Hans Neurath
The Bial-Neurath Family
Duke University
Hans’ research studies at Duke University have dealt primarily with ‘proteins’. “The problem common to many of these investigations,” he wrote, “has been that of the structure and properties of the proteins, singly and combinations in which they occur in tissues and fluids. Representative samples of the proteins that have been investigated are the serum proteins, antibodies, proteolytic enzymes and their specific substrates, insulin, and the muscle proteins.”
When war broke out, he was asked to participate in a multi-laboratory project to detect false positive reactions in the serologic diagnosis of syphilis, a problem of civilian and military concern. False positive reactions were often associated with malaria, leprosy and other viral and bacterial infections. The object of their study was to determine whether the antibodies to syphilis differ demonstrably in chemical or immunological properties from those in sera that give biologic false positive reactions. The test Hans’ group developed eliminated many of the false positive reactions but was later replaced by a more practical test developed by other participating laboratories.
Stimulated by this work and by a publication on the nature of antibodies by Linus Pauling, Hans organized a graduate course on immunochemistry and he managed to stay with his readings “at least two sessions ahead of the class”. Pauling claimed that antibodies had the same chemical structure as ‘normal’ serum globulin but differed primarily in their folding pattern. Questioning the validity of this notion Hans and John Erickson carried out a study project on the comparative antigenic behavior of native and denatured normal globulin. This study came to the conclusion that immunological methods of measuring protein activity were too insensitive to be used as a guide in studying the structure/function relation of proteins generally.
University of Washington
Hans said that his research interests were solicited and stimulated by the simple question: What differentiates proteins that digest from proteins that are digested? He wrote in retrospect: “In many ways, the last 50 years at the University of Washington were the most exciting and rewarding years of my academic life. It was here that I could build up a long-range research program and derive the benefits of previous experiences in conducting basic research on proteins. It was also the beginning of an era that brought to the study of proteins new experimental approaches for their molecular characterization in terms of isolation, end group and sequence analysis, molecular degradation, and limited proteolysis. These were followed by X-ray crystallography and chemical synthesis and by more precise methods of characterizing the specificity and biological activity of proteins and their derivatives. Last but not least, it was the period of the discovery of the double helix and deciphering the genetic code. I was convinced of the merits and necessity of applying any of these methods and advances to our research program on proteolytic enzymes.”
According to his former colleagues Edmond Fischer and Earl Davie, Hans “undertook a seminal study of the pancreatic serine proteases trypsin, chymotrypsin, and carboxypeptidase, focusing in particular on the mechanism by which the zymogens (the inactive precursors of the enzymes) were activated. […] With Earl Davie, he isolated and determined the sequence of the hexapeptide that masks the activity of trypsinogen and, a couple of years later, elucidated the mechanism of activation of chymotrypsin. Such types of consecutive zymogen activations are involved in the initiation and regulation of complex pathways such as the blood coagulation cascade, as demonstrated later by Davie at Case Western Reserve University. […] When Hans initiated his studies on pancreatic carboxypeptidase, it was though magnesium might be the cofactor for the enzyme. But a collaborative study undertaken with Bert Vallee of Harvard showed that the enzyme was actually a zinc-metalloexopeptidase. Indeed, Vallee had constructed a flame-spectrometer that allowed him to detect and measure trace quantities of metals in biological preparations. The establishment of this novel family of proteases marked the opening of an entire new field of investigation. With Ken Walsh and Ralph Bradshaw, Hans set up a remarkably effective protein-sequencing laboratory with which they could determine the primary structure of a variety of proteins. […] By extending those studies to proteases obtained from lower species, Hans and his group could provide experimental proof that the various serine proteases were structurally related and, therefore, had derived from a common origin. This firmly established the concept of structural homology that exists among these enzymes, stimulating further his interest in the evolution of proteins and their complex organization into functional domains.”
Hans Neurath
The Bial-Neurath Family