Inventor of solid-phase peptide synthesis.
The death of Bruce Merrifield on 14 May 2006 brings to a close the life of one of the most original scientists of the second half of the twentieth century. Between 1959 and 1963, Merrifield revolutionized organic chemistry by his invention of solid-phase peptide synthesis. This “simple and ingenious” technique, as it was described in the citation for Merrifield's 1984 Nobel Prize in Chemistry, created a paradigm shift in synthetic chemistry and profoundly affected biomedical research.
Robert Bruce Merrifield was born in Fort Worth, Texas, on 15 July 1921, the only son of George and Lorene (Lucas) Merrifield. He obtained his PhD in 1949 from the University of California, Los Angeles. Immediately after graduating, Merrifield joined the Rockefeller Institute for Medical Research in New York, where he spent his entire career. He became professor in 1966, and was elected to the US National Academy of Sciences in 1972.
At the Rockefeller Institute, Merrifield worked with D. Wayne Woolley on nucleotide biochemistry, and then on the identification and chemical synthesis of putative peptide growth factors. This was the period shortly after the Second World War, when chemists worldwide were devising methods for the preparation of biologically active peptides. These molecules were important targets for organic synthesis, because they constituted a new class of natural product. Synthetic techniques had improved rapidly, but were still rather cumbersome. Using the available chemistries, Merrifield prepared a series of synthetic peptides containing up to seven amino acids, a process that took five years of laborious research. On 26 May 1959, Merrifield wrote in his laboratory notebook: “There is a need for a rapid, quantitative, automatic method for the synthesis of long chain peptides.” He then outlined the principles of a radically new approach to chemical peptide synthesis. Four years later, Merrifield published a seminal paper, entitled “Solid Phase Peptide Synthesis. I. The Synthesis of a Tetrapeptide” in the Journal of the American Chemical Society.
The solid-phase method consisted of chemically attaching the last amino acid of the target peptide to a solid support, then carrying out all the chemical steps necessary to build the peptide's amino-acid sequence, and finally releasing the product from the support. As Merrifield envisaged it, solid-phase synthesis would greatly facilitate the preparation of peptides by enabling the recovery of support-bound intermediate products by simple filtration and washing; in turn, this would enable the use of excess reactants at each step, giving rapid reactions and high yields of the final peptide product.
From the start, Merrifield had also envisaged the automation of chemical synthesis. By 1965 he had implemented this idea in collaboration with John Stewart, a faculty colleague. With Nils Jernberg of the machine shop at the Rockefeller University (as it was known by then), they built an automated synthesizer that could prepare peptides 20 times faster than solution methods, and that allowed the preparation of longer peptide chains.
Solid-phase peptide synthesis was quickly adopted throughout the world, and was used to make numerous analogues of biologically active peptides. Merrifield and his young colleagues concentrated on developing the technique and extending it to new targets. But as solid-phase synthesis was applied to ever-larger molecules, established peptide researchers harshly criticized both Merrifield and his method. It was felt, as a matter of principle, that a technique that prevented the full characterization of synthetic intermediates could not give rise to authentic peptide products. The objections of traditional chemists were ultimately refuted by the systematic development of improved solid-phase synthetic chemistry in Merrifield's and other laboratories during the 1970s and 1980s, and by the emergence of powerful analytical techniques for determining the structure and purity of synthetic peptides. The solid-phase method is now used routinely for the chemical synthesis of peptides and proteins up to 50 or so amino acids in length.
Today, the discovery of vast numbers of potent peptide natural products is leading to a resurgence in pharmaceutical research on peptides. Solid-phase synthesis is the unrivalled technique for the preparation of such compounds in order to determine the chemical basis of their biological function. Merrifield's ingenious concept led directly to the development of efficient methods for preparing synthetic nucleic acids — essential for modern molecular biology and biotechnology. The solid-phase principle is also at the heart of combinatorial chemistry, which enables the simultaneous preparation of thousands of compounds, and which has changed the fabric of medicinal chemistry and drug discovery since the early 1990s.
Bruce Merrifield is survived by Libby, his wife of 56 years, their six children and sixteen grandchildren. He was a devoted family man who loved hiking and camping with his family. In the last 45 years of his life, Merrifield was afflicted with a progressive skin cancer — apparently the result of radiation treatment for acne in his youth. A man of extraordinary resilience, Merrifield bore this devastating illness with grace and fortitude. In his later years, he nursed his wife back to health after she suffered a serious stroke.
In the 1960s and 1970s, the Merrifield laboratory was a hotbed of new peptide science. Those who were fortunate enough to work with Bruce came to know a man who was devoted to the Rockefeller University, to his research group, and to intellectually rigorous science. His unique approach to his discipline was recounted in an excellent autobiographical memoir, Life During a Golden Age of Peptide Chemistry (American Chemical Society, 1993). By creating a completely new approach to organic synthesis, Merrifield pioneered the effective application of synthetic chemistry to the study of biological molecules. His scientific creativity has been equalled by few and rarely surpassed.
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Future Medicinal Chemistry (2009)