KEY POINTS:
In a modest Auckland laboratory, heart specialist Patrick Gladding is solving a genetic riddle that for some patients will mean the difference between life and death. The young researcher examines the genetic blueprints of patients to determine how they will respond to treatment.
He works at the frontier of what is known as personalised medicine, where treatment is based your unique genetic makeup. In some quarters the idea of tailoring treatment to your personal genes is seen as the next holy grail in health treatment.
It's a genetic revolution spreading beyond hospitals and medical laboratories. For around US$1000 anyone can get to know their genome better by sending a saliva or cheek sample to companies offering gene readings of their future.
While personalised genetics promises to tell you more about your ancestry and susceptibility to heart disease, Alzheimer's, cancer and diabetes, there are doubts about the scientific soundness of such services. Not to mention ethical and privacy worries about who controls the genetic libraries the technology creates.
Despite the concerns, many are saying the genome is out of the bottle. And thanks to the internet and a seemingly insatiable desire to know more about ourselves, our bodies and our health, gene-based profiling seems unstoppable.
All of this means Patrick Gladding's astonishing work has made him hot property for American research companies looking to recruit the very best scientists from wherever they can find them.
There are padlocks on the fridge to keep the fish out. It's no joke. In the first week Dr Patrick Gladding got his cold storage, someone at the hospital decided was good place to keep their whole fresh fish. He can laugh about it now, but at the time it wasn't funny. Not when you're about to begin freezing painstakingly gathered vials of DNA and other human blood samples.
It's a stretch of the imagination to call the corner of the tiny room on Auckland City Hospital's Cardiology floor a lab. But the fridge and the narrow bench lined with scientific equipment - platelet analyser, heating block, vortexer, centrifuge and pipettes - plus an indefatigable attitude, serve Gladding well enough. The tools of his trade - bought, begged and borrowed - plus some high tech collaboration with Swedish and Australian university laboratories, have put the 34-year-old research fellow on the verge of something big.
By detecting certain genetic markers - recurring codes in DNA - Gladding has found a way to predict whether coronary patients will have a positive or negative reaction to the anti-clotting drug, clopidogrel, before it's administered. "I think it's going to have major implications for patient treatment, particularly for patients undergoing angioplasty and stenting," says Professor Harvey White, the hospital's director of coronary care and cardiovascular research.
The preliminary finding represents the holy grail for a researcher at the cutting edge of the complex field of pharmacogenomics or personalised medicine. Knowing what drugs will work with who on the basis of what is in their genes has huge implications for medical treatment as we know it. Instead of giving a drug and waiting for a reaction, doctors can look forward to a day when they can tailor treatments specifically to an individual's genetic makeup. It's a promise with two key benefits for patients - increased effectiveness and reduced adverse side effects.
Gladding is something of an oddity at the hospital. Although he's a trained cardiologist, he's opted not for the six figure salary he could command as a senior specialist, but for the relative poverty of immersing himself in pure science. For the past 14 months he has lived off cobbled together research grants from which he also has to pay for his equipment and the services he employs in his work. Is he mad?
"Every now and then I wake up in the morning and wonder what the heck I'm doing. My wife sometimes wonders that. And I look at my kids and that we live in a very average home ... ", says Gladding trailing off wistfully.
But then he remembers what drives him. "The prospect of discovering something new is very exciting - you can help more than one person. You might influence the way lots of people work. The excitement of a discovery becoming something useful far outweighs the money to me."
Pharmacogenomics is still in its infancy, but it does have some success stories, such as herceptin. The breast cancer drug helps one in five women who take it - women who, it turns out, have a mutation in their tumour cells that clearly differentiates them from other types of cancer. What's unusual about herceptin is that the drug is sold with a diagnostic test which determines who will benefit.
Gladding is developing a similar type of test for clopidogrel.
"He can identify those patients where clopidogrel works and those patients where it doesn't," says White. "He's even gone a step further - looking at the patients where it doesn't work and whether a bigger dose may help."
The concept of targeted drugs has obvious benefits for patients. But it has economic implications too. Herceptin is one of the most expensive drugs on the market. That's because it breaks with the blockbuster, one-size-fits-all model of drug development. Like the art house movie, personalised medicine caters to a smaller audience.
If a test such as Gladding's was applied to a large clinical outcome study and proved useful, it could impact on the $7 billion international market for clopidogrel.
On the plus side, a test determining who the drug works for would save money for hospitals and drug agencies like Pharmac. The drug companies might not be so happy. Seeing as much as 20 per cent shaved off their sales is not something they're likely to take lying down.
Whatever the hurdles ahead, late last year, when the research results for those resistant to clopidogrel indicated a tight correlation with genetic markers, Gladding felt pretty good. "I was beaming for a couple of days. But no one believes it yet or thinks that it has value."
Gladding is about to show them. The next phase of his study involves recruiting a second group to validate the test response to clopidogrel. He's also in the process of writing up the research for publication and patenting a genetic test related to his discovery - something he's paying for himself.
Down the corridor in one of the high tech operating theatres a patient is on the table. High tech x-ray imaging machines on robotic arms swing around the huddle of gowned-up cardiologists and assistants. In startling clarity, magnified arteries amid a spidery network of blood vessels, pulse on screen under the watchful eyes of the surgical team guiding a balloon catheter on its path.
It's here, among routine angioplasty and pacemaker procedures, that Gladding's work began. Taking blood samples from coronary patients given clopidogrel to stop microclots forming in the mesh stents about to be placed in their narrowed arteries, Gladding used a portable platelet analyser to test for stickiness in the blood at intervals after the drug was given.
The results told him which patients were "responders" or "non-responders" to the drug. Other studies indicate that for 70-87 per cent of the population clopidogrel works fine, but for the remaining 13-30 per cent, it might not. Similar statistics show up with aspirin and other heart medications. For the non-responders, clotting of the stent is serious and can be fatal. When it occurs, another operation or medication is quickly required.
Gladding also extracted DNA from each of the blood samples and sent it off for mass spectrometry analysis, first to Sweden's Uppsala University and then to the Genome Research facility in Australia.
He focused on several genes which he hypothesised might be relevant to the function of the drug. That helped narrow down the DNA search. Even so, it was like looking for a needle in haystack.
Gladding was looking for "snips", researcher shorthand for SNPs (single nucleotide polymorphisms) - single letter variations in the genome alphabet. Thanks to the Human Genome Project, completed in 2003, we now know that when it comes to our 23 chromosomes, around 26,000 genes, and 1.8 metres of DNA double helix strands, we're 99.9 per cent the same. Snips (SNPs) are the 0.1 per cent bits of DNA code that make us different.
There are about 10 million common SNPs, each occurs roughly every 1200 letters or so, in the 3.5 billion letters that make up the genome - a nine-storey stack of telephone books. As Gladding points out, that makes for a lot of reading. But the task is made easier by technology that scans and identifies genetic sequences and computers that process the vast amount of data gathered.
In fact the technology is getting so good that gene chips, (microarrays) are being used to provide genome mapping services direct to consumers. For around US$985-US$2500 consumers can send in a cheek swab or saliva sample and receive their gene profile that not only tells about their ethnic ancestry, but also rates their risk for certain conditions including asthma, Alzheimer's disease, myocardial infarction (heart attack) and diabetes.
Similar to microprocessor technology, which doubles the number of transistors that can be crammed on to a silicon chip every 18 months, gene chips are also developing at ever-increasing densities. The latest has 1.8 million "probes" of synthetic DNA layered in an array of tiny gene dots on silicon wafers.
(See: "When Biology Meets Silicon").
Because Gladding was already focused on a number of genes, he didn't use microarray technology for his search, opting instead for the more traditional and less costly mass spectrometry. His study was also relatively small - just 60 patients. But it was enough to compare SNPs in the patients resistant to clopidogrel with those for whom the drug worked fine.
What he found was several novel SNPs, not previously associated with the drug response. And that the non-responders all shared SNPs that were mostly absent in the responder group. Of more significance is that something can be done for non-responders - a bedside test to identify them and then decide on the appropriate treatment.
Gladding also needs to run his study with larger numbers - something he could achieve overnight if he could convince drug companies to test the DNA they have banked from other clopidogrel studies. "The problem is drug companies don't like this technology at all, because it means some people won't be getting the drug. They want the drug to be applied to everybody," says Gladding. But there are signs that, whether the drug companies like it or not, personalised medicine is here to stay.
The United States Food and Drug Administration sees pharmacogenomics as way to improve drug safety and has developed guidelines for the collection of DNA data for new drug trials. It's clear too that the drug companies aren't about to ignore pharmacogenomics either. There are also some ironies. A piece of equipment used in Gladding's blood stickiness research - the platelet analyser - was a donation from drug company Sanofi Aventis which also holds the patent for clopidogrel.
At Auckland University's Proteomics laboratory Gladding views graphical representations of some of his blood samples that have been "smashed" into electrically charged fragments and measured as they fly through parabolic arcs inside one of the lab's mass spectrometers. Here, he's looking not for genetic markers, but for proteins produced from the heart in patients under going angioplasty. The hope is to find new proteins that could be a marker for damage to the heart. An offshoot of his clopidogrel research, it's the type of high tech collaboration he would like to be doing more of - searching for molecular clues about how the heart functions in clinical environments.
The buzzword for what Gladding does is translational research - bridging the gap between doctor and scientist, clinical medicine and science. It's a hard road at the best of times and even more difficult in New Zealand, which lacks the collaborative infrastructure for pharmacogenomic research.
He looks on with envy at Australia's IMBcom, an offshoot of the University of Queensland's Institute for Molecular Bioscience. There, doctors work half time in a hospital and half time in their science laboratories. Gladding craves the collegiality - being able to walk down corridors, bump into fellow scientists and chat about things. Not to mention IMBcom's team of intellectual property lawyers tasked with insuring a payoff for every dollar invested.
It's a world Gladding may soon get to experience. He's been offered a research fellowship at the Scripps Research Institute near San Diego, one of the United States' largest private, non-profit research organisations. There he would be among an army of professors, postdoctoral fellows, PhD students, laboratory technicians, and support personnel. Not to mention having access to state-of-the-art equipment, including a Cray supercomputer, high-performance nuclear magnetic resonance spectrometry instruments, and a DNA sequencing laboratory. The downside is living like a student again and uprooting his family from New Zealand.
Not that he's complaining about what he's been able to achieve here. Working in the hospital gives him invaluable access to real world patients. His research has been recognised in a number of Australasian investigator awards and is strongly supported by several of the hospital's high profile cardiologists. And he's indebted to the Green Lane Research and Education Trust, the A+ Trust and others for funding him.
While the hospital gives plenty of support through its Research Office, including a bio-statistician to verify his results and a research co-ordinator to guide him through bureaucratic frustrations, it isn't exactly geared to research. "People voice support for research, but it's not a major driver at the hospital," says director of coronary care White, who sees innovation and optimising patient care through work like Gladding's taking a back seat to cost-cutting.
To the administration Gladding is seen as a cost - even though he regularly teaches trainee doctors in bedside and electrocardiogram skills. "I just do that because that's part of what being a doctor is - I enjoy it and I think it's important." But he also has to pay the going rate for the hospital resources he uses. That includes $200 per DNA extraction - something he got down to $6 by buying his own equipment, taking a short course in molecular biology and doing it himself.
This No 8 wire Kiwi ingenuity attitude is admirable, but the question in Gladding's mind is where to next? Despite nearly a decade of talk about New Zealand developing its biotechnology sector as one of the pathways to a knowledge economy, he despairs at times at how little has developed.
What does he want? "To work among a network of people to allow constant and further development of these kinds of ideas."
If Gladding takes the Scripps job, it's a fair bet his skills will be in high demand off shore. The question someone has to ask is whether another brilliant researcher will be joining New Zealand's brain drain.
PERSONAL GENOME SERVICES
* 23andMe, available in North America and Europe for US$999, www.23andme.com.
* deCODE Genetics, available globally for US$985, www.decodeme.com.
* Navigenics, available later this year for US$2500, www.navigenics.com
