eddy@boulder.Colorado.EDU (Sean Eddy) (06/11/87)
In article <622@unicus.UUCP> craig@unicus.UUCP (Craig D. Hubley) writes: >- Is mitosis sufficiently prone to failure to account for organ decline? > - Statistically, one would expect exponential distribution for > failure of single cells, the rate dependent on mitosis failure, > and perhaps modified by other cell-killing factors > - Does organ failure, medically, occur at the point where > a parallel processing system, mathematically, would fail? > >I've heard that mammal cells appear to suffer a "hard" reproductive limit >of 52 mitosis operations, and that meiosis "resets this counter" to 0. > >- any comment on this, bio-med types? Is it true? >- Would a theory assuming a simple variable or random "counter" in each cell >limiting its reproductive span better explain aging (programmed cells...) The 'hard reproductive limit' you refer to is called the Hayflick limit, and is by no means a hard and fast law. Weismann (1891) proposed that aging was the result of our cells' having finite replicative capacities. The advent of tissue culture techniques showed however that certain cell lines (for instance, the now-famous HeLa line) can be maintained in culture through essentially an infinite number of divisions. It was not realized until later that these cell lines were actually highly abnormal, immortalized cells. Hayflick (1965) did an experiment in which he took cells from human embryos and grew them in vitro. He observed that the cells would go through about 50 divisions (40-60) and then die. Thus this limit of 50 CPD (cell population doublings) is called the Hayflick limit. In actual practice, it is not thought that any human cell approaches 50 divisions during the human lifetime. Cells from older humans will undergo fewer divisions in vitro; the older the source, the fewer divisions. There is considerable variation in this data. Also, the slope of the loss of replicative potential is small, at 0.2CPD lost/year of age. A look at other animals than humans shows a rough correspondence of Hayflick limit with lifespan. Mice have a maximum life span of about two years, and a Hayflick limit of about 9.2 CPD; Galapagos tortoises live to be older than 150 years and have a Hayflick limit of 120 CPD. Individuals afflicted with certain syndromes that accelerate the rate of aging (progeria; Werner's syndrome; Down's syndrome) show lower than normal Hayflick limits. It is, as yet, not clear whether cell death, aging, and the Hayflick limit are the result of a specific 'death program' in the genetics of the individual cells; or whether they are the consequence of progressive accumulation of damage. Programmed cell death is now accepted as a real feature of developmental biology. A well known example is the metamorphosis of amphibians (the loss of a tadpole's tail). If one fuses two cells, one immortalized and one normal, the resulting fusion cell will be mortal; this result (of immortalization being recessive) has been taken to suggest that mortality is due to a genetic program. However, the model suffers from a difficulty in that it becomes necessary to propose how the cell knows when it is time to die. The model of accumulated random damage explains the timing of cell death, and different Hayflick limits can be explained by different repair efficiencies. It becomes difficult to explain cell immortalization by this model however, while programmed cell death can explain immortalization as an escape from the control of the program. I hope that this information is of use in the discussion, though I confess my negligible knowledge of AI makes it unclear to me what we're really discussing... I wanted to point out, however, that researchers in the field seem to consider the models of random damage accumulation and genetically programmed death as being opposed. - Sean Eddy - MCD Biology; U. of Colorado at Boulder; Boulder CO 80309 - eddy@boulder.colorado.EDU !{hao,nbires}!boulder!eddy - - "Why should the government subsidize intellectual curiosity?" - - Ronald Reagan
levy@ttrdc.UUCP (06/14/87)
In article <1343@sigi.Colorado.EDU>, eddy@boulder.Colorado.EDU (Sean Eddy) writes: < Hayflick (1965) did an experiment in which he took cells from < human embryos and grew them in vitro. He observed that the cells < would go through about 50 divisions (40-60) and then die. Thus < this limit of 50 CPD (cell population doublings) is called the < Hayflick limit. In actual practice, it is not thought that any < human cell approaches 50 divisions during the human lifetime. Is this true even for skin cells? Where DOES all the new skin come from as the old skin cells constantly die and flake off, then? (At least I was under the impression that skin cells do this. I also once read an article [Scientific American?] which said, as best as I could understand it, that intestinal cells continually regenerate and get sloughed off during the normal digestive process. That's a lot of cell division, or am I mistaken?) -- |------------dan levy------------| Path: ..!{akgua,homxb,ihnp4,ltuxa,mvuxa, | an engihacker @ | vax135}!ttrdc!ttrda!levy | at&t data systems division | Disclaimer: try datclaimer. |--------skokie, illinois--------|
eddy@boulder.Colorado.EDU (Sean Eddy) (06/14/87)
In article <1756@ttrdc.UUCP> levy@ttrdc.UUCP (Daniel R. Levy) writes: >In article <1343@sigi.Colorado.EDU>, eddy@boulder.Colorado.EDU (Sean Eddy) writes: >< Hayflick limit. In actual practice, it is not thought that any >< human cell approaches 50 divisions during the human lifetime. > >Is this true even for skin cells? Where DOES all the new skin come >from as the old skin cells constantly die and flake off, then? (At >least I was under the impression that skin cells do this. I also once read >an article [Scientific American?] which said, as best as I could understand >it, that intestinal cells continually regenerate and get sloughed off during >the normal digestive process. That's a lot of cell division, or am I >mistaken?) I've been thinking the same thing since I sort of blindly believed the stuff I read. It's close, though, and I might turn out to be right. A big example of massive cell division is erythropoiesis (the production of new blood cells). 3 million new red blood cells are put into circulation every second of an adult's life, on average. If you work this out for a 100 year life span, that's about 1x10E16 cells. 2 to the 50th is a tenth of that. But, if you give me 60 divisions, I have enough potential cells for a hundred lifetimes. I think then, that certain rapidly dividing cell populations (blood cells, intestinal epithelia, etc.) clearly must be approaching 50-60 cell divisions by the end of one's life, if not exceeding the limit as you suggest. It's probably important to note that in Hayflick's experiments, his embryo-derived cells never differentiate to epithelial cells. It's not an in vivo situation, by any means. - Sean Eddy - MCD Biology; U. of Colorado at Boulder; Boulder CO 80309 - eddy@boulder.colorado.EDU !{hao,nbires}!boulder!eddy - - Go Celtics!!
lincoln@randvax.UUCP (06/16/87)
In article <1756@ttrdc.UUCP> levy@ttrdc.UUCP (Daniel R. Levy) writes: >In article <1343@sigi.Colorado.EDU>, eddy@boulder.Colorado.EDU (Sean Eddy) writes: >< Hayflick limit: In actual practice, it is not thought that any >< human cell approaches 50 divisions during the human lifetime. > >Is this true even for skin cells? ....that intestinal cells continually >regenerate and get sloughed off during the normal digestive process. >That's a lot of cell division, or am I mistaken?) 2^50 is a very large number, if every cell had two progeny (which of course they don't) - but the rate of proliferation is impressive. In fifty divisions two cells would produce something like 10,000 lbs of tissue. Thus a little proliferation goes a long way. There is the story about the man who was granted one wish by the king... that the king would place one grain of wheat on the first square of a chessboard, and double it every square thereafter... by 55 he was well on the way toward taking over the entire world. p q \|/ /|\ TOM LINCOLN lincoln@rand-unix.ARPA \|/ "Life is short, art is long, opportunity fugitive, /|\ experimenting dangerous, reasoning difficult."
craig@think.uucp (Craig Stanfill) (06/17/87)
> Hayflick limit: In actual practice, it is not thought that any > human cell approaches 50 divisions during the human lifetime. *** > Is this true even for skin cells? ....that intestinal cells continually > regenerate and get sloughed off during the normal digestive process. > That's a lot of cell division, or am I mistaken?) *** > 2^50 is a very large number, if every cell had two progeny (which of course > they don't) - but the rate of proliferation is impressive. In fifty > divisions two cells would produce something like 10,000 lbs of tissue. Thus > a little proliferation goes a long way. *** If I am correctly informed, in the skin, intestines, and other areas of the body which are constantly renewed, there is a thin layer of rapidly reproducing cells, covered by a layer of non-reproducing but living cells, followed by a layer of dead cells. In essence, after each division one daughter will cease to divide and one will continue to divide. Thus, the number of rapidly reproducing cells stays more or less constant, and the production of new tissue is steady. Of course, sometimes the mechanism (whatever that may be) malfunctions, producing tumors of various sorts.
lincoln@randvax.UUCP (Tom Lincoln) (06/22/87)
In article <5491@think.UUCP> craig@godot.think.com.UUCP (Craig Stanfill) writes: >> Hayflick limit: In actual practice, it is not thought that any >> human cell approaches 50 divisions during the human lifetime. > >> Is this true even for skin cells? ....that intestinal cells continually >> regenerate and get sloughed off during the normal digestive process. >> That's a lot of cell division, or am I mistaken?) >*** >> 2^50 is a very large number, if every cell had two progeny (which of course >> they don't) >*** > >If I am correctly informed, in the skin, intestines, and other areas of >the body which are constantly renewed, there is a thin layer of rapidly >reproducing cells, covered by a layer of non-reproducing but living >cells, followed by a layer of dead cells. In essence, after each >division one daughter will cease to divide and one will continue to >divide. Thus, the number of rapidly reproducing cells stays more or >less constant, and the production of new tissue is steady. Of course, >sometimes the mechanism (whatever that may be) malfunctions, producing >tumors of various sorts. What happens is somewhat inbetween. Blood cells are the best example of a system that has a very active cell cascade, where stem cells divide .. and one waits.. as you suggest.. but then the other divides a number of times (about 6) with all progeny headed for mature cells. The rate of these divisions are modulated by numerous factors. Skin cells and gut cells behave in a somewhat similar way, with bursts of activity and multiple divisions when the erosions become greater than normal. The rest of the time a process is in force that is linear in overall impact, but consists, nevertheless, in bursts of cascaded growth. As Sean Eddy has noted in another article, 2^60 would cover all contingencies, so more than 60 divisions, the upper Haflick limit need not be violated. p q \|/ /|\ TOM LINCOLN lincoln@rand-unix.ARPA \|/ "Life is short, art is long, opportunity fugitive, /|\ experimenting dangerous, reasoning difficult."