Bruce Merrifield, the Henry Ford of the biological world who received the 1984 Nobel Prize in chemistry for automating the previously daunting process of synthesizing complex proteins, died May 14 at his home in Cresskill, N.J., after a long illness. The retired Rockefeller University chemist was 84.
His work made it possible for the first time to manufacture both natural products and variants that are unknown in nature, opening the door to a broad spectrum of research possibilities, as well as the development of new drugs. His techniques were subsequently adapted for assembling DNA molecules, stimulating efforts in genetic engineering.
For The Record
Los Angeles Times Saturday June 03, 2006 Home Edition Main News Part A Page 2 National Desk 1 inches; 41 words Type of Material: Correction
Merrifield obituary: The obituary of Nobel laureate Bruce Merrifield in the May 20 California section said his family moved to California in 1923, when he was 2, during the Great Depression. The Depression began after the stock market crash of 1929.
At the root of his achievements was an idea that the Royal Swedish Academy of Sciences, which administers the Nobels, called "simple and ingenious."
Proteins and peptides are chains of amino acids -- the building blocks of life -- strung together like beads on a necklace. Peptides are shorter chains, containing two to 20 amino acids, that often act as hormones.
Proteins, which contain from 100 to more than 1,000 amino acids, serve as enzymes that carry out chemical reactions within the cell.
Nature produces proteins efficiently, but constructing them in a laboratory is far more difficult. Chemists must activate two amino acids so they will react, then they must purify the product, activate again and add a third amino acid, purify once more, and so on.
Even if the chemist can convert 90% of the starting material into product at each step -- an unusually efficient percentage -- he must start with large quantities to have anything left at the end.
The process is so difficult that American chemist Vincent du Vigneaud won the Nobel Prize in chemistry in 1955 primarily for synthesizing the hormone oxytocin, which contains only nine amino acids.
Merrifield's inspiration was to take the first amino acid in the chain and attach it to a bead of insoluble plastic. He would then flood the amino acid with reagents to add a second amino acid, pushing the reaction efficiency as high as 99.5%. He could do this because, at the end of each step, he could simply flush away the excess reactants, leaving the reaction product attached to the bead and ready for the next step.
The idea looked simple, but it took him three years of intense labor to work out the details.
In 1962, he used the technique to synthesize the hormone bradykinin, which contains nine amino acids, in less than a week. Rockefeller colleague John Stewart, who had spent a year synthesizing three variants of bradykinin using old techniques, employed Merrifield's technology to produce 50 more in the following year.
Merrifield quickly realized that the highly repetitive process could be automated, though few experts agreed with him. Reviewers of his paper on the bradykinin synthesis asked that he delete the "regrettable" mention of the possibility of automation.
Undeterred, Merrifield, Stewart and Nils Jernberg, head of Rockefeller's instrument shop, spent two years assembling a prototype in Merrifield's home basement.
The machine had three basic elements: a series of reservoirs for amino acids, reagents and solvents; a reaction vessel that had suitable plumbing for the introduction of amino acids and other chemicals at the right time and in the right order, and that permitted excess chemicals to be flushed away; and a programmer that controlled all the operations.
With it, they could add six amino acids to a growing peptide in 24 hours, a process that previously had taken several months.
Using the device, Merrifield and colleague Bernd Gutte synthesized the enzyme ribonuclease, which contains 124 amino acids. The process required 369 chemical reactions and 11,391 steps with the device. It was the first complete laboratory synthesis of an enzyme. The original, home-built instrument is in the Smithsonian Institution.
Neither Merrifield nor Rockefeller patented the method or the instrument, and it was soon widely adopted by other institutions and industry. The technique is still used for synthesis of chains containing 100 or fewer amino acids, but genetic engineering techniques subsequently proved cheaper and more efficient for producing larger proteins.
He spent most of the rest of his career refining the technology and synthesizing longer and more complex proteins.
Merrifield later said it took him a long time to come up with the idea.
"People keep asking me if I had a big 'eureka!' moment, but it wasn't like that," he said. "The critical thing was that I had been working in the lab myself" and knew researchers needed a simpler technique. "And this, I'm sure, sat at the back of my head for some weeks or months, and then somehow I got the idea of using a polymer support."