Earlier this year, Steve McCarroll announced that his team haddiscovered the gene that most powerfully drives our risk of schizophrenia. Known as C4, it was previously viewed as an immune-system gene, but clearly, it also does something in the brain. To work out what, McCarroll first needed to know which cells in the brain activate C4.
McCarroll’s lament is a common one. Geneticists are constantly learning about genes that influence our risk of disease, but genes don’t perform in a vacuum. They perform in our cells. And since the 30 trillion cells in your body all share the same genes, you need to know which cells are actually using the gene in question. Where are those cells? What do they do normally, and what goes wrong in cases of disease? And in most cases, without the kind of slog that McCarroll endured, the answers are: we don’t know; no idea; and, ¯\_(ツ)_/¯.
Our cells are the basic unit of our bodies—the stage upon which our genes enact their dramas. And simply put, “we really don’t know our cells.” says Aviv Regev from the Broad Institute. “And so we don’t know ourselves.”
Consider this fairly basic question: How many types of cells are there in the body? Around 200, according toseveral introductory pages from the National Institutes of Health. That figure corresponds to major groups, like neurons, heart cells, muscle cells, and more. But if you ask an immunologist, they’ll tell you there are at least 200 types of immune cells alone. Ask an immunologist who specializes in T-cells, and they’ll tell you there are at least 200 of those.
When I met Regev last year, she spent a good 15 minutes talking about all the variations within our cells. There are subtypes upon subtypes upon subtypes, she said. The retina alone contains at least 100 different classes of neurons. To complicate matters, some types of cells can transform into others. And each subtype can exist in many different states based on its environment, its neighbors, its position in a tissue, and the molecules it encounters.
All of these things, the type and the subtype, the states, the locations, and the transitions … you’d want to know all of them,” Regev told me. She let her words hang, and she smiled gently. Because she had a plan to do exactly that: to know everything.
Over the last few years, Regev has been slowly laying the foundations for compiling a Human Cell Atlas—a complete portrait of our cells in all their staggering diversity. It would list every subtype, how they change over time, where they are found, and which genes they switch on. Much like the first fully-sequenced human genome, it would be a resource so fundamental that biologists will use it many times a day without even thinking about it—a comprehensive, searchable Google Maps for the human body.
Creating such a resource is ambitious to say the least, and would have seemed impossible just five years ago. But thanks to technological advances, Regev and others think that the time is right. “The idea has been bubbling,” says Sarah Teichmann from the Wellcome Trust Sanger Institute. “I had talked with someone about this four years ago. At the time, it seemed a bit crazy. Even now, it seems crazy—but also more feasible. And people are willing to consider it.”
That’s partly due to Regev, who has been evangelizing for the atlas since 2014. She is widely respected, and not just for her boundless energy and fierce intellect. “She’s one of the smartest people I’ve ever met, but also intense, perceptive, compassionate and caring,” says Dana Pe’er from Columbia University.
Case in point: Last June, at a meeting, Regev noticed that Pe’er was suffering from back pain, surreptitiously emailed her to ask if she was okay, and texted a colleague to bring in a more comfortable chair—all while leading a debate between big-name scientists and summarizing their discussion in real time. “The people sitting right next to me didn’t notice a thing,” says Pe’er. “Aviv did, from the other side of the room with a bad field of view.”
Yesterday, in London, Regev and Teichmann convened another meeting of like-minded scientists who were interested in their vision of a cell atlas. The event was effectively a soft launch—not of the atlas itself, but of a budding community that will actually start making it happen.
They already have a funding commitment from the Chan-Zuckeberg Initiative—the recently formed company that is aiming to “cure, prevent or manage all disease by the end of this century.” “The Human Cell Atlas would be a transformative technology that advances all of science,” CZI President Cori Bargmann told the assembled researchers. “We’re pretty much on board with saying that this should happen, and we want to help make it happen with the people in this room.”
As is often the way in science, Regev’s dream for the Human Cell Atlas began with a simple surprise.