- John Burn, professor
We
should all have our genomes sequenced. In 1986 our 5 year old son
planted a conker in our back yard. He explained that he wanted a tree
house so needed a tree. The tree is now ready to receive boarders,
though they will be from our family’s next generation. The Human Genome
Project began at about the same time with similar high aspirations: to
deliver personalised medicine to generations to come.
That
time is now upon us. The cost of gene sequencing has fallen 10 000-fold
in a decade, with another drop by an order of magnitude expected soon.
Setting aside the considerable but surmountable challenges associated
with large segments being duplicated or deleted and stretches of hard to
sequence repeats, we can have a whole genome for the price of a family
package holiday. Even now, bulk sequencing all 20 000 “genes,” the
exome, costs less than £500 (€590; $770).
The Human
Genome Project depended on British discovery, particularly the work of
the Wellcome Trust’s Sanger Institute. No one can match our capacity to
do “genetic medicine” in a coordinated healthcare system at scale. This
is why the UK government has committed £100m to pump prime sequencing of
100 000 whole genomes in the NHS. Only by analysing sequence data and
phenotypes across large patient populations will we understand which
bits of genetic information are clinically relevant. We can and should
lead the world in showing how to put genetic knowledge into patient care
safely and effectively.
Responsible use
Genetic
predisposition plays a central role in most common diseases. It is the
primary cause of most of the rare diseases that collectively afflict 1
in 17 people.1 Clinically relevant discoveries are entering practice at a rate of more than 30 a month.
And
the provisos? First do no harm. Our capacity for interpretation is
still rudimentary so we must have explicit consent to retain sequence
data linked to patients’ records. Our population trusts the health
service to deliver healthcare to all in need, regardless of their
genetic predispositions. We must keep that principle safe along with the
sequence data. That doesn’t preclude partnership with the
pharmaceutical and biotechnology industries: we need them to expand the
exciting list of drugs that can target genetic subgroups and give us the
gadgets and biomarker algorithms to find them.
As we
leave the high ground of “single gene disease,” such as hereditary
cancers and cardiomyopathies, we risk drowning in data and doing harm.
Offering volunteers at risk of monogenic disorders an effective service
in return for them allowing their genomes to be pooled and data mined is
straightforward. Systematic gathering of genomic information where
there has been no request, and any sequence variation discovered lacks
clinical use, is more challenging if consent and follow-up counselling
are to be effective.
Each one of us carries, perhaps, three million sequence variants, of which about 400 contribute to disease predisposition,2
and one or two would cause a severe recessive disease if both partners
pass them to a child. The bioinformaticians need to know it all to
develop robust diagnostic algorithms.
But patients do
not. We must not dump heaps of molecular uncertainty on patients,
families, and their carers. In Nijmegen, the Netherlands, teams of
geneticists try to interpret exomes of patients provided by clinicians,
passing on (with explicit consent) only information about variants of
known relevance plus “incidental” findings of obvious importance (H G
Brunner, personal communication).
Personalised treatment
Genomics
is not just about rare syndromes and predisposition to disease. It
underpins huge variation in our capacity to metabolise drugs, often
leading to serious adverse events, but this is ignored. At the moment
everybody gets the same size shoes and they are asked to hobble back
next week if they don’t fit. We have known for decades many of the
simple genetic variants responsible for such adverse events. We write
more than half a million prescriptions for warfarin each year, knowing
that three genetic variants can help quickly to reach the individual
dose, cutting attendances and adverse events; yet still we just guess.3 Widespread sequencing linked to outcomes will expand such knowledge considerably.
I
remain sceptical of an early transition to providing our genome as part
of our electronic medical records. The sequences we can provide now are
not sufficiently complete, and safe storage and access present
challenges.
When it costs only £100 we can run the
sequencers more than once, extracting necessary information and
discarding the rest. In some situations we will be able to reduce the
question to a genetic test at the point of care.
I am part of a team that’s been working for five years on using nanowires to analyse nucleic acids.4
We are about to test disposable cassettes that will extract, amplify,
and perform specific tests such as drug sensitivity in under 15 minutes
for under £20. The next step will be to provide whole genomes. Others
are also innovating in this field. Whoever wins the race, the strong
probability is a mixed economy of stored whole genomes, disposable
sequencing in hospitals, and cheap, fast genotype panels in some
frontline care settings. The net result will be accurately targeted
diagnosis, treatment, and prevention.
Genomics extends
beyond identifying predisposition to disease. Linking whole genome
sequencing to clinical outcomes will influence drug discovery and
development—for example, the BRAF gene inhibitor vemurafenib to treat
melanoma was developed only a decade after the cancer genome project
identified the target.5
And the tools developed from human genomics will transform another
battlefront—routine high speed sequencing of pathogens will expose their
weaknesses within hours, revolutionising response to epidemics
worldwide.
Meanwhile “point of care” technology will
allow drug resistance of infective agents causing diseases such as
malaria to be studied in real time in the swamp. Whole genome sequencing
is a technical, clinical, and societal challenge. But as Goethe said,
“Whatever you do, or dream you can, begin it. Boldness has genius and
power and magic in it.”
Notes
Cite this as: BMJ 2013;346:f3133
Footnotes
- Competing interests: I have read and understood the BMJ Group policy on declaration of interests and declare the following interests: I am chair of the British Society for Genetic Medicine and genetics lead for the National Institute of Health Research. I am a shareholder and director of QuantuMDx Group, which is involved in nanowire based genotyping and sequencing.
- Read Frances Flinter’s side of the debate at doi:10.1136/bmj.f3132.
- Provenance and peer review: Commissioned; not externally peer reviewed.
