creatures that first originated on Earth 800 million years ago. Comparing the cell atlases to other animals such as cnidarians revealed neuron-like cells in placozoans. Given the phylogenetic position of placozoans, it’s possible they served as the blueprint for the nervous systems in more complex animals, including humans.

“We’ve already made remarkable discoveries into the cellular architecture of life, but these have mostly been the result of individual efforts from different research groups across the world. Unifying these endeavours into a collaborative, cohesive effort, can amplify the potential value of our work exponentially, opening the door to unprecedented discoveries in understanding the diversity and evolution of life,” concludes Dr. Sebé-Pedrós.

Image: Confocal microscopy image of placozoans, one of the animal types researchers at the CRG have created cell atlases for. Credit: Sebastian Najle