Hidden among all the other announcements in last week’s State of the Union address by US President Barack Obama was a promise to fund a new “precision medicine initiative”. The president said it would bring Americans closer to curing illnesses such as cancer and diabetes.
Once funded, the initiative is expected to provide medical researchers with data about the genetic make-up of everyday people. This data will allow them to undertake research into the genetic causes of common diseases and tailor medicines for them.
Precision medicine describes a new approach to the prevention, diagnosis and treatment of diseases. It helps deliver treatment based on the particular variant of the disease by taking the genetic make-up of the ill person into account.
It’s underpinned by two key areas of knowledge that have been building rapidly in the recent past. The first is our understanding of the function of human genes and their role in the development and progression of certain diseases. And the second is the recognition that diseases characterised – and therefore diagnosed – by a particular set of signs and symptoms may arise through fundamentally different biological mechanisms.
One example of such an illness is cystic fibrosis, for which there’s already a treatment based on genetic factors. An inherited condition, cystic fibrosis results from a deficiency in the performance of an enzyme (the cystic fibrosis transmembrane conductance regulator) responsible for moving chloride into and out of the cells. To date, scientists have observed over 1,900 changes in the single gene that codes for this enzyme.
Of these genetic changes, one is very common with a frequency of 70%, while 20 are less common, with a combined frequency of 15%. The remaining genetic changes are very rare. So you can see why although cystic fibrosis is considered to be just one disease, it can be caused by many different biochemical mechanisms.
Medication developed in 2012 can effectively treat cystic fibrosis in people who have specific genetic changes. But it’s estimated these changes are present in only 4% to 5% of cystic fibrosis patients. The medication is ineffective for the others.
Precision medicine is not just about new and better treatments for diseases, it can also provide guidance on how best to apply current treatments through the study of how individual genetics influence the manner in which drugs are absorbed and metabolised. This particular field of precision medicine is called pharmacogenomics.
Technology as the driving force
Precision medicine relies on having ready access to a large amount of information about genes and how they influence health. It’s been driven by recent advancements in DNA sequencing technology, which have drastically increased our ability to generate the data needed to derive this information.
The first human genome to be sequenced (completed in 2003) took ten years, two large global consortia and billions of dollars. The brunt of the sequencing work in what was known as the Human Genome Project was performed using Sanger sequencing, a method that involves pushing DNA molecules of varying sizes through a gel using an electric field.
As they move through the gel, the fragments are sorted by size because smaller fragments travel faster than larger ones. The need for these gels is a major limiting factor for this method as only a small number of samples can be sequenced in parallel on any one machine.
But sequencing technology has changed markedly in 12 short years.
Beginning in 2005, new technologies that utilised a different method of DNA sequencing and did not rely on gels as separation media came to market. Crucially, these technologies could be miniaturised and a single instrument could run multiple samples at the same time.
Instruments using these technologies can sequence between one million and 43 billion DNA fragments at a time, depending on the specific technology used. With these technologies, the cost and time required to sequence a single genome dropped dramatically, from around US$100 million in 2011 to around US$4,000 today.
This drastic reduction in cost led to a proliferation of projects designed to sequence genomes in ever-increasing numbers.
What comes next?
Precision medicine is still a long way off being the default approach to diagnosis and treatment within regular health-care settings. We still don’t know enough about the biological processes that cause disease; we know plenty about what happens when we get sick, but often not how and why.
Sequencing large numbers of genomes – as part of projects that cost millions of dollars and many years to complete – is just the first step towards precision medicine. That data needs to be analysed and compared against the sequence data of healthy and sick people. Hypotheses need to be posed and tested through big longitudinal studies involving many people before meaningful insights can be made and translated into diagnostic tests, treatments and preventive strategies.
All this requires not just access to genomes but detailed clinical information about people that’s routinely collected over time and linked to their genomic sequences.
Another issue that needs to be overcome is the cost of individualised treatments. Drug development is expensive, but the costs are usually offset by the combination of the large number of people who will purchase the new drug and some form of government subsidy.
But precision medicine is designed to develop treatments for smaller numbers of people. Not only does this mean a smaller market across which the cost of drug development needs to be spread, it also means governments may be less likely to offer subsidies. A single year’s supply for the cystic fibrosis drug mentioned above, for instance, currently costs more than US$300,000, making it one of the most expensive drugs available in America.
To realise the potential of precision medicine, the driving force behind it needs to shift from technology to clinical practice and improving health service delivery. Technology has brought us a long way, and no doubt we’re not far from another paradigm shift that will allow us to sequence genomes more quickly and cheaply. But it will only ever get us so far.
Only the incorporation of genomics into health care, with robust electronic record systems, will allow for correlation of genomic data with health status. Our focus needs to be on answering real questions about real people’s health. And ensuring that national health systems are capable of delivering on the promise of precision medicine.