Mapping Every Human Cell

It took the Human Genome Project a decade to lay out our complete genetic code. Since then, advances in sequencing technology have vastly sped up the pace by which geneticists can parse As, Gs, Ts, and Cs, which has allowed biologists to think even bigger—by going smaller. Instead of spelling out all of a person’s DNA, they want to create a Human Cell Atlas that characterizes the genetic material of every single cell in the body. Doing so will create “a reference map of what a healthy human looks like,” explains bioengineer Aaron Streets.

Understanding what makes individual cells unique requires insight into the epigenome—the suite of chemical instructions that tell the body how to make many kinds of cells out of the same string of DNA. “This is where the notion of the epigenome comes into play,” says Streets, who runs a lab at the University of California, Berkeley. All cells may be reading from the same book, but each one’s epigenome highlights the most relevant passages—essentially how and which genes are expressed. Streets is inventing the tools scientists need to zero in on those specifics.

Reading the epigenome is important, says Streets, because, in addition to showing why healthy cells act the way they do, it can also reveal why an individual one goes haywire and causes illness—cancer, for example. Once the markers of a rogue actor are known, he explains, researchers can develop therapeutics that address the question: “How can we engineer the epigenome of cells to fix the disease?”

Characterizing cells is highly interdisciplinary work, which Streets is perfectly suited for. He majored in art and physics but “just wasn’t good at” biology organismal studies. It wasn’t until graduate school, where he worked with a physicist-turned-bioengineer, that he realized how much insights gleaned from math, physics, and engineering could benefit the study of living things.

As a start, this year Streets and his colleagues published a protocol in the journal Nature Methods for reading particularly mysterious parts of the genome. The tool identifies sections within hard-to-read DNA regions that bind proteins—and thus have epigenomic significance—by bookending the strings with chemical markers called methyl groups. To James Eberwine, a pharmacology professor at the University of Pennsylvania and a pioneer of single-cell biology, “it is going to be very useful” for building a cell atlas.

Now, Streets’s lab is building new software to piece together the millions of sequences that comprise a single cell’s genome. And, because mapping every single anatomical cell will require a fair bit of teamwork, the programs they create are shared freely with other scientists who can use the tools to make their own discoveries. “If you look at really huge leaps in progress in our understanding of how the human body works,” says Streets, “they correlate really strongly with advances in technology.”—Y.T.

Publication: Nicolas Altemose, et al., DiMeLo-seq: a long-read, single-molecule method for mapping protein–DNA interactions genome wide, Nature Methods (2023). DOI: 10.1038/s41592-022-01475-6

Original Story Source: University of Arizona