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Paths to Immortality and Back Always Easy to Establish Permanent Cell from T.B.L -"21-'-6-------------------NEWSANDVIEWS----------.......l.::N::::!.Aru~RE~v(~Jl"'-.. 308"""__"'_15_'!MA=RC'_'H:!....!.!I9842:! Ceo proliferation vivo, which seems quite plausible because selection for immortality per se will not begin until normal clonal lifespan is ex­ hausted, it could explain why it is not Paths to immortality and back always easy to establish permanent cell from T.B.L. Kirkwood lines from tumour biopsies and why tumor­ igenesis itself sometimes seems a hit-or­ RECENT exciting developments in the hybridized with three simian virus 40 miss phenomenon. characterization of cellular and viral on­ (SV40)-transformed cell lines and with a So what of the mechanism limiting nor­ cogenes show that the immortalization of variety of cell lines (including HeLa) deriv­ mal cell division? If it contributes to the mammalian cells is an important feature of ed from malignant tumours, in all cases the ageing of the organism as a whole, it must their progression from normality to phenotype of immortality was recessive, be understood in an evolutionary context 4 malignancyl .2 . This finding makes natural although variant immortal cells did arise at as much as in any other • The popular view sense; populations of normal cells exhibit low frequency (around 1 in 105) within of ageing as an adaptive mechanism to pre­ only finite division potential when grown in some of the non-proliferating hybrid vent overcrowding and promote species' culture, and it is commonly held that there populations. These results confirm and adaptability, which lends direct support to is an intrinsic limit to cell proliferation that significantly extend earlier reports of the the hypothesis of programmed cell death, must be overcome in vivo before a cancer dominance of mortality over immortality is regarded by most evolutionary biologists can be formed. (But immortality is not ab­ in human cell hybrids7-9 • as untenablel2. On the other hand, there is solutely required; if the potential for cell More strikingly, Pereira-Smith and quite good support for the view that ageing division is great enough a lethal tumour can Smith have also found that in fusions bet­ is the consequence of the energy-saving be found without it.) At the same time, it is ween some pairs of immortal cell lines, strategy of not repairing cellular damage widely believed that the limited growth of growth is finite but that in others, all too weIl 4•13 • This 'disposable soma' hypo­ cells such as fibroblasts is a contributing hybrids cells can divide indefinitely. This thesis suggests that somatic cells are factor in the process of ageing3 • surprising result is interpreted as support switched to a repair level which is optimally If both these ideas are true, then cancer for the hypothesis of programmed cessa­ efficient from the organism's point of view and ageing are intimately connected at the tion of cell division, the argument being even if less than optimal for the cell. If this cellular level, and if we could but under­ that immortality can arise from various is the case, transformation of a cell to im­ stand the mechanism by which one process distinct dysfunctions in the programme mortality can be understood as a product occurs, we should be better placed to under­ and that, among hybrids between cell lines of clonal selection acting on rare mutations stand the other. Behind the simple dichot­ immortalized in different ways, com­ or epigenetic changes which enhance the omy between finite and infinite cell popul­ plementation can restore the operation of capacity of a cell to cope with damage, ation growth, however, lie complex issues. the programme for mortality. I will, either by repairing it more effectively or by First, there are two quite different types however, explain that this finding does not diluting it with more rapid cell division. It is of theories to explain why cells stop pro­ militate against the alternative hypothesis possible that such a change might be liferating. One postulates a rigourously of random damage as strongly as Pereira­ 'recessive' and, therefore, consistent with programmed series of events specifically Smith and Smith have claimed; in any case, the data of Pereira-Smith and Smith6 • aimed at terminating cell division; the for a trait as complex as immortality, the The advances made in recent months in other, that cells cease growing because they classical concepts of dominance and understanding cell immortalization suggest accumulate random defects, particularly recessiveness may be too narrow. that a new path to unravelling the among macromolecules. The two mechan­ The second study, by Huschtscha and mechanisms of carcinogenesis and cell age­ isms call for quite different explanations of HollidaylO, details the events surrounding ing may have been opened up. In working how cells can escape the ageing process and transformation by SV40 of the human our way down this path, it will be helpful to become immortalized4, although testing diploid cell strain MRC-5, comparing two keep the competing hypotheses of both for this difference is by no means easy. permanent cell lines obtained therefrom. these fields firmly in mind. Looking back Second, while the growth behaviour of a The lines differ in several respects, in­ nearly a hundred years, it is amusing to population of cells is necessarily deter­ cluding morphology, modal chromosome note the sharp prejudice of Vinesl4 , who mined by the replicative properties of the number, glucose requirement and, in par­ wrote of Weismann's theory of cell ageing individual cells within it, the relationship is ticular, stability of the immortal that it is "absurd to say that an immortal not always obvious. If immortal cells give phenotype. substance can be converted into a mortal rise to mortal cells which undergo only a One of the lines (called MRC-5Vl) is substance". Poor Professor Vines has been finite number of divisions before they die, a unusually unstable in that the growth of proved wrong, The conversion appears to culture consisting initially of immortal cells some sub-lines slows over a period of many work both ways, and with any luck we may may nevertheless have only a finite life­ population doublings, the cultures dying soon know why. 0 span5 • This surprising outcome arises out in a manner closely resembling the because the immortal cells are 'diluted' by behaviour of normal cells. By recovering their mortal progeny and, in appropriate cells frozen in liquid nitrogen, the line was T.B.L. Kirkwood is at the National Institute for Medical Research, Mill Hill, London NW7 1.44. circumstances, may become so scarce that kept growing through 750 population they are lost altogether. doublings, raising the question whether the Two recent studies, both by groups with immortal phenotype is carried only by a I. Cairns. J. & I.ogan. J . NalurtYJ4, 582 (1983). long-standing interests in the problems of small sub-population of cells which may on 2. Land. H .. Parada. I..F. & Weinberg, R.A. Science 222, 77 1 (1983). cellular ageing, suggest that the trans­ occasion have been lost. Regrettably, 3. Haynick. I .. Scienr. 4m. 242, 42 (1980). formation of normal cells to immortality Huschtscha and Holliday were unable to 4. Kirk wood. T.B.L.& Crem<r. T. Hum. Gen€!. 60, 101 \ 1982). 5. Kirkwood. T.B.!.. & Holliday, R. J. lheor. Bioi. 53.481 (1 975). may not be as irreversible as is generally test this hypothesis directly by growing in­ 6. Pereira-Smith . O.M. & Smith. J . R. Science 221. 964 (1983). thought, and throw light on some of the dividual clones of MRC-5Vl cells, but in­ 7. Bun n. C. I.. & Tarrant. G. M. ExpICellRes. 127. 385 (198O). difficulties in interpreting the phenomenon dependent studies with HeLa and other cell 8. Muggicton·Harris, A.1.. & De Simone, D.W. Somal. Cell Genel. 6. 689 (1980). of immortalization. lines show that immortal cell populations, 9. Pereira·Smith. O,M. & Smith, l.R. Somal. Cell Genet. 7. Pereira-Smith and Smith6 used fusions even after many generations of selection in 4 11 ( 1981) . 10. Huschtsc ha. L. T. & Holliday. R. J. Cell Sci. 63, 77 (1983). between different combinations of mortal vitro, may contain a sizeable fraction (up to II. Ma rt inez. A.O " , 01. In VilrQ 14, 996 (1978). and immortal somatic cells to see whether 40 per cent) of cells whose potential for 12. Medawar, P.B. in The Uniqueness of the Individual 2nd cdn. 28 (Dover . New York. 1981). cellular immortality is dominant or division is Iimited6, II. If a similar, or even \3 . Kirkwood. T .B.!.. Nalure 270,301 (1977). recessive. When normal cells were more extreme, situation should pertain in 14. Vines . S. H. Nalurt 44l , 62 1 (1889). © 1984 Nature Publishing Group.
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