Biology Reference
In-Depth Information
most costly phases of clinical development, increased
regulatory demands, and looming patent expirations for
a large number of last-decade blockbuster drugs. Others
question whether the decline is more fundamental in nature
and challenge the validity of the modern drug discovery
(MDD) paradigm. That is, will a small molecule with
demonstrated ability to bind and/or alter the activity of the
target protein in vitro with high affinity and/or high potency,
translate into a successful and efficacious new therapy?
Taken together, the causes for the decline in the produc-
tivity of the drug industry are complex. Struggling to
survive, the industry has adopted a risk-averse approach,
one reluctant to explore new target areas, focusing
instead on 'druggable' or 'me-too' proteins that are already
targeted by existing drugs, leaving little hope for diseases
that currently lack therapeutic options. (http: //
www.
number of molecular perspectives. For example, these
genomic technologies quantify (1) RNA expression levels,
(2) genetic interactions, (3) protein abundance, modifica-
tion and activity and (4) the cellular response to drug, the
focus of this chapter. It is important to recognize that
simple tabulation of the data from a single molecular
perspective followed by a search for patterns in the data that
may correlate with, for example, a particular disease, will
not be sufficient to fully understand the systems-level
behavior of the cell. Rather, data from all available
perspectives should be integrated in order to account for
the interactions and dependencies between molecular
elements vital to cellular functions. By integrating these
diverse systems datasets, it is the hope that the ultimate
goal of systems biology
the ability to both understand
e
and predict
the cellular
response to perturbation
e
will be realized.
In this chapter we discuss the contributions of chemo-
genomics to our understanding of the cellular response to
small molecules. In order to appreciate how chemo-
genomics evolved to become a driver of biological
discovery and modern drug discovery, we briefly review the
genomic discoveries that have fundamentally altered our
perception of how drugs act and cells behave. In addition,
because this chapter is primarily based on chemogenomics
in yeast, we provide a short history of the pioneering role of
the budding yeast Saccharomyces cerevisiae in the devel-
opment of genomic technologies. In the final two sections
we discuss the biological discoveries that have been made
using chemogenomic approaches, including their potential
impact on the future of drug discovery.
Biology: The Cell is More Than the Sum
of its Parts
In contrast to the pharmaceutical industry, the HGP has had
an enormous positive impact on the biological sciences,
described by many as a 'genomic revolution'. The HGP set
the stage for a new fearlessness, providing a much-needed
reference from which a substantial number of large-scale
consortia were launched, many ongoing (e.g., the 1000
Genomes Project, ENCODE, the Epigenomics Roadmap
project
[1
3]
) and several successfully completed (e.g.,
International HapMap Project, The SNP Consortium
[4,5]
).
The resulting catalogue of these vast datasets has provided
a strong biological foundation and revealed a biological
complexity far beyond that previously imagined. Combined
with the established genomics concept that the ability of
a gene to function is often dependent on interactions with
other genes, these discoveries have made clear that the
reductionist's one-by-one-approach of studying gene
function in isolation has met its limit, and will be ineffec-
tive in improving our biological knowledge of the cell. In
its place, a systems-level approach that incorporates the
interaction-dependent functioning of genes will be required
if we are to increase our understanding of cellular behavior.
This new approach has taken shape as 'systems biology',
and is based on the concept that by measuring the behavior
of every 'part' of the cell, a coherent set of systems-level
properties of cellular behavior will emerge. Systems-level
approaches have been defined and shaped by genomics,
whereby the cellular state is reported in a single system-
wide profile comprised of individual readouts for every
gene, protein, metabolite or other molecular element in the
cell. These profiles are generated by 'omic' technologies
that allow a cellular state to be measured from an increasing
e
IMPACT OF GENOMICS: SHIFTING THE
PERCEPTIONS OF DRUG AND CELLULAR
BEHAVIOR
The Cell is a Highly Interactive Robust
System
Genomics studies have revealed that the cell is a system of
interconnected, precisely regulated processes in continuous
flux, where bioactive molecules in the cell interact with and
respond to each other, while the cell continuously makes
adjustments to the underlying biological architecture in an
effort to maintain homeostasis. These studies have
demonstrated that cellular behavior is inherently robust.
For example, the deletion of a single gene often results in
little or no phenotype owing to the ability of the cell to
adjust to genetic perturbation through redundant or alter-
nate pathways that allow homeostasis to be maintained. In
support of this robust behavior, metabolic engineers have
long realized that despite having the ability to modulate and
control gene function, the cell stubbornly resists attempts to
