By Angus Dalton
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“If a crystal ball could reveal your personal risk for developing heart disease or breast cancer or Alzheimer’s disease, would you pay to take a look?” wrote the brilliant, 40-year-old US neuroscientist Dr Rahul Desikan in 2019.
Three months later, he was dead. The lab leader, father and DJ, who spun Indian music with American guitar jazz, had been diagnosed with amyotrophic lateral sclerosis, a disease he had studied during a powerful research career.
Scientists hope a swab of saliva or drop of blood could reveal your risk of thousands of diseases. But is that a crystal ball worth looking in to?Credit: Marija Ercegovac
“If I had any hint that I would develop ALS, which has locked me inside my body as though inside a cell ... I would have done anything and everything to stop or slow the devastation this disease has visited on my life,” Desikan continued in Scientific American.
“If only I could have glimpsed into my future.”
One of Desikan’s scientific feats was discovering two new genes associated with the onset of ALS. It was part of his work creating the “crystal ball” he yearned for as his body shut down – a way to probe our genes for warning signs of diseases that may one day kill us.
These genetic crystal balls are called polygenic risk scores. The tests analyse thousands of genetic variants within a person’s genome to estimate their risk of developing deadly diseases later in life.
Rahul Desikan with his wife, Maya Vijayaraghavan. He researched genetics and the brain – using eye movement to type on his computer – until he passed away from ALS in 2019.Credit: Nick Otto for The Washington Post
Some researchers envision these tests will become as routine as having your blood pressure checked at the GP. Desikan hailed them as part of the “new age of genomic medicine”.
The concept holds enormous promise. But there are also enormous problems underpinning the technology, and many scientists question whether these crystal balls are true fortune-tellers or circus tricks.
One Australian researcher, however, is staring down these challengers.
Predict and prevent
Associate Professor Loic Yengo, who leads the Statistical Genomics Laboratory at the University of Queensland, scrutinises genomes to tease out the complex relationship between our DNA and how our lives unfold.
An $8 million fellowship announced on Tuesday from the Snow Medical Research Foundation, a not-for-profit that grants long-term funding to biomedical research, will turbocharge Yengo’s work.
Over the next eight years he’ll lead an analysis of millions of DNA sequences to strengthen the genomic data that underpins our ability to predict future onset of diseases, including two of Australia’s biggest killers – cardiovascular disease and type 2 diabetes.
“For coronary artery disease or type 2 diabetes, between 30 and 50 per cent of the risk can be accounted for by genetic factors,” Yengo says. And about a third of heart attacks strike unexpectedly, he adds, partly because interventions are offered only to those who are already displaying risk factors such as obesity, smoking or hypertension.
Associate Professor Loic Yengo is analysing millions of DNA datasets to improve our ability to predict which diseases could strike us decades down the track.Credit: University of Queensland
“Unfortunately, there are a lot of people who don’t have any of those risk factors, but are still very highly genetically at risk.”
Yengo hopes to build and improve tools such as polygenic risk scores to detect people’s genetic susceptibility to disease 10, 15 or 25 years before symptoms strike. A person who discovers they’re at high genetic risk of heart disease, for example, might put extra effort into staying trim or consider taking cholesterol-slashing statins well before any sign of disease arises.
Cracks in the crystal
The most glaring issue facing the rollout of polygenic scores is that the genomic data that underpins the tests is utterly unrepresentative of society.
At least 78 per cent of genomic data studied by scientists across the world comes from Europeans. And 72 per cent of that data is from just three countries – the US, the UK and Iceland.
“One cannot blindly apply findings from ancestrally European groups to everyone else,” a group of scientists studying the problem warned in The Conversation. For example: “Gene variants predicting high cholesterol in white populations do not lead to the same heart problems in people from rural Uganda.”
The skewed genomic data means that if polygenic testing was rolled out now it would be all but useless for non-Europeans.
“We’re losing about 50 per cent of the accuracy of the scores in Asian populations, and up to 75 per cent of the accuracy is completely lost in African populations,” Yengo says.
“We essentially won’t be able to classify [an African] person at all. That’s terrible. Because if they are really at high risk of a certain disease, you want to know as soon as possible.”
That’s why Yengo and his team will focus on DNA from non-white people – including sequencing DNA from half a million African participants – to balance out the skewed genomic data.
Do the tests work – and should we use them?
Private companies are already selling polygenic risk scores for a range of diseases from Parkinson’s and cancer to coeliac disease, and there are several clinical trials under way, including a University of Melbourne study into whether mouth swab DNA tests at the GP could pinpoint genetic vulnerability to common cancers.
But a paper in BMJ Medicine last year poured cold water on the polygenic testing hype and the technology’s purported potential to revolutionise healthcare.
The authors reviewed 926 polygenic risk scores and found the tests identified only 12 per cent of eventual coronary artery disease cases and 10 per cent of breast cancer cases. The tests’ average hit rate across 310 diseases was 11 per cent.
An analysis in the same journal predicted polygenic risk scores would “never reach a point where they can accurately predict who will and will not develop disease” because non-genetic and environmental factors are more influential than a patient’s DNA in most diseases.
Yengo is more optimistic. “With larger studies, we can discover more genetic factors, and thereby improve the accuracy of the scores,” he says. Boosting the diversity of genomic data will also improve the tests. “I’m really excited and confident that we have a shot.”
But thorny moral questions remain. What’s the point of telling someone they’re at high risk of Alzheimer’s or ALS, afflictions with no cure?
Desikan, for his part, made it clear he would have preferred knowledge to obliviousness. As his muscles deteriorated, he lost his faith in God. But his faith in science redoubled as he hunted for ways to divine the future from DNA helixes, right until the end.
“My mind and soul are strong,” he said before his death. “I am as curious as ever about the brain. I still want to grow as a scientist and push myself every day.
“Even with this lethal disease, I continue to find neurology fascinating and beautiful.”
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