Logical Biology 6 (4): 71-75, 2006

MINI-REVIEW

http://logibio.com

 

© Truthfinding Cyberpress (http://im1.biz/tfcp)

STEM CELL IMMORTALITY

 

 

Are Stem Cells Really Immortal Cells?

 

 

Shi V. Liu

 

Eagle Institute of Molecular Medicine

Apex, NC 27502, USA

 

SVL@logibio.com

 

(Received 2006-08-15; accepted 2006-10-02; published 2006-10-07)

 

 

HIGHLIGHT

 

Stem cells are believed to be immortal.  However, literature evaluation suggests this conventional wisdom may be wrong.  In contrast, increasing scientific evidence and logical reasoning on objective observations suggest that stem cells are mortal, just like any other cells.

 

ABSTRACT

 

Stem cells have been described as immortal cells.  However, careful literature analysis and logical reasoning have led to a conclusion that this conventional wisdom may be wrong.  The root of this misconception on stem cell may be traced back to the fundamental ancestral mistakes in microbiology when microbiologists incorrectly miss-identified the mother cell still lives after its cell reproduction as a “daughter” cell.  This misunderstanding of cell life can be reflected with the labeling of the continued existence of the mother stem cell as a “self-renewal” – formation of another “daughter” cell resembling its mother cell.  Attaching observations on asymmetric cell division and the regular distribution of template DNA stand into one of the two cells formed from one cell to the so-called “immortal DNA stand” hypothesis is logically wrong and scientifically incorrect.  Instead one should consider the retention of the template DNA strand within one cell as a strong argument for naming this cell as the mother cell and clearly distinguish it from the true daughter cell which receives a copied new strand of DNA.  Under no circumstance this biotic reality implies any immortality for the DNA strand or the cell receiving this DNA strand.  It is more likely the old template DNA strand is actually a most liable DNA strand due to its aging status.  To conclusively prove whether the traditional view or the new concept is right scientific experiments based on truly single cell-level tracking or population study using bona fide chronological age-synchronized cells are necessary.

KEY WORDS

 

Stem cell, Immortality, Self-renewal, Cell death, Cell reproduction, Cell aging, Age synchronization, Mother-daughter relation

 


Stem cells are the hottest cells for biomedical research now.  One great selling feature claimed for stem cells are their so-called “immortality”.  Publications on “immortal stem cell” are so many that not only serious research articles are easy to be found in reputable scientific database (at least 167 titles were found in the PubMed searched on August 13, 2006) 1-11 but also many popular books are printed out 12-17.  Entering “immortal stem cell” for a search in Google 436000 links were found.  At the research conference on aging the overwhelming topics were not why organisms die but how some cells are immortal and can be used for extending the life span of organisms.  Believe it or not, the magic medicine that scientists have found to confront aging and mortality is the “immortal” stem cells.

However, are stem cells really immortal?

First I must confess that I am not a stem cell researcher.  However, I am not unfamiliar with stem cell research and the “immortality” claims on stem cell because I have stalked this area of research as a side spare time interest for over 15 years.  As a microbiologist, I have also been dealing with another kind of the so-called “immortal” cells – unicellular microbes – for over two decades.  What I have found is that even these long-believed “prototype” “immortal” cells are truly mortal 18-20.

In comparing stem cell research with microbiological research, I have found the striking similarity in the logical fallacy and methodological mistakes between these separate but closely related scientific disciplines 21-26.  I also realized a key fact, despite so long and/or so intensive research in these fields 27, no one has actually observed the complete life span of any cell (being it a microbe or a stem tissue cell) 22.

Then why microbiologists then and stem cell biologists now claim the immortality for their not well-studied cells?  Well, if it is not for their lack of true knowledge on cells, it may be for the attraction of the commercialism because immortality sells and no one wishes to die.

However, science is about the truth reflecting reality, not just for fulfilling the human wishes.  So placing stem cell “immortality” under the scrutiny of a scientific microscope, let’s examine what evidences there are for supporting such an unusual claim.

A major claim for the “immortality” feature of the stem cell is their capability of the so-called “self-renewal” 28-30.  However, this so-called stemness feature of stem cells may in fact be a misunderstanding of cell due to a fundamental mistake in cell biology that is actually inherited from the same mistakes occurred in the early stage of microbiology.

Microbiologists have long-believed and (at least most) still believe that one mother microbe divides into two daughter microbes 31, 32.  However, this conclusion is not only logically wrong but also scientifically incorrect 21, 22, 24, 25, 33-36.  The alternative view that one mother microbe reproduces another microbe while itself still alive 18 in fact not only fit diverse microbiological observations better but also conform with general biological principles that had been verified with direct observations on many forms of macrobial lives 37-41.

With the same arguments against traditional microbiological mistakes it can be argued that the so-called “symmetric” cell division really does not occur in the sense of the genuine age difference existed between any paired cells formed from one cell 26, 34.  Stem cells, with their cardinal feature of capable of reproducing daughter cells with different features (due to a true sense cell differentiation), actually provided some perfect examples for supporting this chronological age difference.

Now the question is what evidences there are for making a convincing claim for the mother-daughter relationship between two cells formed from one cell?

It turn out evidences are already there in the literature.

First, it has been observed long-time ago that some cells (many of them are now recognized also as stem cells) have the capacity to retail some labels in their DNA strand 42-51.  These so-called “label-retaining cells” (LRC) demonstrated that the life span of cells can be longer than the length of a “cell cycle” (reproduction cycle).  Thus, the equation of cell cycle with life cycle is deadly wrong as was the case in microbiology.  From this understanding, it is also logical to say that the LRCs are actually the original mother cells, not any kind of “renewed” daughter cells with mother-like features.

Secondly, the so-called “immortal” DNA strand 52 in fact merely represents the template DNA strand which is retained by the mother cell after it has repeatedly reproduced daughter cells in successive rounds of reproductions.  The regularity of retaining of template strand DNA in one cell and the distribution of copied DNA strand into another cell of the paired cells formed from one cell demonstrated that the paired cells are exactly mother cell (containing DNA formed on generation earlier) and daughter cell (receiving DNA formed in the new generation time) 53, 54.

Many stem cell biologists 2-4 claim that their cell immortality claim is backed by the DNA immortality hypothesis 52.  However, my careful evaluation of the “immortality DNA” hypothesis revealed that the immortality claim for immortal DNA strand is first a logical confusion and then a scientific mistake.  The regular segregation of DNA strands and, particularly, the invariable distribution (should be more precisely called retention) of template DNA strand in one “daughter” (should be the mother) cell has noting to do with the “immortality” of this DNA strand.  In my view this so-called “immortal” DNA strand may be the most vulnerable DNA strand in the DNA family since it is the chronologically old DNA strands in the chronologically old cells.

To prove that my mortality claim for cell (not just stem cell but all types of cell) and its contained DNA are wrong or to prove that the immortality of cell (stem cell at least) are correct one should at least follow the whole life span of the cell.  In this regard, I challenge cell biologists (which include stem cell biologists and microbiologists) to spent some time to do some real single-cell tracking experiments 37.  Alternatively, some population type cell studies can be performed with truly chronologically age-synchronized cells 19, 20, 25, 41.  A method and apparatus for obtaining bona fide age-synchronized cell population has been invented and patented for public use 23.

With those kinds of truly scientific experiments I guess there would be no more debate on the immortality issue of cells because the facts would speak out by themselves.

 

References

 

1.     Pollock K, Stroemer P, Patel S, et al. A conditionally immortal clonal stem cell line from human cortical neuroepithelium for the treatment of ischemic stroke. Exp Neurol. May 2006;199(1):143-155.

2.     Shinin V, Gayraud-Morel B, Gomes D, Tajbakhsh S. Asymmetric division and cosegregation of template DNA strands in adult muscle satellite cells. Nat Cell Biol. Jul 2006;8(7):677-687.

3.     Rambhatla L, Ram-Mohan S, Cheng JJ, Sherley JL. Immortal DNA strand cosegregation requires p53/IMPDH-dependent asymmetric self-renewal associated with adult stem cells. Cancer Res. Apr 15 2005;65(8):3155-3161.

4.     Karpowicz P, Morshead C, Kam A, et al. Support for the immortal strand hypothesis: neural stem cells partition DNA asymmetrically in vitro. J Cell Biol. Aug 29 2005;170(5):721-732.

5.     Xu C, Jiang J, Sottile V, McWhir J, Lebkowski J, Carpenter MK. Immortalized fibroblast-like cells derived from human embryonic stem cells support undifferentiated cell growth. Stem Cells. 2004;22(6):972-980.

6.     Cooke HJ. Immortalizing the immortal. Nat Genet. Sep 2002;32(1):90-91.

7.     McKay R, Renfranz P, Cunningham M. Immortalized stem cells from the central nervous system. C R Acad Sci III. Dec 1993;316(12):1452-1457.

8.     McKay R, Frederiksen K, Jat PJ, Levy D. Reconstructing the brain from immortal cell lines. Prog Brain Res. 1988;78:647-649.

9.     Holt SE, Wright WE, Shay JW. Regulation of telomerase activity in immortal cell lines. Mol Cell Biol. Jun 1996;16(6):2932-2939.

10.  Muller WA. Pattern formation in the immortal Hydra. Trends Genet. Mar 1996;12(3):91-96.

11.  Sharma HW, Sokoloski JA, Perez JR, et al. Differentiation of immortal cells inhibits telomerase activity. Proc Natl Acad Sci U S A. Dec 19 1995;92(26):12343-12346.

12.  Shostak S. Becoming Immortal: Combining Cloning and Stem-Cell Therapy: State University of New York Press; 2002.

13.  Immortality Institute. The Scientific Conquest Of Death: Libros En Red 2004.

14.  Hall SS. Merchants of Immortality: Chasing the Dream of Human Life Extension Houghton Mifflin 2003.

15.  Guarente L. Ageless Quest: One Scientist's Search for Genes That Prolong Youth: Cold Spring Harbor Laboratory Press 2002.

16.  Olshansky SJ, Carnes BA. The Quest for Immortality: Science at the Frontiers of Aging W. W. Norton & Company; 2002.

17.  West MD. The Immortal Cell: One Scientist's Quest to Solve the Mystery of Human Aging ???; 2003.

18.  Liu SV. Tracking bacterial growth in liquid media and a new bacterial life model. Science in China (Series C: Life Science) (English). 1999;42(6):644-654.

19.  Liu SV, Zhang JJ. Age synchronization of Caulobacter crescentus and implications for prokaryotic aging study. Logical Biology. 2004;4(1):7-15.

20.  Liu SV, Zhang JJ. Crossband in Caulobacter’s stalk is a cell reproduction remnant and bacterial age indicator. Logical Biology. 2004;4(1):16-27.

21.  Liu SV. Logical fallacies and methodological mistakes in microbiology - An overview. Logical Biology. 2000;1(1):25-31.

22.  Liu SV. What is bacterial life? Logical Biology. 2000;1(1):5-16.

23.  Liu SV. Method and apparatus for producing age-synchronized cells. 2004;US patent US6767734B.

24.  Liu SV. Prokaryotic aging: Breaking through the “cell cycle” limitation. Logical Biology. 2004;4(1):1-6.

25.  Liu SV. Age synchronization: Retrospectives and perspectives. Logical Biology. 2004;4(1):88-101.

26.  Liu SV. Understanding the limit of the Hayflick Limit. Logical Biology. 2005;5(1):58-65.

27.  Liu SV. Three billion years of microorganisms, three hundred years of microbiology. Logical Biology. 2000;1(1):32-49.

28.  Morrison SJ, Prowse KR, Ho P, Weissman IL. Telomerase activity in hematopoietic cells is associated with self-renewal potential. Immunity. Sep 1996;5(3):207-216.

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32.  Neidhardt FC, Curtiss R, III., Ingraham ECC, et al., eds. Escherichia coli and Salmonella: Cellular and Molecular Biology. 2nd ed. Washington, DC: American Society for Microbiology; 1996; No. I and II.

33.  Liu SV. Right direction but backward movement: A new finding or a flawed repetition in bacterial aging study? Logical Biology. 2005;5:38-47.

34.  Liu SV. A serendipitous discovery of a likely juvenile phase in life of tissue cells of a multicellular organism. Logical Biology. 2005;5:350-355.

35.  Liu SV. An illogical and unscientific argument against Liu's bacterial/cell life model and its implication for cell synchronization. Logical Biology. 2005;5:335-349.

36.  Liu SV. Will "baby machine" be the next "perpetual-motion machine" of cell synchronization? Logical Biology. 2005;5:356-359.

37.  Liu SV. Single-cell microbiology needs visions. ASM News. 2005;71(4):157-158.

38.  Liu SV. A high time to unify biology under common life principles. Logical Biology. 2005;5(1):66-69.

39.  Liu SV. Searching for the deep root and fundamental mechanism of biotic aging. Logical Biology. 2005;5(1):89-91.

40.  Liu SV. Stop reinforcing misinformation in microbiology. Logical Biology. 2005;5:289-293.

41.  Liu SV. Debating cell-synchronization methodologies: further points and alternative answers. Trends Biotechnol. 2005;23(1):9-10.

42.  Bickenbach JR. Identification and behavior of label-retaining cells in oral mucosa and skin. J Dent Res. Aug 1981;60 Spec No C:1611-1620.

43.  Wei ZG, Cotsarelis G, Sun TT, Lavker RM. Label-retaining cells are preferentially located in fornical epithelium: implications on conjunctival epithelial homeostasis. Invest Ophthalmol Vis Sci. Jan 1995;36(1):236-246.

44.  Cotsarelis G, Sun TT, Lavker RM. Label-retaining cells reside in the bulge area of pilosebaceous unit: implications for follicular stem cells, hair cycle, and skin carcinogenesis. Cell. Jun 29 1990;61(7):1329-1337.

45.  Morris RJ, Fischer SM, Slaga TJ. Evidence that a slowly cycling subpopulation of adult murine epidermal cells retains carcinogen. Cancer Res. Jun 1986;46(6):3061-3066.

46.  Morris RJ, Fischer SM, Slaga TJ. Evidence that the centrally and peripherally located cells in the murine epidermal proliferative unit are two distinct cell populations. J Invest Dermatol. Apr 1985;84(4):277-281.

47.  Morris RJ, Potten CS. Slowly cycling (label-retaining) epidermal cells behave like clonogenic stem cells in vitro. Cell Prolif. May 1994;27(5):279-289.

48.  Clarke RB, Spence K, Anderson E, Howell A, Okano H, Potten CS. A putative human breast stem cell population is enriched for steroid receptor-positive cells. Dev Biol. Jan 15 2005;277(2):443-456.

49.  Potten CS. Keratinocyte stem cells, label-retaining cells and possible genome protection mechanisms. J Investig Dermatol Symp Proc. Sep 2004;9(3):183-195.

50.  Morris RJ, Potten CS. Highly persistent label-retaining cells in the hair follicles of mice and their fate following induction of anagen. J Invest Dermatol. Apr 1999;112(4):470-475.

51.  Shinin V, Gayraud-Morel B, Gomes D, Tajbakhsh S. Asymmetric division and cosegregation of template DNA strands in adult muscle satellite cells. Nat Cell Biol. Jul 2006;8(7):677-682.

52.  Cairns J. Mutation selection and the natural history of cancer. Nature. May 15 1975;255(5505):197-200.

53.  Liu SV. Linking DNA aging with cell aging and combining genetics with epigenetics. Logical Biology. 2005;5:51-55.

54.  Liu SV. A Theoretical framework for understanding biotic aging from molecule to organism in multicellular life. Logical Biology. 2005;5(2):109-116.


 

* This letter was submitted to Stem Cell on 2006-08-15 but was rejected on 2006-09-08.  It was later submitted to Cell on 2006-09-09 (after modification into Cell’s leading edge format) but was rejected on 2006-10-02.  The publication here is the same as it was submitted to Stem Cell except for the added highlight which was from the abstract submitted to Cell.

 

The rejection letter (sent as an email from Editor-in-Chief) of Stem Cell stated that the submission “has been carefully reviewed by two experts from our Editorial Board. Unfortunately, our final decision is that this letter is not acceptable for publication in Stem Cells, mainly because of low novelty.”  The rejection letter (sent as an email) of Cell stated that “The editors at Cell have now had the opportunity to carefully consider your manuscript.  Unfortunately, we are unable to offer to publish your piece as it falls outside of the scope and style of articles that are published in Cell.”

 

It is worthless to argue with Cell if this paper is really outside its “scope and style” since readers of this paper can make their judgement easily.  However, it is necessary to reject the “low novelty” sentence of Stem Cell on this manuscript because it is an absolute lie.  Full explanation of this conclusion can be found in the companion paper published in Logical Biol. 6: 76-79, 2006.