‘Groundbreaking’ map of human cells
A global team led by San Francisco researchers unveiled Thursday the first draft of a “human cell atlas” — a groundbreaking endeavor to identify and map every cell type in the body, and thus provide a reference tool that could transform scientists’ grasp of molecular biology, including how they think about and treat disease.
The draft atlas incorporates nearly 500,000 cells from 24 tissues and organs, including the heart, lung, eye and uterus. Scientists identified more than 400 cell types, including some that were newly discovered, and described in unprecedented detail their molecular makeup and genetic function.
The Tabula Sapiens Consortium — a team of more than 160 scientists from UCSF, UC Berkeley, Stanford and other institutions around the world, and led by experts from San Francisco’s Chan Zuckerberg Biohub — published a paper Thursday describing its work in the journal Science. The work was part of the global Human Cell Atlas effort founded in 2016 to classify the 37 trillion cells that make up the human body.
The atlas carries on the work done by the Human Genome
Project, which compiled the first genetic blueprint of the human body more than 20 years ago, and which is still being expanded and refined. But the human genome, scientists involved in the atlas work said, wasn’t a blueprint so much as a parts list — a catalog of human DNA, exact copies of which are carried in nearly every cell of the body.
It’s how cells use that parts list that defines them. Gene expression — when and what types of genes are turned off and on — determines what role each cell plays in human development: whether it becomes a smooth muscle cell of the large intestine, an immune B cell from the lymph nodes, or an epithelial cell lining the airways in the lungs.
“This is really a companion to the genome, that explains how the parts are used in all the different cells of the body,” said Stephen Quake, senior author of the paper who is an applied physics professor at Stanford and president of the CZ Biohub Network.
“And we’re not done,” he said. No one yet knows exactly how many cell types there are in the human body — before the atlas, guesses ranged from 200 to perhaps 1,000. The Tabula Sapiens team identified 475 distinct types. Its atlas does not include cells from the brain and some other parts of the body.
The draft atlas was made available to scientists around the world several months ago, and already some are using it to improve their understanding of conditions from obesity to cancer. A Stanford scientist who studies a deadly type of brain tumor said he’d referenced the atlas to help determine whether a cell type he hopes to target with drug therapy is found in other places in the body, which could lead to toxic side effects.
Bart Deplancke, a bioengineer at the Swiss Federal Institutes of Technology, said he is eager to use the atlas to inform his work studying adipose tissue. Studying the diversity of cells found in the fatty tissue could help explain how obesity develops, and why some people with obesity don’t experience related diseases like diabetes, while others do.
“This work is truly groundbreaking. I consider this parallel to the human genome, which we thought was truly revolutionary,” Deplancke said.
“We’ve been so successful in fighting disease, but for many tissues and organs, we still don’t have a good understanding of which cell types make up these organs,” he added. “You wonder, how can we even treat disease if we don’t know what the parts are that make up the organs we want to treat? This is what these reference atlases are intending to do, allow us to know which parts of our body are there.”
Single-cell biology — studying the individual cells that form every part of the human body — has been enormously complicated, in large part because of how difficult it is to separate the cells from one another; Deplancke compared it to trying to identify the individual fruit particles that make up a smoothie. It’s especially challenging to isolate rare cell types found in organs that are dominated by more common cells.
Until fairly recently, even once the cells were isolated scientists lacked the tools to efficiently sequence the genetic material in them. That technology was developed about a decade ago.
Scientists need live cells to sequence all of the genetic material. The Tabula Sapiens team collected tissues and organs from 18 recently deceased individuals, including 17 samples from one donor and 14 from another. The process of collecting the donor tissues was itself a monumental effort, requiring close coordination with Donor Network West, a nonprofit organ procurement organization for Northern California.
For each donor, surgeons would first harvest organs that would be used for transplantation. Once that process was done, surgeons would remove tissues for the atlas work — in some cases, that meant lining up multiple surgeons, often in the middle of the night, with very specific expertise in removing the thymus gland, for example. Couriers would then rush the samples to laboratories around the Bay Area to begin the processes of separating cells and sequencing.
“I would stand in the parking lot at Stanford, waiting for the cars to come in the middle of the night,” said Bob Jones, a senior research engineer at Stanford who coordinated the various teams. “We’d be busy from the first call until the middle of the next day. Many of us worked 36 hours straight to make sure all of this flowed.”
Analyzing the data collected from all of the sequencing was another enormous challenge, starting with developing a standardized system for labeling each cell. Experts in computational data analysis spent hours with scientists who specialize in various tissues working out how to annotate the cells, said Angela Pisco, associate director of data science at the Biohub.
“And the real work starts now, because we have the more complex components, but we are still only wanting to understand the puzzle of how the cells work together,” Pisco said. “What cells are next to each other? How do cells talk to each other? Why are some organs more packed with cells than others?”
Three other papers were published Thursday as part of the Human Cell Atlas project. One paper describes a new tool for sequencing frozen cells, and two focus on immune cells.
“What we hope is by using maps like these we can better understand how disease arises in the body, and where precisely disease arises,” said Aviv Regev, head of Genentech research and early development at Roche, who is co-leader of the Human Cell Atlas project.