This map of a developing liver shows single cells as dots, color coded by cell type.
Newcastle University
The National Institutes of Health’s (NIH’s) latest foray into turning emerging technologies into useful data sets is focusing on how the body’s trillions of cells interconnect and interact. The Human BioMolecular Atlas Program (HuBMAP) aims to describe the biochemical milieu and the locations of individual cells in the body’s major organs, researchers write this week in Nature. It uses technology heralded by Science as the 2018 Breakthrough of the Year.
The goal is to “establish a baseline of what constitutes a healthy system,” says HuBMAP grantee Julia Laskin, an analytical chemist at Purdue University in West Lafayette, Indiana. That way, she says, researchers will be able to see what goes awry in disease.
Until recently, biomedical scientists had just a broad-brush view of how organs functioned. In particular, they had succeeded in getting only a sense of gene activity—when genes turn on and off—in specific tissues. Gene activity defines what a cell does. But organs consist of many kinds of cells, each with their own molecular profiles.
In 2016, drawing on technologies that enable researchers to routinely study individual cells, a group of 90 scientists from the around the world launched the Human Cell Atlas (HCA), which aims to catalog how cells operate in different tissues. The effort now involves 1500 scientists from 65 countries, and draws support from many sources, including the Wellcome Trust and the European Union’s Horizons 2020 program, says Aviv Regev, one of the HCA’s founding members and a computational systems biologist at the Broad Institute in Cambridge, Massachusetts.
HuBMAP represents the U.S. government’s commitment to this international grassroots effort, says the corresponding author on the 9 October Nature paper, genomicist Michael Snyder from Stanford University in Palo Alto, California. “Hopefully [HuBMAP] will have a major role in leadership and building the framework” that will help meld the HCA with about a dozen other projects focused on single cell analyses of specific organs, such as the brain, lungs, kidney, and pretumor and cancerous tissue, he explains. Such melding would involve establishing common standards, protocols, and ways of presenting the data. “As much as possible, we want to be able to compare apples to apples and oranges to oranges,” Snyder says.
Overall, NIH envisions spending $200 million on HuBMAP over 8 years. To date, NIH has awarded $54 million over the next 4 years to about 120 researchers. Some teams will study the cells themselves: In addition to determining gene activity and using other omics approaches, they will gather spatial information about proteins, DNA modifications, lipids, RNA, and other key molecules using fluorescent microscopy and imaging methods to build 3D maps of cells. A second group of researchers is tasked with developing the computer tools needed to present these data in a coherent way and to allow researchers to explore the atlas. A third group, which includes Laskin, is developing better technologies for studying these cells. Such development is needed, Laskin says, because with single cells, “You are getting to the point of having a very small amount of material to analyze.”
This NIH support comes from the Common Fund, which builds on efforts straddling many NIH institutes to move a new field forward. For example, the Common Fund supported the Human Microbiome Project, which helped kick-start the current emphasis on the role of bacteria in and on the human body in health and disease. For this new project, NIH’s Richard Conroy says, “The biggest challenge will be getting everybody together at first.” But he expects that once that happens, progress will be fast.
That progress was in evidence this week, as Nature also released two papers that draw on new HCA data. In one, dermatologist Muzlifah Haniffa from Newcastle University in the United Kingdom and her colleagues studied 140,000 cells from a developing liver, as well as 74,000 skin, kidney, and yolk sac cells, and described how the blood and immune systems form. The liver’s ability to make these blood and immune cells changes between seven and 17 weeks postconception, they report in the 9 October issue of Nature.
In the second paper, Prakash Ramachandran, a clinician scientist at the University of Edinburgh, and his colleagues used single cell technology to describe all the cells involved in forming scar tissue in diseased livers. The cells consist of subtypes of three key cells: white blood cells called macrophages, endothelial cells—which line blood vessels—and scar-forming cells known as myofibroblasts, the team reports. Knowing the cells and how they talk to each could lead to ways to block scarring, Ramachandran says.
Data from both papers will be part of the developing atlas, which Conroy describes as a “Google map” for the body, where one can drill down to the molecular details of each cell. This week, the HCA had a meeting in Barcelona, Spain, to see where the effort stands and discuss how to move forward, and NIH will co-host another such meeting in the spring. “What’s exciting,” Regev says, “is how all these pieces are coming together.”