Biology Reference
In-Depth Information
Equally enlightening theoretical systems properties
were imagined beyond small-scale regulatory mechanisms
composed of just a few molecules. Waddington introduced
the metaphor of 'epigenetic landscape', whereby cells
respond to genetic, developmental and environmental cues
by following paths across a landscape containing peaks and
valleys dictated by interacting genes and gene products
[9]
.
This powerful idea, together with theoretical models of
'randomly constructed genetic nets' by Kauffman
[10]
,
suggested that a cellular system could be described in terms
of 'states' resulting from particular combinations of genes,
gene products, or metabolites, all considered either active
or inactive at any given time. Complex wiring diagrams of
functional and logical interconnectivity between biomole-
cules and genes acting upon each other could be imagined
to depict how systems 'travel' from state to state over time
throughout a 'state space' determined by intricate, sophis-
ticated combinations of genotype, systems properties and
environmental conditions. These concepts, elaborated at
a time when the molecular components of biology were
poorly described, remained largely ignored by molecular
biologists until recently (see Chapter 15).
Over the past two decades, scientific knowledge of the
biomolecular components of biology has dramatically
increased. In particular, sequencing and bioinformatics
have allowed prediction of coding and non-coding gene
products at genome scale. Transcriptome sequencing
approaches have revealed the existence of transcripts that
had escaped prediction and which often remain of unknown
function (see Chapter 2). Additionally, the list of known
molecular components of cellular systems, including
nucleic acids, gene products and metabolites, is length-
ening and becoming increasingly detailed. With these
advances came a humbling realization, best summed up as
'too much data, too few drugs' (see Chapter 8). It has
become clearer than ever that knowing everything there is
to know about each biomolecule in the cell is not sufficient
to predict how the cell will react as a whole to particular
external or internal perturbations.
Functional interactions, perhaps more so than indi-
vidual components, mediate the fundamental requirements
of the cell. Consequently, one needs to consider biological
phenomena as the product of ensembles of interacting
components with emergent properties that go beyond those
of their individual components considered in isolation. One
needs to step back and measure, model, and eventually
perturb nearly all functional interactions between cellular
components to fully understand how cellular systems work.
In analogy to the word genome, the union of all interactions
between all cellular components is termed the 'inter-
actome'. Our working hypothesis is that interactomes
exhibit local and global properties that relate to biology in
general, and to genotype
FIGURE 3.1
Systems as a fifth requirement for Life.
requirement for Life
[2]
. Although conceptual, systems
may turn out to be as crucial to biology as chemistry, genes,
cells or evolution (
Figure 3.1
).
Cells as Interactome Networks
The study of biological systems, or 'systems biology',
originated more than half a century ago, when a few
pioneers initially formulated a theoretical framework
according to which multiscale dynamic complex systems
formed by interacting biomolecules could underlie cellular
behavior. To explain cellular differentiation, Delbr¨ck
hypothesized the existence of positive feedback circuits
required for 'bistability', a model in which systems would
remain stably activated after having been turned on, and
conversely, remain steadily inactive once turned off
[3]
.
Empirical evidence for feedback regulation in biology first
emerged in the 1950s. The Umbarger and Pardee groups
uncovered enzymatic feedback inhibition
[4,5]
, and Nov-
ick and Weiner described the positive feedback circuit
regulating the lac operon
[6]
. Monod and Jacob subse-
quently proposed how negative feedback circuits could
account for homeostasis and other oscillatory phenomena
observed in many biological processes
[7]
. These teleo-
nomic arguments were later formalized by Ren´ Thomas
and others in terms of requirements for cellular and whole
organism differentiation based on positive and negative
feedback circuits of regulation, using Boolean modeling as
powerful simplifications of cellular systems
[8]
(see
phenotype relationships
in
e
Chapter 10).
particular.
