Full text of DOI:10.1038/sj.tpj.6500010

Significance of the human genome sequence to drug discovery
O Grenet
11
Evolution and Applications. Oxford Univer-
sity Press, 1999.
Mullikin JC, Hunt SE, Cole CG, Mortimore
BJ, Rice CM, Burton J et al. An SNP map of
human chromosome 22. Nature 2000; 407:
516–520.
map of human genome sequence variation
containing 1.42 million single nucleotide
polymorphisms. Nature 2001; 409: 928–
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epidemiology of single-nucleotide polymor-
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4
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PC et al. Family-based linkage disequilib-
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11 Kruglyak L, Nickerson DA. Variation is the
spice of life. Nat Genet 2001; 27: 234–236.
9
Hoehe MR, Kopke K, Wendel B, Rohde K,
Flachmeier C, Kidd KK et al. Sequence varia-
6
The International SNP Working Group. A
Sequencing Consortium2 created an
initial gene index which contains
15000 known genes and about 17000
Significance of the human genome
sequence to drug discovery
gene predictions estimating
a cor-
rected gene number of 30000–35000.
The pharmaceutical companies are
certainly among the first to be inter-
ested in evaluating and understanding
the regulation of these newly pre-
dicted genes. Every additional gen-
omic piece of information is
important in the sense that each new
gene or function is a potential drug
target. It is interesting to note that
Celera will seek to develop on its own
100–300 medically important genes
for use by pharmaceutical and biotech-
nology companies.5 Although the
genes with unidentified function are
potentially interesting, selecting them
as targets for new compounds may be
cumbersome and expensive: research
programs would have to be initiated
for extensive assessment of their func-
tion and regulation. The possible
absence of clear homology between
these new genes with already known
sequences may necessitate the identi-
fication and/or development of new
biologically relevant in vitro or in vivo
models that will be used in pharmaco-
logical and toxicological studies. Ulti-
mately, and most interestingly, these
investigations could lead to the devel-
opment of new (classes of) compounds
targeting this gene and its function.
All the functions are not equivalent in
terms of ‘targetability’. Thus, the bio-
chemical classes of drug targets are
O Grenet
NOVARTIS Pharma AG, Preclinical Safety, Basel, Switzerland
Towards the end of their research and
development efforts, pharmaceutical
companies seek to deliver safe and
efficient molecules. The availability of
the human genome sequence shall
contribute to reach this goal.
information. It still remains to be
investigated what regulatory features
within the sequence are essential to
the function and regulation of the
approximately 30000 human genes.
Some parts of the human sequence
(approximately 42% according to
Celera’s work estimate) represent what
would be similar to the primary struc-
ture of an unknown protein to which
a function would still have to be
assigned. Expression studies will be
required to complement genomic
information.
The current DNA-array technology
allows the expression monitoring of
thousands of genes. The complete gen-
ome of Saccharomyces cerevisiae has
been sequenced and is available on oli-
gonucleotide DNA arrays.4 Similarly,
the complete human genome may be
The efforts engaged for the sequen-
cing of the human genome and the
data recently published1,2 will affect a
large population both in public and in
private institutions. Since 1953, when
James Watson and Francis Crick
described for the first time the struc-
ture of the deoxyribose nucleic acid
molecule,3 the completion of the
human genome sequencing projects is
possibly one of the major advances in
biology. Unlike the description of the
nucleic acid structure in 1953, the
massive world-wide genome sequen-
cing efforts were brought to the atten-
tion of
a
large public, creating
assembled on
allowing the analysis of virtually all
the transcripts produced by cell
a high-density chip
important expectations and exciting
perspectives in the scientific com-
munity but also in the less expert
population.
It is important to mention that the
results delivered so far are mostly
descriptive and give the essential basis
for further investigations which will
need to be carried out in order to make
the best use of this linear sequence of
a
population or tissue. Such genome-
wide expression profiling at the mRNA
level may designate new genes
involved in a pathway, potential drug
targets or expression markers that can
be used in a predictive or diagnostic
manner.
biased
towards
receptors
and
enzymes.6 Among the new potential
gene targets some will therefore get a
The International Human Genome
www.nature.com/tpj

Significance of the human genome sequence to drug discovery
O Grenet
12
ing clues to describe genetic networks
and may ultimately initiate new ways
of developing compounds (Figure 1).
Towards the end of their research and
development efforts, all the major
pharmaceutical companies seek to
deliver safe and efficient molecules
that would help the largest possible
population. The availability of the
human genome sequence together
with the pharmacogenomic and phar-
macogenetic approaches should con-
tribute to a better selection together
with a faster development of safer and
more effective drugs.
DUALITY OF INTEREST
None declared.
Figure 1 A pharmacogenomics approach to drug development.
Correspondence should be sent to
Dr O Grenet, Novartis Pharma AG, Preclinical
Safety, Basel 4002, Switzerland.
Tel: +41 61 324 1247
Fax: +41 61 324 1027
E-mail: olivier.grenetȰpharma.novartis.com
better mark than others. This ranking
may allow better prioritization of
research programs.
The genomics revolution started
before completion of the human gen-
ome sequencing project and has
helped already, for example, in the
assessment of compound-induced tox-
icity.
sequence variations showed that less
than 1% of the SNPs impact directly
on protein function. A few DNA poly-
morphisms are therefore affected by
natural selection, while most are selec-
tively neutral.7 Among the whole
population of SNPs, however, some of
them are associated with diseases and
can be used in a predictive or diagnos-
tic fashion by pharmacogeneticists to
select the ideal treatment to be pre-
scribed to ‘safe-responder’-patients.
The rationales for these associations
can be explained by evolution mech-
anisms and genetic drifting.8
The publication of the human gen-
ome sequence is the groundwork for
further assessment of post-transcrip-
tional and post-translational events
occurring in a human cell. Gene regu-
lation networks still have to be under-
stood and described.
Interestingly the exons are con-
tained within only 1.1% of the euchro-
matin. This result does not imply that
the other 98.9% are meaningless and
useless, but rather that our current
knowledge of the human genome is
still not deep enough to understand
these more complex and subtle regu-
lation levels.
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8
Pharmacogenomic approaches will
profit from the availability of the com-
plete human genome sequence provid-
genome-wide
examination
of
The Pharmacogenomics Journal