Each cell of
our body carries the same genome. Then what tells some cells to become kidney
cells, and others to become liver cells, and still others to become neurons?
The term ‘cell differentiation’ is used for this phenomenon. How does cell
differentiation occur?
The answer has
to do with 'genetic networks'. But first a word about networks in general. Use
of graph theory and network theory in complexity science has paid rich dividends.
The reasons are not far to see. A complex system comprises of a large number of
individuals, and the individuals interact with one another. We can regard the
individuals as the 'nodes' of a network, and an interaction (if any) between
any pair of nodes can be represented by a line ('edge') joining those two
nodes. Once we have mapped the complex system onto such a network of nodes and
edges, the full power of the mathematics of graph theory and network theory can
be brought to bear on the investigation of the problem. In a genetic network,
the genes are the nodes of the network.
Networks can
be of various types. A random network is one in which the presence or absence of any
edge is a matter of random occurrence; the edges are distributed randomly. If there are N
nodes, and if there is a probability p that any pair of nodes is
connected, then it can be worked out that there are pN(N-1)/2 edges. Random
networks are the simplest imaginable. We shall encounter other types as we go
along.
French
scientists Franรงois Jacob and Jacques Monod
were awarded (along with Andre Lwoff) the Nobel Prize for physiology or
medicine for 1965 for their work on 'circuits' in genetic networks. There are
thousands of genes arrayed along a DNA molecule. And the genes may be either 'on'
(i.e. active) or 'off' (not active). When a gene is on, it is said to be expressing
itself; it is doing the transcription work, directing the synthesis of the
protein it has the code for.
E. coli
are a kind of bacteria. When exposed to lactose (a kind of sugar), they produce
an enzyme (a protein) that can digest lactose. Take away the lactose, and the
enzyme production stops. Jacob & Monod discovered the so-called 'lac operon' and the
underlying gene regulation mechanisms responsible for the sensing of
lactose and the production of the enzyme. They discovered that, adjacent to the gene encoding
a protein called beta galactosidase, a small 'operator' DNA sequence (called 'O')
bound a 'repressor protein' called 'R'. When R was bound to O, the adjacent
gene for beta galactosidase could not be copied into its messenger RNA.
In more
general terms, Jacob & Monod showed that a small fraction of the genes are 'regulatory
genes' which can function as switches.
Such activity is triggered by, say, the availability of a particular hormone in
the surroundings of a cell (or the presence of lactose in the case of E.
coli). This chemical may switch-on a particular gene. The newly activated
gene sends out chemical signals to fellow genes, that can switch them on or
off, depending on the states they are already in. The altered state of each of
these genes then releases, or stops releasing, other chemical signals, which
are received by the genetic switches in the network, altering their states in
turn, in a cascading manner. This continues till the network of genetic
switches settles down to a stable, self-consistent pattern.
The term 'gene
regulation' covers all factors that control gene expression. A gene, or a set
of genes, is said to be expressed if the protein expected to be synthesized by
its expression is found in the cell. Gene-transcription and gene-translation
are obviously the stages wherein this regulation can occur. Other factors which
can regulate gene expression are temperature, pH value, and the presence of
certain molecules (e.g. hormones).
The work of
Jacob & Monod had several implications. For example, it established DNA as
not just a repository of the blueprint for the cell, telling it how to
synthesize the various proteins, but also as an engineer in charge of construction. The DNA was established to
be a molecular-scale computer that computed how the cell was to build and
repair itself, and how it was to interact with the surrounding world.
This work also
solved the mystery of cell differentiation. It was concluded that each type of
cell corresponds to a different pattern
of the genetic network, influenced by the presence of specific hormones etc.
Although there is only a single genome involved, the genome can have many
stable patterns of activation or expression, each corresponding to a different
cell type (liver, kidney, brain, etc.). Thus the genome was viewed as a complex
network of interacting components, which control homeostasis and
differentiation through very specific control circuits among the genes.
[Homeostasis is the ability of higher animals to maintain an internal
consistency.]
Stuart Kauffman carried the genetic-circuit idea still
further. He had introduced in 1969 the notion of Random Boolean Networks (RBNs). We have
seen above how genes in a genetic circuit may be on or off. He made the
simplifying assumption that each node (gene) has two discrete (binary) states:
1 for on, 0 for off. Suppose there are N such nodes. An RBN is a random
network of N binary-state nodes (representing genes in our case) with,
say, K inputs to each node representing regulatory mechanisms.
As I shall
explain in the next post, Kauffman went many steps further than Jacob &
Monod, and demonstrated that even randomly
constructed networks of high molecular specificity can undergo homeostasis and
differentiation. This was a remarkable result because it meant that HIGHLY
ORDERED DYNAMICAL BEHAVIOUR CAN ARISE EVEN FOR RANDOMLY CONSTRUCTED GENETIC
NETWORKS, GETTING JUST A FEW INPUTS PER GENE.
How may species like E. Coli have stabilised their DNA blueprint for millions of years, while others swap genes and are ever evolving?
ReplyDeleteBacteria cannot be classified into species. I shall explain that when I discuss the work of Lynn Margulis.
ReplyDeleteNevertheless, your question is a tough one for me, and I shall have to read up on that.
ReplyDeleteI hope you do not mind sir. Your elucidations are the most interesting and the best I've ever come across.
DeleteThanks a lot for the interest, and the questions.
DeleteThe most interesting text on this interesting topic that can be found on the net ... cell phone holder for car
ReplyDeleteProf Prem raj Pushpakaran writes --- 2020 marks the 100th birth year of Edmond Henri Fischer who studied reversible protein phosphorylation as a regulatory switch!!!
ReplyDelete