On the trail of protein sequences

I was somewhat taken aback when asked to write an article for a History issue of Bioinformatics, because not by any stretch of the imagination am I a ‘bioinformaticist’. I have no formal training in computer or information science. By education, I am a biochemist whose early experience was in the area of proteins. Bioinformatics was not a term that existed when I began my scientific career. My introduction to computers came about from an interest in biochemical evolution, a subject that first fascinated me many years ago when I was a graduate student. The laboratory in which I did my graduate training was working on blood proteins—especially those involved in blood coagulation—and a number of chance factors led me to inquire how this quite complicated process could ever have evolved. Blood clotting in humans was known to depend on the coordinate interplay of a dozen or more protein factors. This was a period when the notion of one gene–one polypeptide chain was beginning to be generally accepted, and it seemed unlikely to me that the entire melange could have evolved in one fell swoop. Rather, there must have been a series of gene duplications involving these clotting factors, just as had been recently suggested for some of the chains of hemoglobin. I was an early advocate of the ‘all new proteins from old proteins’ school of thought. The question arose, if one knew the amino acid sequences of all these clotting proteins, could the order of the duplicative events be reconstructed? As it happened, the question was moot, because none of their sequences was known at the time, and determining even one of them would have been an arduous undertaking. Accordingly, I took a different tack, concentrating on a search to find the phylogenetic distribution of the clotting factors. In particular, I sought out the most primitive creatures which exhibit the thrombin-catalyzed conversion of fibrinogen to fibrin. In the end, I found that all vertebrates, even jawless fish like the lamprey, had this ability (Doolittle et al., 1962).