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发帖数: 472 | 1 http://www.cell.com/molecular-cell/fulltext/S1097-2765(11)00331
Fifty Years after Jacob and Monod: What Are the Unanswered Questions in Molecular Biology?
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Tomorrow's Molecular Biology
Marc W. Kirschner
Harvard University
Today, the term molecular biology has a rather prosaic sound. After all,
there is little in contemporary biology that isn't molecular. It's hard to
remember that 50 years ago, molecular biology was distinctly countercultural
. Whereas biochemistry proudly traced its roots to the sober field of
chemistry, molecular biology stood for pure bravado and opportunism. Its
immodest goal was to understand the program of life from gene to phenotype.
Has it fulfilled its promise? The operon theory of Jacob and Monod stands as
one of its signal achievements, but a modern view of how the circuit
actually works illustrates its limitations as well as its accomplishments.
To fully understand the lac operon requires precisely the kind of
biochemistry and physical chemistry that early molecular biologists eschewed
. Today, the path from genotype to phenotype looks nothing like a precise
Boolean circuit. It is ridden with interactions of low specificity, futile
cycles, and redundancy. The eukaryotic chromosome is messy and complex,
perhaps ultimately understandable but hardly predictable. Whatever new field
emerges will have to transcend space and time, connecting molecules not
just to reactions of high specificity but to byzantine pathways concerned
with cellular, tissue, and organism homeostasis. It must move beyond binding
and catalysis to encompass cellular morphogenesis, development, and
physiology, each with its own metalogic. It is obvious that molecular
biology cannot do this with the same intellectual tools it possessed at its
birth. Tomorrow's molecular biologists might wish to look to their
predecessors, take risks, and defy convention.
Regulatory Circuitry
Lucy Shapiro and Harley McAdams
Stanford University
The Jacob/Monod explanation of E. coli's lac operon provided the initial
concepts of bacterial genetic circuitry that we now know to be an integrated
system involving the entire cell. This system includes not only
transcriptional networks, but also regulation by dynamically localized
phospho-signaling proteins and proteases that together control the orderly
activation of subsystems and, in some species, asymmetric cell division. Key
regulatory proteins in the Caulobacter cell-cycle control network are
widely conserved among the α-proteobacteria, but connectivity to other
subsystems has been rewired to reflect the environmental niches and fitness
strategies of individual species. Thus, much like the kernels of gene
regulatory networks proposed by Eric Davidson to regulate metazoan body plan
development, the core connectivity is conserved, while the periphery
connectivity is highly plastic under evolutionary pressure. Moving forward,
a concerted and focused effort to develop a whole-cell- or system-level
understanding of the integrated regulatory circuitry in a few well-chosen,
single-cell eukaryotes will have high payoff. Multicellular organisms will
introduce another level of complexity because the essential properties of an
integrated regulatory system are emergentthey cannot be recognized or
studied in the absence of detailed knowledge of the constituent subsystems
or without system-level analysis needed to understand the functioning of the
whole. Clearly, these challenges and their resolution will yield valuable
and far-reaching insights when applied to understanding cells and tissues
whose regulatory systems have been co-opted by viruses or oncogene function.
Oper-ating in Chromatin
Genevieve Almouzni
Institut Curie
The operon model by Jacob and Monod has for 50 years been a major conceptual
framework to explain how gene activity is regulated. This vision, which can
be applied to E. coli all the way up to the elephant (Jacques Monod),
provides a basis for understanding the rich complexity of gene regulation.
One challenge that molecular biology faces today is to study the genome as
it exists in the cell: packaged in chromatin and organized within the
nucleus, as a template that can respond to external signals. Indeed, it will
be important to move beyond the simple linear mode of regulation using
individual elements and to integrate the concepts of space, time, and
cellular context into our understanding of gene regulation. To accomplish
this, the ability to map and image, with high resolution, both genome
organization and function as an integrated network will be key. Then, to
further determine the plasticity of the system and how, in the context of a
whole organism, each cell lineage emerges with its own characteristics
during development, will have to come into the picture. Finally, an
intriguing question that will keep many people busy is how the memory of
cell identity is preserved throughout cell division and what, beyond mere
DNA, is actually transmitted. The future promises a lot of excitement for
the next generations of biologists, as imagining multiscale gene regulatory
mechanisms is just as fascinating as orchestrating an intricate opera.
Integrated Regulation
Phillip A. Sharp
Massachusetts Institute of Technology
The lac operon model for gene regulation introduced a fundamental paradigm
that has persisted over the past half century. In modern terms, the model
indicates that DNA binding factors such as transcription factors are the
master regulators in controlling cell fate and responses to environmental
signals external to the cell. This paradigm neatly explained Yamanaka's
landmark experiment on induction of pluripotent stem cells from somatic
cells by introduction of genes encoding the transcription factors Oct 4,
Nanog, and Sox2 (Takahashi, K., and Yamanaka, S. [2006]. Cell 126, 663676).
In fact, more recent experiments have shown that many cell types can be
transformed to another cell type by expression of specific transcription
factors. The discovery of cell-type-specific regulatory RNAs, however,
challenges the concept that sequence-specific DNA binding factors are the
master regulators of cell identity. Indeed, since most cells are stable
units of functions through divisions, all regulatory factors must interact
in feed-forward and feedback systems to maintain a homeostatic state. One
major challenge of the coming decades is to integrate the system of
interactions between various types and layers of regulatory factors to model
this homeostatic state. Consistent with the model of Jacob and Monod, it
would probably be wise to start to analyze these complex layers of
regulatory factors beginning at recognition of genomic sequences.
Human Development and Disease
Richard A. Young
Whitehead Institute for Biomedical Research
The major challenge I see for molecular biology is to learn how human
development and disease are programmed in the genome. This will require that
we discover how cell state is controlled in hundreds of cell types. How
transcription factors, chromatin regulators, noncoding RNAs, and signaling
pathways contribute to the regulatory circuitry of cells is a fundamental
and challenging problem, and knowledge of this circuitry is certain to give
us new insights into disease processes. Reprogramming experiments tell us
that a small number of master transcription factors can establish and
maintain cell state, so for at least some cell types, it seems possible to
tackle the core elements of this problem in the near future.
As more human genomes are sequenced, there is increased interest in the
contribution of sequence variation to human health and disease. Although
alterations in the levels and functions of transcription factors and other
regulators are known to contribute to many diseases, little is known about
the effect of sequence variation on the functions of these regulators. Thus,
new approaches are needed to understand how variation contributes to
altered regulatory circuitry, both within and between cells, and to learn
when this variation contributes to disease.
Meaningful Networks
Uri Alon
Weizmann Institute of Science
My favorite mystery is how networks of billions of communicating cellssuch
as the immune system and central nervous systemgenerate meaning. How do they
make sense of the world and generate proper responses to unforeseen
contexts? It is not clear yet whether networks on this scale can be
understood by human beings. Whereas the molecular networks in individual
cells are beginning to be understood as integrated circuitry made of
recurring circuit elements with defined functions, it is not clear if one
can define analogous circuits on the level of communicating cells.
Understanding immune and nervous systems, and even characterizing their
hugely complex states, may require concepts and experimental methods beyond
the current horizon.
As a profession, I believe that our main challenge is the increasing
competition and isolation of researchers. I hope that this can be addressed
by the rising movement to add education and discussion of the subjective and
emotional aspects of doing science: how people can fruitfully mentor,
communicate, choose problems, and give and receive feedback. I don't mean
vacuously being nice to each other; I mean interacting to reach our full
potential as scientistsfollowing our curiosity to figure out how natural
systems work. |
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