Gene genie out of the bottle

00:48, Jul 23 2013
BACK IN THE LIMELIGHT: Angelina Jolie appears at film premieres in Spain and London after announcing she had undergone surgery to have both her breasts removed.

Imagine this. You walk into your GP's surgery. You've been complaining of heart palpitations, or you have a boil on your bum, or maybe you're a bit anxious because you've just had a significant birthday and realised you're the age at which a close relative was diagnosed with a serious disease.

After taking your blood pressure, and maybe getting you to say "aah", your doctor swivels to her keyboard and taps in your National Health Index (NHI) number. Up pop a series of screens containing information about you: warnings of sensitivity to certain drugs, guidance on likely diagnoses, suggestions on lifestyle decisions.

Certain sections are greyed out, with a big padlock symbol on them. These are the bits of potentially devastating information you haven't yet decided whether you want to know. But beneath the padlocks it's all there - a wealth of data derived from a few millilitres of saliva or blood or some cells from inside your cheek, which you supplied a few days or weeks earlier, or maybe even the day you were born.

GENOME TECHNOLOGY: The ability to sequence your genes is becoming cheaper and more widely available.

Welcome to the wonderful world of everyday genomic medicine.

In fact, the scenario above is still a futuristic fantasy, but only just.

In May, Hollywood star Angelina Jolie revealed she had undergone a double mastectomy after a test showed she had the BRCA1 gene variant, which is associated with a very high risk of breast cancer.


Jolie's announcement has fuelled public interest in the everyday value of genetic research, but it was already well on its way, driven in part by its increasing affordability.

In the decade since 2003, when the Human Genome Project announced it had finally sequenced a single human genome, the cost of reading the 3 billion-odd As, Ts, Gs and Cs of the DNA inside each of your cells has plummeted.

That first human genome cost $3.4 billion to figure out. The current price is about $7000, and for $2000 you can sequence just your "exome" - a small but significant subset of the genome, which contains the lion's share of interesting genetic information. For just $125 you can send off a bottle of your spit and get back a trainer-wheel gene test from providers such as the American 23andMe, which sequence an even smaller subset of your exome and spit out a report on a few hundred health conditions and traits.

As the price collapses, research and clinical practice are swiftly changing, with the most immediate benefits appearing in the areas of rare childhood diseases, cancers, and certain cardiovascular and neurodegenerative disorders. It seems inevitable that genome sequencing will continue to radiate outwards,

from university researchers to specialist doctors and, ultimately, to GPs at the primary-care coalface.

Some experts, though, think New Zealand isn't getting there fast enough.

That's why a loose consortium of academics, clinicians, bioinformaticians and ethicists is busy recruiting participants for an informal nationwide "trial" of exome sequencing in clinical settings, due to kick off in a matter of weeks.

It is part experiment, part PR exercise. The sequencing will be done by the government-backed gene-tech hub New Zealand Genomics Ltd, headed by Dr Tony Lough.

Illumina, the United States company that builds the million-dollar-plus "massive parallel sequencing" machines that transform your spit, blood or cheek swab into data has chipped in $30,000 of the chemical soups needed to run their machine.

Time-consuming data analysis will be shared around NZ Genomics and its partners at Auckland, Otago and Massey universities.

Otago University paediatric geneticist Dr Stephen Robertson is one of the trial's organisers. The point, he says, "is to demonstrate loud and clear that this stuff has arrived, and we should be using it".

Just 48 exomes will be sequenced, so the consortium is cherry-picking cases where sequencing is likely to prove useful and where patients' consent for research has already been established. This means Robertson has been mainly recruiting paediatric and oncology (cancer) specialists, who will then invite their patients to take part.

"Some pragmatic decisions have been made, which have probably left some people out in the cold for now.

"There are lots of clinicians around New Zealand - cardiologists would be an example - who'd want to jump at this."

It isn't strictly academic research, Robertson says. It's more about showing New Zealand patients, policymakers and purseholders what can be done. A digest of the trial's results will be released in a "white-paper" type document in six to 12 months.

Robertson acknowledges Illumina isn't funding the trial "out of charity.

"They want to plant the seed in New Zealand, but they want to plant a seed which has been acknowledged very broadly as being of clinical value."

Reading the genome is turning out to have an extraordinary array of uses, but it has also spawned speculative, even fantastical, claims about what the future might hold.

So, what use, right now, is there in having the three-gigabyte computer file of someone's full genome (or the rather smaller file of their exome)?

For a start, Robertson says, genome sequencing is proving enormously useful to paediatricians such as him.

An example, when parents have a child with a "non-specific developmental delay" (a polite term for serious mental retardation), "they can often be frozen with fear about having another child".

"They don't want double trouble."

Sequence the child's genome, and you can tell whether the problem is a one-off.

"A sizeable fraction of it has been shown to be a new mutation that's happened either in the egg or sperm cell," Robertson says, and that means those parents can be told the chances of it happening with their next child is low, "so they can go on and complete their family with confidence".

It is also useful against cancer. Aside from looking at cancer-risk genes such as BRCA1, cancer doctors are looking at a patient's genome when deciding on a drug therapy: there is a growing body of data about the effects of a given drug on people with particular genetic markers.

Cancer doctors are also sequencing the genome of a patient's tumour cells and comparing them with the patient's normal cells, to help figure out the best way to kill the cancer, while preserving healthy cells.

There are also many smaller-scale discoveries, and some of them suggest this article's futuristic introduction is not too fanciful after all.

Those heart palpitations? Maybe you have atrial fibrillation and could use the blood-thinning drug warfarin. The problem is it is really hard to find the right dose of warfarin - too much and you bleed, too little and you clot.

Helpfully, it turns out there are a couple of key genes that determine your response to warfarin. Dial them up in your data, and much of the dosage guesswork can be bypassed. Perhaps it is not worth getting your genome sequenced for this purpose alone, but if the data is sitting there anyway, why not use it?

That boil on your bum? The standard antibiotic a GP will dispense for your painful staph infection is flucloxacillin. Unfortunately, the drug causes a nasty jaundice in about one in 12,000 users. Fortunately, people who react like that have a single genetic variation that can be easily spotted in your data. If your GP knew that, they could give you a different antibiotic at the outset.

One of the holy grails of genome sequencing, though, is the idea that it can be used to predict your future diseases.

And here Robertson urges caution.

Sure, your genome will provide advance warning of many conditions, especially those where just one or a few genes are involved.

It is good to know if you are at very high risk of certain kinds of breast cancer and bowel cancer. There is a fairly common heart disease called hypertrophic cardiomyopathy (broadcaster Paul Holmes suffered from it), which can be spotted in your genes long before your heart muscles start to thicken.

But what about genes that give you bad news you cannot do much about, or choose not to know?

A child of someone with the devastating neurodegenerative condition Huntington's disease has a 50 per cent chance of getting it themselves, but looking at their genome removes all doubt.

Take a close look at your ApoE gene on chromosome 19, and you could learn you have worse-than-average odds of getting Alzheimer's disease, Parkinson's disease and other disorders that cannot yet be effectively treated.

"If someone told me I had a genetic variation that predisposed me to Alzheimer's, I'm not sure I'd thank them for that," Robertson says.

However, the big false hope of genetic sequencing, he says, is the idea that eventually you will be able to look at someone's genome and predict all the calamities that might befall them.

"The whole idea that genetics is such a deterministic force in our biology that we can use it as a crystal ball is really naive."

The problems that afflict the average, moderately healthy person - nasty coughs, type-2 diabetes, heart disease, many cancers - are usually controlled by a huge number of genes interacting in a complex way with each other and the environment, which makes predictions almost impossible.

"We've evolved over hundreds of thousands of years to have a sort of switchboard that has compensatory ways of dealing with what the environment throws at us," Robertson says.

"Evolution dices its risk up into small packages. That's what is going to make it hard for us doctors to try to reaggregate all the diced-up risk and find some kind of answer.

"I suspect for a rudely healthy person with a bland family history, the whole genetic thing is going to be a bit disappointing."

Auckland University associate professor Dr Cristin Print, an expert in biotechnology and bioinformatics, is part of the NZ Genomics trial's steering group.

He hopes the trial will enthuse people about the "tremendous power" of genomic sequencing, but he agrees there are misconceptions.

He says it is important to realise how little we still know about the human genome.

The cost of sequencing has plummeted. "But the really expensive part remains in the biological and medical understanding of the data. There are literally millions of ways of looking at a genome. Even clinicians have a struggled understanding what all these results mean."

It could be many years, even decades, before the science, medicine and political imperatives align, and New Zealand has a nationwide system where GPs can tap into a patient's genome record each time they write an antibiotic script.

Long before then, though, doctors will need to get up to speed with genomics, as a result of patient pressure.

23andMe is just one of the many companies now offering direct-to-consumer genomic sequencing.

Cristin Print says he knows a few GPs who have had patients come in with their 23andme reports asking what they mean, "and it's a struggle".

Rob Murray, spokesman for the Royal New Zealand College of General Practitioners, says while some GPs are being quizzed by patients about their commercial gene tests, it is not yet common.

He says genomics are "definitely on the college's radar", and have been added to the curriculum for GPs and registrars' professional development.

Print says the interpretive material that comes with some direct-to-consumer products can be worryingly close to "genetic horoscopes". But he sees this kind of consumer empowerment as an increasingly important facet of healthcare.

He sees huge potential also in online sites such as, which provides a well-structured forum where members talk about their symptoms and their treatment. That data is then collated and sold to major healthcare providers and drug manufacturers.

"That sort of thing is increasingly powerful," Print says, "and New Zealanders are participating in it, and increasingly these people are having their exome sequenced by 23andMe or some other organisation".

It makes little sense, Print says, for professionals to ignore what their patients are finding out for themselves.

"I guess our role as slightly more conservative physicians and researchers is to make sure that there is an element of truth, that expectations are reasonable, and that people are not being stressed or misled by the information they find."

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