Editorial: Bruce Merrifield atthe “Crossroads of Chemistryand Biology”

Bruce Merrifield, the 1984 Nobel laureate in chem-istry and inventor of solid phase peptide synthesis,was born in Fort Worth, Texas, on July 15, 1921.Exactly one month before Merrifield’s 80th birthday,several hundred of his scientific friends and col-leagues, including many former and present researchco-workers, gathered in San Diego, California, for aspecial Satellite Symposium to the 17th American/2nd International Peptide Symposium. The sessionbegan with the reading of a personal letter of greetingsand congratulations from President George W. Bush.This was followed by the world premiere showing ofan hour-long historical video “Peptide and ProteinSynthesis: Origin and Development” specially pro-duced for this occasion by members of the PlanningCommittee. The video features a script by Merrifieldand clips from interviews with numerous leaders inthe field from Asia, Europe, and the Americas. Next,six eminent scientists described their cutting-edge re-search corresponding to the theme of the Symposium:“Crossroads of Chemistry and Biology.” This specialedition of Biopolymers (Peptide Science) representsthe written complement to the scientific program, andadds a contribution by Garland R. Marshall, who wasMerrifield’s first graduate student and recipient, at thePeptide Symposium earlier in the same week, of thehighest honor of the American Peptide Society, theMerrifield Award.

Bruce Merrifield’s inspirational personal and sci-entific odysseys are described in his 1993 volumeentitled Life During a Golden Age of Peptide Chem-istry: The Concept and Development of Solid-PhasePeptide Synthesis, from the American Chemical So-ciety (Washington, DC) Profiles, Pathways, and

Dreams series, which makes for highly compellingreading. Merrifield’s childhood years were influencedby the Great Depression, and by the time he startedMontebello High School in Southern California, hisfamily had moved 25 times and he had attended 11different schools. His undergraduate and doctoralstudies were carried out at the University of Californiaat Los Angeles, and his Ph.D. studies, under thedirection of Max Dunn, concerned microbiologicalassays for nucleic acid constituents. Merrifield grad-uated on June 19, 1949. A day later, he marriedElizabeth (Libby) Furlong, and the following day thecouple headed east to the Rockefeller Institute forMedical Research (now The Rockefeller University)in New York City. Indeed, Merrifield’s entire aca-demic career unfolded on the Rockefeller campus,starting as an Assistant with D.W. Woolley, a pioneerin vitamin research, authority on antimetabolites, andleading researcher on serotonin. Merrifield was pro-moted to Associate Professor in 1958 and to fullProfessor in 1966.

Merrifield’s laborious achievement of a 7% yieldin the synthesis of a small peptide with strepogeninactivity made clear to him the need for simpler, faster,and more efficient procedures. In 1959, Merrifieldconceived the bold idea of carrying out synthesis on apolymeric support and, four years later, published hisseminal Journal of the American Chemical Societypaper that provided the experimental documentationof a successful tetrapeptide synthesis. Merrifield’sdetermination and perseverance were rewarded inshort order with syntheses in the Rockefeller labora-tories of biologically active peptide hormones such asbradykinin, angiotensin, oxytocin, and insulin, and

Biopolymers (Peptide Science), Vol. 60, 169–170 (2001)© 2001 John Wiley & Sons, Inc.

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culminated with the total synthesis of the 124-residueenzyme bovine pancreatic ribonuclease A. The latterwork, published in 1969 concurrent to a series ofpapers from a team at Merck, proved unambiguouslyAnfinsen’s hypothesis that the primary sequence of aprotein determines its three-dimensional structure.

Continued efforts by Merrifield and co-workersfrom the 1970s to the present day have had a dualfocus on extending and optimizing the basic solidphase chemistries and applying them to furnish com-pounds that are used to tackle important biologicalproblems associated with peptide and protein science.Concurrently, the solid phase principle has becomeincreasingly accepted and integrated into the fabric ofthe scientific enterprise. Solid phase techniques havebeen developed for the preparation of classes of bi-omacromolecules beyond peptides, including carbo-hydrates and nucleic acids. The ready availability ofDNA oligonucleotides chemically synthesized by thesolid phase method plays a central role in gene map-ping and protein engineering studies. Immobilizationof reagents and substrates on polymeric supports isused by chemists and biochemists in a variety ofcreative ways to understand reaction mechanisms andto achieve challenging molecular transformations.Combinatorial solid phase synthesis is a burgeoningnew paradigm for drug discovery and development ofnew materials.

Showcasing the “Crossroads of Chemistry and Bi-ology” that exemplifies Bruce Merrifield’s scientificinterests, the first article in this issue, by K. C. Nico-laou, describes how solid phase methodology is nowequal to the challenge of multistep organic synthesesof complicated organic molecules that are naturalproducts or analogues thereof that incorporate sub-stantial structural diversity tied to the requirements ofbiological screening. Next, James P. Tam presents thelatest progress on concepts, methods, and strategies toachieve orthogonal peptide ligations, and in this wayto realistically access functional protein-like struc-tures. The contribution by Wesley L. Cosand andco-workers illustrates succinctly how state-of-the-artproteomics research tools, coupled to the extensive

databases just emerging from the sequencing of thehuman genome, is providing new opportunities in thepharmaceutical industry. Then, Richard A. Houghten,one of the founders of combinatorial chemistry, re-views a number of efficient solid phase methods togenerate very large libraries of small organic com-pounds that can serve as leads for therapeuticallypotent structures. The article by Peter G. Schultz andhis team provides an elegant case study in proteinengineering, featuring phage-display evolution andthe use of nucleotide analogues, with the ultimate goalto map cellular signaling pathways. Murray Good-man’s contribution reviews current research topicsfrom his laboratory that emphasize solid phase re-agents, solid phase couplings, and syntheses of potentpeptidomimetics where a solid phase route is shownto be considerably superior to a solution precedent.Finally, Garland R. Marshall illustrates emerging con-cepts about the interactions of peptides and peptido-mimetics with receptors (focusing on G-protein cou-pled receptors such as rhodopsin) by collating infor-mation from crystallographic and NMR structuralwork, chemical syntheses followed by determinationsof structure–function activity relationships, and com-putational studies.

The reader of this issue becomes privileged to thescientific legacy of Bruce Merrifield. Furthermore, asbecame evident from an afternoon session of the Mer-rifield Symposium that followed the lectures, Bruce iswarmly beloved and admired for his grace, modesty,integrity, and courage. Merrifield’s career has shown thevalue of having a good scientific idea, believing in it, andoptimizing it to fruition. He revolutionized chemistrywith his discovery of an expeditious method to makepeptides, and he has articulated one of the truly innova-tive ideas of chemistry, the solid phase principle. BruceMerrifield, in his 80th year, continues his laboratoryresearch and so serves as an inspiration to the nextgeneration of peptide scientists.

GEORGE BARANY

ARTHUR M. FELIX

Issue Editors

170 Editorial