- LungMAP data resource amasses information about how lungs develop in mice and humans
- High-resolution microscopic lung imagery helps scientists study lung cell type and function
- Understanding lung development will allow doctors to apply new strategies for positive health outcomes in premature babies
In 2016, over a dozen scientists and engineers toured a neonatal intensive care unit, the section of the hospital that specializes in the care of ill or premature newborn infants. Visiting the newborns helped put into perspective the reason for this gathering of researchers—lung development—and for their collaboration over the coming years.
James Carson of the Texas Advanced Computing Center (TACC) was part of this group. He and his colleagues have been working on the Molecular Atlas of Lung Development Program, known as LungMAP, funded by the National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health.
For the past five years, the LungMAP team has been building an open access data resource of the developing lungs in both laboratory mice and humans, in order to further our knowledge of how the lung begins to breathe. The resource contains highly detailed datasets of genes, proteins, lipids, and metabolites in the context of cell types and lung anatomy. Carson says LungMAP is now a uniquely comprehensive data resource on lung development.
"Thousands of babies are born prematurely every day," says Carson, co-PI on the project. "With normal development, the lung has the shape and cell types to breathe plenty of air upon birth. However, a premature lung may not be able to breathe enough air at birth, and it is a challenge to help the lung develop normally those first few months. There can be health effects that continue into adulthood without proper lung development."
"We're gathering data that's never been collected before," Carson says. "In the past, how scientists described lung development was limited by the methods available for measuring and capturing pictures. However, with access to the latest technologies for detecting molecules, we're learning about new types and subtypes of cells, and passing that information onto the whole community of lung researchers."
The first 5-year phase of the project, which is now in its final months, focused on characterizing the details of healthy lung development in mice and humans. The researchers are hoping to be part of the second phase of the project which will include a new focus on understanding diseases in the human lung.
Collaboration across the country
The large, collaborative project involves researchers at universities, medical schools, federal laboratories, and companies. They are collectively organized into six separate centers, four providing data collection and research, one providing human tissue samples, and one serving as the data coordinating center.
TACC is part of the Center of Lung Development Imaging and Omics, which also includes Pacific Northwest National Laboratory (PNNL), Baylor College of Medicine, and the University of Washington. TACC's role is focused on providing data storage and curation of tens of thousands of images, most of which are larger than 100 megapixels.
Charles Ansong at PNNL is the principal investigator of this research center. He and the project team at PNNL use proteomics and lipidomics to determine how much of each protein and lipid are in a tissue sample.
"We've done an excellent job over the past five years in pushing technology development to make measurements in smaller and smaller tissue samples," Ansong says. "Now we're able to perform single cell proteomics—so that given a single cell, we can detect and measure quantity for hundreds of different proteins."
The data from mouse tissue samples is collected both before and after birth, in order to give insight into all the stages of lung development. This information helps researchers understand what cells in the lung need to do to get to the point where they can support breathing properly.
"We're trying to figure out all the different cell types and where those cell types are," Ansong says. "Sometimes cells start as one type and then change to another type, depending on what stage of development they're in. The datasets from our center allow researchers to see where genes, proteins, lipids, and metabolites are located and in what quantities."
Carson says that it's not as useful to look at genes that every cell has in equal amounts. "We're more interested in genes that are unique to a specific cell type and function. With help from our collaborators at other LungMAP centers, I think we succeeded in identifying the most important genes for understanding lung development."
Cecilia Ljungberg at the Baylor College of Medicine collects the images from the donor mice. She also performs the tissue preparation, sectioning, and a technique called high-throughput in situ hybridization. This process is used to reveal the location of specific "messenger" ribonucleic acid sequences in tissues, a crucial step for understanding the organization, regulation, and function of genes.
From there, Ljungberg and her colleagues use a high resolution microscope to take images of these tissue sections, and upload them into CyVerse's BisQue. This powerful computational tool gives life scientists the ability to handle huge datasets, perform analyses, and evaluate, curate, and share images.
"The amount of data collected is pretty staggering," Ljungberg says. "So far, we have looked at more than 700 different genes at four different developmental stages in mice, and collected more than 20,000 images, with each image focused on a particular gene at a particular age."
"LungMAP.net contains all of the data from the different research centers,” Carson says. “For any given molecule, one can access a summary page of activity across development, and you can begin to see trends in the different cell types."
At this point in the project, the focus is on human lungs. The team is wrapping up the processing of approximately 5,000 images representing normal lung development in humans. With mice, each tissue section consists of a cross-section of the entire lung or lung lobe. However, human lungs are a lot larger. "The cross-section of the entire human lung doesn't fit on a standard glass slide, so we utilize sampling strategies instead," Carson says.
In the first phase of LungMAP, the NHLBI sought large quantities of highly detailed data sets using high throughput imaging and omics technologies.
"For Phase two, they're interested in progressing to high resolution 3D imaging and single cell type technologies,” Ansong says. “And they're interested in taking out the mouse and focusing on human lungs and diseases, which is good because by studying the human we're getting closer to direct impacts," he says.
The researchers involved believe the primary benefits will be felt in the near future. "Our goal is to fully understand the lung before and after birth so that doctors can apply new strategies to increase positive health outcomes for premature babies," Carson says.