After spending 13 years and $2.7bn, the Human Genome Project announced in 2003 that it had successfully mapped our DNA, paving the way for a new era of medicine that would deliver “the right treatment, for the right patient, at the right time”.
The UK’s then health secretary, John Reid, welcomed the news by echoing a popular belief at the time. “Genetics promises a more personalised approach to healthcare,” he said. “With interventions tailored to each person’s own genetic profile.”
Twenty years later, some say the “era of precision medicine” has arrived. But others disagree. They argue that the gains have been small, and pursuing them may have diverted attention from the preventable causes of common diseases. Has precision medicine delivered on its early promise, and could the billions poured into it have been better spent on simple public health interventions? The answers may be more nuanced than anticipated.
Precision medicine’s impact may be less well defined than the name suggests because, ironically, it involves a breaking down of old certainties. “Our traditional approach to how we manage and categorise disease is to assume that if we say somebody’s had a heart attack, everyone who’s had a heart attack has had the same thing, and that’s not true,” says Prof Sir Mark Caulfield, former director of the UK’s 100,000 Genome Project.
Dame Anna Dominiczak, regius professor of medicine at the University of Glasgow agrees. “There isn’t one breast cancer. There are several subtypes. Knowing this will always give us progress and better treatments.”
Dominiczak is editor-in-chief of Precision Medicine, a journal launched a year ago, which defines its namesake as “an approach to maximise the effectiveness of disease treatment and prevention by taking into account variability in genes, environment and lifestyle.”
But some doctors and academics say that too much emphasis is placed on our genes, and not enough on environment and lifestyle. That’s the argument of a new book, Tyranny of the Gene: Personalized Medicine and Its Threat to Public Health, by Prof James Tabery, a philosopher of science and bioethics at the University of Utah.
“There’s this paradox where the more we learn about the human genome, the less we should expect it to actually have significant impacts for most patients,” Tabery says. “And yet we’re increasingly accelerating towards it, even though there’s plenty of information to suggest that if we really wanted to combat common diseases, we should be focusing on environmental causes.”
Part of the problem lies in managing expectations. Going into the Human Genome Project, geneticists believed humans to have perhaps 100,000 genes, and that variations in just one or two might be responsible for the likes of diabetes, Parkinson’s, cancer, and even longevity itself. Instead, the project found we have only about 20,000 genes, making it more likely that diseases would be caused by complex combinations of dozens or even hundreds of genes.
Savile Row v Gap
Hoping to learn how these combinations worked, geneticists started performing large-scale genome-wide association studies (GWAS), but as their sample sizes grew larger, genetic explanations for common diseases became more elusive. “Every time those studies get bigger and bigger, that is an implicit concession on the geneticists’ part that the effect size of the genes is getting smaller and smaller,” Tabery says.
That concession partly explains why the word personalised has been replaced with precision. “Personalised healthcare to me implies that I can tell you precisely which treatments will work for you and maybe for nobody else,” says Mark Caulfield. “That is definitely a risk of misleading people.”
The biologist Steven Rose once suggested precision medicine is less like visiting Savile Row for a tailor-made suit, and more like picking up a small, medium or large T-shirt from Gap, but Caulfield and others believe it can still play an important role in healthcare. “What it allows us to do … is to identify for some people – not for all – who should receive certain treatments,” says Caulfield. “If that can minimise side-effects or harm, or maximise benefit and gain, that’s got to be worth it.”
Caulfield and Dominiczak point to improved treatments for forms of cancer and coronary artery disease, tests to predict adverse reactions and inefficiencies in existing drugs, and advances in treating rare conditions where just a handful of genes really are to blame. One example – a drug for chronic myelogenous leukaemia called imatinib – has improved the eight-year survival rate of patients from 20% to up to 87%.
“It’s very good that now people with chronic myeloid leukaemia who are largely in their 60s or older have an extension of life,” says Nigel Paneth, emeritus professor of epidemiology, biostatistics, and paediatrics at Michigan State University. But in terms of public health, he argues, this and other precision treatments are “a modest achievement”.
Paneth points to a metric called the population attributable risk fraction (PARF), which describes how much of a disease might be prevented if a given cause – such as genetic abnormality – could be eliminated. “Most genomic studies have tiny effect sizes,” he says. “And because most of the targeted genes are rare, they have virtually negligible PARFs.”
Even if widely applicable treatments aren’t forthcoming, Dominiczak argues that genetic research still helps us understand disease better, and can assist in prediction and prevention. It’s known, for example, that women with a BRCA1 mutation have a 60%–80% risk of developing breast cancer, and there are also “polygenic risk scores”, which use the data from GWAS to assess a patient’s risk of developing a disease compared with others in the population. The hope is that if a person knows they’re at greater risk of developing a condition such as diabetes or lung cancer, they will modify their habits.
“If polygenic risk scores work fantastically and the psychology and sociology of human beings helps us to modify behaviours, perhaps we live longer, happier lives because of precision medicine,” Dominiczak says.
But Nigel Paneth is sceptical. “They don’t seem to have very much predictive power over and above what you can get in five minutes in the doctor’s office,” he says, citing a paper that suggests these scores contribute only 1% to the prediction of ischaemic heart disease.
He also notes that studies which suggest an awareness of genetic risk will not necessarily alter behaviour. “It turns out that knowing you have a genetic risk isn’t such a great behavioural motivator as you might hope.”
Tabery doubts precision medicine will help the majority of people. “For those it does help, it helps them in a way where they’re in these small populations,” he says. “And … lots and lots of resources have to be invested.”
Some of those investments are by pharmaceutical companies, which may spend billions of dollars to develop a new drug. If that drug is helpful to only a small number of patients, Tabery says, those companies must recoup their costs with high prices.
In countries with insurance-based healthcare systems such as the US, expensive drugs can take an enormous toll on individuals, leading some clinicians to identify a new side-effect: “financial toxicity”. But they can have an impact on systems such as the NHS as well.
“A new drug offers some health benefits to those patients that receive it,” explains Mark Sculpher, director of the Centre for Health Economics at the University of York. “But depending on the cost of that drug, you may end up with other patients losing more health, because that’s resources taken from them. So you can have this negative overall population health effect if you pay too much for a drug.”
Multifactorial diseases
If the goal is to improve public health overall, Paneth suggests efforts could be better spent elsewhere. “We’ve cut heart disease death rates by 70%, 80% in the US in the last 50 years,” he says. “None of that’s down to anything genetic. That’s due to understanding the antecedents of heart disease and beginning to control them.”
“If you look at the resources poured into the genomics agenda,” Paneth says, “it’s very, very large, but with very little yield.”
“An ounce of prevention is worth a pound of cure,” James Tabery writes in his new book, echoing advice first attributed to Benjamin Franklin – and this might be worth heeding.
The rates of cancers in people under 50 have been increasing in many parts of the world since the 1990s, a 2022 study found. “Genetics definitely play a role in hereditary cancers,” says senior study author Shuji Ogino, a professor of pathology at Harvard Medical School. “But in this early onset cancer epidemic, both genetics and environment appear to play roles. We see a lot more increase in sporadic cases where environmental causes are significant.”
Diet, pollution, lack of sleep and stress are causing adverse health effects, especially among society’s poorest. “This is a tip of the iceberg of increasing many chronic complex multifactorial diseases,” Ogino says. “Cancer, cardiovascular disease, diabetes, obesity, liver disease – those are increasing almost simultaneously.”
Caulfield says the need to attend to environmental factors doesn’t mean we should ignore our genes. “The two are a symbiotic ecosystem that conspire together to provoke disease.” But given what sceptics argue are the relatively modest contributions of genomics research to overall public health, should we be allocating resources differently?
“I think a very large amount of resources go to genomics,” says Sculpher. “Whether it’s disproportionate needs an understanding of what the anticipated benefits are. I am sceptical about whether resource allocation in research considers sufficiently carefully the potential benefits of that research.”
“I’m not asking that we suddenly put an end to all genomic research,” says Paneth. “I’m saying that when we allocate funds to scientific studies, we should sit back and think, OK, what can we do with this money to improve the health of the public in the most efficient ways?”
The definition offered in Precision Medicine acknowledges that genes, environment and lifestyle all need attention, but for Tabery, the balance is severely skewed. “What we get is just people paying lip service to this other stuff,” he says. “But practically, economically, resource-wise and time investment-wise, it’s just about molecular genetics.”
Tyranny of the Gene: Personalized Medicine and Its Threat to Public Health by James Tabery is published by Alfred A Knopf (£25). To support the Guardian and Observer, order your copy at guardianbookshop.com. Delivery charges may apply
