Research Interests:

Dynamics of ‘Network Motifs’ in Single Living Human Cells

A major goal in Systems Biology is to understand how complex protein networks give rise to cellular behaviors. One way to approach this problem is by breaking down the networks into basic recurring structural elements (building blocks), which have been called ‘Network Motifs’. We combine experimental and theoretical approaches to study the dynamics of ‘network motifs’ in diverse systems in human cells and wish to bring new insights into how networks function in allowing cells to make specific behavioral decisions. Our aim is to understand the general principles of network motifs in terms of their structure, function and design, and to provide a detailed explanation of how they perform specific tasks in response to different stimuli.

In particular we are interested in the p53 network and the p53-Mdm2 negative feedback loop motif. Our recent single cell studies showed that in response to DNA damage, p53 is expressed in a series of discrete pulses with fixed mean height and duration, which do not depend on the amount of DNA damage. However, identical cells exposed to the same amount of damage show varying numbers of p53 pulses. Our experimental results allowed us to construct a mathematical model that describes a novel damage-sensing “checkpoint”. We suggested that the p53-Mdm2 feedback loop repeatedly tests for DNA damage, acting as a ‘digital clock’ that releases well-timed quanta of p53 until the damage is repaired or the cell dies. We are currently developing an experimental system for the validation of our model and mainly interested in the following questions:

• How does the cell evaluate the level of DNA damage it has suffered and transfer this information to p53?

• What combination of p53 pulses and p53 modifications triggers a given cell fate program?

• What is the dynamical behavior of the p53-Mdm2 motif in response to different stresses?

• Can we ‘rewire’ the p53 network to affect p53 digital behavior and the cell fate?

We plan to extend our studies on the p53 network, as well as to study other well-characterized network motifs in human cells. In the long term, we wish to build a dictionary of functional circuit elements that will allow us to understand the overall properties of a network based on the behavior of its motifs components. We are optimistic that Dthese studies will help us predict how a network will behave in response to new stimuli, or how a network can be modified or rebuilt to give a desired output.

Selected Publications:

Eric Batchelor, Caroline S. Mock, Irun Bhan, Alexander Loewer & Galit Lahav. (2008). Recurrent Initiation: A Mechanism for Triggering p53 Pulses in Response to DNA Damage. Molecular Cell 30(3): 277-289.

Naama Geva-Zatorsky, Nitzan Rosenfeld, Shalev Itzkovitz, Ron Milo, Alex Sigal, Erez Dekel, Talia Yarnitsky, Paz Pollack, Yuvalal Liron, Zvi Kam, Galit Lahav and Uri Alon. (2006). Oscillations and variability in the p53 system. Molecular Systems Biol. 2: E1-E13.

Alex Sigal, Ron Milo, Ariel Cohen, Naama Geva-Zatorsky, Yael Klein, Inbal Alaluf, Naamah Swerdlin, Natalie Pertsov, Tamar Danon, Tal Raveh, Anne Carpenter, Galit Lahav and Uri Alon. (2006). Widespread cell-cycle dependence of nuclear proteins reveals by dynamic proteomics in individual living cells. Nature Methods 3(7): 525-31.

Alexander Loewer and Galit Lahav (2006). Cellular Conference Call: External Feedback Affects Cell Fate Decisions. Cell 124: 1128-113.