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RAG1 RAG2 Discovery and VDJ Recombination

30:12 recording · AUTO · 2 speakers

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Brief overview

David Schatz explains how he found RAG1 and RAG2, and how a transposon created adaptive immunity.

  1. A genetic gamble found the recombinaseWhile other labs took biochemical approaches, Schatz put a VDJ assay into fibroblasts and transferred whole genomes to find the rare cell that could recombine.
  2. RAG1 needed RAG2 to workRAG1 alone was far less active than expected; RAG2 sat right next to it in the genome, and together they produced a fountain of VDJ recombination.
  3. Adaptive immunity started with a transposonA RAG-like transposon inserted into an immunoglobulin domain-like exon in one early jawed vertebrate, and every jawed vertebrate alive descends from that individual.
Executive Summary AI
  • In a special Immune booster recorded 5 May 2025 at the American Association for Immunologists meeting in Honolulu, Cindy Leifer hosts David Schatz, the Waldemar von Zedwitz Professor and Chair of Immunobiology at Yale University School of Medicine, whose career has been spent explaining how the body builds a T cell repertoire able to see anything.0:47
  • Schatz traces his start to two chemist parents and a night when he was about 11 and his father burst through the door saying he had discovered something nobody else in the world knew, followed by a chemistry teacher, a biochemistry degree, two years studying philosophy, and a PhD in David Baltimore's lab at MIT and the Whitehead Institute.2:18
  • Instead of the biochemical hunt for the recombinase that occupied the 1980s, he transferred whole genomes of donor DNA into fibroblasts carrying a sensitive VDJ recombination assay, and with Margie Ottinger walked the chromosome through six genomic libraries until a northern blot showed a 7 KB RAG1 message — RAG1 alone was weak, but RAG2 sat right beside it and the pair gave a fountain of VDJ reco6:30
  • Both he and Ottinger went straight into faculty positions, at Yale and Harvard, and the evolutionary work that followed shows RAG1 and RAG2 began as a transposon — preceded by a RAG1-only element called transib — which jumped into the exon of an immunoglobulin domain-like gene in one early jawed vertebrate and gave rise to every jawed vertebrate now on the planet.11:42
  • Asked how he stays fresh, Schatz says he is driven by wanting to understand how things work rather than by application, calls basic science the engine and roots that keep the translational tree from withering, and tells trainees the key advice is to know yourself; his fun facts are roughly 30 snakes in the family house and a long career as a Dungeons and Dragons dungeon master.18:37
Key Quote
“he burst in the front door and said, we discovered something today that nobody else in the world knows.”
— David Schatz2:52
Key Quote
“you put them together into the fibroblasts and you get a fountain of VDJ recombination.”
— David Schatz8:47
Key Quote
“And it was, you just held up that northern blot and you just said, there it is.”
— David Schatz11:06