Wednesday, January 30, 2008

Nobel Laureate: Bruce Merrifield


The Nobel Prize in Chemistry 1984.

"for his development of methodology for chemical synthesis on a solid matrix"

In 1984, Bruce Merrifield (1921 - 2006) was awarded the Nobel Prize in Chemistry for discovering a method of synthesizing polymers on a solid matrix. The technique laid the groundwork for the development of peptide and nucleotide synthesizers that are now common in biochemistry laboratories.

The presentation speech was delivered by Professor Bengt Lindberg of the Royal Academy of Sciences.

Nobel Laureates
Your Majesties, Your Royal Highnesses, Ladies and Gentlemen,

The chemical reactions which take place in living organisms are not spontaneous, but require the involvement of catalysts. These catalysts are called proteins and are composed of chains of amino acids called peptides. A number of hormones and other substances which regulate different life processes are also peptides. There are about 20 naturally occurring amino acids which are found in such peptides and since the chains can be very long, the number of possible variations is virtually unlimited.

Today we know the structures of a very large number of proteins and peptides. Important contributions to this area of knowledge were made by Fredrick Sanger, who received the Nobel prize in 1958, and Stanford Moore and William H. Stein, Nobel prizewinners in 1972. A very important contribution was also made by the Swedish researcher Per Edman, who unfortunately died relatively young and whose method for the controlled degradation of peptides is now generally used.

The chemical synthesis of peptides is an important task. The principle used in such synthesis is simple and was developed a relatively long time ago by Emil Fischer, who received a Nobel prize in 1902, although for completely different discoveries. Expressed simply, this principle involves the binding together of two amino acids which have been appropriately modified to give a dipeptide. This dipeptide is then combined with a third modified amino acid to give a tripeptide and so on.

Even if the principle is simple, in practice it is difficult to synthesize peptides, since a large number of individual steps is involved. After each step the desired product must be separated from by-products and unreacted starting material and this takes time and involves loss of the product. When Vincent du Vigneaud synthesized a peptide hormone, oxytocin, which is a nonapeptide, for the first time, this represented a great step forward which was rewarded with the Nobel prize for 1955. To use a similar approach for synthesizing a peptide containing 100 or more amino acid residues is truly a heroic task, requiring a very large amount of work and chemicals. This task can be compared to climbing a high mountain peak in the Himalayas, which begins with a large expedition carrying much equipment and ends, if all goes well, with a few lightly equipped alpinists reaching the top.

Therefore, Merrifield's development during the 1960's of a method for carrying out peptide synthesis on a solid matrix revolutionized the field. He attached the first amino acid to an insoluble polymer, a plastic material in the form of small spheres. Subsequently, the other amino acids were added one after one and only after the entire peptide chain had been synthesized was it released from the polymer. The advantages of this method are considerable. The complicated purification of the product after each synthetic step is replaced by simply washing the polymer to which the peptide is attached, so that loss of product is avoided completely. At the same time, the yield for each individual step is increased to 99.5% or better, a goal which cannot be achieved with conventional methods, but which is extremely important in syntheses involving a large number of steps. Finally, this method can be automated and automatic peptide synthesizers are now commercially available.

Thousands of different peptides of different sizes, as well as proteins, peptide hormones and analogues of these compounds have now been synthesized using this method. One milestone in this respect was the synthesis of an active enzyme, ribonuclease, containing 124 amino acid residues, by Merrifield and his coworkers.

The approach of performing a multistep synthesis with a compound attached to a solid matrix as the starting material has also been used in other areas. The most important of these is undoubtedly the synthesis of oligonucleotides, which are needed in hybrid DNA research. In this case as well an automated apparatus which can be programmed to synthesize desired products has been constructed. Although Merrifield has not worked in this area himself, it is clearly his ideas which have found a new application here.

Professor Merrifield,

Your methodology for chemical synthesis on a solid matrix is a completely new approach to organic synthesis. It has created new possibilities in the fields of peptide-protein and nucleic acid chemistry. It has greatly stimulated progress in biochemistry, molecular biology, medicine and pharmacology. It is also of great practical importance, both for the development of new drugs and for gene technology.

On behalf of the Royal Swedish Academy of Sciences I wish to convey our warmest congratulations and ask you to receive your prize from the hands of His Majesty the King.

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