Over the last two decades, cryogenic electron microscopy (cryo-EM) has transformed from what Dr. Andrew Ward calls the “outcast of structural biology” to one of the most promising technologies in the field. Ward, professor of integrative structural and computational biology at Scripps Research Institute, speaks with moderator Brandon DeKosky, assistant professor of chemical engineering at the Massachusetts Institute of Technology, about the evolution of cryo-EM and how its direct detector transformative technology enables scientists to craft favorable antibody responses.

Ward also talks about cryo-EM’s technological advantages when working with proteins, sterilizing immunity, and designing accurate structural biology pipelines that lead to next-generation vaccines. Finally, Ward offers his predictions about the immunological breakthroughs he thinks structural biologists will accomplish in the very near future.

BIOs

Andrew Ward, PhD, Professor of Integrative Structural and Computational Biology, Scripps Research Institute
Andrew Ward is a professor at the Department of Integrative Structural and Computational Biology at Scripps Research Institute in La Jolla, California. He received his Ph.D. from Scripps Research in the lab of Ronald Milligan, 2008, and continued with postdoctoral training in the laboratory of Dr. Geoffrey Chang between 2008-2010, also at Scripps Research. In 2010, he began as an assistant professor at Scripps. The Ward lab uses electron microscopy to image viral and malarial surface antigens in complex with neutralizing antibodies to generate structural data to improve antibody-based therapies and rationally design vaccines. The Ward lab has published extensively on cryo-EM studies of HIV envelope glycoprotein, including the first high-resolution structure of the soluble stabilized SOSIP trimer and full-length membrane-embedded trimer. This previously elusive target galvanized HIV subunit vaccine efforts, one of which began human clinical trials in 2020 as part of a large international effort.

The Ward lab also determined the structure of the first human coronavirus spike protein in 2016, which enabled structure-based vaccine design to create stabilized, pre-fusion subunit vaccine candidates for SARS CoV-2 spike proteins. These '2P' mutations are the basis of a patent and consequently have been used to develop the mRNA and other subunit vaccines for SARS-CoV-2 (COVID-19) by companies such as Moderna and Pfizer/BioNTech. Additionally, the Ward lab has recently invented an entirely novel method (EMPEM) to rapidly map polyclonal antibody epitopes in immune sera using single-particle electron microscopy. This approach can comprehensively interrogate the immune response to natural infection or vaccination in real-time (in days to weeks instead of months to years) and unprecedented depth. The knowledge acquired of the nature and range of epitopes on human pathogens targeted by antibodies throughout an infection or vaccination is now being used to design better vaccines, vaccine regimens, and epitope-specific monoclonal antibody discovery for immunotherapeutic development. The Ward lab has recently extended this technology to sequence antibodies directly from cryoEM data of polyclonal antibody-antigen complexes, further accelerating our understanding of combatting deadly human pathogens and discovering new monoclonal antibody therapeutics.

Brandon DeKosky, Ph.D., Assistant Professor of Chemical Engineering, Massachusetts Institute of Technology
Dr. Brandon DeKosky is an assistant professor in the Department of Chemical Engineering at MIT and a core member of the Ragon Institute of Massachusetts General Hospital, Harvard, and MIT. Research efforts at the DeKosky lab have developed a suite of high-throughput single-cell platforms for large-scale analyses of adaptive immunity. These efforts advance new approaches in biologic drug discovery and cataloging the vast genetic and functional diversity of adaptive immune cells in multiple disease settings. Key application areas include infectious disease interventions, especially malaria and HIV-1 prevention, and the development of personalized cancer therapeutics.

Dr. DeKosky has been awarded several honors for his research program. His Ph.D. research was supported by a Hertz Foundation and NSF Graduate Fellowship. In 2016, DeKosky was awarded a K99 Pathway to Independence Award and an NIH Early Independence Award and began a joint faculty appointment at the University of Kansas Departments of Chemical Engineering and Pharmaceutical Chemistry. He has also received the Department of Defense Career Development Award, the Biomedical Engineering Society Rising Star Award, and the AIChE Young Faculty Futures award. In 2021, Dr. DeKosky began a new position as an assistant professor in a joint appointment at MIT Chemical Engineering and The Ragon Institute.