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Logical Biology 6 (4): 71-75,
2006 |
MINI-REVIEW |
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http://logibio.com |
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© Truthfinding Cyberpress (http://im1.biz/tfcp) |
STEM CELL
IMMORTALITY |
Are Stem Cells Really Immortal Cells?
Shi V. Liu
Eagle Institute of Molecular Medicine
(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.
29. Reya T. Regulation of hematopoietic stem cell
self-renewal. Recent Prog Horm Res. 2003;58:283-295.
30. Molofsky AV, Pardal R, Iwashita T, Park IK,
Clarke MF, Morrison SJ. Bmi-1 dependence distinguishes neural stem cell
self-renewal from progenitor proliferation. Nature. Oct 30 2003;425(6961):962-967.
31. Cooper S. Bacterial Growth and Division:
Biochemistry and Regulation of Prokaryotic and Eukaryotic Division Cycles. New
York: Academic Press, Inc.; 1991.
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.