The long and winding code

It would take decades and cost billions, they said. Tim Radford tells how it was done

The Human Genome Project began as a leap into the dark, and ended by ushering in a new information age. Critics said it it would cost insane sums of money, take decades to complete and deliver only a stream of data encoded in an alphabet of four letters, nine-tenths of which would have no meaning at all.

When scientists proposed the idea in the 1980s, it took hours of painstaking effort using exquisitely tricky chemistry, to "read" even a few thousand bits of DNA. The cost was put at $5 to $10 for each one of the four "letters" - sometimes called nucleotides, sometimes base pairs - in the 3 billion-letter human alphabet. When, in the teeth of grumbling from fellow biologists, foot-dragging by politicians in Britain and America and explicit public concern in Germany, the project gathered momentum, the international cost was set at $3bn in total - $1 for each base pair. Right now the cost has fallen to 10 or 20 cents.

The first "rough draft" is complete, thanks to astonishing advances in robotics and computing, and subtle tricks with electrochemistry.

The challenge was to decipher the entire DNA of one representative human, selected from a group of anonymous donors. But the DNA of one human is an invisible double-stranded molecule arbitrarily chopped up by nature into 46 chromosomes - 23 inherited from the mother, 23 from the father - and folded into impenetrable tangles. It was then, and still is impossible to read in that form: impossible even to see, let alone manipulate.

So researchers took lengths of human DNA and inserted them into bacteria, and then grew the bacteria, much in the way dairymen "grow" yoghurt, allowing each bacterial specimen to "clone" the same bit of DNA indefinitely, so that it could be preserved in dishes in a human DNA "library".

But that was the equivalent of simply tearing random paragraphs out of a book, hoping to read them later.

So the first step was to try to make a "map" of the human genome: to establish recognisable genes, or telltale lengths of DNA, at points along all the chromosomes so that those given the challenge of "reading" the sequence would start with a rough idea of where, in a particular chapter, their paragraph might fall. That effort continued throughout the 90s, as individual groups in the worldwide community of biologists began to identify then locate genes associated with diseases such as muscular dystrophy and cystic fibrosis.

By this time, too, teams within the Human Genome Project, in industry, in the medical charities and in government research laboratories were getting experience with the genetic codes of complex creatures such as yeast, a little member of the mustard family called Arabidopsis, the nematode worm or the fruit fly.

Since DNA is the machinery of evolution, the genes of all creatures would show similarities, and make recognition easier.

All the researchers used a technique developed by Frederick Sanger, the Cambridge scientist who deciphered the protein structure of insulin, won a Nobel Prize for it, and then went back to his laboratory to decipher the code of DNA. A feat which earned him another Nobel prize.

The Sanger method, then done by hand (but now by specially commissioned robots) was simple. You shredded the DNA sample into a large number of lengths ending up with very short bits, medium lengths and long bits. If you did it often enough, you would end up with bits of every possible length. Then you would tag the end of each with a fluorescent dye, dribble them into a tiny, jelly-filled capillary tube the thickness of a human hair, using electricity to help them settle. The shortest would settle first, then the next shortest and so on until the fragments were in order.

When you had enough fragments, all overlapping each other, you could get a computer to match them, rather like reassembling the Bible from fragments that said "Saul" or "Psalm" or "Solomon".

But the process also has to be fast. To read a base-pair sequence of a human being out loud - at, say, five letters a second - it would take 20 sleepless years. The original Sanger method could deliver thousands of letters a day, but the project demanded millions.

So what began as a meticulous matter of test tubes and syringes and white-coated laboratory staff became rooms full of robots: St Louis, Missouri; Cambridge, England; Cambridge, Massachusetts or Rockville, Maryland. Biology, invented by gentlemen-amateurs became big science, demanding engineering skills and computing power far greater than needed for the Apollo programme. Although the researchers have blown a whistle, posted their latest results and declared a milestone passed, it isn't complete.

"There is roughly 10%we haven't sequenced," says Don Powell, a molecular biologist at the Sanger Centre in Cambridge. "The attitude in the Human Genome Project is that we are putting this data out, it is only going to be done once and it absolutely has to be done properly. Everybody is agreed you need to do everything tenfold in order to get yourself down to 99.99% accuracy. We will achieve better than that. Because the genome is only going to be sequenced once to this level of completion - no other organisation is going to do all this finishing and all the work to plug all the holes we can - it has to be done properly."