The yeast gene sequence itself, like any other, is no more than a factory manual, containing information on castings, mouldings and blanks but also on various extraneous bits which are removed before the assembly line gets them. Then, as in the Mercedes factory, the parts have to be put together to make a functional piece of machinery. Even that is of no use to someone who cannot drive, and even a skilled driver is no help when dumped in a strange city without a road map. To understand the workings of the cell demands even more.
DNA dismantlers, like car wreckers, generate only a box of bits and pieces; the biological equivalents of the nuts, bolts, relays, springs, struts, wires and all the other things needed to make an automobile. The shape of a human protein can be inferred from a DNA sequence, but even usually gives no hint as to how it fits into the cellular machinery. Yeasts are simpler, and rather more is known about their mechanics. Life’s unwillingness to change allows the yeast machine to be used to explore our own cells. One approach in the human gene hunt is rather like fishing. Take a protein whose job is known, and attach a molecular hook and a separate float to it. Insert it into a male (or a cell showing what passes for maleness in yeasts). Then, mate that alluring individual to a female and drift his gene past all her thousands of cell parts until one takes the bait by slotting into it. The float causes the female cell to light up and the match is made.
A fishing expedition with two hundred or so bait proteins from yeast captured more than a thousand genes in human cells. One whole set of yeast proteins attached themselves to a single human protein that tells the cell when to start dividing and when to stop. The yeast bait is similar to one that, when it goes wrong, causes human cancer: and a quick test proved that the newly hooked human equivalents represented crucial parts of our own cells’ brake and accelerator systems. Such a discovery is of great interest to medicine, and marked the first step in what may become an era of hunting for genes in complex creatures with a lure based on more humble beings.
The genetic languages spoken by different organisms are close indeed; close enough, in fact, to give an even chance that a newly-discovered human gene sequence will be related to something else, either another of our genes or one from a creature remote from ourselves. Human genetics has been transformed. No longer does it start with an inherited change (such as a genetic disease) and search for its location. Instead, it uses the opposite strategy, with a logic precisely opposite that of Mendel: from inherited particle to function, rather than the other way around. Genetics is the first science to have accelerated by going into reverse.
The first breakthrough of this new approach was the successful hunt for the cystic fibrosis gene in 1990. It gave a hint as to what was possible and was the introduction to the advances that led to the complete map a mere decade or so later. The job cost one hundred and fifty million dollars, but the costs per gene have now dropped by hundreds of times.
Cystic fibrosis is the most common inherited abnormality among white-skinned people. In Europe, it affects about one child in two thousand five hundred. Until a few years ago those with the disease died young. Their lungs filled with mucus and became infected. Those with the illness find it hard to digest food as they cannot produce enough gut enzymes. Its dangers have long been recognised. Swiss children sing a song that says ‘The child will die whose brow tastes salty when kissed.’ These symptoms seem at first sight unrelated, but all are due to a failure to pump salt across the membranes which surround cells. Medicine has improved the lives of those affected, but few survive beyond their mid-thirties.
Family studies showed long ago that the disease is due to a recessive gene that is not carried on the sex chromosomes. In 1985, pedigrees revealed that it was linked to another DNA sequence which controls a liver enzyme, although it was not then known upon which chromosome that was. Within a year or so, a kindred was discovered in which this pair of genes was linked to a DNA variant that had already been mapped to chromosome seven. The relevant segment of that chromosome was inserted into a mouse cell line, cut into short lengths and the painful task of sequencing begun. By 1988 the crucial region had been tracked down to a segment of DNA one and a half million base-pairs long. Fragments were tested to see if (like the yeast and human sequences later found to control cell division) they had sequences in common with the DNA of other animals as, if they did, the order of letters must have been retained through evolution because they did some unknown but useful job. Several such sections were uncovered. One had an order of DNA letters similar to that of other proteins involved in transport across membranes. It followed the pattern of inheritance of cystic fibrosis. The gene had been tracked down.
The cystic fibrosis gene is a quarter of a million DNA bases long, although the protein has only about one and a half thousand amino acids. Computer models of its shape show that it spans the cell membrane several times, just as expected for a molecule whose job is to act as a pump. Many families with the disease have just one change in the protein: a single amino acid is missing. That changes its shape and stops the new protein from going to the right place in the cell. Instead it is picked up and destroyed by the internal quality-control network.
The discovery of the gene allowed carriers (together with foetuses bearing two copies) to be identified. Unfortunately, cystic fibrosis which once seemed a simple disorder, can, we now know, be caused by many different DNA changes that vary from place to place and from family to family. The illness gave the first hint about the unexpected and unwelcome complexity that the full map was to reveal.
Mapping exploded after that first discovery. At first, the mappers behaved like any explorer in a new territory. A cartographer does not start with a plan of the beach which is then extended in excruciating detail until the whole country is covered. Instead he picks out the major landmarks and leaves the details until later, when he knows what is likely to be interesting. Before today’s triumph of technology, most mappers were concerned with a small proportion of the genes, those that lead to inherited disease.
All the most important single-gene inherited illnesses were tracked down within a few years. Huntington’s Disease leads to a degeneration of the nervous system and death in middle age. It was once called Huntington’s Chorea (a word with the same root as choreography) after the involuntary dancing movements of those afflicted. An eighteenth-century Harvard professor claimed that those with the disease were blasphemers as their gestures were imitations of the movements of Christ on the Cross and some sufferers were burned. It is a dominant, but with a nasty twist: because of the late onset of symptoms, those at risk are left in uncertainty about their predicament. In 1983 came a breakthrough helped by great good luck. Soon after the search started, the approximate site of the Huntington’s gene was found by following its association with a linked DNA variant some distance away on the same chromosome. Then, luck ran out, and it took ten years to find the gene. It has now been tracked to the tip of chromosome 4. The shape of the protein which has gone wrong – huntingtin, as it is with some lack of imagination called – has been worked out to give, for the first time, some insight into the nature of the disease, which involves nerve cells in effect committing suicide when the aberrant protein (which looks like nothing else in the cell) instructs them to do so. Many more damaged genes soon fell victim to the genetic explorers and were pinned onto the map.
Type in the four letters OLIM – On Line Inheritance In Man – into any search engine and a list of ten thousand inherited diseases at once appears; symptoms, inheritance patterns, and, for nearly all, chromosomal grid reference. From the hunt for inherited illness, the search shifted to a wider set of genes. No longer were diseases needed as a first clue. To look for genes only when they go wrong is like trying to work out the principles of the internal combustion engine from car breakdowns. Now, the machine itself can be dismantled and its mechanism inferred directly.
When a gene makes something, it generates a complementary molecule – a messenger, as it is known – which transfers information from DNA to the main part of the cell. Because it produces nothing, most