For over four centuries, scientists have endeavored to chart the intricate landscape of human cells since the invention of the microscope. Despite these efforts, many components of cellular structures remain elusive to our understanding. Dr. Leah Schaffer, a postdoctoral research scholar at the UC San Diego School of Medicine, highlighted the gap in current knowledge, stating, "We know each of the proteins that exist in our cells, but how they fit together to then carry out the function of a cell still remains largely unknown across cell types."

In a remarkable development, Schaffer and her dedicated team at UC San Diego, working alongside researchers from Stanford University, Harvard Medical School, and the University of British Columbia, have successfully created a detailed and interactive map of U2OS cells, a cell line associated with pediatric bone tumors. Their groundbreaking research combines high-resolution microscope imaging with the biophysical interactions of proteins, allowing them to unveil the subcellular architecture and the complex protein assemblies that exist within these cells.

The newly developed map has revealed protein functions previously unknown to researchers and is expected to enhance understanding of how mutated proteins contribute to diseases, particularly childhood cancers. Furthermore, this comprehensive map will serve as a vital reference point for future studies aimed at developing similar maps for other cell types. The findings from this significant research are set to be published in the prestigious journal Nature on April 9, 2025.

Dr. Trey Ideker, co-senior author of the study and a prominent professor of medicine at UC San Diego, expressed a critical observation about the current state of cell biology. He remarked, "Based on cell biology 101 and textbook pictures of cells, you might think that we understand everything about a cell. But what's remarkable is that for no human cell type do we really have a proper parts catalog and assembly manual." This reflects an ongoing challenge in the field, wherein a comprehensive understanding of cellular mechanisms is still developing.

The research team employed a sophisticated technique known as affinity purification to isolate individual proteins while documenting their interactions with one another. They meticulously analyzed over 20,000 images of the interiors of cells, marking them with fluorescent dyes to illuminate the locations of proteins of interest sourced from the Human Protein Atlas. By integrating this extensive dataset encompassing more than 5,100 proteins, the researchers successfully identified 275 distinct protein assemblies of various sizes within U2OS cells.

Dr. Emma Lundberg, another co-senior author of the study and an associate professor of bioengineering and pathology at Stanford University, noted a historical bias in scientific understanding. She explained, "Historically, scientists have been biased by the notion that one gene codes for one protein that has one function. However, there is now an increasing number of known multifunctional proteins, and while we're probably still underestimating how many there are, this study demonstrates the importance of multimodal data integration to reveal these multifunctional properties." This acknowledgment of protein multifunctionality could shift the focus of research methodologies in cell biology.

The researchers discovered 975 functions previously unknown for various proteins within the map. For instance, C18orf21, a recently identified protein, was found to be involved in RNA processing. Meanwhile, the DPP9 protein, recognized for its role in cleaving proteins at specific sites, has been implicated in interferon signaling, a crucial pathway for combating infections.

In an innovative twist, the team utilized GPT-4, a large language model artificial intelligence tool akin to ChatGPT, to enhance their understanding of individual proteins and how they function within protein assemblies. This AI-assisted approach dramatically reduced the time required for analysis compared to traditional methods, according to Clara Hu, a biomedical sciences doctoral candidate in Ideker's lab. The AI tool, documented in a recent publication in Nature Methods, summarized the overarching themes of each protein assembly and suggested names for them, which were then incorporated into the cell map.

Dr. Schaffer compared navigating the U2OS cell map to exploring an online geographical map, stating, "You're able to really explore, zoom in, and see what proteins are part of these different communities, and then see where those communities are located." Clara Hu added, "As you increase resolution, you can see even more detail-level information." This level of detail is crucial for researchers who aim to understand the cellular mechanisms underpinning various diseases.

The research team is currently focused on refining the map further, allowing for high-resolution zoom capabilities for users. This U2OS cell atlas is anticipated to not only advance our understanding of childhood cancers but also to act as a blueprint for scientists seeking to map other cell types, utilize artificial intelligence to uncover the functions of less understood proteins and protein complexes, and discern the mechanisms involved in a wide array of disease processes.

Other co-authors on this groundbreaking study include Gege Qian, Dorothy Tsai, Nicole M. Mattson, Katherine Licon, Robin Bachelder, Yue Qin, Xiaoyu Zhao, Christopher Churas, Joanna Lenkiewicz, and Jing Chen from UC San Diego, along with Kei Ono and Peter Zage at UC San Diego; Kyung-Mee Moon and Leonard J. Foster at the University of British Columbia; Abantika Pal, Neelesh Soni, Andrew P. Latham Aji Palar, Andrej Sali, and Ignacia Echeverria at the University of California San Francisco; and Steven P. Gygi, Laura Pontano Vaites, Edward L. Huttlin, and J. Wade Harper at Harvard Medical School; as well as Anthony Cesnik, Ishan Gaur, Trang Le, William Leineweber, and Ernst Pulido from Stanford University.

This ambitious study received funding from several prestigious organizations, including the National Institutes of Health (NIH), Schmidt Futures, the Wallenberg Foundation, and the Gran Gustafsson Foundation. The information for this article was provided by the University of California - San Diego, with the original piece authored by Susanne Clara Bard. Note that the content may be subject to editorial adjustments for style and length.