Nobel Laureate: Michael Smith

 

The Nobel Prize in Chemistry 1993.

"for contributions to the developments of methods within DNA-based chemistry: for his fundamental contributions to the establishment of oligonucleotide-based, site-directed mutagenesis and its development for protein studies"


Michael Smith (1932 - 2000) won the Nobel Prize in Chemistry for developing the technique of site-directed mutagenesis. Today this is a common technique in biochemistry labs. It enables researchers to specifically alter a nucleotide in a gene in order to study its effect. It is frequently used in structural biology labs to explore the roles of varous amino acid residues in the function of a protein.

Smith's work was based on the development of DNA sequencing technology in the 1970s and on extensive work on the formation of DNA:DNA double-standed hybrids with oligonucleotides containing mismatches.

Here's the Press Release describing Michael Smith's contribution (there was a co-recipient but we don't mention him unless we have to).

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Nobel Laureates

Background

Chemically, the genetic material of living organisms consists of DNA (deoxyribonucleic acid). DNA molecules consist of two very long strands twisted around each other to form a double helix. Each strand is formed of smaller molecules, nucleotides, that represent the letters of the genetic material. There are only four different letters, designated A, T, C and G. The two DNA strands are complementary, being held together by A - T and G - C bonds. It is only when the genetic code is to be read off e.g. for protein building in the cell that the two strands are separated. The genetic information in DNA exists as a long sentence of code words, each of which consists of 3 letters which can be combined in many different ways (e.g. CAG, ACT, GCC). Each three-letter code word can be translated by special components within the cell into one of the twenty amino acids that build up proteins. It is the proteins that are responsible for the functions of living cells, including their ability to function, among other things, as enzymes maintaining all the chemical reactions required for supporting life. The proteins' three-dimensional structure and hence their function is determined by the order in which the various amino acids are linked together during protein synthesis.

Site-directed mutagenesis

The flow of genetic information goes from DNA via the translator molecule RNA to the proteins. By re-programming the code of a DNA molecule, e.g. changing the word CAC to GAC, it would be possible to obtain a protein in which the amino acid histidine is replaced by the amino acid aspartic acid. In nature, such mix-programming of the genetic material (mutation) occurs randomly, and is nearly always fatal to the organism. However, a dream of biochemical researchers has been to alter a given code word in a DNA molecule so as to be able to study how the properties of the mutated protein differ from the natural. It was through Smith's oligonucleotide-based site-directed mutagenesis that this dream became reality. As early as the 1970s Smith learned to synthesize oligonucleotides, short, single-strand DNA fragments, chemically. He also studied how these synthetic fragments could bind a virus to DNA. Smith then discovered that even if one of the letters of the synthetic DNA fragment was incorrect it could still bind at the correct position in the virus DNA and be used when new DNA was being synthesized. At the beginning of the 1970s Smith was a visiting researcher at Cambridge and the story goes that it was during a coffee-break discussion that the idea arose of getting a reprogrammed synthetic oligonucleotide to bind to a DNA molecule and then having it replicate in a suitable host organism. This would give a mutation which in turn would be able to produce a modified protein. In 1978 Smith and his co-workers made this idea work in practice. They succeeded both in inducing a mutation in a bacteriophagic virus and "curing" a natural mutant of this virus so that it regained its natural properties. Four years later Smith and his colleagues were able for the first time to produce and isolate large quantities of a mutated enzyme in which a pre-determined amino acid had been exchanged for another one.

A protein with a changed (mutated) amino acid can be
produced with site directed mutagenesis. A chemically
synthesized DNA fragment with a changed code word is bound
to a virus DNA which is multiplied in a bacterium. The DNA
molecule with the changed code word is reduplicated and can
be used for producing the changed protein.
Smith's method has created entirely new means of studying in detail how proteins function, what determines their three-dimensional structure and how they interact with other molecules inside the cell. Site-directed mutagenesis has without doubt revolutionised basic research and entirely changed researchers' ways of performing their experiments. The method is also important in biotechnology, where the concept protein design has been introduced, meaning the construction of proteins with desirable properties. It is already possible, for example, to improve the stability of an enzyme which is an active component in detergents so that it can better resist the chemicals and high temperatures of washing water. Attempts are being made to produce biotechnically a mutated haemoglobin which may give us a new means of replacing blood. By mutating proteins in the immune system, researchers have come a long way towards constructing antibodies that can neutralise cancer cells. The future also holds possibilities of gene therapy, curing hereditary diseases by specifically correcting mutated code words in the genetic material. Site-directed mutagenesis of plant proteins is opening up the possibility of producing crops that can make more efficient use of atmospheric carbon dioxide during photosynthesis

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