Kat Arney

Unpacking the Human Genome Project

Hold the front page! Some white-coated genius somewhere has found a gene for violence: suddenly our streets will be a safer place. Or how about genes for obesity and ageing, so we can look forward to becoming a nation of pert young things? On a more sinister note, what could be done with genes for child abuse, homosexuality, or immortality? With regard to our looks, brains and even personalities, there seems to be no end of scientists telling us what's in the genes. But how much do we really know? Is this just a clever game of bluff, played between the man in the street and the man in the labcoat?

At the Sanger Centre, near Cambridge, you can see for yourself

a pipeline of genetic information. This is part of Britain's contribution

to the International Human Genome Project, conceived in 1990 to

sequence the human genome and identify the estimated 40,000 genes

within it. Day and night letters of the genetic code A, C, T and

G spell out the human genome as it streams across a large LED display,

fresh from the DNA sequencing machines. This stream is literally

the water of life, and those that sup here have a hard task indeed.

In the 1940's, pioneers such as Oswald Avery discovered that DNA

was responsible for passing on inherited information. The field

of molecular genetics was born, and promptly exploded. We now know

that a mere 5% of all our DNA is genuine genes, translated into

proteins by the machinery in the cell. The remainder is a mixture

of regulatory sequences, dead genes and junk DNA. The task of picking

out the specks of gold from the sand seems hard enough, without

even thinking about their function. This year, coincident with the

50th anniversary of the elucidation of the structure of DNA, a complete

version of the human genome is due to be published. Previous versions

have been released, to much media fanfare, but those versions still

contained gaps and errors. This new version will be the best so

far. But a string of letters without a purpose is like a recipe

book with no titles, pictures or methods: we need to know what we

are making with these genes. "Functional exploration of the

genome" has become the new scientific buzz-phrase, but how

is it done?

Classical genetic experiments, carried out in organisms such as

fruit flies, mice and tiny nematode worms, identify the functions

of genes by first looking for mutant characteristics (a mutant phenotype).

Mutants are created by exposing embryos, eggs and sperm to ultraviolet

light or toxic chemicals, causing DNA damage and alteration of gene

function. Complex experiments then follow in which proteins, bits

of DNA or chemicals are added to defective cells or embryos in an

attempt to restore a normal phenotype. Genes correcting these mutations

can then be identified and sequenced, and their normal functions

described. As it is somewhat unethical to use this approach with

humans, and suitable naturally-occurring mutations are rare, research

was restricted to experiments with cultured human cells or cell

extracts.

The advent of large-scale genomic sequencing now allows scientists

to do so-called reverse genetics. Sequences of unknown genes can

be fed into large databases, and tested for similarity (homology)

to previously sequenced genes. Organisms as diverse as yeast, flies,

mice and man have been found to show high levels of homology between

many gene families, reflecting the common evolutionary root of these

species. In this way, we can guess at the functions of human genes

without having to identify mutants. Having the DNA sequence of a

gene makes it relatively easy to make the corresponding protein,

which can be added to cultured cells or cell extracts. These experiments

are important, as genes do not work in isolation - proteins and

DNA must interact with each other in order to create a functional

cell. Some proteins bind to DNA and switch genes on whilst others

switch them off. Division, death, and ageing of a cell are determined

by its genes, and the magic carrot of a cure for cancer is dangling

enticingly under the noses of scientists as they seek to understand

these processes.

But this rosy future has some thorny ethical and legal issues.

Insurance companies may be unwilling to cover people with risky

genes, whilst employers may demand a clean bill of genetic health

before offering top jobs. Would prospective parents want to genetically

vet their embryos before bringing them to birth? An apocryphal story

tells of a criminal in America who pleaded that he was carrying

a gene for violence as his defence. When his lawyers tried to prove

it, they were sued by the man's father for defamation of his family's

character. As we await the publication of the completed genome sequence

we can only guess that more surprises are yet to come.

- June 2004

About the Author

Kat Arney is a writer and member of the naked scientists radio programme. She is based at Cancer Research UK