Stephen Cooper

Stephen Cooper
University of Michigan | U-M · Department of Microbiology and Immunology

phD

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143
Publications
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5,252
Citations

Publications

Publications (143)
Article
It is widely accepted that there exists a “resting” or “quiescent” state where a growing cell leaves the cell cycle to enter what is often called the “G0‐phase.” I propose that there is no biological reality to the “G0‐phase.” The experimental basis for proposing a G0‐phase is re‐examined and re‐analyzed here showing that the G0‐phase is an anthrop...
Article
Full-text available
The field of cell cycle studies is dominated by the incorrect idea that one can treat an entire culture to produce a synchronized culture. If this predominant method cannot work, at all, then an enormous amount of work on the cell cycle must be re‐evaluated. Here, criteria are presented for determining whether a culture is “truly” synchronized. No...
Article
Full-text available
The concepts of Ludwik Fleck (1896–1961), a microbiologist, historian, and philosopher of medicine, can be used to analyze the conservative nature of scientific ideas. This is discussed and applied to ideas dominant in the understanding of the eukaryotic cell cycle. These are (a) the G1-phase restriction point as a regulatory element of the mammali...
Article
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Three studies of gene expression during the division cycle of Schizosaccharomyces pombe led to the proposal that a large number of genes are expressed at particular times during the S. pombe cell cycle. Yet only a small fraction of genes proposed to be expressed in a cell-cycle-dependent manner are reproducible in all three published studies. In ad...
Patent
Full-text available
A streaming video interface component receives video frames from a streaming driver before the frames are received by a consuming application. The streaming video interface component provides the video frames to a video effect rendering component which renders video effects selected by a user. The video frames with the rendered video effects are th...
Patent
Full-text available
A system, device, and method for virtually connecting a media device to a computing device are disclosed. One embodiment comprises a method to operate a virtual media device in a computing device, wherein the virtual media device that is controlled by a remote media device. In this manner, a computing device may stream media data to and from the re...
Article
Length measurements during the division cycle of 86 individual Schizosaccharomyces pombe cells demonstrate that length grows exponentially with no change in the growth rate and no Rate Change Point (RCP) observed for any cell. These results support the proposal that length extension, or cell growth, is exponential during the division cycle. The fin...
Article
The current model of the eukaryotic cell cycle proposes that numerous genes are expressed at different times during the cell cycle. The existence of myriad control points for gene expression leads to theoretical and logical problems for cell cycle control. Each expressed gene requires a control element to appear in a cell-cycle specific manner; thi...
Article
Full-text available
Accurate cell-size determinations support the prediction that serum starvation and related whole-culture methods cannot synchronize cells. Theoretical considerations predict that whole-culture methods of synchronization cannot synchronize cells. Upon serum starvation, the fraction of cells with a G1-phase amount of DNA increased, but the cell-size...
Article
It has been proposed that cyclical gene expression occurs at a large number of different times during the cell cycle. The existence of a large number of cycle-specific variations in mRNA and protein during the eukaryotic cell cycle raises the problem of how cell-cycle variations are regulated. This is the "infinite regression" or Russian Doll probl...
Article
The Schaechter-Maaløe-Kjeldgaard papers, which have their 50(th) anniversary this year, have major implications for understanding the cell cycle, control of cell growth, control of cell size, metabolic control, the basic bacterial growth curve, and myriad other bacterial and eukaryotic growth phenomena. These ideas have broad applications that shou...
Article
Jef Boeke (personal communication) has pointed out that other laboratories, working with yeast strains that have been separated for over 10 years (and thus are separated by thousands upon thousands of generations of growth), obtained results similar to that from his laboratory. Boeke points out that such differences as expected by the redundancy in...
Article
Full-text available
It has been predicted that whole-culture methods of synchronization cannot synchronize cells. We have tested whether thymidine block, one type of whole-culture synchronization, can synchronize L1210 cells. We demonstrate experimentally that the thymidine block method cannot produce a synchronized culture. Although thymidine-treated cells are arrest...
Article
Microarray analyses have led to the postulated existence and identification of numerous genes that are believed to be expressed and presumably to act in a cell-cycle-specific manner because their expression varies during the cell cycle. It is important to see how protein variation can be produced from mRNA variation. We have calculated the protein...
Article
Full-text available
It is widely accepted that numerous genes are expressed in a cell-cycle dependent manner, with cycle-specific variations in mRNA content or peaks of protein content during the cell cycle. These proposed variations raise the problem of how varying cell cycle gene expression is regulated. This is the "infinite regression" problem or Russian Doll prob...
Article
Full-text available
Problems with whole-culture synchronization methods for the study of the cell cycle have led to the need for an analysis of protein content during the cell cycle of cells that have not been starved or inhibited. The membrane-elution method is a method that allows the study of the cell cycle by producing a culture of unperturbed, synchronized cells....
Article
Bates and Kleckner have recently proposed that bacterial cell division is a licensing agent for a subsequent initiation of DNA replication. They also propose that initiation mass for DNA replication is not constant. These two proposals do not take into account older data showing that initiation of DNA replication can occur prior to the division eve...
Article
Bacterial checkpoints, analogous to those proposed to exist in eukaryotic cells, offer insights into the definition of a checkpoint. Examination of bacterial "checkpoint" or arrest phenomena illustrate problems with a too-casual application of the checkpoint idea to eukaryotic phenomena. The question raised here is whether there are cellular proces...
Chapter
A dividing bacterial cell must, on average, have precisely twice as much of everything found in a newborn cell. How does a bacterial cell ensure that all cell components are duplicated between divisions, and how does a cell ensure that it does not divide prior to duplicating all of its components? These questions have been investigated by studying...
Article
Full-text available
It has been predicted that nocodazole-inhibited cells are not synchronized because nocodazole-arrested cells with a G2-phase amount of DNA would not have a narrow cell-size range reflecting the cell size of some specific, presumably G2-phase, cell-cycle age. Size measurements of nocodazole-inhibited cells now fully confirm this prediction. Further,...
Article
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Two approaches to understanding growth during the cell cycle are single-cell studies, where growth during the cell cycle of a single cell is measured, and cell-culture studies, where growth during the cell cycle of a large number of cells as an aggregate is analyzed. Mitchison has proposed that single-cell studies, because they show variations in c...
Article
Serum starvation of astrocytes for a period of time followed by refeeding has been proposed as a method to produce synchronized astrocytes. Here, it is proposed that the method neither synchronizes cells nor satisfies rigorous criteria for cell synchronization. The proposed non-selective, whole-culture synchronization protocol cannot, in theory, sy...
Article
Full-text available
Two contrasting experimental descriptions of P1-plasmid replication during the cell cycle of Escherichia coli have been described. One set of results led to the proposal that replication of P1-plasmid occurs at a specific time during the cell cycle over a wide range of growth rates and follows rules similar to that governing bacterial chromosome re...
Article
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The paper of Liu, Gaido and Wolfinger on gene expression during the division cycle of HeLa cells using the data of Whitfield et al. are discussed in order to see whether their analysis is related to gene expression during the division cycle. The results of Liu, Gaido and Wolfinger demonstrate that different inhibition methods proposed to "synchroni...
Article
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Conlon and Raff propose that mammalian cells grow linearly during the division cycle. According to Conlon and Raff, cells growing linearly do not need a size checkpoint to maintain a constant distribution of cell sizes. If there is no cell-size-control system, then exponential growth is not allowed, as exponential growth, according to Conlon and Ra...
Article
Whole-culture or batch synchronization cannot, in theory, produce a synchronized culture because it violates a fundamental law that proposes that no batch treatment can alter the cell-age order of a culture. In analogy with the history of perpetual-motion machines, it is suggested that the study of these whole-culture 'synchronization' methods migh...
Article
There have been numerous proposals suggesting that whole-culture methods - in which all cells in a growing culture are treated identically - can synchronize cells. An explicit defense of these methods has been presented (Spellman and Sherlock, this issue, pp. 270-273, ). Here, this defense of whole-culture 'synchronization' is subjected to a critic...
Article
Microarrays have been applied to the determination of genome-wide expression patterns during the cell cycle of a number of different cells. Both eukaryotic and prokaryotic cells have been studied using whole-culture and selective synchronization methods. The published microarray data on yeast, mammalian, and bacterial cells have been uniformly inte...
Data
Full-text available
Appendix 1- Criteria For A Good Microarray/Synchrony Experiment
Data
Appendix 2. statistical analysis of gene expression during the division cycle
Article
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An analysis of different classes of forced or batch synchronization methods reveals why these methods, in theory, do not produce synchronized cultures. Cells may be aligned for a particular property after specific treatments, but these aligned cells do not correspond to any particular cell age during the normal cell cycle. The experimental methods...
Article
Full-text available
The restriction point in the G1 phase of the mammalian cell cycle is the oldest, best-known, and widely accepted control point regulating division cycle in mammalian cells. Origins of the restriction point and its subsequent history are reanalyzed here. The initial proposal of the restriction point has an alternative explanation, which is that cell...
Article
Full-text available
The frequency of labeled mitoses (FLM) method for analyzing cell-cycle phases necessitates a determination of cell-cycle interdivision times and the absolute lengths of the cell-cycle phases. The change to flow sorting (FACS) analysis, a simpler, less labor intensive, and more rapid method, eliminated determinations of absolute phase times, yieldin...
Article
Full-text available
Microarray analysis of gene expression during the yeast division cycle has led to the proposal that a significant number of genes in Saccharomyces cerevisiae are expressed in a cell-cycle-specific manner. Four different methods of synchronization were used for cell-cycle analysis. Randomized data exhibit periodic patterns of lesser strength than th...
Article
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Article
A eukaryotic “baby machine” has been developed that produces synchronized cultures that display up to four synchronous cell cycles. 1 That such cells can be produced implies that methods unable to produce successive synchronized cell cycles may not actually synchronize cells. But most important, the baby machine method now opens the way for the stu...
Article
Full-text available
The Schaechter-Bentzon-Maaløe (SBM) experiment, performed more than 40 years ago, provides an important lesson for the analysis of the eukaryotic cell cycle. Before this experiment, temperature shifts had been used to synchronize bacteria and determine the pattern of DNA synthesis during the bacterial division cycle. These experiments indicated tha...
Article
Microarray analysis of gene expression patterns for thousands of human genes has led to the proposal that a large number of genes are expressed in a cell-cycle-specific manner. The identification of cyclically expressed genes was based on Affymetrix microarray analysis of gene expression after double-thymidine block synchronization. A statistical r...
Article
It has been proposed that lovastatin arrests cells in the G1-phase of the division cycle, and that release from lovastatin inhibition produces a synchronized culture. A new method of methocel time-lapse-videography has been used to analyse cell division patterns following lovastatin treatment. Release of L1210 cells from lovastatin inhibition faile...
Article
The curved, comma, or bent shape of Vibrio cholerae is attributed to, and explained by, the normal helical growth of the cell. The comma-like shape of V. cholerae is not due to an asymmetrical positioning of peptidoglycan such that some chains of peptidoglycan are placed so they are more spread out on one side of the cell and squeezed together on t...
Article
Full-text available
It is widely accepted that phosphorylation of the retinoblastoma (Rb) protein during the G1 phase of the mammalian division cycle is a major control element regulating passage of cells into S phase and through the division cycle. The experiments supporting G1-phase-specific Rb phosphorylation and the historical development of this idea are reviewed...
Article
The curved, comma, or bent shape of Vibrio cholerae is attributed to, and explained by, the normal helical growth of the cell. The comma-like shape of V. cholerae is not due to an asymmetrical positioning of peptidoglycan such that some chains of peptidoglycan are placed so they are more spread out on one side of the cell and squeezed together on t...
Chapter
Bacteria growing in a suitable medium increase in number by having each cell increase in size, and then each cell divides to produce two daughter cells. The increase in cell number in a culture is therefore a result of the activity of the cell during the division cycle, between the period of birth by division and the subsequent division. Keywords:...
Article
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The continuum model of the mammalian division cycle proposes that there are no G1-phase specific controls or events. The G1 phase is simply the time when processes begun in the previous cell cycle are completed. In this review, the continuum model is applied the variability of the G1-phase, the existence of G1-less cells, the ubiquitous G1-phase ar...
Article
Phosphorylation of the retinoblastoma protein (Rb) during the G1-phase of the mammalian cell division cycle is currently believed to be a controlling element regulating the passage of cells into S-phase. We find, however, that the suspension-grown cell lines U937, L1210, and MOLT-4 contain exclusively hyperphosphorylated Rb. Furthermore, when adher...
Article
There have been various proposals for the pattern of F-plasmid replication during the division cycle. Here we show that the recent studies of Gordon et al. (Cell 90, 1113-1121, 1997) on the duplication and segregation of green fluorescent protein (GFP) labeled replication origins of the Escherichia coli chromosome and the F plasmid during the divis...
Article
There have been various proposals for the pattern of F-plasmid replication during the division cycle. Here we show that the recent studies of Gordon et al. (Cell 90, 1113–1121, 1997) on the duplication and segregation of green fluorescent protein (GFP) labeled replication origins of the Escherichia coli chromosome and the F plasmid during the divis...
Article
Synchronization of mammalian cells by starvation-refeeding or by inhibition-release are among the most commonly used techniques for division cycle analysis. An alternative analysis--in the form of a Gedanken or thought experiment--is presented, casting doubt on the utility of this synchronization method. Arresting cell growth produces a culture whe...
Article
Full-text available
https://deepblue.lib.umich.edu/bitstream/2027.42/154318/1/fsb2fasebj123367.pdf
Article
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Zetterberg and Larsson proposed that the restriction point divides the G1 phase into two parts. Cells before this point are able to leave the division cycle and enter a G0 phase; cells past this point are unaffected by a short period of low serum. Additional results of Zetterberg and Larsson--1) cycloheximide treatment affects cells in the same way...
Article
Increasing the concentration of cyclins in mammalian cells leads to a shortening of the G1-phase of the division cycle. This observation has been interpreted as indicating that these cyclins act during, and are rate limiting for, passage through the G1-phase. Here it is argued that it is not possible to interpret experiments involving cyclin overex...
Article
Full-text available
A round mutant of Escherichia coli, when grown in Methocel medium, forms chains of cells and does not form tetrads. This implies that successive division planes of the round mutant are parallel rather than perpendicular. These results differ from a previous proposal that division planes in this round mutant are perpendicular to the prior division p...
Article
We have calculated the optimal shape, i.e. the length-to-width ratio of a bacterial cell, that allows a bacterial cell to move most efficiently through liquid. For a cell of a given size, a minimum exists in the force required to move through any liquid when the length of the cell is approx. 3.7 times greater than the width. As this is in approxima...
Article
Sequence analyses of mRNA from cells arrested with either a G1 phase DNA content or an S phase DNA content were interpreted as indicating that these two cell populations differentially expressed particular transcripts (Earle-Hughes et al. Genome Sci Technol 1, 89-128, 1996). Approximately 13% of the total transcript population appeared to be differ...
Article
We have calculated the optimal shape, i.e. the length-to-width ratio of a bacterial cell, that allows a bacterial cell to move most efficiently through liquid. For a cell of a given size, a minimum exists in the force required to move through any liquid when the length of the cell is approx. 3.7 times greater than the width. As this is in approxima...
Article
DnaK protein is involved in the initiation of DNA synthesis from the Escherichia coli chromosome as well as from the replication origins of phage lambda and P1. The synthesis of dnaK mRNA and protein has been reported to vary during the cell cycle of Caulobacter crescentus (Gomes et al., 1990). We have measured the expression of DnaK protein during...
Article
Full-text available
HPLC analysis of peptidoglycan synthesis in Salmonella typhimurium strain 2616 has revealed that: (i) there is observable variation in the composition, but no significant variation in the overall degree of cross-linking, of newly synthesized peptidoglycan during the division cycle; (ii) the types of muropeptide that constitute peptidoglycan do not...
Article
The effects of mecillinam, ampicillin and cephalexin on peptidoglycan synthesis in Salmonella typhimurium 2616 have been studied at equivalent concentrations or "isoactivities". Using antibiotics at isoactivities allows a direct comparison of the biochemical effects of different antibiotics. When mecillinam was added at different times during the d...
Article
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A modified procedure for determining the pattern of peptidoglycan synthesis during the division cycle has allowed the measurement of the rate of side wall synthesis during the division cycle without the contribution due to pole formation. As predicted by a model proposing that the surface growth of the cell is regulated by mass increase, we find a...
Chapter
The rate and topography of peptidoglycan synthesis during the division cycle of Salmonella typhimurium strain 2616 was determined by comparing incorporation of diaminopimelic acid (DAP) into peptidoglycan to incorporation of radioactive amino acids into protein (Cooper, 1988). The observed ratio of DAP incorporation to amino acid incorporation duri...
Article
Full-text available
P1 prophage replication during the Escherichia coli division cycle has been analyzed by using the membrane-elution technique to produce cells labelled at different times during the division cycle and scintillation counting for quantitative analysis of radioactive prophage DNA. P1 prophage replicates during a restricted portion of the bacterial divi...
Article
The cell-cycle replication patterns of two mini-F plasmids have been examined using the membrane-elution technique (to produce cells labelled at different times during the division cycle) and scintillation counting (for quantitative analysis of radioactivity incorporated into plasmid DNA). The mini-F plasmid pML31, which contains the oriV and oriS...
Article
Full-text available
The cell-cycle replication pattern of the R6K plasmid has been investigated by using the membrane-elution technique to produce cells labelled at different times during the division cycle and scintillation counting for quantitative analysis of radioactive plasmid DNA. The high-copy plasmid R6K replicates exponentially in a cell-cycle-independent man...
Article
Full-text available
When the growth of the gram-negative bacterial cell wall is considered in relation to the synthesis of the other components of the cell, a new understanding of the pattern of wall synthesis emerges. Rather than a switch in synthesis between the side wall and pole, there is a partitioning of synthesis such that the volume of the cell increases expon...
Article
Full-text available
When the growth of the gram-negative bacterial cell wall is considered in relation to the synthesis of the other components of the cell, a new understanding of the pattern of wall synthesis emerges. Rather than a switch in synthesis between the side wall and pole, there is a partitioning of synthesis such that the volume of the cell increases expon...
Article
Full-text available
F plasmid replication during the Escherichia coli division cycle was investigated by using the membrane-elution technique to produce cells labeled at different times during the division cycle and scintillation counting for quantitative analysis of radioactive plasmid DNA. The F plasmid replicated, like the minichromosome, during a restricted portio...
Article
The complex division cycle of Caulobacter crescentus is the consequence of the history of pole development. The newly formed poles are not complete at division and require an additional sequence of synthesis to produce the ultimate stalked pole. The observed cell-cycle-specific protein synthesis and the apparent differentiation of newborn cells are...
Article
Full-text available
The relationship between the experimental measurement of the cross-linking of bacterial peptidoglycan and the mode of its insertion is analyzed. The cross-linking value, in practice and in theory, is independent of the pattern of strand insertion. Since the measure of the mode or pattern of insertion is the acceptor/donor radioactivity ratio (ADRR)...
Article
Peer Reviewed http://deepblue.lib.umich.edu/bitstream/2027.42/27692/1/0000076.pdf
Article
Discordant results on the synthesis of c-myc gene products during the division cycle are reanalyzed and shown to be understood in light of the continuum model. It is proposed that there is no G1-phase dependence of c-myc synthesis. The large amount of data supporting G1-specific syntheses and a G(0) state must be re-examined.

Questions

Question (1)
Question
Sometimes people try to replicate a published result such as gene expression variation during the cell cycle and fail, and thus do not publish as this is a "negative" result and journals generally require a "positive" result.  I would love to get some responses in this area.
For the past 36 years I have been skeptical of cycle-specific gene expression and have published many papers on the subject attacking what I call the "standard model" of passage through the cell cycle.
Some of the key papers (a selection of many more) that deal with this problem are:
Shedden, K. & Cooper, S. Analysis of cell-cycle-specific gene expression in human cells as determined by microarrays and double-thymidine block synchronization. Proc Natl Acad Sci USA 99, 4379-4384 (2002).
Cooper, S. Analysis of cell-cycle-specific gene expression in Saccharomyces cerevisiae as determined by Microarrays and Multiple synchronization methods. Nuc Acids Res 30, 2920-2929 (2002).
Cooper, S. & Shedden, K. Microarrays and the relationship of mRNA variation to protein variation during the cell cycle. J Theor Biol 249, 574-581 (2007).
Cooper, S. On a heuristic point of view concerning the expression of numerous genes during the cell cycle. IUBMB life 64, 10-17 (2012).
Cooper, S. Rethinking synchronization of mammalian cells for cell-cycle analysis. Cell Mol Life Sci 6, 1099-1106 (2003).
Cooper, S. Is Whole-culture synchronization Biology's "Perpetual Motion Machine"? Trends in biotechnology 26, 266-269 (2004).
Cooper, S. Gene espression during  the cell cycle: Obfuscation of original cell-cycle expression data by Normalization. Journal of Cells 1, 1-7 (2015).
Cooper, S.  Schizosaccharomyces pombe grows exponentially during the division cycle with no rate change points. FEMS Yeast Res 13, 650-658 (2013).

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