Why do white horses eat more than black horses?

Authors


I have known Bruce Merrifield since 1972. In many ways, I was a wandering scientist without a base and without a home. In my mind, Bruce Merrifield's laboratory was my scientific home, and Bruce Merrifield my scientific father. And it will always be that way. Whenever, I returned from my wanderings and wherever my ideas took me, I knew I could come back and see Bruce and tell him my stories and share my ideas.

The first time I met Bruce Merrifield was after I came back from Cambridge, England having spent time in Fred Sanger's laboratory sequencing an unstable small RNA that looked like a putative messenger. It had an initiator codon, a clear reading frame and a terminator codon. Bruce Merrifield was immediately interested in the research problem.

He asked me to present my theoretical and experimental work to him. This was actually the first time I ever presented my work with the idea of analyzing messenger RNA sequences for patterns. Still being a graduate student, when one was not sure whether he would become a scientist or not, and whether one's thesis was only of interest to himself, this recognition was very generous and supportive. It formed the basis of my feeling that I could always come to Bruce to present any idea or work that I had done and that it would be listened to, gently critiqued and, then, elaborated upon and then given a suggestion as to which direction to pursue.

Bruce Merrifield introduced me to Bruce Erickson, who took me under his wing and we immediately started the synthesis using the single vessel with the rotating clamp. We synthesized a 13-amino acid peptide coded by the M3 sequence.1

This synthesized peptide NH2MET–ILE–ILE–ARG–ALA–PHE–GLU–VAL–THR–ALA–SER–ARG–ALA–PHE–COOH was the first peptide ever synthesized by solid phase peptide synthesis from the coding of a nucleic acid sequence.

During the last couple of years of Bruce's life we outlined experiments in conjunction with Elizabeth “Libby” Merrifield and Norton Zinder to make ligands for the whole human genome. We knew from Brenner's work that the number of actual coding sequences was quite small. The number of coding sequences in the genome was somewhere between 20,000 and 30, 000. This meant we could synthesize peptide targets from the whole genome chemically on beads. Then we could use either a recombinant phage library constructed at Zinder's laboratory at the Rockefeller University or a chemical combinatorial library, which Bruce was starting to synthesize. The two would give different binding peptides which could be analyzed to determine the different constraints on a phage library versus a chemically synthesized library. We intended to make a binding ligand for every target in the human genome. This is a project that should be continued and completed for Bruce. It was during the discussions about the combinatorial library that he was going to synthesize when he asked me the question “Why do white horses eat more than black horses?” The question had a rationale. The size of the library would be determined by the number and concentration of each peptide. Therefore, the answer was “because there are more white horses”. I did not remember the punch line until Libby Merrifield reminded me recently; and it sat on my head for years.

I last saw Bruce in the hospital at Lenox Hill in New York in January 2006. I came over to deliver a new paper and a new idea about miRNA. Even though he was very sick, he still encouraged me and nodded his interest and support. I do not allow myself to believe Bruce is still not here. For over 30 years, I use to come and go and he was always here to visit, to listen, to help, to encourage, and create something new.

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