Robert Bruce Merrifield, biochemist and organic chemist: born Fort Worth, Texas 15 July 1921; chemist, Philip R. Park Research Foundation 1943-44; research assistant, UCLA Medical School 1948-49; assistant to Associate Professor, Rockefeller Institute for Medical Research (later Rockefeller University) 1949-57, Assistant Professor 1957-66, Professor 1966-84, John D. Rockefeller Jr Professor 1984-92 (Emeritus); Nobel Prize in Chemistry 1984; married 1949 Libby Furlong (one son, five daughters); died Cresskill, New Jersey 14 May 2006.
The biochemist and organic chemist Bruce Merrifield won the 1984 Nobel Prize in Chemistry in recognition of his outstanding achievement in the methodology of the chemical synthesis of proteins.
He spent his entire research career at the Rockefeller Institute of Medical Research (now Rockefeller University) in New York, which he joined in 1949 to begin work on peptide growth factors. Peptides are made up of amino acids, joined together sequentially like beads on a string by a repeating linkage known as the peptide bond. Peptides typically might have up to, say, 20 or 30 amino acid residues; proteins are constructed in the same fashion, but are much larger entities and typically might have 300 amino acids in the chain and may even reach 1,000 or more. There are 20 different sorts of amino acids in the normal biological repertoire, and thus the number of combinations is astronomically huge. The resulting amino acid sequence in turn defines the biological activity of any given peptide or protein.
Merrifield joined the Rockefeller at a key period in the history of protein chemistry. The first determination of the amino acid sequence of a protein, the hormone insulin, was being pioneered in Cambridge by Frederick Sanger, who won the Nobel Prize in Chemistry in 1958 for his efforts; and two other giants of the subject, Stanford Moore and William Stein, were already at work at the Rockefeller embarking on their own approach to amino acid sequence analysis based on the enzyme, ribonuclease, which was to win them the Nobel Prize in Chemistry in 1972.
Chemical synthesis of peptides had been attempted since 1902 following the original work of Emil Fischer that established the nature of the peptide bond, and a great step forward was the synthesis of the peptide hormone, oxytocin, containing a row of nine amino acids, in the laboratory of Vincent du Vigneaud (Nobel Prize in Chemistry, 1955).
The interest in academic circles but also in the pharmaceutical industry was intense, because of the widening recognition of peptides and proteins as a class of important biologically active molecules. But how to extend the laborious methods of classical organic chemistry, which had until then had been used to put the amino acids together one by one in a repetitive series of reactions and tedious separation of intermediate products? If one was ever to tackle the synthesis of large peptides, let alone proteins, the problems appeared insuperable.
In 1959, Merrifield came to the conclusion that a new approach was called for, and in 1963 published his paper "Solid Phase Peptide Synthesis. I. The Synthesis of a Tetrapeptide" in the Journal of the American Chemical Society. The departure was radical: what would end up as the last amino acid in the chain was chemically attached to a solid polymer and the relevant amino acids were then chemically linked one by one to generate a growing peptide chain until the far end was reached, the synthesis was complete and the desired protein could be released from the solid support.
The elegance lay in the advantage that, after each reaction, by-products and any remaining starting materials were readily extracted from the mix, enabling a staggering rise in the yield to up to 99 per cent at each individual step. Some more traditionally minded chemists were disturbed by what they saw as a cavalier disregard of the time-honoured principle of characterising the product of the reaction at each stage. But Merrifield, now with a colleague, John Stewart, and his team pressed on.
Within a few years they had automated the methodology (one could now, or so it seemed, load up the instrument with reagents and a computer program defining the amino acid sequence desired and retire for the night) and the Merrifield method soon swept all before it. A pinnacle was reached in 1971 in Merrifield's own laboratory with the complete synthesis of the enzyme ribonuclease, which contains 124 amino acids of which the sequence had been determined by Moore and Stein, and a demonstration of its acquisition of full biological activity. The opposition was gradually silenced. One of Merrifield's colleagues, Richard DiMarchi, is quoted as saying: "He answered his critics with data and dignity."
In due course, the solid-phase methodology that Merrifield had pioneered found its way into the synthesis of nucleic acids too, which are essential for many procedures in molecular biology and biotechnology and are necessary to the nucleic acid sequencing techniques that underpin the genome projects of the last 10 years. One can see it too in the now popular combinatorial chemical approaches to the widespread synthesis of libraries of pharmaceutically active compounds.
Robert Bruce Merrifield was born in Texas in 1921 and, his parents having moved to California in 1923, took a BA in chemistry and then a PhD in biochemistry at the University of California, Los Angeles in 1949. He went straight from UCLA to the Rockefeller Institute, where he worked first as an assistant to D.W. Woolley and was introduced to peptide growth factors. He became an assistant professor in 1957 and was promoted to full professor at Rockefeller University in 1966, later being named John D. Rockefeller Jr Professor in 1983, a post he retained until his retirement in 1992.
He was elected to the US National Academy of Sciences in 1972 and awarded numerous prizes, among them the Lasker Award for Basic Medical Research in 1969 and the Gairdner Foundation Award in 1970, before the Nobel Prize in 1984. He explained much about himself and his approach to science, not least revealing his quiet relentlessness, in an autobiography, Life During a Golden Age of Peptide Chemistry (1993).
All who met Bruce Merrifield found him a courteous, methodical and unassuming man. He married his wife Elizabeth (Libby) in 1949, the day before they left Los Angeles for New York; they had a son and five daughters, and 16 grandchildren, to all of whom he was devoted. He had suffered from a progressive skin cancer for many years - perhaps the result of radiation he had received in his youth as a treatment for acne. He bore this, like the criticism of his science in the 1960s and early 1970s, with grace and fortitude.
In autumn 1986, Bruce Merrifield asked whether he could visit the Royal Institution in Albemarle Street, writes Sir John Meurig Thomas. As he put it, he wanted "to relive an event that had taken place in the early 1960s" when my predecessor but one as Director (Sir Lawrence Bragg) had invited Professor Wayne Woolley to present a Friday-evening discourse on the subject of metabolites, on which Woolley was a world authority. Woolley was Merrifield's senior colleague at Rockefeller University.
When Merrifield arrived at the Royal Institution, he urged me to take him to its lecture theatre and, at the famous kidney-shaped lecturer's bench, I was told by my guest that he had carried out all the intricate lecture-demonstrations for his mentor, Woolley, who was completely blind.
For many years I wondered how it was that the blind Professor Woolley was able to lecture with such sensitivity, intelligence and gifts of innocent showmanship (so Merrifield told me) that large sectors of his audiences were unaware of his blindness. And why had he been invited to the Royal Institution in the first place?
The answer to the second question soon emerged. Bragg, whose right-hand man in the 1960s was David Phillips (later Lord Phillips of Ellesmere) had become deeply interested in enzymes, and knew that Woolley, Merrifield, John Stewart and their colleagues in New York were engaged in devising ways to synthesise enzymes and their shorter analogues, peptides.
It was not until five years ago, in a conversation with Professor Alick Bearn, the then Executive Director of the American Philosophical Society and a former colleague of Merrifield and Woolley at Rockefeller University, that the answer to the first question came. Woolley, as I was told, suffered from severe diabetes and lost his vision shortly after Merrifield's arrival from the West Coast. But, undaunted, he continued with his experimental work. One of his habits was to work at night, and when the cleaners would arrive in the morning and turned on the lights they were alarmed to see Woolley at his bench.
Notwithstanding his affliction, he could lecture as if his vision were perfect. He would sometimes return to the blackboard and add a hydroxyl group to a carbon atom in a complicated macromolecular species, the formula of which he had earlier chalked up.
He and Merrifield were the closest of friends until his death in 1966. Merrifield took over his lab and he never forgot the debt that he owed Woolley.