New models question old assumptions about how many molecules it takes to control cell division

February 25, 2009

Blacksburg, Va. -- A single cell - whether a yeast cell or one of your cells - is exquisitely sensitive to its surroundings. It receives input signals, processes the information, makes decisions, and issues commands for making the proper response. As with any control system, noise - errors, slip-ups, mis-reads - can get in the way of correct decision making. Virginia Tech biologists and engineers have created a mathematical model to explore the roles of noise in controlling the basic events of the cell cycle - DNA replication and cell division.

Their work will appear the week of February 23 in the Online Early Edition of the Proceedings of the National Academy of Sciences (PNAS) and later in the print version of the special feature issue on complex systems. The article, "Exploring the Roles of Noise in the Eukaryotic Cell Cycle," is by postdoctoral associate Sandip Kar; William Baumann, professor of electrical and computer engineering; Mark Paul, professor of mechanical engineering; and John Tyson, University Distinguished Professor of biological sciences.

Their efforts to accurately calculate the effects of noise in a yeast cell revealed flaws in two accepted notions about information processing in single cells: about the numbers of messenger RNA (mRNA) molecules in a cell, and about how long they live.

A fundamental challenge of systems biology is trying to understand the molecular basis of decision making in a single cell. "Information processing is done by a molecular network consisting of interacting genes and proteins," Tyson said. "You could compare it to a computer that is based on integrated circuits or to a mechanical control system based on sensors, wires and servomotors -- except that information processing in cells is unique in two ways. First, the cell is a sloppy, liquid environment, with molecules bouncing around and reacting with one another. Second, cells are extremely tiny; therefore sensitive to random fluctuations in the number of molecules being created or destroyed at any given moment."

Nonetheless, the ebb and flow of molecules in a cell must reliably convey instructions for such essential processes as DNA replication and cell division.

How big are the molecular fluctuations expected in a single yeast cell? Physicists estimate molecular fluctuation using a rule-of-thumb that the size of typical fluctuations is the square root of the average number of molecules. "If there are on average 900 molecules of a particular protein in a cell, then we can expect fluctuations of plus or minus 30 molecules, or 3.3 percent," said Tyson. "That is not too bad."

For DNA there might be a severe problem, Tyson noted, "because there is only one copy of every gene in a yeast cell. But cells are equipped with an elaborate and expensive mechanism to replicate DNA molecules and not allow the random fluctuations predicted by statistical physics."

The weak link in the is mRNA: the molecule that carries information from the gene to the cell's ribosomes, where proteins are made.

The literature reports that there is on average only 1 mRNA molecule per gene per cell, in yeast, and that each mRNA molecule lives, on average, for 15 to 20 minutes before it is degraded. "This is intriguing," said Tyson, "because the physicist's rule-of-thumb would predict very large fluctuations in mRNA abundance - sometimes 1, sometimes 0, sometimes 2 or 3 or 4 -- which means the noise among mRNA molecules is huge, and it propagates to the level of the encoded protein."

The noisy fluctuations in protein level may be 50 percent instead of 3 percent. "There is no way the control system can work in the face of such large fluctuations," Tyson said. "It would be completely unreliable."

Progression through the cell cycle is indeed a noisy process, with typical flucutations of 15 to 20 percent for the time taken to complete the process. To achieve this level of control, the Virginia Tech researchers conclude, in their PNAS paper, that 1) the average number of specific mRNA molecules must be 5 to 10 times larger than the generally accepted value, or 2) the half-life of mRNA molecules must be 10 to 20 times shorter than the reported value, or 3) the cell must have specific mechanisms for noise reduction in its mRNA populations. Or some combination of these strategies.

"At least we have an accurate model that tells where the questions are," Tyson said. "Computational cell biologists address puzzles like this one by building reliable mathematical models, based on basic principles of physics and chemistry, that address the roles of noise and noise reduction mechanisms in living cells."

Tyson, Baumann, and Paul are lead investigators on an NIH National Institute of General Medical Sciences funded research project that also includes Yang Cao, assistant professor; Cliff Shaffer, professor; Layne Watson, professor; and Adrian Sandu, associate professor, all of Virginia Tech's computer science department in the College of Engineering.

The group is continuing to build more elaborate and accurate models of molecular noise in the cell cycle control system of yeast cells and to compare these models to the latest experimental measurements of molecular fluctuations in single cells.

Virginia Tech

---

---

	The Cell Cycle: Principles of Control (Primers in Biology) (Primers in Biology) by David O. Morgan (Author) The Cell Cycle is an account of the mechanisms that control cell division, beginning with a description of the phases and main events of the cell cycle and the main model organisms in cell-cycle analysis, including Xenopus, Drosophila, and yeasts. Later chapters focus on the molecules and mechanisms of the cell-cycle control system, including the cyclin-dependent kinase family of protein kinases, the cyclins that activate them, and the signaling molecules that regulate them, and discuss cell-cycle control in development and the failure of controls in cancer.
	Cell Division and Genetics (Cells and Life (2nd Edition)) by Robert Snedden (Author) This title explains what happens when cells divide. Cell division is the way in which organisms grow. Even when an organism is fully grown, some cells continue to divide to replace those that have become old or damaged. This book explores the complex relationship among chromosomes, genes, and DNA. It then examines the special form of cell division involved in reproduction, and how characteristics are passed on from one generation to another so that a pig gives birth to piglets and not kittens!
	Cell Specialization And Reproduction: Understanding How Cells Divide And Differentiate (The Library of Cells) by Amy Romano (Author) Explore how organisms grow and how specialized cells, tissues and organs develop. Includes in-depth coverage of cell processes with illustrations identifying key components of each cell at each stage. Presents concepts such as cell differentiation as well as the pros and cons of stem cell research and cloning.
	Dynamics of Cell Division (Frontiers in Molecular Biology) by Sharyn Endow (Editor), David Glover (Editor) This volume focuses on the structural aspects of cell division, ranging from nuclear envelope breakdown to cytokinesis and partitioning of the cytoplasm. It examines spindle assembly and chromosome behavior in mitosis and meiosis, centromere and kinetochore structure and regulation, telomeres, the role of centrosomes, and mechanisms by which overall regulation is achieved. Written as a companion volume to Cell Cycle Control, this book provides an up-to-date account of developments in this exciting area of cell biology.
	Synchrony in Cell Division and Growth by E. Zeuthen (Editor) This book has hardback covers.Ex-library,With usual stamps and markings,In fair condition, suitable as a study copy.No dust jacket.
	The Cell Division Cycle in Plants: Volume 26, The Cell Division Cycle in Plants (Society for Experimental Biology Seminar Series) by J. A. Bryant (Editor), D. Francis (Editor) First published in 1985, information is presented and summarised in this account of how plant cells divide. The chapters give information on control points in the cell cycle, on DNA replication and on the stages of cell and chloroplast division. The specialist authors together provide a general overview which will interest and inform all advanced students of the subject.
	Cell Division Control in Plants (Plant Cell Monographs) by Desh Pal S. Verma (Editor), Zonglie Hong (Editor) This volume examines the molecular basis of all aspects of cell division and cytokinesis in plants. It features 19 chapters contributed by world experts in the specific research fields, providing the most comprehensive and up-to-date knowledge on cell division control in plants. The editors are veterans in the field of plant molecular biology and highly respected worldwide.
	Mitosis: The movements of chromosomes in cell division (Columbia biological series) by Franz Schrader (Author)
	Population Balances in Biomedical Engineering: Segregation Through the Distribution of Cell States by Martin Hjortso (Author) The population balance modeling is a statistical approach for achieving accurate counts of any populations. It is an efficient way of counting traffic on roadways as well as to bacteria in lakes. In the biomedical world, it is used to count cell populations for the creation of biomaterials. Despite their undisputed accuracy, they have been underutilized for design and control purposes due to two main reasons: a) they are hard to solve and b) the functions that describe single-cell mechanisms and appear as parameters in these models are typically unknown.
	Bacterial Growth and Division: Biochemistry and Regulation of Prokaryotic and Eukaryotic Division Cycles by Stephen Cooper (Author) How does a bacterial cell grow during the division cycle? This question is answered by the codeveloper of the Cooper-Helmstetter model of DNA replication. In a unique analysis of the bacterial division cycle, Cooper considers the major cell categories (cytoplasm, DNA, and cell surface) and presents a lucid description of bacterial growth during the division cycle. The concepts of bacterial physiology from Ole Maaløe's Copenhagen school are presented throughout the book and are applied to such topics as the origin of variability, the pattern of DNA segregation, and the principles underlying growth transitions. The results of research on E. coli are used to explain the division cycles of Caulobacter, Bacilli, Streptococci, and eukaryotes. Insightful reanalysis highlights significant...