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Control of Cell Division: Models from Microorganisms [CANCER RESEARCH 28, 1802-1809,September 1968] Control of Cell Division: Models from Microorganisms Arthur B. Pardee Program in Biochemical Sciences, Moffett Laboratory, Princeton University, Princeton, New Jersey 08540 Control of Cell Division of a few years ago on the bacterial division cycle are sum One approach to the discovery of a difference between nor marized (12). The reviews furnish a guide to the literature mal and malignant cells is to investigate the regulation of cell before 1966. division. Normal tissues are regulated so that their cells are in a steady-state balance between duplication and destruction. Bacterial Division Malignant cells appear to duplicate unceasingly and are not Most investigations of bacterial division have been carried out with the closely related Gram-negative staining organisms in balance with the rest of the organism; they appear to have lost a control mechanism for cell division. Our problem is to Escherichia coli and Salmonella typhimurium. These organisms are implied unless otherwise stated. Gram-positive Bacillus determine how normal control mechanisms function, how they are deranged in malignant cells, and how they can be restored. species have been used for some fundamental studies on chro The working hypothesis of this article is that the funda mosome replication and for morphologic investigations. It is mental biochemical events which regulate cell division are too early to say whether important differences of cell division similar in both bacteria and higher organisms. This hypothesis regulation exist between different bacteria. Major points of will be useful at present to the extent that bacteria provide bacterial division and chromosomal duplication are illustrated a logical framework for ideas and experiments regarding an schematically in Chart 1. imal cell division. Bacteria increase their mass and cytoplasmic components Research with microorganisms has frequently furnished val (total RNA and protein) approximately exponentially with uable models for workers with higher organisms. Well-known time if they are uncrowded and well nourished. A transverse examples are biochemical pathways, gene structure and func barrier or septum appears periodically at the middle of the rod-shaped cell. Light and electron microscopy show that in tion, and control mechanisms at the levels of both enzyme syn E. coli this is created by an inward-growing furrow of the cell thesis and catalytic activity. Even for hormone action, a phe nomenon which does not appear in bacteria, fundamental in membrane which lies just inside the more rigid cell well. In Gram-positive organisms the septum appears simultaneously sights have been provided by microbiology through ideas of metabolic control. Studies of cell division with microorganisms across the entire cytoplasm; wall material is formed on the might similarly provide a valuable source of concepts and a septum. Following this, the daughter cells separate. They are frame of reference for workers with animal cells. The obvious nearly of equal size (coefficient of variation ± 10%) in a differences, morphologic and temporal, between the two sys constant environment. A compensation mechanism must re tems may well be only variations on a basic theme. store unusually sized cells to the average upon the following This article- will attempt to present an organized picture of division, since a negative correlation between the size of mother current beliefs regarding bacterial replication. Our knowledge and daughter cells is observed. The precise distribution of size of bacterial division is increasing rapidly, though it is far from suggests a close relation between total cell mass and the timing complete. Conflicting reports are published; some of these no and spacing of septum formation. The actual separation of doubt will prove important, but now they are interesting the cells is less precisely timed (±20%), probably because of randomness of the movements which shake the cells apart mainly to specialists. These differing results probably reflect (16). the complexity of cell division, which must depend on the in Nuclear bodies can be observed by light microscopy with fluences of poorly appreciated experimental variables originating staining or phase, or in the electron microscope. There are from all parts of the cells and from the environment. The author has tried to piece the data together into a sort of "best- often two or four to an organism, depending on nutrition. The guess" guide. In no sense is a critical review of the entire lit septum is formed between the central pair. These nuclear bodies contain bacterial DNA. They are believed to be attached to erature intended. This would obscure the main concepts in a the cell membrane, or in the case of Bacillus to complex mem mass of detail. No attempt will be made to give a historic brane structures named mesosomes (9). There is no evidence perspective, or even to give credit to individuals where it is of nuclear membranes or of any of the complex mitotic ap certainly due. References will be to a limited set of very recent paratus found in animal cells. In this connection, it should be articles which can provide the next level of understanding and remembered that an entire bacterium is scarcely larger than references to earlier work. an animal mitochondrion (1 to 3 cu /*). Fortunately, several of the most active groups have recently Freely growing bacteria divide as often as once every 40 summarized their efforts (9, 14, 16, 22). This author's views min in a synthetic medium which contains a single well-utilized 1802 CANCER RESEARCH VOL. 28 Downloaded from cancerres.aacrjournals.org on September 26, 2021. © 1968 American Association for Cancer Research. Models from Microorganisms BACTERIAL CYCLE / Ornimin = 40 min Growth Membrane Replicase Attachment DNA Origin 30 min 20 min Chart 1. The bacterial cycle, a schematic representation. carbon source such as glucose. They can divide twice as frer tion, and vice versa. DNA replication should be, in part, con quently in very well-supplemented media, or many times more trolled by the events of cell division. Cell components other slowly with inferior carbon sources such as acetate. The cell than DNA do not have to be so closely coordinated with cell size and number of nuclear bodies decreases several-fold as the division; they exist in numerous copies and can be distributed medium becomes poorer. The main requirement for division approximately equally by chance. is neither a constant time nor a critical mass that is the same Bacterial DNA is found in the nuclear bodies, as shown for under all conditions. A subtler control is suggested by the example by radioautography of bacteria which have incor differences in composition and the complex adjustments in porated thymidine-3H. In the resting state, each nuclear body macromolecular syntheses that bacteria undergo when they are consists of a single molecule of double-stranded DNA of length transferred from one medium to another (16). about 1.3 mm (about 1,000 times as long as the bacterium) Bacteria, unlike most cells of higher animals, do not reach and molecular weight about 3 X 10*. Radioautographs of care a limit of division even in colonics on solid media. Bacteria fully lysed E. coli show the DNA to be circular, at least part stop dividing only when they reach high concentrations in of the time. These morphologic studies are completely sup liquid media. The cells become smaller when they reach this ported by genetic mapping which shows the E. coli chromo terminal stage of their growth; they then resemble bacteria some to carry all of its over 100 known genetic markers in a which are growing on a poor carbon source. When they are single, circular order. Bacillus subtilis has a similar chromo resuspended in fresh medium, they start growing again only some; the evidence for a circular structure has so far been after a time lag. The basis for these changes, especially of found only in germinating spores (25). failure to divide, is not well understood, but in some instances A chromosome starts to replicate at a definite, heritable lack of oxygen or nutrients, or accumulation of toxic products origin. Replication is semiconservative, each of the two new including hydrogen ions is responsible. strands being base-paired by hydrogen bonds to an old strand of the opposite polarity. Recent studies using density labeling The Cycle of DNA Replication suggest that each new strand is covalently linked to the term Duplication of bacterial DNA must be coordinated with inus of an original strand (25). All three double strands re cell division so that each daughter cell obtains a full comple main together at the origin, forming a Y-shaped fork which ment of hereditary material. Timing of DNA duplication during opens toward the replication point. The replicase is thought to the bacterial cycle is represented schematically in Chart 1; be attached to the cell membrane; the old DNA moves into the DNA is illustrated at about VLOOOitsrelative length. One this replication point and the replicas emerge, so that a second anticipates some sort of coupling mechanism which permits the Y-shaped fork completes a loop within the larger circular chro cell division mechanism to sense the progress of DNA replica mosome (see Chart 1). The DNA at the replication fork seems SEPTEMBER 1968 1803 Downloaded from cancerres.aacrjournals.org on September 26, 2021. © 1968 American Association for Cancer Research. Arthur B. Pardee to be more easily denatured than the bulk of the DXA (10). replication increases, as if building blocks become limited. The As the chromosome moves through the replication point, genes time of chromosome replication is not sufficiently long to double in number one after the other in the order of their occupy the entire division cycle but takes place only during the sequence on the chromosome.
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