Biomedical Engineering Reference
In-Depth Information
The less specifically a drug acts, the more wide-ranging will its side effects be.
Most assays aiming at characterizing the specificity of a drug rely either on or-
ganismal-level observations or on the activity of individual macromolecules.
Few assays are available to explore the entire spectrum of molecular interactions
a candidate pharmaceutical might engage in. Genomics, and specifically the
analysis of protein networks, holds the promise to change that.
The word "network" evokes the image of objects (organisms, cells, proteins,
genes, etc.) that interact with each other, usually in some complex fashion.
However, browsing through the experimental literature in functional genomics,
one quickly realizes that researchers in the field seem to have adopted a much
broader sense of the word. Many studies in this area bear the word "network" in
the title, but the studies do not identify interacting objects, be they genes or pro-
teins. Instead, many of these studies provide circumstantial evidence—mostly
through gene expression—for gene products that might be part of a network.
That is, they identify genes that are expressed—either as mRNA or as protein—
at similar levels during a particular part of an organism's life cycle, in a particu-
lar environmental condition, in a mutant strain, during development, or in a dis-
eased organ. Co-occurrence of gene products under such conditions is then taken
as an indication that the gene products may be part of a network that is "active"
under the particular condition studied. I will use the notion of a protein network
here in both the stronger sense above and in this weaker sense. The development
of techniques to identify networks in the weak sense is more advanced, as are
their medical applications.
This introductory survey of protein networks and their biomedical applica-
tions has three parts. First, I introduce some of the most promising approaches to
study protein expression on a very large scale, that is, to identify protein net-
works in the weak sense. Second, I introduce experimental approaches to iden-
tify direct protein interactions on a genome-wide scale, that is, to identify
protein networks in the strong sense. Finally, I present some examples of how
network information can be profitably used in medical applications. At this point
in time, most pertinent and publicly available experiments aim to provide a
proof of principles rather than fully mature clinical applications. The literature I
cite is by no means exhaustive, but intended to provide guidance for further
reading.
2.
LARGE
-
SCALE APPROACHES TO IDENTIFY
PROTEIN EXPRESSION
The approach with the longest track record of identifying expressed proteins
on a genome-wide large scale is two-dimensional protein electrophoresis. A
second approach, mass-spectroscopic analysis of complex protein mixtures,
holds great promise for the future. Both approaches identify individual proteins
