Getting Up Close And Personal

Sydney Morning Herald

Thursday May 15, 2008

Steve Dow

A map of your genetic destiny and tailor-made medications are closer, and cheaper, than you think, writes Steve Dow.

A new genetic era is dawning, and this time medicine is getting personal. Cancer, stroke, heart disease, osteoporosis - in the next few years a computerised sequencing of your genome generated within an hour and costing $1000 or less could tell you whether you have inherited or developed genetic mutations that can cause these diseases and, in some cases, your chances of responding to or resisting treatment.

Not only will such a scan focus your efforts to eat better and exercise, but molecular researchers will also use tailor-made medications to target dodgy genes at the core of many illnesses.

A decade after the first genetic medication for cancer, trastuzumab, became available, the era of personalised medicine has finally arrived. Trastuzumab, an antibody drug marketed as Herceptin, was aimed at up to one in three breast cancer patients who produced too much of the protein HER-2/neu, which leads to ferocious tumour growth. More recently it has been discovered that when the deadliest form of lung cancer - non-small-cell cancer - occurs in patients who are female or Asian or who have never smoked, it is often due to a growth factor mutation: enter the drugs gefitinib, marketed as Iressa, and erlotinib, sold as Tarceva, designed to hit these genetic targets.

Despite doubts over whether gefitinib improves lung cancer patients' chances of long-term survival, personalised medicine is gathering steam. Another drug, imatinib, or Glivec, has successfully targeted the gene mutation BCR-ABL, which triggers some cases of chronic myeloid leukaemia.

The future? Ever more specialised drugs tailored to ever-smaller subsets of patients.

"All the Cassandras will say, 'Oh, this is going to cost more,"' Professor John Mattick, of the University of Queensland's Institute for Molecular Bioscience, says. "But, if you can target an expensive, leading-edge drug to people who are going to benefit from it, and not bother to give it to those who are not going to benefit, you'll see enormous savings."

Geneticists and molecular biologists predict that within five years a person will routinely have his or her DNA sequenced and compared to a "normal" template, such as that produced by the Human Genome Project.

Completed in 2003, the international research program's results - identifying human genes plus sequences of DNA's 3 billion chemical base pairs - continue to be analysed. When the project began in 1990 it was anticipated there were about 100,000 protein-coding genes. Now, it is thought there are just 20,000 to 25,000, making the hunt for mutations a little easier for scientists - up to a point.

Last year, when the co-discoverer of the structure of DNA, Dr James Watson, and a US genomic researcher, Dr Craig Venter, each published their personal genomes, it was found the number of rare and unique genetic variations between the individuals was much greater than earlier thought. This finding magnified the need for science to pursue more personalised medicines.

In January the Wellcome Trust announced in Britain that British, US and Chinese researchers had commenced work on the 1000 Genomes Project. This project will sequence the genomes of at least 1000 people from around the world to build the "most detailed and medically useful picture to date of human genetic variation". Its results will be published on public databases.

Serious concerns about life insurance and employment denial for those with mutations are again sparking debate, yet in wealthy countries such as Australia earlier concerns that only the elite would gain access to their DNA sequence and genetic aberrations may be ill-founded.

The retail price of a genome microarray scan has fallen in the past couple of years, from $90,000 to about $10,000. The current technology sequences about "three human genome equivalents" of an individual - given our DNA is sequenced and fragmented randomly - to ensure fairly comprehensive coverage so that the most common disease markers are picked up.

But there are new technologies emerging that are capable of sequencing up to 30 human genome equivalents in an hour, Mattick says. "It's now feasible within a year or three - maybe five at most - that we'll be doing a human genome for less than $1000; maybe even $100."

Testing of course is a moot point until scientists gather enough information about the range of genetic variation across the community, and how mutations increase individuals' chances of, say, cardiovascular disease, or cancer.

Some of the information is already at hand, such as the breast cancer familial genes BRCA1 and BRCA2, which for many women will prompt the agonising decision of whether to have mastectomies before getting disease.

Exhaustive yet affordable genome sequencing will be ready long before it yields many other dire secrets for individuals. Mattick says the intersection between computing, nano, optical and DNA technologies is almost beautiful to talk about. "DNA sequencing on nano-sized particles that are using enzymes that emit photons of light, and the machines counting photons and converting that into DNA sequences - it's testimony to the technological brilliance of modern society," he says.

Finding all the genetic markers and putting them into everyday medical practice is still a pretty tall order, says Melbourne-born Professor Richard Gibbs, the director of the Human Genome Sequencing Centre at Baylor College of Medicine in Houston.

But he says genetic discoveries and personalised medicine are "rising now and will rise more sharply and the impact of the individual pieces will become greater".

Most scientists point to about 2013 as a tipping point for personalised medicine. The linking of particular mutations to cancers is "already well under way", Professor John Shine, the executive director of Sydney's Garvan Institute of Medical Research, says. "We're now in the phase of using that information to try to develop new drugs, and that's probably about a five-year process," he says.

In the Journal Of The American Medical Association special genome issue, published in March, a Cleveland scientists showed lowered activity of the paraoxonase 1 gene, linked to HDL or "good" cholesterol, could increase heart attack, while a second study from the Netherlands showed variants of the gene LRP5 increases the risk of bone fractures and lowered bone mineral density.

While individual gene aberrations provide targets for therapeutics, they can also cause drug resistance. Secondary cell mutations in leukaemia and lung cancer patients can block the effectiveness of the new drugs. But personalised medicine is proving technologically brilliant there, too: biotech companies such as Genzyme in the US have developed tests to detect which patients will be resistant to Glivec and Tarceva.

In Australia, researchers at Murdoch University in Perth published a study sponsored by the drug company GlaxoSmithKline in The New England Journal Of Medicine in February, reporting on the success of a blood test for a gene, HLA-B*5701, which is strongly associated with hypersensitivity side-effects - fever, rash, gastro and respiratory problems - in 5 per cent to 8 per cent of people who take the HIV antiretroviral drug abacavir, marketed as Ziagen. The new genetic test means abacavir can be prescribed more precisely.

Last August, the US Food and Drug Administration advised that stroke patients taking the blood thinner warfarin first take genetic testing to determine whether a higher or lower dose was safer. Genotype testing is also expected to become regular for genetic predisposition to high lipid amounts, to refine treatment for heart disease.

© 2008 Sydney Morning Herald

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