The EconomistMarch 14th 2020 Technology Quarterly |Personalised medicine 71W
hen a clinicianshowed Dr Nizar’s sons a pain chart, they
asked her what the smiley face at one end of the scale meant.
The boys do not know, Dr Nizar says, what it is like to live without
pain. Not all the diseases caused by calamitously failed single
genes are quite that awful. But unlike the more generalised geno-
mic influences on health—those to which everyone is heir, but few
know about—people with serious congenital diseases have no es-
cape or respite; their symptoms are inescapable. And so, too, for
the most part, are their diseases. Genomics makes the diagnosis of
such diseases, especially the rare ones, easier and more precise,
and it has revealed what is going on in some of them in useful
ways. It has not yet, though, provided much by way of cures. Now
this is beginning to change.Those who deal with rare genetic diseases talk of the “diagnos-
tic odyssey”. This is the process, familiar to viewers of “House”, a
television show, of repeatedly suggesting a cause for a rare disease,
testing, ruling out and suggesting again. In real life such odysseys
do not to fit into a tense hour of screentime; until recently they
used drag themselves out for five years or so, according to Mark
Caulfield of Genomics England. Dr Nizar’s took even longer, large-
ly because only a handful of doctors on the planet have any experi-
ence with Jansen’s disease. Even over eight seasons, Dr House and
his team never saw a single case.
In Britain and many other rich countries, genomic testing has
the length of the odyssey down to months or even weeks, says Dr
Caulfield. This matters because, even when genetic diseases can-
not be cured, knowing the precise nature of the defect often mat-
ters—and the earlier it is known, the better. When a Mexican clinic
for children with birth defects had 60 of its patients sequenced,
subsequent changes in diagnosis led to revisions in the care given
to almost half of them.
Sometimes the correct care has dramatic results. Jessica was
four years old when sequencing showed that the disease affecting
her movement and development stemmed from a misprint in a
gene called SLC2A1. This meant her cells did not make enough of a
protein that transports sugar into the brain, thus leaving it chroni-Broken
Damaged genes can reveal a lot about human biologyCongenital diseaseD
octors havelong appreciated that
the same dose of medicine will not
necessarily have the same effect on
different patients. Today they are able to
predict how patients will respond to
hundreds of drugs. One of the ways in
which people differ biologically is in how
they metabolise drugs, a process largely
dependent on enzymes in the liver that
can vary a lot from person to person, and
which are genetically determined. Dif-
ferences in enzymes can lead two pa-
tients with the same disease, and the
same treatment, to end up with a five-
fold difference in the amount of working
drug molecules in their blood.
Sometimes such differences will
mean that the drug is not circulating at a
high enough level to work. Sometimes it
is circulating at too high a level and
causing toxic side-effects. Though side-
effects sound peripheral they are a huge
medical problem. In Britain 6.5% of
hospital admissions are related to ad-
verse drug reactions.
The study of how genes affect an
individual’s response to drugs is known
as pharmacogenetics, and it is flourish-
ing. The nhsin Britain is looking at
applying pharmacogenetic tests to the
treatment of 65 different medical condi-tions within the next few years.
One example of the technique’s poten-
tial is found with warfarin, a commonly
used blood thinner that has what doctors
call a “narrow therapeutic window”: the
distance between a level in the blood too
low to do good and a level too high for
safety is small. Variations in an enzyme
gene called CYP2C9, which allow warfarin
to stay in the blood for longer, are quite
common in white Europeans and Ameri-
cans. This makes it harder to find the best
therapeutic dose and increases the likeli-hood of adverse effects such as bleeding
on the brain. Complications with warfa-
rin cause about one-third of emergency
hospital visits for older Americans.
Part of the problem with warfarin is
that for a long time there was no real
substitute, so it was used despite its
drawbacks. The various selective seroto-
nin-reuptake inhibitors used to treat
depression offer a different challenge.
Both their effectiveness and their side-
effects are influenced by enzymes pro-
duced in the liver. A test produced by
Myriad, a genetic-testing company,
makes it possible to look at the genes for
such enzymes before an antidepressant
is prescribed and appears to limit side-
effects and improve clinical outcomes.
In chemotherapy, too, genetics can
guide the choice of treatment in ways
that other indicators cannot. That mat-
ters since the drugs are so powerful.
Some are so toxic that four patients in
100 will die from treatment, says David
Kerr, a professor at Oxford University.
Keith Gadd, an English farmer, died five
weeks after a successful operation to
remove a tumour from his bowel, be-
cause he was unable to metabolise the
chemotherapy he had been given to
lower the risk of his cancer returning.Genes also play a role in choosing treatmentsGenes and treatmentSide-effects include death