Paul Jaschke

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Stanford University

Paul is a Biological Engineer with diverse research experience ranging from mapping chlorophyll biosynthesis pathways to designing and building synthetic virus genomes. He started off his science career at the University of Alberta (Canada). After achieving an Honors B.Sc. in Biochemistry in 2003 Paul took a year off and traveled the Pacific. During that time he worked on natural products chemistry at the University of Queensland in Brisbane Australia.

Paul started his Ph.D. in the Beatty Lab at the University of British Columbia in 2004. While at UBC Paul discovered that a photosynthetic bacteria called Rhodobacter sphaeroides was capable of re-routing its chlorophyll biosynthetic machinery around a blockage to generate a new type of chlorophyll. Paul is currently focused on building viruses to understand them and pioneering a synthetic biology method called negative genomics.

Tue July 9 | 2:00 - 4:00
ABSTRACT: Taming genome complexity via bacteriophage X174 synthetic genome design

Our capacity to read and write DNA has outpaced our ability to design useful and predictable DNA sequences. Synthesizing genomes could enable powerful new approaches to biological discovery, however, due to the overwhelming complexity of biological systems, most designs have largely recapitulated natural sequences. To advance synthetic genome design methods we focused on the 5.4 kb X174 bacteriophage genome because it is: (1) small enough to enable rapid prototyping of new designs, and (2) complex, displaying an intricate architecture encoding 11 overlapped genes spanning all reading frames. Two approaches were used to reduce the complexity of the X174 genome while addressing important biological questions. Gene overlaps are common in nearly every genome and their functional significance is controversial. We investigated the origin of gene overlaps by designing a fully decompressed synthetic genome ‘X174.1f’, that contained no overlapping genetic elements. We describe our genome design, construction, and successful redeployment. Phenotypic comparisons between wild type and X174.1f showed there were minimal observable differences between the two viruses, and no essential information in the gene overlaps. Additionally, the results suggest that gene decompression is a viable approach to reducing genome complexity. Secondly, we developed a method of genome simplification called ‘negative genomics’ that seeks to address a fundamental question of genome annotation: at what point can we confidently say we have found all the genes? To establish all potential open reading frames (ORFs), other than the 11 known genes, we searched the X174 genome using computational gene-finding tools. Finding 85 candidate cryptic ORFs we designed a new genome, called ‘X_clean’, with 88% of these cryptic ORFs erased via synonymous changes. Testing the prototype X_clean genome revealed that it is capable of forming plaques but is phenotypically different from wild type, suggesting previously undiscovered functions associated with the disrupted ORFs.