The GeneChip can track down illnesses before they strike. Report by Roger Highfield and Paul Forster
DOCTORS will, within a few years, be able to take a mouth swab, rummage through your genes and assess your risk of disease, thanks to the development of a revolutionary "GeneChip" that can perform a vast and sophisticated genetic analysis in record time.
The past two decades have witnessed an extraordinary advance in scientists' understanding of the genetic control of development and disease, with the help of techniques such as genetic engineering, cloning, and sequencing - the ability to decipher the language of the genes written in our three-billion "letter" code.
The GeneChip, a laboratory on a chip made by Affymetrix in Santa Clara, promises to revolutionise genetic diagnostics by accelerating the speed at which new genes that cause disease are identified, providing major advances in medicine.
However, the widespread use of the chip will also accelerate the number of ethical dilemmas to be faced by society as employers and insurance companies discriminate against those at risk of disease, with fears of a genetic underclass.
An increasing number of parents will be confronted with lists of diseases that their unborn children may be likely to inherit, and abuses of genetic information may abound.
"What we are looking at is where to use the technology to bring real benefits and real choices," said Dr Stephen Fodor, Affymetrix's brains behind the chip. "The immediate goal will be to understand more about the biological implications of genetic variability."
Developed by Dr Fodor's team at the Silicon Valley company Affymax, the GeneChip is able to conduct genetic analysis by exploiting the way one strand of DNA sticks to another with a complementary genetic code. Dr Fodor took the technology used to print microchips and instead used it to produce vast arrays of single-stranded DNA for tests.
The power of the technology, now inherited by Affymetrix, derives from the ease and speed with which around 400,000 different genetic sequence combinations can be engineered on to the chip, a piece of glass slightly larger than a thumbnail.
Dr Fodor's team developed semi-conductor fabrication techniques, which work in a way that is analogous to developing a photograph, to lay down huge arrays of short DNA fragments with known sequences, in effect encoding vast amounts of genetic information on the chip.
These sequences are used to "interrogate" a patient's DNA sample, which is fluorescently labelled and washed over the chip. Complementary sequences stick together, revealing their presence under laser light. When there are matching sequences, that part of the area probed in the glass chip glows. By examining the results, scientists will have a a diagnostic tool more powerful than anything genetic engineers have ever seen.
The company is now tooling up to produce 30,000 GeneChips a month. The potential is huge. Last June, Affymetrix offered six million shares for sale, even though it had never shown a profit.
The success is already spawning efforts to improve the technology. At present, the arrays are on glass, and the presence of complementary strands is revealed only by the use of an optical scanner. If the DNA sequences on the chip could be read directly by circuitry, the procedure could be cheaper.
That may be possible, in the light of a discovery about the physical properties of DNA made by Dr Thomas Meade of the California Institute of Technology. Electrons normally struggle to travel along a single strand of DNA. But for the double helix - the mutually entwined complementary strands - he found that electrons could scoot along it with ease, providing an electrical signal to announce when a sequence of interest has been found.
THE IMPLICATIONS of the device for the individual are awesome: in the not-too-distant future, Affymetrix and its partner Molecular Dynamics hope to develop a handheld gene reader that could enable a GP to tell us what disease, or diseases, we are going to suffer from before there are any symptoms; even what diseases may kill us in the future.
The reason is down to the vast quantities of genetic information that are spilling forth from the Human Genome Project, a worldwide enterprise to map and sequence the human genetic code, which consists of three billion genetic "letters". Hence the grant to Affymetrix of nearly $6 million from the US government's National Centre for Human Genome Research.
Genetic information comes in two varieties. Some genes act like bullets - if you test positive for the fatal neurological disorder Huntington's Chorea, there is little you can do. Other genes act like cigarette smoke, raising the risk of, say, cancer. Whatever types you are interested in, the GeneChip offers the means to hunt them down rapidly.
The GeneChip can, for example, search for the normal version of a gene, and all the variants where there is a "spelling mistake"; that is, where one of the four basic genetic letters is exchanged for another. Just such a mistake leads to haemophilia, for example.
The ability to screen for vast numbers of gene sequences simultaneously will also allow scientists to attack molecular biology at a new level: we are beginning to find out which of a human being's 100,000 genes are at work in a brain cell, for example. But by using a handful of GeneChips, we can watch the choreography of up to 6,000 genes, seeing how they are switched on and off during a normal cell cycle. "We can start to unravel the cell's circuitry," says Dr Fodor.
The first commercial application of the GeneChip is a probe designed to help researchers identify mutations in the genetic code of the Aids virus that cause resistance to anti-viral drugs such as AZT, helping doctors to select the best treatment.
The team is developing a GeneChip to study the p53 gene, which has become a byword for tumours. Whether cancer is found in the liver, skin, the breast, bladder or lung, it probably contains a defective version of the gene.
"In the short term the most important use of the GeneChip will be in the identification of gene mutations and polymorphisms [changes in the sequences of genes] that predispose us, or our children, towards infectious diseases," says Dr Barry Ross, director of research strategy at Glaxo Welcome.
The aim of this and complementary efforts using classical methods is to produce a book of man, linking varieties of certain genes with risk of disease or a trait, such as sexual orientation or anxiety.
"Five or 10 years, or more, down the line, the technology will be critical in bringing gene-based diagnostics into the clinic, where it will have a dramatic impact on the fundamental way in which medicine is practised," says Dr Ross. "It will help us design more effective medicines. It will help focus treatment, and it will help people who have a genetic predisposition to a disease to adjust their lifestyles accordingly . . . people will really benefit."
