Zuckerkandl was raised in Vienna, Austria in a household of intellectuals, but his family relocated in 1938 to Paris, and later Algiers, to escape the racial policy of Nazi Germanywith respect toJews. At the end of World War II, he spent one year at the University of Paris, then came to the United States to study physiology—earning a master's degree in 1947 from the University of Illinois, under C. Ladd Prosser—then returned to the Sorbonne to complete a Ph.D. in biology. Zuckerkandl developed a strong interest in molecular problems; his early research at a marine biology lab in Roscoff emphasized the roles of copper oxidases and hemocyanin in the molting cycles of crabs. In 1957, Zuckerkandl met renowned chemist Linus Pauling, who was becoming interested in molecular diseases and molecular evolution as an outgrowth of his activism on topics concerning nuclear power. They arranged a post-doctoral fellowship, and Zuckerkandl returned to the United States to work with Pauling at the California Institute of Technology beginning in 1959. He is an atheist.
Zuckerkandl's first project under Pauling was the application of new protein identification techniques—a combination of paper chromatography and electrophoresis that produced a two-dimensional pattern—to hemoglobin. The peptide fragments of hemoglobin samples from different species, partially broken apart by digestive enzymes, would produce unique patterns that could be used to estimate differences of protein structure. Zuckerkandl, Jones and Pauling published a comparison of several species' hemoglobin identification patterns in 1960, observing that the degree of dissimilarity of protein patterns corresponded approximately to the phylogenetic distance between source species. However, the method was not conducive to quantitative comparisons, so Zuckerkandl began working on the determination of the actual peptide sequence of the α and β chains of human and gorilla hemoglobin. In 1962, Pauling and Zuckerkandl published their first paper using the molecular clock concept. Like a number subsequent collaborative papers, it was not peer-reviewed—it was an invited paper in honor of Albert Szent-Györgyi—and they intentionally took the opportunity to "say something outrageous". The paper used the number of differences in the α and β chains of hemoglobin to infer the time since the last common ancestor for a number of species, calibrated based on paleontological evidence for humans and horses. Though the paper did not provide any explanation for why amino acid differences in a protein should accumulate at a uniform rate, it did show that the results were fairly consistent with those of paleontologists. During the succeeding years, Zuckerkandl worked to refine the molecular clock. In 1963, he and Pauling invented the term "semantides" for biological sequences—DNA, RNA, and polypeptides—that have evolutionary information and argued that such sequences could be the basis for constructing molecular phylogenies, suggesting that the "molecular clock" method might be useful for other semantides besides proteins. Emanuel Margoliash's first publication of sequence data for cytochrome c allowed comparison of the rates of molecular evolution for different proteins, which Zuckerkandl discussed at a 1964 conference in Bruges. Zuckerkandl also adjusted the mathematics of the "clock" to account for the observation that some positions in an amino acid sequence were more stable than others, and the likelihood of multiple substitutions at the same position. In September 1964, he attended the important Evolving Genes and Proteins symposium, where he and Pauling presented their most influential paper. The paper, primarily Zuckerkandl's work, named the "evolutionary clock" and presented a derivation of its basic mathematical form. Though Zuckerkandl and Pauling saw the clock as compatible with natural selection, it would later become the basis of the neutral theory of molecular evolution, in which genetic drift rather than selection is the driving force of evolution at the molecular level.
