When the "unexpected" scientific discovery was announced, Gao Pu was dining at home with two colleagues. Despite the lively conversation, the computer performing complex calculations behind him continually caught Gao Pu's attention. He would check on it every so often.
Suddenly, Gao Pu, in front of the computer, exclaimed in surprise, and his two friends quickly gathered around. The newly resolved structure of the cGAS (a novel innate immune receptor)-DNA (cGAS's recognition ligand) complex displayed a small molecule that had never been seen before. The high-resolution electron density map on the computer indicated that the little secrets of "nature's craftsmanship" were being unraveled in this small room.
Reflecting on this scene from over a decade ago, Gao Pu can still feel the joyous shock. Today, as a researcher at the Institute of Biophysics, Chinese Academy of Sciences (hereinafter referred to as the Institute of Biophysics), he continues his exploration in the field of scientific research he loves.
In the recently concluded year of 2023, Gao Pu won the Tan Jiazhen Life Science Innovation Award, the Chinese Academy of Sciences Young Scientist Award, and the National Science Fund for Distinguished Young Scholars, based on his years of work in the field of nucleic acid immune response. However, compared to these tangible achievements, he seems to prefer talking about the "intellectual joy" and "emotional value" that scientific research brings him.
Half "Unboxing Mystery Boxes", Half "Cracking Cases"
Starting from and eventually returning to the Institute of Biophysics, Gao Pu’s research has always been on cellular immune responses and regulation against abnormal nucleic acids, which is the "spear" and "shield" battle occurring within cells.
In 2005, he was admitted to the Institute of Biophysics for a joint Master-PhD program. There, in the research group led by academician Liang Dongcai, he studied the bacterial immune response system to abnormal DNA, namely the restriction-modification system. Later, he went to the United States for postdoctoral research in Dinshaw Patel's group at the Memorial Sloan-Kettering Cancer Center, focusing on the immune response pathway to abnormal DNA in mammals—the cGAS-STING pathway.
The immune response to abnormal nucleic acids is a crucial and core mechanism of danger perception in cells, a process that exists widely in almost all host systems from bacteria to mammals. An in-depth understanding of such immune mechanisms can directly support the prevention and treatment of various human diseases and the development of potent nucleic acid manipulation tools.
Gao Pu's early focus was on the structural basis of macromolecular complexes during the nucleic acid immune response. The exciting scene at the beginning of the article marks an important scientific discovery he made during his postdoctoral period—observing a cyclic dinucleotide molecule cGAMP containing special 2'-5' phosphodiester linkages in the catalytic pocket of the DNA-activated immune receptor cGAS. This work not only systematically revealed the structural basis of cGAS recognizing DNA and completing the catalytic process but also discovered the chemical structure of a novel immune messenger for the first time. Moreover, this study also directly led to the approval and application transfer of three international patents, with Gao Pu as one of the main contributors.
For Gao Pu, structural biology research has helped reveal many important mechanisms in the field of nucleic acid immune response, but he does not want to swim only in familiar waters. He hopes to comprehensively use various technical methods centered around his long-term focus area and systematically answer interesting and important scientific questions.
"The pleasure of structural biology research is a bit like unboxing mystery boxes. The moment the answer is revealed, you can immediately obtain a wealth of scientific information, which is thrilling and impactful; on the other hand, the pleasure of functional research is like a detective solving a case, reasoning and exploring amidst complex information and clues. Although most of the time it is relatively mundane, it has more aftertaste—at least for me, both types of scientific research enjoyment are important," Gao Pu said.
In Gao Pu's current research group, about half of the people are engaged in molecular mechanism research led by structural biology, while the other half are conducting pure functional exploratory research—half "unboxing mystery boxes" and half "cracking cases".
Deciphering the Attack and Defense Battle Within Cells
Immune response and regulation are both interesting and useful.How cells recognize danger, fend off pathogen invasion, how pathogens and tumors bypass immune barriers, or even directly kick the immune guardians out of the battlefield... These quiet battles in our bodies fascinate Gao Pu.
In 2021, Gao Pu's research group published their first pure functional research progress in "Molecular Cell". The study mainly explored how herpesvirus suppresses the host's cGAS-STING pathway and achieves immune escape by downregulating its immune activity.
According to conventional speculation, this process should be realized by the virus protein binding directly to cGAS, "hijacking" and inhibiting cGAS activation. Therefore, Gao Pu's team first attempted to prepare a complex of the virus protein and cGAS an
