|
Polish
Academy of Sciences |
address: Kasprzaka 44/52 01-224 Warsaw, Poland tel.: +48 22 3432000 fax/tel.: +48 22 3433333, 6325276 email: ichf@ichf.edu.pl |
Warsaw, 15 December
2010
Imprecise
copies - it's statistics that makes the cells different
Why a cloned cat looks different than the original? A new answer to that
question is found by the researchers from the Institute of Physical
Chemistry of the Polish Academy of Sciences in Warsaw. Using computer simulations and theoretical
calculations they discovered a new statistical law. It explains the simplest
and therefore probably the most widespread mechanism, by which a growing
population of genetically identical cells forms groups performing different
functions.
Under certain
conditions, a population of reproducing cells can spontaneously divide into two
groups with distinctly different functions. The researchers have since long
been looking for the reasons of such a spectacular process but the mechanisms
found so far were complicated and did not explain all observed cases. It were
only theoretical calculations and computer simulations carried out by
scientists from the Institute of Physical Chemistry of the Polish Academy of Sciences (IPC PAS) in Warsaw that provided the simplest
explanation. "We discovered a statistical law that is responsible for cell
differentiation", says Dr Anna Ochab-Marcinek from the IPC PAS. The new
statistical mechanism will possibly allow to rationalize one of the sources of
bacteria's resistance to antibiotics and help understand why monozygotic twins
and cloned organisms are not their identical copies. A paper describing the
discovery has just appeared in the "Proceedings of the National Academy of
Sciences", a prestigious scientific journal published by the US National
Academy of Sciences.
Already in the middle of the past century it has been noticed in laboratory
studies that an Escherichia coli population could divide into two groups
with one of them showing expression of a specific gene, e.g., the gene
responsible for production of an enzyme to digest a specific type of sugar,
whereas in the other group the same gene remained inactive. The effect is known
in science as population bimodality. The observation was intriguing, as all the
cells had the same DNA and were kept under the same conditions. Moreover,
despite the lack of changes in the gene set, subsequent cell generations were
able to inherit new functions. The researchers from the IPC PAS set themselves
the task of discovering the simplest possible mechanism that is responsible for
such an unexpected behaviour of cells. For that purpose, they carried out
theoretical calculations followed by a verification with a series of Monte
Carlo simulations. The theoretical and computational work involved the most
important chemical reactions that take place in a living cell.
The genetic information in cells is contained in the DNA structure, the
proteins, however, are synthesised based on the sequences in the messenger RNA
(mRNA). To produce a protein encoded in a gene, the information must be first
transferred from DNA to mRNA. The transfer process (transcription) is
controlled by molecules called transcription factors. After attachment to DNA,
these molecules may repress (then they are called repressors) or promote
(activators) the gene translation. "A cell is a bag with a plenty of various
molecules, moving randomly due to thermal motions. So, it may happen that after
cell division one daughter cell will include more transcription factors than
the other," describes Dr Anna Ochab-Marcinek from the IPC PAS. Using computer
simulations, the researchers analysed, how a different number of repressors or
activators affects the cell population.
The computer simulations carried out at the Institute of Physical Chemistry of the PAS mapped fluctuating
concentrations of proteins produced by each cell during the development of
population. As the number of molecules of a specific type in a cell is
relatively low, the cell divisions result in an unequal distribution of
repressors or activators among the daughter cells. As a result, the cell
population growth leads to appearance of cells that produce a significantly more
protein than other cells or do not produce it at all.
The dependence between the production rate of a specific protein and the
number of repressors or activators in a cell is not proportional. The effect is
referred to as a nonlinearity as the plot showing how the number of protein
molecules depends on the number of transcription factors (the so called
transfer function) is not a straight line. The researchers from the IPC PAS
have shown that the nonlinearity is responsible for formation of two distinct
groups in the population: in one of them the gene is active, whereas in the
other - it is not.
The division of a cell population into two groups is of significant
evolutional importance. The differentiation increases the survival chance for a
part of the population, if any changes unfavourably affecting one of the groups
would occur in the environment. "It is known that bacteria mutate and become
more resistant to drugs. We have shown the simplest mechanism by which the very
nature of bacteria and the underlying laws of statistics increase the survival
probability of at least a part of the population, even if no mutations have
occurred," says Dr Ochab-Marcinek.
The researchers from the IPC PAS have also introduced a simple method of
geometric construction that can be used to predict when a specific cell
population can develop a cell differentiation. The method consists in plotting
of a straight line that intersects the axes of the coordinate system at points
corresponding to the measured burst frequency of the transcription factor
production in a population and the magnitude of these bursts. If the straight
line intersects the gene response curve - known from the laboratory
measurements - then the cell population starts to develop bimodality. With such
a simple geometrical operation one can easily explain the results of earlier
experiments performed by other research groups, for instance the appearance of
bimodality in population only at specific antibiotic concentrations.
"As the mechanism we discovered is the simplest
among all possible ones, we suppose that, unavoidably, it is very common in
cells," says Dr Marcin Tabaka, a co-discoverer of the phenomenon. "The
statistical law we discovered describes how a random disorder inside individual
cells transforms into an order leading to a differentiation of population that
is of benefit for its survival," sums up Dr Ochab-Marcinek.
The project has been completed under a TEAM Programme of the Foundation
for Polish Science, co-founded by the EU European Regional Development Fund
(TEAM/2008-2/2).
The Institute of Physical
Chemistry of the Polish Academy of Sciences (http://www.ichf.edu.pl/) was
established in 1955 as one of the first chemical institutes of the PAS. The
Institute's scientific profile is strongly related to the newest global trends
in the development of physical chemistry and chemical physics. Scientific
research is conducted in nine scientific departments. CHEMIPAN R&D
Laboratories operating as part of the Institute implement, produce and
commercialise specialist chemical compounds to be used, in particular,
in agriculture and
pharmacy. The Institute publishes approximately 300 original research papers
annually.
CONTACTS:
Dr Anna
Ochab-Marcinek
Institute of
Physical Chemistry of the Polish Academy of Sciences
tel. +48 22 3433123
email: ochab@ichf.edu.pl
RELATED LINKS:
Website of the Institute of Physical Chemistry of the
Polish Academy of Sciences (PAS).
Press releases of the Institute of Physical Chemistry
of the Polish Academy of Sciences (PAS).
SCIENTIFIC
PUBLICATIONS:
"Bimodal
gene expression in noncooperative regulatory systems"; Anna Ochab-Marcinek,
Marcin Tabaka; Proceedings of the National Academy of Sciences of the United
States of America; doi: 10.1073/pnas.1008965107
http://www.pnas.org/content/early/2010/11/30/1008965107.abstract
IMAGES:
IChF101215b_fot01s.jpg HR: http://ichf.edu.pl/press/2010/12/IChF101215b_fot01.jpg
The statistical law,
discovered by scientists from the Institute of Physical Chemistry of the Polish
Academy of Sciences (IPC PAS) in Warsaw, describes how a random disorder inside
individual cells transforms into an order leading to a differentiation of
population. Above: Dr Anna Ochab-Marcinek, one of the co-discoverers. (Source: IPC PAS, Grzegorz
Krzyżewski)