(Hartwell mentioned, systems biology, "phenomenology")
2. ON THE COUPLED NETWORK OF GENE EXPRESSION MACHINES
T. Maniatis and R. Reed (Harvard University, US) discuss gene
networks, the authors making the following points:
1) Eukaryotic gene expression is a complex stepwise process that
begins with transcription initiation, elongation and
termination. During transcription, the nascent pre-mRNA is
capped at the 5' end, introns are removed by splicing, and the
3' end is cleaved and polyadenylated. The mature mRNA is then
released from the site of transcription and exported to the
cytoplasm for translation. Superimposed on this pathway is an
RNA surveillance system that eliminates aberrantly processed or
mutant pre-mRNAs and mRNAs. Distinct machines carry out each of
the steps in the gene expression pathway. Despite the unique
reactions they catalyse, each machine also interfaces both
physically and functionally with other machines in the pathway
as detailed in several recent reviews(1-5).
2) The authors discuss evidence that coupling is even more
extensive than previously imagined. Indeed coupling occurs not
only between sequential steps in the gene expression pathway but
also between the earliest and latest steps. Coupling may solve
many of the logistical problems inherent in the gene expression
pathway. For example, the production of mature mRNA requires
that the nascent pre-mRNA is sufficiently stable to complete its
synthesis, processing and export. One of the many functions of
the 5' cap is to protect the pre-mRNA from degradation. By tight
coupling between the capping and transcription machineries,
rapid capping of the nascent pre-mRNA is ensured, thereby
protecting it from degradation.
3) Coupling also plays a critical role in gene expression by
tethering machines to each other and to their substrates, a
mechanism that dramatically increases the rate and specificity
of enzymatic reactions. The possible consequences of tethering
are illustrated by metazoan pre-mRNA splicing where small exons
must be recognized in a vast sea of introns. This recognition
problem may be solved at least in part by coupling transcription
to splicing, which results in tethering splicing factors
directly adjacent to the nascent pre-mRNA as it emerges from the
polymerase. Tethering in general is widely used for regulating
the activities within individual cellular machines. As with the
example of splicing above, tethering is also used to coordinate
activities between machines.
4) In summary: Gene expression in eukaryotes requires several
multi-component cellular machines. Each machine carries out a
separate step in the gene expression pathway, which includes
transcription, several pre-messenger RNA processing steps, and
the export of mature mRNA to the cytoplasm. Recent studies lead
to the view that, in contrast to a simple linear assembly line,
a complex and extensively coupled network has evolved to
coordinate the activities of the gene expression machines. The
extensive coupling is consistent with a model in which the
machines are tethered to each other to form "gene expression
factories" that maximize the efficiency and specificity of each
step in gene expression.
References (abridged):
1. Bentley, D. Coupling RNA polymerase II transcription with
pre-mRNA processing. Curr. Opin. Cell Biol. 11, 347-351 (1999)
2. Hirose, Y. & Manley, J. L. RNA polymerase II and the
integration of nuclear events. Genes Dev. 14, 1415-1429 (2000)
3. Proudfoot, N. Connecting transcription to messenger RNA
processing. Trends Biochem. Sci. 25, 290-293 (2000)
4. Shatkin, A. J. & Manley, J. L. The ends of the affair:
capping and polyadenylation. Nature Struct. Biol. 7, 838-842
(2000)
5. Cramer, P. et al. Coordination between transcription and
pre-mRNA processing. FEBS Lett. 498, 179-182 (2001)
Nature 2002 416:499
Web Links: gene expression network
Related Background:
CELL BIOLOGY: FUNCTIONAL MODULES IN BIOLOGICAL ORGANIZATION
The term "phenomenology" has a variety of meanings, but in this
report we are concerned with only one meaning of the term: we
take the term "phenomenology" to refer to a scientific approach
that focuses on explanations based on formal relationships among
observed entities or processes, as opposed to an approach
("reductionist") that focuses on explanations based on analysis
of the fundamental constituents of such entities or processes.
Using the terms in this way, we have the following examples: a)
Thermodynamics is a phenomenological approach to the behavior of
a gas; statistical mechanics is a reductionist approach to the
behavior of a gas. b) Mendelian genetics is a phenomenological
approach to the inheritance of traits; molecular genetics is a
reductionist approach to the inheritance of traits. One can
think of similar dichotomies in almost every field in science.
The term "reductionist" has had an unfortunate history in
biology, where it has been used to characterize the idea that
any biological entity or process can be "explained" in terms of
the laws of physics and chemistry. Certainly, the behavior of
every entity or process in the natural world is ultimately
totally dependent on the laws of physics and chemistry (which
leads to the idea that the behavior can "in principle" be
derived ["explained"] from such laws), but the actual practical
possibility of any explanations of the behavior of observable
entities or processes in terms of the laws of physics and
chemistry depends on the current state of our knowledge
concerning both the observables and the fundamental laws. In the
practice of science, it can be argued that it does not matter
much which approach is used, phenomenological or reductionist,
provided the approach produces results that are useful, or which
help in understanding the behavior of the entity or process, or
which suggest new and intriguing questions. Beyond this, the
discussion properly belongs in the domain of philosophy and not
science.
The above preamble is necessary in the context of the present
report, since the report concerns a recent article in which a
group of authors (2 molecular biologists, a biophysicist, and a
physiologist) call for a more "phenomenological" approach to
cell biology, an interesting idea, since cell biology is not one
of those areas of biology where such appeals are common. During
the last 50 years, in fact, cell biology has experienced a
remarkable flowering based on the application of fundamental
biochemistry, biophysics, and molecular biology to entities and
processes recognizable at the cellular level (i.e., micron-scale
objects).
L.H. Hartwell et al (4 authors at 3 installations, US) present
an essay calling for a transition from molecular to "modular"
cell biology, the authors making the following points:
1) The authors begin their essay with the following statement:
"Although living systems obey the laws of physics and chemistry,
the notion of function or purpose differentiates biology from
other natural sciences. Organisms exist to reproduce, whereas,
outside religious belief, rocks and stars have no purpose.
Selection for function has produced the living cell, with a
unique set of properties that distinguish it from inanimate
systems of interacting molecules." [Editor's note: Contrast with
this the remarks in the relevant background material below.]
2) The authors propose that a major challenge for science in the
21st century is to develop an integrated understanding of how
biological cells and organisms survive and reproduce. The
authors suggest that cell biology is in transition from a
science that was preoccupied with assigning functions to
individual proteins or genes, to a science that is now
attempting to cope with the complex sets of molecules that
interact to form "functional modules".
3) The authors define a "functional module" as a discrete entity
whose function is separable from those of other modules. This
separation depends on chemical isolation, which can originate
from spatial localization or from chemical specificity. For
example, a ribosome, the module that synthesizes proteins,
concentrates the reactions involved in making a polypeptide into
a single particle, thus spatially isolating its function.
Modules can be insulated from or connected to each other. The
authors suggest that in the future, the higher-level properties
of cells, such as their ability to integrate information from
multiple sources, will be described by the pattern of
connections among their functional modules.
4) The authors point out that the number of cellular functional
modules that have been analyzed in detail is very small, and
each of these efforts has required intensive study. The authors
suggest that biologists need to study more functions at the
modular level and develop methods that make it easier to
determine the relationship of inputs to outputs of modules,
their biochemical connectivity, and the states of key
intermediates within them.
5) The authors suggest that the best test of our understanding
of cells will be to make quantitative predictions about their
behavior and test them. This will require detailed simulations
of the biochemical processes occurring within the modules. "But
making predictions is not synonymous with understanding. We need
to develop simplifying, higher-level models and find general
principles that will allow us to grasp and manipulate the
functions of biological modules."
6) The authors summarize their essay: "Cellular functions, such
as signal transmission, are carried out by 'modules' made up of
many species of interacting molecules. Understanding how modules
work has depended on combining phenomenological analysis with
molecular studies. General principles that govern the structure
and behavior of modules may be discovered with help from
synthetic sciences such as engineering and computer science,
from stronger interactions between experiment and theory in cell
biology, and from an appreciation of evolutionary constraints."
Editor's note: The essential idea here can be presented as
follows: Consider a computer, a machine with a "purpose" -- to
compute. A computer operates on its inputs in specific ways to
produce specific outputs. A "flow diagram" of computer dynamics
is a phenomenological description of the behavior of the
machine. A complete "wiring diagram" of electrical entities and
events in the machine is a reductionist description of the
behavior of the machine. (Of course, from the perspective of
quantum mechanics, the wiring diagram is itself
phenomenological.) Suppose we are given a machine and know
nothing about it except that it operates on inputs to produce
outputs. If our problem is to predict the behavior of the
machine in response to particular inputs, there will come a time
when a flow diagram, albeit "phenomenological", will be of
immense value in understanding how the machine works. What the
authors propose is that much of the future of cell biology will
lie in the construction of the equivalent of detailed and
predictive flow diagrams for the internal operations of
biological cells.
Nature 1999 402supp:C47
ScienceWeek scienceweek.com
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