A new technique creates cell-surface-based glycan arrays that are more lifelike than the usual ones assembled by attaching glycans directly to solid supports. Glycans, carbohydrate oligomers, decorate prokaryote and eukaryote cell surfaces. They can serve as markers of cancer, inflammation, and other conditions and play key roles in processes like cell recognition and tissue development. Researchers screen glycan arrays to identify proteins that recognize and bind specific glycans involved in these diseases and processes. But protein interactions with glycans attached directly to nonnatural solid surfaces may not always faithfully represent those that occur on live cells. Matthew Scott Macauley and Peng Wu of Scripps Research Institute California and coworkers therefore developed a chemoenzymatic method to create cell-based glycan arrays (Nat. Commun. 2018, DOI: 10.1038/s41467-018-03245-5). Starting with Chinese hamster ovary cells in microtiter plate wells, the researchers used different glycosyltransferase enzymes to add natural and unnatural sugars to diversify the cells’ native glycans. By screening the cell-containing wells with glycan-binding proteins, they identified for the first time cell-surface glycans that recognize Siglec-15, a potential target for osteoporosis drugs. When tested in human cells, one of the glycan “hits” showed anti-osteoporosis activity—inhibiting the formation of osteoclasts, cells that absorb bone tissue. The researchers hope the living arrays will be useful for identifying glycan-binding protein ligands in a more natural way than has been possible before.