Greg Cubitt has not had an easy life. In his 61 years he’s escaped death at least three times, suffering several workplace accidents and one assault, plus he has an ongoing battle to control his heart disease and type 2 diabetes. A massive heart attack in 2012 was not his first nor his last. Both his father and uncle died in their 50s after several heart attacks.
But in Cubitt’s case, he’s had an ally who has brought him close to winning his battle with diabetes. Since he was 18, he’s been a patient of Dr William Ferguson, a GP in Kumeū, Auckland, who has been using genetic testing for clients whose health conditions defy standard treatment.
In 2016, Tokoroa-based Cubitt was doing his best to stick to a low-fat (for his heart), low-carb (diabetes) regime, but his blood glucose levels were out of control and by then he’d already had five heart attacks. Ferguson told him to get up to Auckland and prepared to give him “the big talk” about taking his meds.
Then Ferguson got the results back from a genetic test he’d ordered on Cubitt. He called him in and said whatever carb intake you’re on, halve it. Within a few weeks, Cubitt’s diabetes was under control and he stopped the drugs for that condition.
Ferguson couldn’t believe it. But the blood glucose results spoke for themselves – they were back within the normal range.
The genetic profiling also spelled good news for Cubitt’s cardiovascular health. Results showed he had a gene variant that impaired his ability to produce folate in its active form. Active folate has a protective role in the lining of blood vessels, so Ferguson put him on an active folate supplement.
Cubitt believes this intervention, on top of surgery, has lengthened the time between heart attacks, which used to happen every three years.
Tailored diets
Using our genetic make-up to guide medical treatment is known as precision medicine. It includes genomics – using an individual’s genetic information to predict susceptibility to disease and decide treatments; pharmacogenomics – determining which drugs you may have a reaction to based on your genetics (see A test helping Kiwis use their genetic data to avoid drug reactions is in the works); and nutrigenomics – understanding nutrient effects on your genetic make-up and tailoring diets to influence health.
For 14 years precision medicine has been Ferguson’s passion, teasing out genetic reasons for patients’ responses to treatment and finding solutions that include essential nutrients. He is a pioneer in the field, devoting thousands of hours to study and research and overseas conferences on the “omics”.
The GP of more than 40 years is inspired by seeing huge variations in genetic responses, such as the reactions shown by 800 people in a 2015 Israeli study to eating a slice of bread. For a few, their blood glucose level barely changed. For others, their levels went stratospheric within an hour or two.
Such findings make a nonsense of advocacy for a low-carb, high-fat diet, but equally for widespread uptake of low-fat, high-carb diets. One size does not fit all, says Ferguson. Treating all patients the same when prescribing drugs or even certain diets and vitamin supplements is like expecting everyone to wear a size 9 shoe.
A long time coming
Precision medicine’s potential has been overpromised and has underdelivered for the past couple of decades, says Cristin Print, a University of Auckland genomics researcher and professor of molecular medicine and pathology. The obstacles to progress range from a shortage of practitioners qualified in genetics to a health system geared to treatment rather than prevention.
But although patients cast their eyes enviously across to Australia, the UK and North America – which are speeding ahead with genomic testing across large populations – momentum is growing in New Zealand.
“The government is really organising itself to get behind this work,” says Print, pointing to a long-term briefing document released in August on precision healthcare. “It’s fairly early with lots of smaller projects, but exciting times for us because we’re finally seeing things moving across New Zealand.”
Most of the time, Ferguson sticks to prescribing conventional treatments in his practice, but for patients not responding to the standard drugs – about 80-100 individuals since 2010 – he has offered DNA testing.
And he’s had many successes. His proudest moment was the case of a 12-year-old officially described as having a “misconduct disorder”. The boy’s mother got in touch. Her son was having serious problems at school, was diagnosed with ADHD and dyspraxia, had few friends and was prone to aggression and meltdowns. There were mental-health issues on both sides of the family. Her son was highly anxious and at times had thoughts of suicide.
Initially, Ferguson was reluctant to take on such a complex case but eventually he saw the family and noticed the boy had signs of deficiency in vitamin B6 and zinc. Without genetically testing him but recognising similar characteristics among other patients he had tested, Ferguson suggested B6, zinc and melatonin supplements to help him sleep, and in the meantime sent samples to Australia to measure histamine levels.
By the time the results came back, the boy’s mood had already improved as a result of the supplements. The test showed high histamine levels, in addition to the low zinc and B6 confirmed by a urine test.
High histamine can indicate a deficiency in SAMe (S-Adenosylmethionine), a naturally occurring compound that helps to control about 40 different biochemical pathways in the body. SAMe is also available as an over-the-counter supplement.
“I thought, right, we’ve only got one shot here, and that might actually change things. Let’s give him some SAMe.
“Two months later, he was still sleeping well and there were very positive reports coming in from the school. He was no longer experiencing mood swings or talking to himself or hearing voices. His parents described a vast improvement.”
The boy’s mother credits Ferguson with saving her son’s life. He went on to do well at school, studied computer science at AUT and started his first proper IT job last year.
“Because he’s on the supplements, I think that’s kept him on an even keel,” she says. “He’s able to come home and he’s able to talk about his feelings. Before, he would physically lash out at me because he was so stressed and didn’t know how to cope.
“If it wasn’t for William and his thoroughness, and believing that there was another way besides drugs, [he] wouldn’t be here.”
Ferguson says SAMe can be “unbelievably helpful” for some, but for others it can make them worse.
Mental health is an area ripe for genetic profiling to help target treatments, rather than the more usual “suck-it-and-see” approach with drugs. “The reality is many of these brain disorders are actually probably genetic and epigenetically programmed. Mental illness has definitely been, if you like, commandeered by the talk-therapy view that if there’s something wrong with you it’s because something bad happened when you were young, right? That is the paradigm.
“But if you look at all of the major long-term cohort studies looking for the origins of mental illness, even including the [New Zealand longitudinal] Dunedin Study, at most only 30% can be attributed to early adverse life experience. That means for 70% of it nobody knows what the bloody hell it’s caused by. But it does run in families.”
Heart risk
If many mental-health problems have a genetic or biochemical cause, the causes of heart disease – which kills 27 New Zealanders a day – are equally wide-ranging. “There are at least 400 known risk factors for cardiovascular disease but we obsess over about half a dozen of them,” says Ferguson. And we take those risk factors and, using evidence-based medicine, create predictive algorithms to say how much risk you are at.”
But lots of people ending up in hospital coronary-care units do not trigger any alarm bells on the algorithm. A study in 2008 showed of the 229 patients in Auckland Hospital after a heart attack, 84% were not previously thought to need treatment.
“I remember doing one of those genetic profiles on somebody who ostensibly had no real risk factors for cardiovascular disease yet he was loaded with gene variants that, you know, over and over again, had an association with CVD. And on the basis of that I said, ‘Look, you need to have a calcium score test,’ which is a CT scan that measures how calcified your coronary arteries are. Well, he was off the 95th percentile. And yet, you know, there was nothing wrong with his cholesterol or blood pressure.”
Clearly the standard evidence-based treatment is not the answer for everyone, Ferguson says. While it works well for many, if not most, when you’re up against a wall and not responding to the usual drugs it’s time to dig further.
But Ferguson may have done his dash for now. He’s no longer offering genetic profiling. He’s “out of time and out of money” and, like many other GPs, is having to focus on core business to survive. Like other overwhelmed practices, he’s also not accepting new patients.
Skills shortage
If you’re a patient who’s taken your 23andMe DNA testing results along to your GP to find out what it all means and found the doctor can’t tell you, you’re not alone. Peter Dearden, co-director of Genomics Aotearoa and head of biochemistry at the University of Otago, says one stumbling block to a widespread rollout of genetic testing is too few experts in the field to analyse results.
The cost of whole-genome sequencing has dropped to about $700 but the real cost is in interpreting what it means for the patient, Dearden says.
He says from a technological perspective the way forward is clear, but genomic testing can’t be rolled out across the country until practitioners qualified in genetics can cope with tens of thousands of requests for analysis. The workforce needs investment.
The health system clearly lags behind other countries and DNA testing businesses such as 23andMe. But sometimes the results contain inaccuracies or lack nuance. “It would be really nice to have some way of doing it so people are not trying to make decisions on their own based on these results.”
10-year plan
Research has shown applying genetics in healthcare is cost-effective, through identifying susceptibility for certain diseases and guiding treatments, Dearden says.
There’s a general consensus that New Zealand lags behind countries it compares itself with – Australia, the UK and the US. But last August, the Ministry of Health published its “long-term insights briefing” on precision medicine. It’s a nuts-and-bolts document that talks of developing, over the next 10 years, systems and processes for decision-making on precision health technologies, the data and physical infrastructure needed, and safeguards and informed consent procedures. It emphasises the need for equitable outcomes, “ensuring Māori needs and aspirations are being met (for example, protecting taonga such as human tissue, which incorporates DNA, whakapapa and data)”.
Director-general of health Dr Diana Sarfati says she would be disappointed if no substantial progress is made within 10 years. Her plan includes leveraging off the work done in other Western countries to find cost-effective ways of using genomics to get better outcomes for patients.
Australia has launched initiatives such as the Australian Genomics Health Alliance to advance genomics in healthcare. Meanwhile, the UK has set up a national genomic medicine service, which will become part of routine clinical care. Last year, an NHS pilot of pharmacogenomic testing for patients taking statins, antidepressants and proton pump inhibitors (PPIs) began.
Here, the Health Research Council is funding three genomics-based research projects spanning the role of inflammation in dementia, using phages instead of antibiotics to treat infection, and tumour biology. Funding this year amounts to $1.1 million.
Health New Zealand Te Whatu Ora’s director of improvement and innovation Dale Bramley says the agency is in the early stages of considering the long-term insights document and “has not yet considered what an appropriate publicly accessible genetic testing programme would look like”.
The health ministry’s Sarfati says genomics offers lots of potential benefits but there are also potential harms. Also, some tests are either not particularly useful or not cost-effective. “We need to identify those that are really good value for money and provide benefits to patients, and make sure they are scaled up in a consistent way across the country.”
For example, consistent availability in New Zealand of genetic testing in cancer diagnosis was important, with lung cancer being a prime example (see “Targeting cancer” page 20). But treatment and testing have to go hand in hand because there’s no point in offering a test for a genetic marker when no treatment is available, she adds.
There’s a slender tier of geneticists – about 10 full-time equivalents – in the three main centres who shoulder the workload of specialist genomic tests and analysis. Much of the Genetic Health Service’s work is diagnosing genetic disorders and familial cancers, a well-known example of which is the BRCA gene that increases the risk of breast and ovarian cancers. Genetic testing for very sick children or babies where a rare disorder is suspected has also been running for years.
Focus on babies
In the lab at the Liggins Institute at the University of Auckland, director Justin O’Sullivan promises to “blow my mind” with his latest technology. On the desk is a little black box and here, says O’Sullivan, a molecular microbiologist, is where the magic happens.
Under a programme begun last November, critically ill children in neonatal and ICU care at Starship Hospital and their parents can be “trio sequenced” (DNA testing of the mother, father and baby) in the lab, with a turnaround of seven days (soon to be four) in acute cases. The alternative is sending off the tests to Finland, for example, which can take several weeks.
After the DNA is extracted, it’s a case of “spot the difference” between the DNA of the parents and baby to find changes specific to the child, says O’Sullivan. “We then use international databases and literature to determine if these variants have been associated with the child’s disease characteristics anywhere before.”
So far O’Sullivan has worked on five cases and helped find the cause of the problem in three of those.
Starship paediatrician and metabolic consultant Callum Wilson says the babies he sees can have multiple problems and although genetic testing can improve outcomes and help in finding the right drugs or treatment, in some cases a palliative approach is still best.
“We certainly wouldn’t counsel parents and say, ‘Hey, do this test and we get the answer – we can cure your child.’ Because unfortunately we’re not quite at that stage where we can fundamentally treat the genetic disorder. That’s the next chapter – treating the genetic underlying problem. And that’s going to be the revolution.”
O’Sullivan has ambitious plans for a national rollout of trio sequencing, saying the programme could be scaled up to do 8-12 cases a week. “We’re trying to open the programme up and over the next few months will be applying for ethics approval so more people in the community who have suspected conditions can apply to come into the programme and be sequenced.”
O’Sullivan would also like to support GPs such as Ferguson.
The Liggins programme has $2.2 million in funding from the Dines Family Charitable Trust, Kelleher Charitable Trust and Tautoko Fund, which means it can offer trio sequencing for free with funding expected to cover the next 3-4 years.
Data is taonga
Interpreting genetic information usually requires looking at vast overseas databases such as gnomAD, says Dr Kate Neas, national clinical director of Te Whatu Ora’s Genetic Health Service NZ. “Whether it’s disease-causing or not rests on us knowing what’s normal for this particular part of the information.”
But while this might work for New Zealanders of European descent, for Māori and Pacific people, what’s normal in your genetic lineage may not be included on a database like gnomAD.
“If you’re, say, a Pacific person and your part of the Pacific nations is not included, then it might be that everyone from your part of the Pacific has a different normal variation at that point. But if we haven’t studied your population we won’t know that. So there’s a risk of over- and under-calling genetic changes if we don’t have a good understanding of the population.”
Retaining control over your personal genetic information is not something to be taken lightly, and for Māori especially this data is taonga. A programme funded by the Ministry of Business, Innovation and Employment, begun in 2019, has led to Rakeiora, which stores genomic data so it cannot be accessed without a series of safeguards provided by kaitiaki – a group made up of Māori and Pākehā scientists.
Dr Helen Wihongi, co-lead of the cancer arm of the Rakeiora programme, says keeping data safe is an ethical duty. “When people donate their data and tissue it’s under certain conditions and you can’t use it for anything else unless you seek permission.” Not to mention health insurance companies wanting to take a peek.
Rakeiora has genomic data mainly for research purposes, while NZ Variome, running alongside, is for improving treatment and diagnosis. Co-lead Cristin Print says the Variome project is designed to plug the data gaps for Pacific and Māori communities. “It’s really understanding the fine-grain genomic information for Māori whānau in order to provide better care.”
Rakeiora is still in draft form but will be progressively moving into using large sets of consented information over the next five years. “I think the possibilities are very exciting,” says Print. “But it also brings responsibilities for us ethically and with security.”
Targeting Cancer
Lung cancer is New Zealand’s biggest cancer killer but in the past 15 years, targeted treatments have given those with the advanced disease the chance to live longer, with fewer side effects.
Auckland thoracic oncologist Dr Laird Cameron says benefits to patients with one of the most common types of lung cancer are huge and patients whose cancer has spread widely can now live many years, even when it has spread to the brain.
“Targeted therapy for patients with non-squamous, non-small cell lung cancer [NSCLC] is not experimental – it’s established,” Cameron says.
In the chemotherapy-only era, only about 6% of patients with NSCLC survived five years. Now up to 50% of these patients live five years or longer. He says many hundreds of patients have benefited from these treatments.
A diagnosis of lung cancer will involve testing the DNA of a cancer cell for variants in a list of genes known to cause lung cancer. Nine of these “oncogenes” can be treated.
The first, EGFR, was discovered in 2004, and in the past two decades discoveries of targetable lung cancer genes and the development of corresponding new treatments have rapidly progressed.
Targeted therapy has been in use in New Zealand since 2010, when the first drug that slowed down growth of the EGFR inhibitor was funded. It is also used for other cancers, such as melanoma.
Instead of patients going to hospital for intravenous chemotherapy, most targeted therapies involve taking daily tablets at home. There are fewer side effects and many patients with advanced cancer can lead active lives, Cameron says.
“In the same way the current nine genes were discovered to be treatable in lung cancer, more will be discoverable in lung cancer and other tumour types.”
This is the second of a three-part series into how genetic data will revolutionise diagnosis and medical treatment. You can read our introductory story here and the third story here.