According to Arjun Raj, an assistant professor of bioengineering in the School of Engineering and Applied Science, the field of biology has traditionally been about looking at the average properties of cells all at once, which can make it difficult to learn more about individual cells and how they’re different from one another.

“It’s almost like you took a bunch of fruit and put it in a blender and ended up with a smoothie,” Raj says. “A smoothie doesn’t really reflect any of the individual constituents, but we know that the individual constituents—for instance skin cells, liver cells, and muscle cells—are all different from each other.”

Rather than using the conventional approach of looking at the average properties of cells, the Human Cell Atlas, a project that Raj is a part of, is creating reference maps of every cell type in the human body as a basis for both understanding human health and diagnosing, monitoring, and treating disease. The project recently received 38 pilot grants, one of which covers Raj’s research, from the Chan Zuckerberg Initiative (CZI) Donor-Advised Fund, an advised fund of Silicon Valley Community Foundation.

“For hundreds of years, people have been classifying cells based on morphology, whether cells look different than others,” Raj says. “But in the last 50 years in molecular biology, we’ve been realizing that there’s this whole molecular viewpoint of cells, too. We take a picture of cells and we see these different shapes and so forth, but underlying that is the fact that we have a genetic code that gets read out differently in every cell. It’s like they have the same hardware but they’re kind of running different software on top of it.”

One of the goals of Human Cell Atlas researchers is to profile what gets read out of the genetic code differently across all the various cells. This data would allow them to come up with a “molecular portrait” of every cell type in the human body, which may lead to the discovery of new cell types.

“We could find new types of immune cells, skin cells, and all these different things that we all thought were the same because they kind of look the same under the microscope,” Raj says. “But now, using these new tools, we could potentially reveal hidden differences that we just didn’t know about before.”

Raj’s group has been developing a toolset for measuring RNA, which Raj says is an easy way to determine which genes are active in a given cell. Deciphering which cells or genes are on or off in these different cells can help researchers build that molecular portrait.

“What we’ve developed in the lab,” he says, “are ways that allow us to visualize single molecules of specific RNA. If I have a particular gene and I want to see if this gene is active in a particular cell type, we can actually use these probes to look under the microscope and see individual spots—each spot being a single molecule of RNA—and we can really get very quantitative measurements.”

One of the major problems with this method is that it requires very high-powered microscopy since the individual molecules it’s looking at have very dim signals. Being able to make those signals brighter is an important step for accomplishing the types of things the researchers hope to do.

“One question we hope to answer,” Raj says, “is whether there’s a way [we] can visualize gene activity in a more zoomed out view, but still maintaining the quantitative nature of our tools and their powerful ability to detect these molecules in a specific way.”

As part of the CZI grant, Raj’s lab is developing a method that allows them to exponentially amplify the signal in the cell itself. This will enable them to take the dim signals and maintain all the positive things about them while also making them significantly brighter under the microscope. In particular, the grant will give them the opportunity to expand the tool to allow it to measure multiple genes at the same time as well as use it to look at human tissue samples and see the activity of genes. 

“We could do things like take a cancer cell and find where it came from, what it’s most like, in what ways it changes its type into something else, and what’s driving those changes,” he says. “When we’re blending everything up into smoothies, it’s really hard to tell how diseases are changing things. That’s part of the power of the Human Cell Atlas.”