Transient-Mediated fate determination in a transcriptional circuit of HIV
Leor S. Weinberger (University of California, San Diego), Roy D. Dar (University of Tennessee), and
Michael L. Simpson (Center for Nanophase Materials Sciences, Oak Ridge National Laboratory)
One of the
greatest challenges in the characterization of complex nanoscale systems
is gaining a mechanistic understanding of underlying processes that
cannot be directly imaged. Recent research at the CNMS1 explored
a novel technique of discovering the details of these interactions
the measurement of the structure of stochastic fluctuations that occur
in neighboring nanoscale system components that can be directly imaged.
In this work [Nature Genetics, 40(4), 466-470
(2008)], in collaboration with a researcher at the University of California,
San Diego, these techniques
were used to discover key operational details of a biochemical switch
that determines the fate of HIV-infected cells.
report from the Basic Energy Sciences Advisory Committee has identified
understanding the role of stochastic fluctuation in biological
systems as key to realizing the “dreams of nanoscience.”2 Like
the systems envisioned emerging from nanoscience, the genetic and biochemical
processes that generate the complex and versatile behavior of cells
are highly functional, densely packed, information processing systems
that operate in highly fluctuating environments. It is of great interest
to researchers interested in the future design of complex synthetic
nanoscale systems to learn how complex cellular functionality is maintained
within, and in some cases even enhanced by, this highly noisy environment.
The functional role of fluctuations is especially pronounced in decision
circuits that choose between two divergent fates, such as the HIV developmental
switch at the center of this research. Especially notable in this study
is that while the results of decisions were visible, the mechanism
of decision making could not be directly imaged. Instead, the mechanistic
understanding was found in the structure of fluctuations. This work
suggests that a variety of nanoscale phenomenon that cannot be directly
imaged may be probed by looking into the noise.
carried out in the Center for Nanophase Materials Sciences, Oak Ridge
National Laboratory by Roy D. Dar (University of Tennessee Graduate
Student in Physics) and Michael L. Simpson. Coauthor and collaborator
Leor S. Weinberger was a Lewis Thomas Fellow at Princeton University
and is presently a faculty member in the Biochemistry Department
at the University of California, San Diego (UCSD).
D. W., M. S. Allen, J. M. McCollum, R. D. Dar, J. R. Wilgus, G. S.
F. Samatova, C. D. Cox, and M. L. Simpson, “Gene
Network Shaping of Inherent Noise Spectra,” Nature 439,
2See Chapter 5, Realizing the Dream Of Nanoscience: Energy And Information
On The Nanoscale
From Directing Matter and Energy: Five Challenges for Science and the
Imagination, A Report from the Basic Energy Sciences Advisory Committee
(A) Snapshots from the time-lapse fluorescent microscopy of immune cells
expressing HIV genes and a green fluorescent protein (GFP) reporter.
(B) Time course of GFP fluorescence in the cells showing the very large
stochastic fluctuations in which the decision making takes place. Mechanistic
details about the function of the biochemical switch were found by detailed
analysis of these fluctuations.