Under The Microscope: Missing links

Why Mapping The Genome Is Only Half The Story

"ALTERS impediments marriage me of not not or to true is minds with love love which let it alteration the finds bends remover remove admit when."

These words from the beginning of one of Shakespeare's sonnets offer a clue to the subject matter of a poem - it seems to be about love and marriage - but give no real idea of the ideas expressed. This is analogous to knowing the complete DNA sequences of the human genome - identifying each of the 100,000 or so genes that control our development and our lives. Each of the genes is like a single word in the poem and tells us nothing about how the genes will act or relate to each other; knowing the genome is only the beginning.

But will it not be possible to work out from the genome how the whole functions? No, no more than the sonnet can be reconstructed from its words. The key to understanding living systems is proteins; genes merely provide the information for making proteins. While the genome will tell us which proteins cells can make, it will not tell us the shapes of the proteins nor their functions (which are determined by shape), unless they are very similar to those that we are already familiar with. It may never be possible to predict the shape of a protein from the gene that codes for it - that will only be achieved through other methods, eg by seeing how X-rays are altered when they meet it.

Worse still, it will be extremely difficult to work out how the proteins will interact with one another, particularly when one realises that tens of thousands of proteins are involved in communication within a cell. When a signal reaches a cell membrane it sets off a cascade of protein interactions within that cell that can lead to a particular gene being turned on or off. This process is not unlike the Rube Goldberg cartoon in which a man has an apparatus for raising his umbrella when it rains: the rain causes a prune to expand and so light a lighter, which starts a fire, which boils a kettle, which whistles and frightens a monkey, which jumps on to a swing, which cuts a cord, releasing birds which raise the umbrella as they fly away. The genome on its own will never reveal its sequence, just as the monkey alone would never put the umbrella up.

A very different example is the genetic disease Huntington's chorea. Patients inherit an abnormal gene which causes brain cells to die, producing severe neurological problems. It is now known that this is due to a faulty gene making an abnormal protein. This protein is made in the nerve cells of the brain and causes them to die, which causes the disease. This sequence of events could never have been deduced from the genome but required an great deal of research.

Genes become activated during embryonic development; this involves cell- to-cell signalling in a well-defined spatial pattern, and this pattern cannot be deduced from the genome alone but requires understanding of developmental processes. The embryo also changes in shape dramatically - the flat sheet of cells which make up the spinal cord and brain folds up into a tube -which requires cellular forces not to be found in the genome. As for the functioning of the brain, the genome on its own tells us nothing.

The New Millennium will be the age of post-genomic research, so: "Let me not to the marriage of true minds/Admit impediments."