Michael Smith

Organic Chemistry

Won the Nobel Prize in chemistry in 1993 for discovering site-directed mutagenesis: that is, how to make a genetic mutation precisely at any spot in a dna molecule.

"In research you really have to love and be committed to your work because things have more of a chance of going wrong than right. But when things go right, there is nothing more exciting."

Molecular biology is the study of biological systems at the level of individual chemicals and molecules. Michael Smith was an expert on the chemistry of DNA — the molecule that makes up genes, the instructions required to create every part of an organism. DNA is a large molecule that is like a twisting chain. Actually it is two chains twisted together. Smith worked on genomics, the sequencing of the DNA of an organism to understand how it works.

Smith won fame and fortune by developing a new way to create mutations in living organisms. Plant and animal breeders rely on naturally occurring beneficial mutations that result in improved plants and animals. Conversely, unwanted natural mutations can cause diseases such as cystic fibrosis or sickle-cell anemia. Smith found a way to create a specific mutation by precisely changing any particular part of the DNA in an organism. This has allowed countless researchers around the world to develop special bacteria, plants and animals with new qualities or abilities that either do not occur naturally or would take years and years of trial and error in breeding to achieve. With further research, his technique might even be used to correct mutations that cause disease.

Before Smith’s technique of site-directed mutagenesis, there was no way to create specific mutations. Geneticists had to expose a bunch of organisms to radiation or chemicals that would result in all sorts of mutants, then select the one they wanted. It was all by chance, and it could take a long time to get exactly the right mutation.

Site-based mutagenesis.

1. A small portion of a long DNA molecule showing the backbone (in light grey) made of deoxyribose, a type of sugar. The backbone sugar segments are all the same, but they can have one of four different basic “connectors” — adenine, thymine, cytosine and guanine (A, T, C and G in the figure) — that couple with complementary connectors on a second sugar chain. An A on one side always matches up with a T on the other. Similarly, C always matches up with G. These couplings are called base pairs. A DNA strand is made up of two chains, one a mirror image of the other (that is, if one side’s sequence goes ATCG, then the other side will be TAGC). In real DNA the chain could continue up for millions of base pairs and down for thousands more. The sugar elements (A, T, G and C) are known as nucleotides and their sequence is what makes up the genes in an organism.

2. The nucleotide guanine. The phosphate sugar is on the left and the basic group is on the right. Note the two hydrogen atoms and one oxygen atom poking out on the extreme right to form the chemical bond with cytosine on the sister chain.

Michael Smith’s idea for which he won the Nobel Prize was to slip a synthetic stretch of nucleotides — called an oligonucleotide — into one DNA chain. “Synthetic” means the nucleotide was created in a test tube, not by nature. The synthetic segment is added to normal DNA using standard chemicals for breaking and reforming DNA chains. But there is one thing wrong with this synthetic oligonucleotide: it has an adenine where there should be a guanine. This is done on purpose to create a mutation. (Remember, A normally combines with T, and G goes with C.) The four nucleotides below and above the adenine act as a kind of address that causes this stretch of DNA to match up to the correct place on the other DNA strand. (In humans, it turns out that you need only 17 nucleotides to define a unique match somewhere among the three billion nucleotides of the entire genome.)

When this new altered DNA is put back into an organism, say a bacterium, and it divides in the normal process of growth and reproduction, one half of the DNA will recombine normally and will produce a correct copy of the original gene — a normal bacterium. The other side with the synthetic oligonucleotide will create a mutation, because a thymine is sitting where there should be a cytosine. The resulting mutant bacterium might have some new appearance or function that it never had before.

With Smith’s technique, geneticists can mutate a gene in three ways: substitution, deletion and addition. Precise substitution of one or more nucleotides in a DNA sequence is shown here. Scientists can also delete nucleotides or add extra nucleotides to the sequence.


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In a 1996 interview, Smith predicted a change in the way people do biological research. He was right. With the completion of the human genome project in 2003, the total sequence of the DNA in all the genes for a human being — the human genome — is known. Genomes have now been completely decoded for many plants and animals.

Those genes have the code or “recipe” for the tens of thousands of proteins that make up people, plants, insects or other animals. As time goes by, geneticists are amassing more and more genetic information detailing what the genome encodes. According to Smith, the hard part will be discovering which part of the genome does what, picking out what is crucial, and learning how to recognize the most important bits of DNA.


Explore Further

Donald Voet and Judith G. Voet, Biochemistry, The Expression and Transmission of Genetic Information, Wiley, 2004.

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