Explorers need maps. That’s as true for hikers blazing trails as it is for molecular biologists striving to cure disease. A new atlas of the lungs, recently published in Nature, is the most comprehensive map ever of that vital organ.
A team of researchers from Stanford University in Palo Alto, CA and the Chan Zuckerberg Biohub at Stanford and in San Francisco, used single-cell RNA sequencing to analyze the gene expression of 75,000 individual lung cells. They identified 58 different cell types, based on the pattern of genes turned on or off in each cell during the analysis. Forty-one of those cell types were already known based on histology, but 14 are new to science. While this is not the first attempt to map the cells of the lung, it is the most comprehensive, says Stanford molecular biologist Mark Krasnow, a senior author of the work.
A “nearly complete” understanding of the lung’s cell types, where those cell types are located, and the pattern of genes that predict their function are the major contributions of the study, he notes. Such a thorough understanding of the healthy lung will help researchers predict which cells are most likely to undergo cancer-causing mutations and track the progression of disease from the very first cell. Bioengineers designing synthetic lungs for surgical transplants could also benefit from a blueprint of a healthy lung.
Molecular biology is in the midst of a major push to map the cells of the human body, organ-by-organ. “It’s an amazing explosion right now,” Krasnow says, based largely on single-cell RNA sequencing, a technique first introduced in 2009.
Three years ago, Krasnow’s research group was working on an atlas of the lung using single-cell RNA sequencing in mouse and lemur models. But in October of 2017, a colleague diagnosed with lung cancer came to Krasnow’s office, the day before surgery, and offered his own tissue. Sixteen hours later, Kyle Travaglini, a Stanford PhD student in Krasnow’s group and co-lead author of the recent work, waited just outside the operating room in a gown and scrubs, ready to transport some of the resected lung tissue—both healthy and diseased—on ice back to the lab.
In the Nature study, Travaglini analyzed only the healthy lung tissue, both from his Stanford colleague and two other donors. He used a chemical solution and blender to separate the tissue into a suspension of individual cells. Then Travaglini extracted and sequenced each cell’s RNA to learn which genes each expressed. Cells with similar gene expression patterns were grouped together.
The analysis yielded 58 different cell types. Forty-one of them expressed characteristic genes, already associated with a known lung cell type. But 14 hadn’t been described in the literature. “Those are the most exciting,” Travaglini says. He then stained intact tissue with a dye targeted to those new cells to map their locations in the lung—for example, along the airways—hinting at their function. A separate study characterized two of the newly identified cell types, which are both associated with the alveoli. One is a capillary stem cell. If that cell could be made synthetically, Krasnow says, the cell could, in principle, be used to regenerate alveolar blood vessels in patients with severe infections such as COVID-19. He thinks such an application could be feasible in the next five years.
“The lung has always been known to be composed of a great variety of cells,” says lung developmental biologist Wellington Cardoso, who was not involved in the new work. Expanding the number of known lung cells from around 40 to nearly 60 became possible with single-cell technology, he notes. Cardoso, who’s based at Columbia University Irving Medical Center, lauds the study for identifying new cell types and the characteristic genes associated with them.
Next up, Krasnow, Travaglini, and collaborators are turning their attention to diseased lung tissue. They are now using single-cell RNA sequencing to study lung tumors from their colleague and the other donors. Krasnow anticipates that publication will come out in 2021 and sees the recent work as an important precursor. “You can’t understand the disease well,” he says, “until you understand normal healthy tissue.”
Other recent papers recommended by Journal Club panelists: