Albert Lasker Award Laureate: R. Bruce Merrifield
Like their larger cousins, proteins, peptides have an enormous diversity of biological roles. They include hormones and neurotransmitters; some have antibiotic or metabolic functions; still others are involved in signal transduction and nutrient absorption. As such, synthetic peptides offer a bounty of research and therapeutic potential. Though their structure is simple to describe — they are short chains composed of any combination of the 20 amino acids — their synthesis was a painstaking, error-prone procedure well into the 20th century. In 1964, R. Bruce Merrifield, a member of The Rockefeller Institute, published what is still one of the most often-cited papers in scientific history, describing the process that changed peptide synthesis forever and opened a floodgate of research. For his development of solid-phase peptide synthesis, Dr. Merrifield received the 1969 Albert Lasker Basic Medical Research Award.
Research in both breaking down and building peptides was an intense preoccupation for scientists for many decades. In the 1940s, Rockefeller Institute members Stanford Moore and William H. Stein succeeded in disassembling many biologically important proteins and identifying their amino acids, an essential step for resolving the structure-function relationship of any protein; the work garnered them the 1972 Nobel Prize. Even earlier, near the turn of the 20th century, German chemist Emil Fischer, another Nobel laureate, had discovered the chemical reaction that would allow individual amino acids to be joined together in a chain, creating a peptide. It was for many decades a tortuously slow method, as after each amino acid addition, the chain had to be separated from by-products and catalyst molecules, a process that often involved degradation of the peptide. American biochemist Vincent du Vigneaud’s synthesis in 1953 of the hormone oxytocin — which contains a mere nine amino acids — was an unprecedented accomplishment, awarded the 1955 Nobel Prize. Because many peptides comprise 100 or more amino acids, however, the challenge of protein synthesis remained a Matterhorn yet to be scaled.
Dr. Merrifield first came up with the idea for solid-phase peptide synthesis in 1959 and spent the next four years perfecting it. In his process, an insoluble, porous resin in the form of tiny spheres is fixed with “linkers” to which peptide chains can be attached. The linker forms a covalent bond with the first amino acid, rendering the peptide immobile until released from the polymer by a special reagent like trifluoroacetic acid. This anchoring step ensures that none of the peptide is lost in the purification step that follows the addition of each amino acid. A further innovation of Dr. Merrifield’s technique was the use of an excess of amino acids and reagents, which ensured complete bonding and significantly sped up the process.
Because a molecule can have several labile atoms, ensuring that two amino acids are bonded together at particular points can be complicated by the possibility of direct mutual attraction between other atoms of the molecule. Dr. Merrifield avoided undesired particle aggregation, as the phenomenon is known, by using tert-butyl, a molecule that attaches to the free amino acid and “protects” it from improper bonds during the chemical reaction. In his process, the protected amino acid is coupled to the end of the chain; a “deprotecting” reagent is applied and the released tert-butyl washed away; another protected amino acid is combined with a coupling reagent to achieve a new bond and coupling reagents are then washed away. The deprotection reagent can then be reapplied, and the cycle is continued.
Dr. Merrifield’s method increased the chemical reaction efficiency of the process to 99.5 percent, reducing what previously took years to accomplish to a matter of days. The process also lent itself well to automation, and today there are numerous commercially available peptide synthesizers, a development that greatly stimulated work in biochemistry, molecular biology, pharmacology and biomedicine. Over several years, Dr. Merrifield’s laboratory synthesized numerous peptides, including bradykinin, which lowers blood pressure by dilating blood vessels; angiotensin, the functional opposite of bradykinin; desamino-oxytocin, a more-potent version of the female reproductive hormone oxytocin; the metabolic hormone insulin; and ribonuclease A, which cleaves single-stranded RNA and is also harnessed as an anticancer therapeutic.
Born in 1921 in Fort Worth, Texas, Dr. Merrifield spent most of his young life in southern California and received both bachelor’s and doctoral degrees in chemistry from the University of California, Los Angeles. He then accepted a post as research assistant at what was then The Rockefeller Institute for Medical Research, becoming assistant professor in 1957, associate professor in 1958. professor in 1966. He was named John D. Rockefeller Jr. Professor in 1984 and remained at Rockefeller until his retirement in 1992. In addition to the Lasker Award, Dr. Merrifield received the Nobel Prize in Chemistry in 1984 and the Gairdner Foundation International Award in 1970. He died in 2006.