112 



Cellular Structure and Activity 



amoeba is kept small by cutting off a piece 

 every clay the cell may survive for months 

 without ever dividing (Hartmann, '26). We 

 can consider this situation the simplest and 

 most primitive relationship between growth 

 (cytoplasmic synthesis) and cell division. R. 

 Hertwig ('03) based his theory of mitosis 

 on it. He believed that the change in nu- 

 clear-cytoplasmic ratio due to cell growth 

 was the primary stimulus to cell division. 

 It soon became evident, however, that cyto- 

 plasmic growth and division are not neces- 

 sarily connected; the stimulus for division 

 therefore must be sought outside of a simple 

 quantitative relationship between nucleus 

 and cytoplasm. In certain algae division can 

 be suppressed while growth continues, and 

 giant cells are formed. Release of the inhibi- 

 tion is followed by a series of rapid divisions 

 until the usual size is restored again. Under 

 different circumstances several divisions fol- 

 low each other without interphasic growth 

 and dwarf cells are produced (Hartmann, 

 '33). By exchanging nuclei between amoebae 

 that had just divided and cells entering mi- 

 tosis, Commandon and de Fonbrune ('42) 

 analyzed the function of cytoplasmic and 

 nuclear growth in mitosis. They found that 

 the nuclear-cytoplasmic volume ratio is not 

 important, but that both the nucleus and 

 cytoplasm have to be in a special state of 

 maturity for mitosis to occur. 



Eggs have often been used to study mito- 

 genesis, either through fertilization or ar- 

 tificial parthenogenesis. Some physiologists 

 expected to find a common factor in mitotic 

 stimulation and the stimulation of nerve 

 and muscle. According to Lillie increased 

 permeability of the cell membrane was such 

 a factor. Heilbrunn substituted the increased 

 cytoplasmic viscosity as a common factor and 

 suggested that the mitotic gelation was the 

 primary stimulus to division (see Heilbrunn, 

 '52b). This hypothesis, however, is hardly 

 more satisfactory as a theory of mitosis than 

 the previous ones. It deals with certain 

 phenomena that accompany the division of 

 the cell but not with the fvmdamental proc- 

 ess leading to the complex chain reaction 

 from chromosome synthesis to formation of 

 mitotic organelles, chromosome movements 

 and division of the cell. 



In recent years more emphasis has been 

 placed on biochemical changes in the cell 

 during mitogenesis. The cytologist has failed 

 so far in the understanding of mitogenesis 

 because the essential changes in the cell take 

 place before any microscopically visible man- 

 ifestations appear. A better understanding of 



mitogenesis has to be based on a study of 

 the shifts in enzyme systems, metabolic path- 

 ways and synthetic mechanisms during ante- 

 phase following the mitotic stimulvis. 



A cell about to enter mitosis needs energy 

 that is obtained mainly from a breakdown of 

 carbohydrates thi'ough glycolysis or respira- 

 tion. Any factor that increases the amount of 

 substrate available to the cell therefore in- 

 creases the number of cells in division. Daily 

 rhythms in the number of dividing cells are 

 explained by the variable amounts of car- 

 bohydrate available to the cells (Blumenthal, 

 '50; Bullovigh, '52). Changes in vasculariza- 

 tion are responsible for waves of mitoses and 

 certain hormones (estrogen, testosterone) 

 stimulate mitosis, apparently by increasing 

 the carbohydrate supply to the cells affected 

 (cf. Bvdlough, '52). It has long been known 

 that starvation suppresses cell division. With 

 renewed feeding there is commonly a great 

 increase in the number of divisions, followed 

 by a new minimum. Apparently, in dividing 

 tissues, energy sources affect the length of 

 antephase, but not the entrance into a "ready 

 state." Starvation thus leads to a piling up 

 of "ready" cells and when feeding starts 

 again all these cells go through mitosis at 

 once until all the "ready" cells are ex- 

 hausted (cf. Kornfeld, '22). 



It was shown above that DNA is synthe- 

 sized during antephase. Continuation of mi- 

 tosis depends, therefore, also on the avail- 

 ability of precursors, enzymes and coenzymes 

 involved in nucleic acid synthesis. Addition 

 of such factors stimulates cell division (cf. 

 Norris, '49). 



The relationship of thiols to cell division 

 seems to be well established through the work 

 of Hammett, Voegtlin, Chalkley and espe- 

 cially Rapkine. The pertinent literature has 

 been reviewed by Brachet ('50a). Sulfhydryl 

 compounds stimulate cell division in plants 

 and in animals, in tissue culture and in 

 vivo. Compounds combining with — SH, on 

 the other hand, inhibit mitosis reversibly. 

 Rapidly growing tissues are especially rich 

 in — SH. An attractive hypothesis of the 

 role of — SH has been suggested by Rapkine 

 and expanded by Brachet ('50a). The changes 

 in — SH in the cell are related to a reversible 

 denaturation of proteins. Denaturation of 

 proteins and associated conversion of globvi- 

 lar into fibrous proteins is thought to occur 

 during the formation of asters, spindles and 

 other mitotic gels. The — SH groups freed 

 upon denaturation would then reduce oxi- 

 dized glutathione in the cell. This could 

 account for the observed increase in free 



