Human Cell Atlas pioneer explains why it’s such a milestone

yUnder your skin lie entire aquatic worlds, where trillions of cells shoot, strike, twist and secrete, performing all the complex tasks to keep you alive. They all share the same genetic code. But what they do with it is the difference between a neuron and a twitching muscle fiber.

About a decade ago, a group of scientists began doing a cytometry of every tissue in the human body to see which cells actually live there, using a powerful new technology called single-cell RNA sequencing. It illuminates the parts of the genome that the cell uses to do its unique task. Since then, the international collaborative effort, called the Human Cell Atlas, has grown to include more than 2,000 researchers from 83 countries. And on Thursday, they reported a major breakthrough: creating detailed maps of more than 1 million cells across 33 members.

Historic tissue atlases of four studies have been published in the journal Science. “You can think of it as Google Maps of the human body,” Sarah Tishman, chair of cytogenetics at the Wellcome Sanger Institute and co-chair of the Human Cell Atlas, told reporters on Tuesday.

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In one study, her team sequenced RNA from 330,000 single immune cells from throughout the adult body, and in another, they cataloged the development of immune cells in prenatal tissues. They discovered that as the infection-fighting T cells evolved, they learned as much to talk to each other as they did from their mother tissues. Deciphering this molecular code could allow researchers to better engineer T cells to do things like fight cancer. “The ideas have implications for treatments that enhance or dampen the immune response to fight disease and for designing vaccines,” Tishman said.

A third research paper, led by co-chair Aviv Regev, one of the pioneers in single-cell sequencing who is now leading research and development at Genentech, described how researchers from the Broad Institute created a cross-tissue atlas of 200,000 cells from frozen tissue. Using machine learning, they scanned an atlas to identify the cell types associated with 8,000 genetic diseases. “We hope by using maps like this we will be able to better understand the exact place in the body where the disease originates,” Regev told reporters. “This will allow us to develop more accurate diagnoses and new treatments.”

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Stephen Quick, President of the Chan Zuckerberg Biohub Network and a member of the Human Cell Atlas Organizing Committee, contributed to an update from the Tabula Sapiens Consortium, which, unlike many other efforts, collects sequences from single donor cells. To date, it provides an image of nearly 500,000 cells from 24 members of 15 recently deceased individuals.

STAT spoke with Quake about the scientific milestones and what’s coming next. Excerpts from the conversation below, edited slightly for clarity.

The consortium has now mapped more than 1 million individual cells across 33 members, a significant achievement, and a first draft, if you will, of the human cell atlas. How do you feel?

This is an important moment. Around 2011, 2012, there were four or five people in different corners of the world saying we should build a cell atlas of an organism. So it’s good to see it all now paying off. But yeah, it’s definitely a first draft. In this way, there is a good analogy with the Human Genome Project.

When the first human genome was published, it was a genome project. There were all kinds of loopholes and missing but they were incredibly useful stuff. Now, 20 years later, we’re seeing the first human genomes from telomere to truly expired telomeres, which adds value. And I think of these cell atlases the same way. These are drafts. We’re not saying we’ve found every type of cell in the human body, or even every tissue, but boy it would be very useful.

How did researchers start using it?

I have a colleague who wants to use it to study brain cancer. He was finding potential drug targets and wanted to look elsewhere in the body for unexpected toxicity. I think a lot of people have taken this approach. They have a drug target that’s important for a disease and they want to know where that protein is expressed — what other types of cells are, what other tissues are — because making a drug against that target can affect other tissues than you want them to.

Another good example is a paper actually researched by one of my students, Sivan Forberian, in which I used the atlas to understand something about liquid biopsies. She realized she could use Tabula Sapiens to analyze cell-free copies and original cell types. This has generated great interest in the diagnostic community.

With the idea in hand, could you look at the signatures of the disease coming from the RNA circulating in someone’s blood and trace it back to the specific cells where this malfunction occurs?

exactly right.

The Human Cell Atlas Consortium has taken a kind of one-at-a-time approach, with different research groups working on the tissues of their expertise. How are Tabula Sapiens different?

What we’ve brought to the table is figuring out how to conduct these multi-organ experiments. Which was a great collaboration in itself. You know that the idea of ​​taking all of these organs from a single donor has never been done before. And because these are living donors, we really have to get everyone out there, where these people are operated on. [The Tabula Sapiens project worked with an organ procurement organization to preserve tissues while surgeons were harvesting organs for donation.] This is a major administrative challenge. It was a huge raise for me personally because I had always run a small lab. I had to learn how to do the big sciences.

But one of the great advantages of looking through tissues from the same person is that you can control all kinds of things like genetic background, epigenetic influences, and environmental exposure. This allowed us to do things like study linkage. Each gene contains different pieces that can be split in or out, depending on the piece used. What is not well known is whether splicing is cell type dependent. And we were able to map that here to find very interesting differences in splice use according to cell type and discovered a whole bunch of new splices that hadn’t been seen before.

The Human Cell Atlas is a successor to the Human Genome Project, which I mentioned earlier. In what ways do you see it moving forward the tradition of the great sciences as defined in that era and in what ways is it charting a new legacy?

It certainly shares some aspects of the great science. It requires a lot of coordination between a lot of groups, a lot of people all over the world. It addresses a problem that cannot be done otherwise, because we need all those diverse experiences and contributions. But it’s also different in two ways.

It is more collective. The Human Genome Project has been somewhat of a notoriously harsh.

What do you attribute it to?

It’s probably a function of the characters. The genome project included some big characters who didn’t really get along. Aviv and Sarah, the co-chairs of this project, and I have a much better relationship. Also in this case there is no private effort, so there is no competition between the public and private sectors.

Another difference is the cost. The first human genome cost $3 billion. We made a strategic decision to wait until the technologies became more affordable. Had the genome project waited up to five years, it would have been a lot cheaper. I spoke to Craig Venter [who led the private effort to sequence the human genome] About this, and I asked him if it was worth doing it earlier. “Oh it was definitely worth it. “We learned a lot,” he told me. Not sure I agree with this assessment. But the Human Cell Atlas teams were all on the same page about doing this when we felt the cost and benefit were right.

And that’s important because I think what we’re trying to do is much more difficult than sequencing the genome. The reason being genome sequencing is this incredibly well-defined chemical problem. This is a test tube with some chemicals in it. Tell me what chemicals are – a chemical is a DNA molecule. While understanding the nature of these cells is more complex. It’s not a chemical problem, it’s a biological problem. It is difficult to strip it in a simple measurement.

Because what you’re really doing is redefining the parameters of what it means to be this type of cell or that type of cell. Not just how the cell looks or where it lives, but these genetic programs that run each one of them. So how do you decide how deep to go – where to make these cuts?

That’s a good question, and one that’s been open for a long time. What is the difference between cell state and cell identity? From my point of view, I don’t think it’s a solved question yet. Society is still wrestling with it. We are still studying what the basic nature of these things is.

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