With rare exceptions, each of the trillions of cells in our body carries an exact copy of the human genome, which contains between 20,000 and 25,000 protein-coding genes. But to perform the specialized functions that make life possible, organs like the kidneys, lungs, heart, and brain rely on tissues built from distinct cell types, which arise when individual cells grow to express only one particular subset of genes in the genome. .
Until recently, the diversity of gene expression across cell types, known as the transcriptome, was difficult to decipher. But with the rapid rise of single-cell biology, scientists have created tools and techniques that reveal precisely which genes are expressed by the individual cells that make up tissues and organs. In addition to providing a deeper understanding of normal biology, these single-cell approaches promise to pave the way for new therapies, as diseases typically strike specific cell types.
However, in an article published in Sciencethe Tabula Sapiens Consortium, a team of more than 160 experts led by scientists at the Chan Zuckerberg Biohub, has unveiled a massive digital atlas that maps gene expression in nearly 500,000 cells from 24 human tissues and organs, including the lungs , skin, heart , and blood.
The Tabula Sapiens Cell Atlas is the largest to include multiple tissues from the same human donors, and the first to include histological images of the tissues, and to incorporate details of the microbial communities living alongside the human cells that make up the different compartments of the intestine.
“The quality and breadth of this data is unprecedented,” said lead author Stephen Quake, D.Phil., Lee Otterson Professor of Bioengineering and Professor of Applied Physics at Stanford University, for whom Tabula Sapiens is the fulfillment of a 20 year “obsession.” Quake, who is also president of the CZ Biohub network, added, “This atlas will allow scientists to ask and answer questions about human health and disease that they have never been able to address before.”
The new paper is one of four major collaborative studies published in Science this week, all of whom have created comprehensive, freely available inter-tissue cell atlases as part of the international Human Cell Atlas (HCA) consortium. HCA is supported by a wide range of global funders, including the Chan Zuckerberg Initiative (CZI). Additional funding for Tabula Sapiens was provided through CZI’s Single Cell Biology program.
“This collection of work is truly inspiring,” said Jonah Cool, Ph.D., science program manager for single-cell biology at CZI. “This exceeds the expectations we set for ourselves when CZI embarked on funding single cell biology research and tool development. The technological advances they demonstrate as well as the biological insights provided are important milestones for the field. reference resources such as those sought by the Human Cell Atlas.
The Tabula Sapiens project brought together contributions from a wide range of experts, including surgeons and tissue specialists for each organ included in the study. “This effort really demonstrates all the potential we can unlock when we embrace the idea of team research,” said Angela Oliveira Pisco, Ph.D., Tabula Sapiens Consortium Fellow, Associate Director of Data Science for CZ Biohub Quantitative Cell Science Team. “We coordinated a precise, cohesive, and comprehensive effort with over 160 people, and that in itself is a marvelous feat for science.”
Through a close partnership with Donor Network West, a Northern California nonprofit organ procurement organization, Tabula Sapiens offers one of the broadest views available of healthy cells throughout the body. “The study maps the building blocks of biospecimens obtained through a rather unique project and demonstrates the remarkable value of non-transplanted tissues and organs for preclinical research,” said Ahmad Salehi, MD, Ph.D., Director of research from Donor Network West. .
In a single session, for example, dozens of surgeons, scientists and recovery coordinators worked through the night to collect cells from 17 tissues and organs from a single human donor within an hour of removal. life support and organ harvesting. for transplantation. This rapid approach provides the ability to study differences in cell types without the degradation in data quality that can occur when using frozen tissue. Additionally, the use of samples from a single donor simplifies data analysis, eliminating the need to control for genetic, age-related, and environmental differences between individuals.
“If we read enough RNA fragments, it’s like having a high-resolution telescope that can see in 25,000 dimensions,” said Bob Jones, senior research engineer in Stanford’s Department of Bioengineering and a member of the Tabula Consortium. Sapiens. “It’s an incredible detail.”
Tabula Sapiens uniquely includes an analysis of alternative splicing products, a cellular process by which different RNA transcripts can arise from a single gene, leading to many protein variants. “Because multiple RNA transcripts can come from each of our 25,000 genes, it becomes very difficult to functionally characterize each gene and what it may encode in the ‘wet lab,'” said Consortium member Julia Salzman. Tabula Sapiens, Ph.D., associate professor of biomedical data science and biochemistry at Stanford. “This type of research cannot be driven by experimentation, it must be driven by data.”
In a surprise already unveiled by Tabula Sapiens, Salzman said, researchers found that sets of housekeeping genes — so called because they were thought to manage basic functions the same way in every cell — likely had many more roles in the body than he was. thought before. And in the scientific paper, the team reports that CD47, a protein implicated in both cancer and the buildup of dangerous plaques on artery walls, can differ dramatically from cell to cell, a discovery that could guide the development of drugs that are more effective or have fewer side effects. The scientific paper also reveals that the gut microbiome is “patchy” rather than uniform – data from Tabula Sapiens shows that distinct microbial populations exist within inches of each other in the digestive tract.
“We are already revealing important new biology that we simply would not have had the opportunity to know without Tabula Sapiens,” Salzman said. “With this atlas, we have a huge opportunity to improve our understanding of how the human body works.”
Tabula Sapiens is accessible through a free and easy-to-use data portal, which provides links to all components of the multimodal atlas. “We are committed to making our data easily and widely accessible,” Biohub’s Pisco said. “Enabling scientists with different skill sets to take full advantage of incredible resources like Tabula Sapiens will accelerate scientific progress.”
A user-friendly, open-source tool called cellxgene (“cell by gene”), developed by CZI’s Science Technology group, means that even scientists without a computer background can use Tabula Sapiens in their work. The tool, integrated into the Tabula Sapiens portal, is already helping scientists address a variety of questions, such as understanding which cell types are most prone to deleterious genetic mutations, how immune cell populations differ in various organs and identification of tissues vulnerable to attack. by the virus that causes COVID-19.
“Our cellxgene tool helps scientists, like those at the Tabula Sapiens Consortium, answer fundamental questions about human biology in seconds, not years,” said Phil Smoot, Chief Science and Technology Officer and vice president of engineering at CZI. “We are excited to see how other scientists will leverage this platform to further our understanding of human health and disease.”
Multi-tissue cell atlases provide insight into immunity and disease
The Tabula Sapiens: a unicellular multi-organ transcriptomic atlas of man, Science (2022). DOI: 10.1126/science.abl4896. www.science.org/doi/10.1126/science.abl4896
Provided by Chan Zuckerberg Biohub
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