False-color scanning electron micrograph of the exoskeleton of Drosophila melanogaster, in an area of the head close to the eye region. (Anne Weston, Francis Crick Institute)

Science owes much to the humble fruit fly (Drosophila melanogaster), which is more similar to a human than its appearance may suggest. Of the approximately 14,000 protein-coding genes in the fly genome, about three-quarters have a human counterpart. This striking similarity, combined with the facts that these tiny bugs have an extremely short generation time and are easy to raise in a lab, has led to numerous breakthrough discoveries in the fields of genetics, developmental biology, and neurobiology. 

The fruit fly has been an essential model organism in biological research since the early 1900s, when Thomas Hunt Morgan and his colleagues closely examined thousands of flies to confirm the theory of chromosomal inheritance—that genes are located on chromosomes. Since then, experiments with fruit flies have led to advances in understanding and treating sleep disorders, cancer, heart disease, and neurodegenerative diseases such as Alzheimer’s and Parkinson’s.  

Now, in a major contribution to fruit fly biology, CZ Biohub researchers have collaborated with an international team of scientists to create the Fly Cell Atlas, published on March 4, 2022 in Science. A valuable resource for biologists worldwide, the atlas contains data from more than half a million cells, and distinguishes cell types in 15 tissues by revealing differences in gene expression. 

Aiming for cohesiveness

In recent years, with the rise of single-cell genomic technology, scientists have been able to study Drosophila tissues at unprecedented resolution, looking at the expression of all genes simultaneously in each individual cell. Such fine-grained insights can help to decipher how certain cells differ from and interact with their neighbors, and how they form and function in a given tissue. 

With the fruit fly as popular as ever in biomedical research, this type of single-cell analysis has quickly gained traction in the research community. These data have been generated by many different laboratories, however, using different protocols and different genetic backgrounds, which makes it difficult to accurately compare gene expression across cells and tissues, says Stein Aerts, a computational biologist at KU Leuven in Belgium.

Aerts is one of the cofounders of the Fly Cell Atlas Consortiuma team that grew organically when a group of specialists in the Drosophila research community gathered in Leuven in 2017. While discussing the state of the field over glasses of Belgian beer, the group forged plans to create the first complete map of gene expression in every fruit fly cell. 

To accomplish this daunting task, Bart Deplancke, a bioengineer and geneticist at École Polytechnique Fédérale de Lausanne in Switzerland and co-leader of the Consortium, reached out to Steve Quake and colleagues at the CZ Biohub because of their deep experience creating single-cell atlases. Quake and his team had just completed the Tabula Muris mouse cell atlas and were beginning work on a human cell atlas, the Tabula Sapiens, when they agreed to collaborate with the Drosophila researchers to develop a fly cell atlas.

“The cell is such a rich and complex object, much more complicated than the genome at some level,” Quake says. “And we’re poised to now really understand it in a fundamental way by using these cell atlases to create molecular definitions of all the cell types in the organism.”

To jump-start the project, Bill Burkholder, director of scientific program management at the Biohub, organized a two-day gathering of the Fly Cell Atlas team in San Francisco in August, 2019. “During that meeting, as we were describing the steps we took to build Tabula Muris and Tabula Muris Senis, we could see the group embracing this new idea of team science,” recalls the Biohub’s Angela Oliveira Pisco, associate director of Data Science. “It looked as if for the first time they were sure the Consortium would succeed.”

Excited about the new opportunity, “we told them we would share everything with them, our tools and our experimental techniques,” Quake says. “And we agreed to do a large fraction of the experiments ourselves.”

A massive team effort

“This was really a titanic piece of work,” says Liqun Luo of Stanford University, who also co-led the endeavor. “The entire consortium involved 158 experts from 40 different laboratories across the world, and it was supported both technically and financially by the CZ Biohub.”

Two early-career researchers on opposite sides of the Atlantic spearheaded the data generation and analyses: Jasper Janssens, a graduate student at KU Leuven, and Hongjie Li, assistant professor at Baylor College of Medicine and until recently a postdoc in Luo’s lab at Stanford

The team adopted two complementary strategies to achieve their goal, Janssens explains: “We sequenced genetic material from dissected tissues so we knew the identity of the tissue source, but we also sequenced genetic material from the entire head and body to ensure that all cells were sampled.”

The Biohub then served as the project’s “experimental node,” Quake says, responsible for processing all the samples, performing all the genetic sequencing, and creating the sequencing libraries. “It was great to see that we could transfer our intellectual leadership in how you make a cell atlas of an organism in general to this group of motivated people who wanted to do it for the fly,” he says.

In addition to Quake and Pisco, Biohub-affiliated scientists and alums participating in the work included Norma Neff, leader of the Genomics and Sequencing Platform; Angela Detweiler, Genomics Platform scientist; Chief Technical Officer Jim Karkanias, Aaron McGeever, senior software engineer in Data Sciences; Research Associate Jia Yan; Rene Sit and Michelle Tan, both now at ArsenalBio, Sai Saroja Kolluru, now at 10X Genomics; Felix Horns, a former graduate student in the Quake lab now at Caltech; former Biohub Investigator Jure Lescovec of Stanford; and Maria Brbić, postdoc in the Lescovec group.

The next frontier

The result is a thorough cell atlas for the adult fruit fly, comprising genetic data for more than 580,000 cells representing more than 250 distinct cell types. “Our Fly Cell Atlas will constitute a valuable resource for the research community as a reference for studies of gene function at single-cell resolution,” says Norbert Perrimon, a Drosophila geneticist at Harvard Medical School, who co-led the project. 

Understanding gene expression at the cellular level can help Drosophila researchers model human diseases with a deeper knowledge of the distinctive cell types they’re studying in their experiments. The Fly Atlas Consortium has made all its data freely available online for further analysis through multiple portals, or for custom analyses using other single-cell tools. 

The development of cell atlases for various organisms is “one of the next great frontiers in biology,” says Quake. “If the last 20 years were the genomic age, the next 20 years will be the age of cell biology, and the cell atlases are the foundation on which a lot will be built.”