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Introduction to Systems Biology

How does the cell know when to produce a protein? Why does it produce this protein? How does it produce this protein so accurately, in transcription, timing, and concentration? It is amazing that the cell functions as precisely as it needs to in response to various stimuli. What is more amazing is that the cell's actions are a result of stochastic processes.

Dr. Uri Alon of the Weizmann Institute of Science frames his book, An Introduction to Systems Biology, in this context. The first couple of chapters introduces the reader to transcription networks, the cell's signal processing and protein regulation network. A simple example: when signal Sx enters the cell, it binds to protein X, activating it to X*. X* then attaches itself to a strand of DNA that allows the transcription process for protein Y to begin. In this indirect way, protein X regulates protein Y. Abstracting, one can view the cell's proteins as nodes in a very large graph with directed edges indicating which proteins regulate which. Dr. Alon goes on to show that there are several subgraphs that occur far more frequently in the trasncription networks than in randomized graphs and that there are very distinct and pronounced biological reasons for proteins to interact in these recurring patterns.

After describing several of the most important "network motifs" as these patterns are called, Dr. Alon discusses the robustness of the cellular network design. How can the cell survive let alone develop in such a varied environment? On a smaller scale, how can the right amino acid be added to the growing protein? Dr. Alon describes cellular error checking with a simple analogy (p. 176 for those keeping track), and then builds upon this idea to show some of the solutions nature has provided against a changing environment.

In the last section of the book, Dr. Alon discusses optimal gene circuit design. This is an interesting notion because there are many ways to define the word optimal in this context. Alon uses growth rate as an indicator and makes some calculations to show that the optimum level of expression will roughly maximize growth rate. He notes the speed with which this adjustment occurs; for example, E. coli modifies its optimal level of production (not to be confused with normal fluctuations of production in response to short-term stimuli) of the lactose processing protein in response to the presence of lactose within a few hundred generations.

Alon concludes with an inspiring passage on the simplicity of cellular design that can be abstracted from its busy production schedule. Modularization and motifs, for example, are two key concepts we recognize and use in our technology. Engineers know that a good solution to a problem can withstand varying parameters. Even better solutions can be modified very slightly to solve many other problems. Alon's book shows quite clearly that nature has created the best, combining powerful and robust solutions with simple and reusable elegance.

 UPDATE: Some have asked what the error checking (kinetic proofreading) analogy is. I have reproduced it below (I hope no one minds).

 "As an analogy to kinetic proofreading, consider a museum curator who wants to design a room that would select Picasso lovers from among the museum visitors. In this museum, half of the visitors are Picasso lovers and half do not care for Picasso. The curator opens a door in a busy corridor. The door leads to a room with a Picasso painting, allowing visitors to enter the room at random. Picasso lovers that happen to enter the room hover near the picture for, on average, 10 min, whereas others stay in the room for only 1 min. Because of the high affinity of Picasso lovers for the painting, the room becomes enriched with 10 times more Picasso lovers than nonlovers.

 The curator wishes to do even better. At a certain moment, the curator locks the door to the room and reveals a second, ony-way revolving door. The nonlovers in the room leave through the one-way door, and after several minutes, the only ones remaining are Picasso lovers, still hovering around the painting. Enrichment for Picasso lovers is much higher than 10-fold.

If the revolving door were two-way, allowing visitors to enter the room at random, only a 10-fold enrichment for Picasso lovers would again occur. Kinetic proofreading mimics the Picasso room stratagem by using nearly irreversible, nonequilibrium reactions as one-way doors." 

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