Bridging structural biology and clinical research through in-tissue cryo-electron tomography

Structural biology is a field of research that investigates the structure and organization of macromolecules to decipher their functional mechanisms. Traditionally, it has adopted a reductionist approach out of necessity, focusing on the high-resolution analysis of macromolecules outside their natural cellular contexts. This contrasts sharply with clinical research, which examines human biology holistically through patient studies and cellular disease models, albeit with less detailed structural insights. Recent advancements are bridging this gap, enabling the study of macromolecular structures within more complex biological systems, from single cells to multicellular organisms and primary human tissues. These developments signal a pivotal shift within structural biology from traditional methodologies towards a more integrated understanding of biological complexity. Here, we highlight recent technological advancements that facilitate structural studies in tissue environments, showcasing the discoveries made possible with these approaches and the prospect of their applications in human clinical research. This commentary of the Sparks of Science series from the Catalysts program reflects on the contribution of technological advances in cryo-EM to medically relevant studies.