Atlas of multi-organ cells “Tabula sapiens” already brings surprises to biologists

With rare exceptions, each of the trillions of cells in our body carries an exact duplicate of the human genome, containing 20,000 to 25,000 genes that encode a protein. But to perform specialized functions that make life possible, organs such as the kidneys, lungs, heart, and brain rely on tissues built from distinctive cell types that arise when individual cells develop to express only a specific subset of genes in the genome. .

Until recently, the diversity of gene expression has varied cell types, known as a transcript, was difficult to decipher. But with the rapid growth of unicellular biology, scientists have created tools and techniques that accurately show which genes are expressed individual cells of which tissues and organs are composed. In addition to a deeper understanding of normal biology, these unicellular approaches promise to pave the way for new treatments because diseases typically affect certain cell types.

Now in an article published in Art ScienceThe Tabula Sapiens consortium, a team of more than 160 experts led by scientists from Chan Zuckerberg Biohub, has unveiled a massive digital atlas depicting gene expression in nearly 500,000 cells of 24 human tissue and organs including lungs, skin, heart, and blood.

The atlas of Tabula Sapiens cells is the largest, which includes several tissues from the same human donors, and the first, which includes histological images of tissues as well as details of microbial communities living next to human cells that make up different departments. inside.

“The quality and scope of this data is unmatched,” said senior author Stephen Quake, Ph.D., professor of bioengineering Lee Otterson and professor of applied physics at Stanford University, for whom Tabula Sapiens is implementing a 20-year program. “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 work is one of four major collaborative studies published in Science this week they all created comprehensive and publicly available cross-cell cell atlases as part of the international Human Cell Atlas (HCA) consortium. HCA is supported by a wide range of global sponsors, including the Chan Zuckerberg Initiative (CZI). Additional funding for Tabula Sapiens was provided through the CZI Unicellular Biology Program.

“This collection of works is really inspiring,” said John Cool, Ph.D., a fellow in the single-cell biology research program at CZI. “This exceeds the expectations we set when CZI began funding research and development of tools in unicellular biology. technological advances what they demonstrate as well as the biological understanding provided are important milestones for this area. These studies are a significant step towards great reliable reference resources, such as those conducted in the Atlas of Human Cells ”.

The Tabula Sapiens project brought together the contributions of a wide range of experts, including surgeons and tissue specialists for each organ that was included in the study. “These efforts really demonstrate the potential we can unleash if we embrace the idea of ​​team research,” said Angela Oliveira Pisco, Ph.D., a member of the Tabula Sapiens consortium, Ph.D., deputy director of data science at Quantitative Cell Science CZ Biohub. “We have coordinated a clear, consistent and comprehensive effort with more than 160 people, and that in itself is a remarkable feat for science.”

Through a close partnership with Donor Network West, a nonprofit organ procurement organization in Northern California, Tabula Sapiens provides one of the most widely available views on healthy cells throughout the body. “The study reflects the building blocks of biosamples purchased in a rather unique project and demonstrates the excellent value of non-transplanted tissues and organs for preclinical research,” said Ahmad Salehi, MD, research director at Donor Network West. .

For example, in just one session, dozens of surgeons, scientists, and recovery coordinators worked all night to collect cells from 17 tissues and organs from a single human donor within an hour of life support and organ harvesting. for transplantation. This rapid approach makes it possible to study differences in cell types without the deterioration in data quality that can occur when using frozen tissue. In addition, the use of samples from a single donor simplifies data analysis, eliminating the need to control genetic, age, and environmental differences between people.

“If we read enough RNA fragments, it’s like a high-resolution telescope that can see in 25,000 dimensions,” said Bob Jones, a senior research engineer at the Department of Bioengineering at Stanford and a member of the Tabula Sapiens consortium. “It’s an incredible detail.”

Tabula Sapiens uniquely involves the analysis of products of alternative splicing, a cellular process by which different RNA transcripts can arise from a single gene, leading to many protein variants. “Because several RNA transcripts can come from each of our 25,000 genes, it becomes very difficult to functionally characterize each individual gene and what it can encode in a wet lab,” said Jubula Salzman, Ph.D., a member of the Tabula Sapiens consortium. Associate Professor of Biomedical Sciences and Biochemistry at Stanford. “This kind of research can’t be done experimentally – it has to be data-driven.”

In one of the surprises already published by Tabula Sapiens, Salzman said, researchers found that sets of management genes – so called because they were thought to perform basic functions in each cell about the same – probably have far more roles in the body than was before. previously thought. And in research, the team reports that CD47, a protein involved in both cancer and the accumulation of dangerous plaques on artery walls, can vary greatly in shape from cell to cell, which could drive drug development. more effective or have fewer side effects. Scientific work also shows that the gut microbiome is “inappropriate” rather than homogeneous – Tabula Sapiens data show that different microbial populations exist just a few inches apart in the digestive tract.

“We are already revealing an important new biology that we simply could not have known about 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 available through free and easy to use data portal, which offers links to all components of a multimodal atlas. “We strive to make our data easily and widely available,” Pisco of Biohub said. “Sharing scientists with diverse backgrounds to make full use of incredible resources, such as Tabula Sapiens, will accelerate scientific progress.”

A handy open access tool called cellxgene (“cell by gene”), developed by the CZI scientific technology team, means that even scientists without computational training can use Tabula Sapiens in their work. The tool, built into the Tabula Sapiens portal, is already helping scientists address a variety of issues, such as understanding which cell types are most susceptible to harmful gene mutations, how immune cell populations differ in different organs, and identifying tissues vulnerable to attack. the virus that causes COVID-19.

“Our cellxgene tool helps scientists like the Tabula Sapiens consortium answer fundamental questions about human biology in seconds, not years,” said Phil Smoot, head of science and technology and vice president of CZI technology. “We are excited to see other scientists take advantage of this platform to further understand human health and disease.”

Provided by Chan Zuckerberg Biohub