Concepts and Mechanisms in Mitosis
PBIO 558
Chip Asbury
Linda Wordeman
A Short History of Mitosis: the Early Days
The year is 1888; Heinrich Hertz first produced very-high-frequency electromagnetic
radiation, proving its similarity to light, the smoky melancholy of the Café te Arles was
captured on canvas by Paul Gaugin, and Vincent van Gogh painted his celebrated Selfportrait before the easel. This is also the year that the term chromosome first appeared in
the literature in a review article by Wilhelm Gottfried Waldeyer (1836-1921). Waldeyer
proposes the word chromosome should be used for the elements seen in nuclear division.
In illustrating the mitotic process, Waldeyer argued that a satisfactory theory of
karyokinesis still needed to be constructed. This was in contrast to his contemporaries
who maintained that the essential features of the process were already known.
[From: Key word: Chromosome by H. Zacharias, 2001 Chromosome Research 9:345-355.]
Evolving at this time, in the late 1800’s was the understanding that, instead of
constituting a continuous scaffold within the nucleus which coalesce into random entities
during cell division, chromosomes are individual entities as summarized in a 1890 review
by Oscar Hertwig:
“The chromosomes are independent individuals which retain their
independence even in the resting nucleus. Based on this assumption,
Boveri has formulated the theory of heredity: The scaffold of every
nucleus consists of a certain number of individuals, one half of which are
descendents of the paternal chromosomes and the other are descendents of
the maternal chromosomes of the egg. He has concluded, as Van Beneden
and Weismann did before, that a reduction by half must occur in the
number of nuclear elements prior to fertilization”
[Hertwig, O. 1890. Vergleich der Ei- und Samenbildung bei Nematoden. Eine
Grundlage fur cellulare Streitfragen. Arch. Mikr. Anat. 36:1-138; translated by H.
Zacharias, Chrom. Res. 9:345-355]
Theodor Boveri (1862-1915) took this hypothesis a step
further by suggesting that accidental alterations in
chromosome numbers may lead to the transformed malignant
state. Boveri cites German tumor biologist David
H a n s e m a n n (1858-1920), whose observations of
asymmetric cell divisions in cancer cells provide support for
the disease relevance of proper chromosome number may
have even been the genesis of the original chromosomal
theory of cancer. Proving this relationship between
chromosome number and tumorigenesis experimentally is
quite difficult as Boveri modestly acknowledges in the
introduction to his classic book offered in English translation
by his wife Marcella Boveri:
“When I published the results of my
experiments on the development of double-fertilized sea-urchin eggs in
1902,1 I added the suggestion that malignant tumors might be the result of
a certain abnormal condition of the chromosomes, which may arise from
multipolar mitosis. Even then I considered giving my reasons for this
Concepts and Mechanisms in Mitosis
PBIO 558
Chip Asbury
Linda Wordeman
assumption more fully in a special paper. But the skepticism with which
my train of thought was met by investigators who were competent to give
an authoritative opinion made me abandon this intention. I was forced to
admit that a theory in this field can be of value only if it gives an impulse
to new and definite lines of research; above all to an experimental
verification. And who should decide to take up such investigation if not the
originator of the theory himself? So I have carried on for a long time the
kind of experiments I suggested, which are so far without success, but my
conviction remains unshaken.
1
Ueber mehrpolige Mitosen als Mittel zur Analyse des Zellkerns. Wurzburg, C. Kabitzsch,
1902, und Verh. D. phys. Med. Ges. Zu Wurzburg, N.F. Bd. 35.”
[From: The Origin of Malignant Tumors by Theodor Boveri. 1929. The Williams &
Wilkins Co. Barltimore MD. P. 1.]
Illustrations of cells with chromosomes and
mitosis, from Flemming’s book Zellsubstanz,
Kern und Zelltheilung, 1882.
1
Fibrillar structures of the spindle were
described early on by the German
anatomist Walther Flemming (18431905).1 He also coined the term
“mitosis” in the early 1880’s from the
Greek word for thread.2 For a number
of years the existence of the “spindle
fibers” or microtubules was in
dispute. Some people saw them, but
others did not. Many suggested that
the fibrous elements were some sort
of coagulative fixation artifact. We
now know that microtubules are quite
labile and likely to disassemble under
the influence of temperature changes
or certain buffer components, a
condition which likely contributed to
the general disagreement on their
existence. It was Shinya Inoue3 who
used polarization microscopy to
confirm the existence of birefringent
spindle fibers in living cells using
showing that these fibers were similar
or identical to what had been
observed in well-fixed samples. He
and others also used polarization
optics to demonstrate the labile nature
Flemming, W. Beitrage zur Kenntniss der Zelle und ihrer Lebenserscheinungen. Arch.
Mikroskop. Anat. 16:302-436 (1878) and 18:151-289 (1880). Reprinted in: J. Cell Biol.
25:581-589 (1965).
2
W. Flemming, Zellsubstanz, kern und zelltheilung (Verlag Vogel, Leipzig, 1882).
3
S. Inoue and K. Dan. 1951. Birefringence of the living cell. J Morph 89:423-456.
Concepts and Mechanisms in Mitosis
PBIO 558
Preanaphase
Chip Asbury
Linda Wordeman
Telophase
50 µm
Cell division in a sand dollar embryo viewed by polarized
light. Inoue and Kiehart. 1978. In Cell Reproduction: in Honor of
Daniel Mazia. E. R. Dirksen, D.M. Prescott and C.F. Fox, eds.
Academic Press Inc. New York 433-444.
of
the
spindle
birefringence, which
disappears after mitosis
and in the presence of
microtubule poisoning
drugs. Truly explosive
work on microtubules
began with the introduction of glutaraldehyde
as a fixative4. This fixative
was so reliable that now
all researchers were able to
see microtubules in the
electron microscope in any
tissue examined even
when previously none
could be discerned.
In addition to the microtubules the kinetochore is fundamentally important to proper
chromosome segregation. First reported by Metzner (1894)5, many of the conclusions
concerning the behavior of the kinetochore were based on the appearance of the whole
chromosome. Even in fixed cytological specimens it was difficult to ignore the possibility
that the kinetochore represented some sort of
locale for force transduction.
Meiosis II in the pollen mothercell of Lillium. Mottier, 1903.
4
In 1903 David Mottier noted that the bending of
the daughter chromosomes “may be caused by a
pushing or pulling of the spindle fibers during
meta- or anaphase.”6 It was Gunnar Ostergren
that developed this hypothesis further to suggest
that each chromosome is subject to a pull in the
poleward direction that increases with the distance
between the kinetochore and the pole. As the sister
kinetochore responds to an equal and opposite pull
the chromosome will come to rest at an
equilibrium position midway between the spindle
poles.7 This has been a key hypothesis driving
D. Sabatini et al. 1963. Cytochemistry and electron microscopy. J. Cell Biol. 17:19-58.
Metzner R (1894) Beitrage zur granulalehre. I. Kern und kerntheilung. Arch Anat
Physiol :309–348.
6
Mottier. 1903. The Behavior of the chromosomes in the spore mother-cells of higher
plants and the homology of the pollen and embryo-sac mother cells. Bot. Gazette 35:250283.
7
Ostergren and Prakken. 1946. Behavior on the spindle of the actively mobile
chromosome ends of rye. Hereditas 32:473-494.
5
Concepts and Mechanisms in Mitosis
PBIO 558
Chip Asbury
Linda Wordeman
chromosome research for decades. However, recent, in some cases very recent data
suggests that forces do not vary monotonically with distance from the spindle pole but are
instead generated in part by the kinetochore itself, which integrates a variety signals to
determine their position on the spindle (Kapoor and Compton, 20028). Nevertheless, the
idea, first promulgated by Ostergren that chromosome movement represents a balance of
antagonistic forces remains a reasonable model to this day.
General Historical References
Mitosis: The movement of chromosomes in cell division. 2nd Edition, 1953 by Franz
Schrader. Columbia University Press, New York.
The Origin of Malignant Tumors by Theodor Boveri. 1929. Williams & Wilkins Co.
Baltimore.
Zacharias, H. 2001. Key word: Chromosome. Chrom. Res. 9:345-355.
The Cytoskeleton: An Introductory Survey by Manfred Schliwa. Cell Biology
Monographs Vol. 13. Springer-Verlag Wien, New York.
Mitchison, T.J. and E.D. Salmon. 2001. Mitosis: a history of division. Nat. Cell Biol.
3:E17-21.
Microtubules penetrating the kinetochore of the green algae Oedogonium cardiacum.
From M. Schibler and J. Pickett-Heaps (1980) Eur. J. Cell Biol. 22:687-98.
8
Kapoor, T., and D. A. Compton. 2002. Searching for the middle ground: Mechanisms of
chromosome alignment during mitosis. JCB 157:551-556.