A Revolution in R&D

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Efficiency improvements in target discovery account
for the remaining savings.
The Uncertainty
For these vast savings to materialize, two requirements
will have to be met. First, disease genetics
must prove scientifically feasible for the relevant
common diseases. Second, not only must studies in
humans work; in addition, the targets they identify
must be drugable; failing that, identifying the disease
genes is pointless, and all the effort that has
gone into finding them will be wasted. (See sidebar,
“Drug-Resistant?—Are Disease Genes Drugable
Targets?”)
Feasibility—the Limitations of Technology
Fundamental technological concerns still hover over
disease genetics. Can it actually be done? The results
so far have been very modest. The bonanza of
clearly documented disease-susceptibility genes for
common multigenic diseases has yet to materialize.
Candidate gene studies, for instance, are by definition
limiting: they focus on a subset of genes defined
by a prior hypothesis, and therefore risk excluding
some crucial culprits. And genome-wide linkage
studies, although highly successful in addressing
single-gene diseases, have proved disappointing for
DRUG-RESISTANT?—ARE DISEASE GENES DRUGABLE TARGETS?
The skeptics pose an awkward question: Will disease-related
genes ever prove to be drugable in significant
numbers? The record so far is hardly encouraging.
Some disease genes, such as CFTR in cystic
fibrosis, were identified long ago, yet have failed to
generate therapeutics. The infrequency of success
stories, such as Ceredase—a drug for type I
Gaucher’s disease that was essentially a creation of
disease genetics—only highlights the general trend
of failure.
These long-identified disease genes tend to be for
single-gene disorders, however. And such disorders
are by their nature difficult to cure. They are binary
phenomena: the gene is broken, you get the disease.
the more common multigenic kind of disease: a disease-related
gene might be accurately pinpointed in
affected families (such as the BRCA1 breast cancer
susceptibility gene), only for it then to show very low
prevalence outside the families used in identifying
it. True, these two approaches might become more
tractable now, in the wake of the sequencing of the
human genome and the development of comprehensive
SNP maps (catalogs of the characteristics
and locations of SNPs in the genome).
As for genome-wide association studies, considered
by many experts to be the most promising of all,
they have only recently became practicable: all the
requisite tools (a full genome sequence with a SNP
map to match, genotyping technologies, and so on)
appear to be in place. But the approach remains virtually
untested, owing to the still exorbitant cost of
genotyping. The preferable form of genome-wide
association studies would clearly be the indirect
kind—still covering the entire genome, but genotyping
far fewer SNPs—yet even here the current
cost is a prohibitive $400 million or so for each disease
investigated. Within five years, however, genotyping
costs are expected to fall to $20 million or
less, and the essential proof-of-concept tests can
then take place more routinely. (See sidebar,
Finding a small-molecule therapeutic to repair a completely
defective protein is an extremely difficult challenge.
(Indeed, Ceredase is a protein therapeutic.)
Most disorders, by contrast, are attributable not to a
single gene but to multiple genes, and perhaps other
factors too. This means that the system as a whole
can still function, just hampered to a greater or
lesser degree. Such cases benefit from patching up,
so drugs can be beneficial without actually constituting
a cure. There is little reason to doubt that
such palliative drugs will soon emerge in abundance,
as disease genetics becomes ever faster at
identifying some of the genes implicated in multigenic
disorders.