The Human Cell Atlas Is Biologists' Latest Grand Project

Aviv Regev speaks with the urgent velocity of someone who has seen the world with an extraordinary new acuity, and can’t wait for you to hurry up and see it too. At a meeting of 460 international scientists gathered last week in San Francisco, the computational biologist bombarded her audience with a torrent of results from her lab at the Broad Institute of MIT and Harvard, where she is pioneering powerful new tools for understanding what we humans are really made of—and what makes us fall apart.

“Where do disease risk genes act?” she fired into the crowd. “Which molecular communications are being disrupted? Which cell programs are being changed? These are the next generation of questions we can now ask.”

For centuries, scientists like Regev have known that clues to our elemental humanity were hiding in the basic unit of life: the cell. The cell has captivated scientists ever since Robert Hooke stuck a sliver of cork under his microscope in the 17th century and observed an “infinite company of small boxes,” drawing a parallel between the structures he saw through his instrument’s eyepiece and a monastery’s spare rooms. But only in the last few years has the technology existed to investigate the internal workings of individual cells at scale. Using these methods, scientists are now embarking on one of the most ambitious efforts in the history of biology.

Dubbed the Human Cell Atlas, the project intends to catalog all of the estimated 37 trillion cells that make up a human body. Led by Regev and Sarah Teichmann, the head of cellular genetics at the UK’s Wellcome Trust Sanger Institute, the international consortium aims to assemble much more than a laundry list of cell types. By decoding the genes active in single cells, pegging different cell types to a specific address in the body, and tracing the molecular circuits between them, participating researchers plan to create a more comprehensive map of human biology than has ever existed before. If successful, this map will knit together information about how cells organize into tissues, how they communicate, and how things go wrong. Such a resource could one day have huge implications for understanding and treating human disease.

Just how huge? Last week’s meeting offered a brief, but dazzling glimpse. It was sponsored by the Chan Zuckerberg Biohub, a two-year-old biomedical research center backed by Facebook founder Mark Zuckerberg’s philanthropic investment group, CZI. The Biohub’s co-president, Stephen Quake, also a Human Cell Atlas organizer, welcomed a parade of the project’s founding members to the stage to share their latest work.

Ed Lein, a neuroscientist at the Allen Institute explained how he’s spent the last two years building a taxonomy of all the cells found in one tiny patch of the human brain. By sequencing the active genes in those cells, his team has already identified 80 different kinds, including a totally novel neuron found only in humans. “We see that basically everything is rare,” said Lein. And that’s just in one corner of the brain. Understanding how those neurons network across the rest of the organ will require the work of many other labs. “This problem is so enormous that it necessarily has to be a community effort,” Lein told WIRED in an interview last year about his role as a member of the Human Cell Atlas’s brain working group.

Some Atlas participants, like Lein, are deep-divers. Sten Linnarsson at the Karolinska Institute in Sweden takes a broader, more shallow approach. His lab is using gene expression measured across time to observe how quickly cells take on new identities in developing tissues. By capturing snapshots of cells every few hours, and seeing how their gene patterns change, it’s possible to predict what they’ll be doing in the future. A lot of Linnarsson’s work to this point has been done in mice, but as scientists like Lein add more and more human brain data, Linnarsson can start applying his ideas to humans. “We expect to be able to make large branching trees tracing the developments paths of cells in the human brain,” said Linnarsson.

These findings are already transforming biology as we know it. But it’s results from Regev’s work that perhaps offer the best example of how the Human Cell Atlas might revolutionize medicine as well.

In a recent pair of studies published in Nature, Regev and her collaborators at Massachusetts General Hospital discovered a new, rare type of lung cell, with similarities to salt-balancing cells found in the gills of freshwater fish and frog skin. Concentrated in this unique cell was activity of the CTFR gene, mutations to which cause cystic fibrosis. Regev now believes it probably plays a key role in the disease, breaking the widely held view that a much more ubiquitous cell type was responsible for expressing the disease-causing gene.

Imagine you wanted to design a drug or a gene therapy to target such a gene. Knowing where it’s doling out damage is essential to making a medicine that’s effective with the fewest side effects. Cystic fibrosis is fairly straightforward—one gene causing chaos in one organ, the lungs. But other diseases are much more complicated. A reference map of what all the healthy cells in the body look like would be invaluable for comparing with diseased tissues to see where things went wrong. This is one way the Human Cell Atlas could lead to medical breakthroughs.

Another is matching cancer patients to the right treatments.

A promising new class of drugs, called checkpoint inhibitors, gives the immune system free reign to attack tumor cells. But it doesn’t work for everyone; some people appear to develop resistance. By looking at gene expression in melanoma cells taken from patients before and after treatment, Regev’s team discovered that some people’s tumors were impervious from the get-go. Despite having a mutation that should have made the drug effective, some tumor cells had flipped on a set of resistance genes. And wherever they appeared in the tumor, they blocked immune cells from getting in.

With this knowledge in hand, Regev’s team tested whether you could reverse that resistance, by combining the checkpoint inhibitor with drugs that are known to manipulate those genes. In mice, they saw a dramatic effect. The unpublished work is forthcoming in the journal Cell, and her collaborators at the Dana Farber Cancer Institute are now pursuing clinical trials to assess the efficacy of the combined therapy approach in humans. The Human Cell Atlas will be a place to collect all these genetic programs that can disrupt treatment. The oncology space is moving quickly to adopt routine sequencing to match patients’ unique tumor mutations to targeted medicines. The next step is screening for how a patient’s cancer cells toggle genes on and off in ways that interact with various medicines.

“I like moving fast,” says Regev, who launched her own company, Celsius Therapeutics, in May, to help advance her findings more quickly into medicines for cancer and autoimmune disease (it is not involved in the clinical trial mentioned above). But she’s cautious to separate that business from her academic work and role at the Human Cell Atlas, where her job is to convince people to share their hard-earned data, in which important biomedical discoveries might be lurking.

“From the beginning we have designed this as a public good and an open resource to enable science around the world,” says Aviv. It’s meant to be a generally useful reference for how healthy tissue behaves, like the human genome was for DNA. When it comes to medicine, the real power will come from combining that reference atlas with data from diseased populations, she says: “That’s where the interesting translational discoveries will be, much of which we cannot yet even imagine.” In some ways the Human Cell Atlas is Regev’s way of encouraging the world, “Come on, hurry up, imagine them already.”