Appendix B: 

 "The Alta Surnmir 



that would get around the problems. The answer was no. but the process of thinking 

 about it forced many novel ideas to the surface. 



George Church began to ruminate on the ideas that culminated in multiplex sequencing. 

 He said later that discussions with Maynard Olson. Richard Myers, and others helped 

 him crystallize his inchoate ideas. (David Smith recalled watching George Church 

 disappear in a cloud of new-fallen powder one afternoon, and worrying about the future 

 of DNA sequencing technology.) 



Richard Myers showed work using RNase I to cut (and thus make detectable) single 

 base pair mismatches; he and Leonard Lerman showed early data using gradients of 

 denaturing agents embedded in electrophoresis gels as a way to detect heteroduplexes 

 and mismatches. Myers credits his roommate for the conference. Maynard Olson, with 

 clarifying his ideas and permitting him to expand the RNase I method to mismatches 

 other than C-A mutations. In a trip report to the Office of Technology Assessment. 

 Michael Gough characterized the Church and Myers presentations as technological 

 wonders and called the two young scientists, then largely unknown, the "two biggest 

 surprises" of the meeting (Gough. 1984). 



Charles Cantor showed how his and David Schwartz's first pulsed-field gel electro- 

 phoresis method could separate megabase-sized DNA fragments, resolving individual 

 yeast chromosomes and thus introducing an enormously powerful method to assess 

 DNA structure on this scale. He also showed his and Cassandra Smith's first macro- 

 restriction digest of the Escherichia coli genome, which suggested the tantalizing 

 possibility of physically mapping entire genomes by combining restriction cleavage and 

 pulsed-field gel electrophoresis. 



Maynard Olson showed early results of attempting to construct a physical map of 

 Saccharofuyccs ccrcvisiac using overlapping clones, and also showed good separation 

 of megabase-sized DNA using a modification of the Schwartz-Cantor electrophoresis 

 technique. Mendelsohn's DOE report noted that "while Olson's method would not 

 presently be chosen for analyzing human mutation rates, his philosophy of paying 

 careful attention to and investing in the quantitative, methodological details of DNA 

 technology had a recurrent and important impact on the meeting" (Mendelsohn, 1985). 

 Olson later brought the same core ideas to the National Research Council Committee 

 on Mapping and Sequencing the Human Genome, where those ideas, combined with 

 an expansion of goals to include genetic mapping, helped to forge a consensus that 

 dedicated genome projects were scientifically worthwhile (National Research 

 Council, 1988). 



At Alta, Elbert Branscomb described the state of the art in using flow cytometry and 

 immunofluorescence to detect altered protein products on the surface of red cells. 

 Branscomb later became the computer modeler and one of the architects for the 



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