November 13, 2011 - Intrinsic vs. Extrinsic Fluctuations in Protein Number presented by Yuval

When: November 13, 2011 12:00
Where: Physics 377
Presenter: Yuval Elhanati (Naama Brenner's group, physics)
Link to paper: http://www.pnas.org/content/early/2011/06/30/1018832108.full.pdf+html

Separating intrinsic from extrinsic fluctuations in dynamic biological systems

Andreas Hilfinger and Johan Paulsson

Department of Systems Biology, Harvard University, 200 Longwood Avenue, Boston, MA 02115

From molecules in cells to organisms in ecosystems, biological populations fluctuate due to the intrinsic randomness of individual events and the extrinsic influence of changing environments. The combined effect is often too complex for effective analysis, and many studies therefore make simplifying assumptions, for example ignoring either intrinsic or extrinsic effects to reduce the number of model assumptions. Here we mathematically demonstrate how two identical and independent reporters embedded in a shared fluctuating environment can be used to identify intrinsic and extrinsic noise terms, but also how these contributions are qualitatively and quantitatively different from what has been previously reported. Furthermore, we show for which classes of biological systems the noise contributions identified by dual-reporter methods correspond to the noise contributions predicted by correct stochastic models of either intrinsic or extrinsic mechanisms. We find that for broad classes of systems, the extrinsic noise from the dual-reporter method can be rigorously analyzed using models that ignore intrinsic stochasticity. In contrast, the intrinsic noise can be rigorously analyzed using models that ignore extrinsic stochasticity only under very special conditions that rarely hold in biology. Testing whether the conditions are met is rarely possible and the dual-reporter method may thus produce flawed conclusions about the properties of the system, particularly about the intrinsic noise. Our results contribute toward establishing a rigorous framework to analyze dynamically fluctuating biological systems.

August 7, 2011 - Phenotypic variability presented by Yuval

When: August 7, 2011 12:00
Where: Physics 377
Presenter: Yuval Elhanati (Naama Brenner's group, physics)
Link to paper: http://www.pnas.org/content/104/48/18982

Phenotypic variability of growing cellular populations

Ting Lu, 

Tongye Shen, 

Matthew R. Bennett,

Peter G. Wolynes, and 

Jeff Hasty

1.  University of California at San Diego, La Jolla, CA 92093

1. The dynamics and diversity of proliferating cellular populations are governed by the interplay between the growth and death rates among the various phenotypes within a colony. In addition, epigenetic multistability can cause cells to spontaneously switch from one phenotype to another. By examining a generalized form of the relative variance of populations and classifying it into intracolony and cross-colony contributions, we study the origins and consequences of cellular population variability. We find that the variability can depend highly on the initial conditions and the constraints placed on the population by the growth environment. We construct a two-phenotype model system and examine, analytically and numerically, its time-dependent variability in both unbounded and population-limited growth environments. We find that in unbounded growth environments the overall variability is strictly governed by the initial conditions. In contrast, when the overall population is limited by the environment, the system eventually relaxes to a unique fixed point regardless of the initial conditions. However, the transient decay to the fixed point depends highly on initial conditions, and the time scale over which the variability decays can be very long, depending on the intrinsic time scales of the system. These results provide insights into the origins of population variability and suggest mechanisms in which variability can arise in commonly used experimental approaches.