Kelly conducts extensive research on telomeres – protective nucleoprotein complexes that cap chromosome ends in eukaryotic cells and play an integral part in protecting them against premature ageing or shortening due to enzyme telomerase activity – using cryo-EM and other structural biology tools such as cryo-EM. Kelly’s work holds great clinical relevance as loss of telomeres leads to premature ageing while increased upregulation of telomerase is often found among cancerous patients.<\/p>\n
Kelly’s group uses both structural biology and functional in-cell approaches to study how telomeres are maintained and how their shortening leads to cellular stress and DNA damage. Collaborating with Yiliang Ding’s group at John Innes Centre and Rhiju Das’s group at Stanford University, they have determined a dimeric model of human telomerase which has revealed an important dimerization interface that may serve as a hotspot for premature ageing disease mutations. Furthermore, their work has also identified how RNA-based telomerase recruits nucleosomes at telomere ends to counteract shortening.<\/p>\n
Cryo-electron microscopy has revolutionized our understanding of life. This cutting-edge imaging technique enables scientists to observe proteins, viruses and cell components near-naturally without using complex staining or crystallization processes.<\/p>\n
Cryo-EM was first developed four decades ago. This technique involves flash-freezing biological samples into glassy states before using electron beams to probe them for structures of subatomic particles within. Since its inception, cryo-EM technology has evolved significantly; three of its developers even won a Nobel Prize this year!<\/p>\n
The Grant Lab’s focus is to enhance the image quality produced by cryo-EM and address some of its obstacles that have prevented its full potential from being realized. They work towards improving sample preparation processes as well as pushing resolution limits at which dynamic structures can be solved. They also develop and use image processing methods for turning blurry 2D images into clear 3D reconstructions.<\/p>\n
As soon as a sample is loaded into a transmission electron microscope operating at cryogenic temperatures, a series of images are captured using scanning with a focused beam of electrons to produce 3D tomograms of it. Their resolution varies according to how many electrons were collected and their orientation in the sample.<\/p>\n
Cryo-EM has quickly become the go-to method in structural biology due to advances in hardware and software. Capable of producing atomic-level detail on complex biological molecules, viruses and cell components – such as membrane proteins, mitochondria and ion channels – as well as 3D imaging of large macromolecular assemblies and their interactions.<\/p>\n
The Grant lab is one of the pioneers of cryogenic electron tomography (CEMRC), founded by Morgridge Institute for Research’s Midwest Center for Cryogenic Electron Tomography (CEMRC). Researchers working through CEMRC collaborate to advance and explore all applications of cryo-EM, such as studying drug interactions with complex protein assemblies; understanding virosome structures and viral packaging mechanisms; as well as deciphering 3D architecture of viruses.<\/p>\n