Part XVIII: Robert Bruce Merrifield, 1984 Prize in Chemistry
By Joseph Luna
By the time Bruce Merrifield sat down to write in his lab notebook in May 1959, a scientific puzzle had been twirling in his head for quite some time. What he wrote next summarized a Nobel-worthy problem and offered a bold but totally unproven solution, all in three sentences. It turned out to be an impeccably succinct opening salvo, not just for a research career, but for an entire field.
“There is a need for a rapid, quantitative, automatic method for the synthesis of long chain peptides. A possible approach may be the use of chromatographic columns where the peptide is attached to the polymeric packing and added to by an activated amino acid, followed by removal of the protecting group and with repetition of the process until the desired peptide is built up. Finally the peptide must be removed from the supporting medium.”
To unpack this a bit: Merrifield spotted the need to take amino acid building blocks and string them together to form a peptide of his choosing (or if a really long peptide, a whole protein). His idea in essence was to use a solid support to get an amino acid to hold still, so that he could methodically link amino acids together sequentially. Finally, the immobilized chain of amino acids, the peptide, could be released and studied.
At a time when molecular biology was just getting off the ground, Merrifield’s understated first sentence belies a history of protein chemistry already more than half a century old, as well as his own frustration at making the small peptides he was interested in studying. After joining Wayne Wooley’s research group as a post-doc at Rockefeller in 1949, Merrifield applied his biochemistry training by isolating and characterizing “strepogenins” a catch-all term for small peptides that stimulated bacterial growth. The standard practice was to isolate these peptides from a biological source, but this approach almost always generated scholarly (aka vicious) pushback: it was very difficult to rule out contamination. If a compound could be crystalized as a means of isolating it to “purity”, most biochemist naysayers would generally be assuaged.
Chemists, however, were an entirely different breed of naysayer. They would only be convinced by chemical synthesis of a pure compound, characterized at each intermediate step as a measure of quality, and where, by definition, no biological contaminant could be introduced since no life form (other than the chemist’s hands) was required. For this reason, most biochemists weren’t really considered chemists: they merely isolated and characterized what they thought were active compounds, but they could very well be fooling themselves. Justus von Leibig’s famous chemical dictum “Tierchemie ist Schmierchemie” (Biochemistry is sloppy chemistry) stung hard for the better part of a century.