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A unifying concept: the history of cell theory

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A unifying concept: the history of cell theory

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After the first observations of life under the microscope, it took two centuries of research before the 'cell theory', the idea that all living things are composed of cells or their products, was formulated. It proved even harder to accept that individual cells also make up nervous tissue.
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NATURE CELL BIOLOGY | VOL 1 | MAY 1999 | | cellbio.nature.com
E13
A unifying concept: the history of
cell theory
Paolo Mazzarello
After the first observations of life under the microscope, it took two centuries of research before
the ‘cell theory’, the idea that all living things are composed of cells or their products, was
formulated. It proved even harder to accept that individual cells also make up nervous tissue.
ith the invention of the microscope
at the beginning of the seventeenth
century, it became possible to take
a first glimpse at the previously invisible
world of microscopic life. A bewildering
array of new structures appeared before the
astonished eyes of the first microscopists.
The Jesuit priest Athanasius Kircher (1601–
1680) showed, in 1658, that maggots and
other living creatures developed in decaying
tissues. In the same period, oval red-blood
corpuscles were described by the Dutch nat-
uralist Jan Swammerdam (1637–1680),
who also discovered that a frog embryo
consists of globular particles
1,2
.
Another new world of extraordinary
variety, that of microorganisms, was
revealed by the exciting investigations of
another Dutchman, Antoni van Leeuwen-
hoek (1632–1723). The particles that he saw
under his microscope were motile and,
assuming that motility equates to life, he
went on to conclude, in a letter of 9 October
1676 to the Royal Society, that these parti-
cles were indeed living organisms. In a long
series of papers van Leeuwenhoek then
described many specific forms of these
microorganisms (which he called ‘‘animal-
cules’’), including protozoa and other uni-
cellular organisms
3–5
.
But the first description of the cell is gen-
erally attributed to Robert Hooke (1635–
1702), an English physicist who was also a
distinguished microscopist (see photo-
graphs below). In 1665 Hooke published
Micrographia
, the first important work
devoted to microscopical observation, and
showed what the microscope could mean
for naturalists. He described the micro-
scopic units that made up the structure of a
slice of cork and coined the term ‘‘cells’’ or
‘‘pores’’ to refer to these units.
Cella
is a
Latin word meaning ‘a small room’ and
Latin-speaking people applied the word
Cellulae
to the six-sided cells of the honey-
comb. By analogy, Hooke applied the term
‘‘cells’’ to the thickened walls of the dead
cells of the cork. Although Hooke used the
word differently to later cytologists (he
thought of the cork cells as passages for flu-
ids involved in plant growth), the modern
term ‘cell’ comes directly from his book
6
.
Bridge between life and ‘non-life’?
The existence of an entire world of micro-
scopic living beings was seen as a bridge
between inanimate matter and living organ-
isms that are visible to the naked eye
7
. This
seemed to support the old aristotelian doc-
trine of ‘spontaneous generation’, accord-
ing to which water or land bears the
potential to generate, ‘spontaneously’, dif-
ferent kinds of organism. This theory,
which implied a continuity between living
and non-living matter,
natura non facit sal-
tus
, was disproved by the masterful experi-
ments of the Italian naturalist Lazzaro
Spallanzani (1729–1799)
8
. He and other
researchers showed that an organism
derives from another organism(s) and that
a gap exists between inanimate matter and
life. (But it was a century later before the
idea of spontaneous generation was defini-
tively refuted, by Louis Pasteur, 1822–1895;
ref. 9.) As a consequence, the search for the
first elementary steps in the
scala naturae
was a motif in early-nineteenth-century
biological thought: what could be the mini-
mal unit carrying the potential for life?
W
Under the microscope: drawings of the instruments used by Robert Hooke (left) and the
cellular structure of cork according to Hooke (right) (reproduced from
Micrographia
, 1665).
‘‘there is one universal principle
of development for the
elementary parts of
organisms... and this principle is
in the formation of cells’’
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historical perspective
E14
NATURE CELL BIOLOGY | VOL 1 | MAY 1999 | cellbio.nature.com
The cell theory
Hints at the idea that the cell is the basic
component of living organisms emerged
well before 1838–39, which was when the
cell theory was officially formulated. Cells
were not seen as undifferentiated struc-
tures. Some cellular components, such as
the nucleus, had been visualized, and the
occurrence of these structures in cells of dif-
ferent tissues and organisms hinted at the
possibility that cells of similar organization
might underlie all living matter.
The abbot Felice Fontana (1730–1805)
glimpsed the nucleus in epithelial cells in
1781, but this structure had probably been
observed in animal and plant cells in the
first decades of the eighteenth century
7,10
.
The Scottish botanist Robert Brown (1773–
1858) was the first to recognize the nucleus
(a term that he introduced) as an essential
constituent of living cells (1831). In the
leaves of orchids Brown observed “a single
circular areola, generally somewhat more
opake than the membrane of the cell... This
areola, or nucleus of the cell as perhaps it
might be termed, is not confined to the epi-
dermis, being also found not only in the
pubescence of the surface... but in many
cases in the parenchyma or internal cells of
the tissue”
11
. Brown recognized the general
occurrence of the nucleus in these cells and
apparently thought of the organization of
the plant in terms of cellular constituents.
Meanwhile, technical improvements in
microscopy were being made. The principal
drawback of microscopes since van Leeu-
wenhoek’s time was what we now call ‘chro-
matic aberration’, which diminishes the
resolution power of the instrument at high
magnifications. Only in the 1830s were ach-
romatic microscopes introduced, allowing
more precise histological observations.
Improvements were also made in tissue-
preservation and -treating techniques.
In 1838, the botanist Matthias Jakob
Schleiden (1804–1881) suggested that
every structural element of plants is com-
posed of cells or their products
12
. The fol-
lowing year, a similar conclusion was
elaborated for animals by the zoologist
Theodor Schwann (1810–1882). He stated
that “the elementary parts of all tissues are
formed of cells” and that “there is one uni-
versal principle of development for the ele-
mentary parts of organisms... and this
principle is in the formation of cells”
13
. The
conclusions of Schleiden and Schwann are
considered to represent the official formu-
lation of ‘cell theory’ and their names are
almost as closely linked to cell theory as are
those of Watson and Crick with the struc-
ture of DNA
4,14
.
According to Schleiden, however, the
first phase of the generation of cells was the
formation of a nucleus of ‘‘crystallization’’
within the intracellular substance (which he
called the ‘‘cytoblast’’), with subsequent
progressive enlargement of such condensed
material to become a new cell. This theory
of ‘free cell formation’ was reminiscent of
the old ‘spontaneous generation’ doctrine
(although as an intracellular variant), but
was refuted in the 1850s by Robert Remak
(1815–1865), Rudolf Virchow (1821–1902)
and Albert Kölliker (1817–1905) who
showed that cells are formed through scis-
sion of pre-existing cells
7
. Virchow’s apho-
rism
omnis cellula e cellula
(every cell from a
pre-existing cell) thus became the basis of
the theory of tissue formation, even if the
mechanisms of nuclear division were not
understood at the time.
Cell theory stimulated a reductionistic
approach to biological problems and
became the most general structural para-
digm in biology. It emphasized the concept
of the unity of life and brought about the
concept of organisms as “republics of living
elementary units”
7
.
As well as being the fundamental unit of
life, the cell was also seen as the basic ele-
ment of pathological processes. Diseases
came to be considered (irrespective of the
causative agent) as an alteration of cells in
the organism. Virchow’s
Cellularpathologie
was the most important pathogenic concept
until, in this century, the theory of molecu-
lar pathology was developed.
Protoplasmic constituents
After Schleiden and Swann’s formulation of
cell theory, the basic constituents of the cell
were considered to be a wall or a simple
membrane, a viscous substance called ‘‘pro-
toplasm’’ (a name now replaced by Köl-
liker’s term ‘‘cytoplasm’’), and the nucleus.
It soon became evident that the protoplasm
was not a homogeneous fluid. Some biolo-
gists regarded its fine structure as fibrillary,
whereas others described a reticular, alveo-
lar or granular protoplasmic architecture.
This discrepancy resulted partly from arte-
factual and illusory images attributable to
fixation and staining procedures that
caused a non-homogeneous precipitation
of colloidal complexes.
However, some staining of real cellular
components led to the description of differ-
entiated elements, which were subsequently
identified. The introduction of the oil-
immersion lens in 1870, the development of
the microtome technique and the use of
new fixing methods and dyes greatly
improved microscopy. Towards the end of
the nineteenth century, the principal
organelles that are now considered to be
parts of the cell were identified. The term
‘‘ergastoplasm’’ (endoplasmic reticulum)
was introduced in 1897 (ref. 15); mitochon-
dria were observed by several authors and
named by Carl Benda (1857–1933) in 1898
(ref. 16), the same year in which Camillo
Golgi (1843–1926) discovered the intracel-
lular apparatus that bears his name
17
.
The protoplasm was not the only struc-
ture to have a heterogeneous appearance.
Within the nucleus, the nucleolus and a
stainable substance could be seen. Moreo-
ver, a number of structures (ribbons, bands
and threads) appeared during cell division.
As these structures could be heavily stained,
they were called ‘‘chromatin’’ by Walther
Flemming (1843–1905), who also intro-
duced the term ‘‘mitosis’’ in 1882 and gave
a superb description of its various
processes
18
. Flemming observed the longi-
tudinal splitting of salamander chromo-
somes (a term introduced only in 1888 by
Wilhelm Waldeyer, 1836–1921) during
metaphase and established that each half-
chromosome moves to the opposite pole of
the mitotic nucleus
18
. This process was also
observed in plants, providing further evi-
dence of the deep unity of the living world.
The neuron theory
There was, however, a tissue that seemed to
belie cell theory — nervous tissue. Because
of its softness and fragility, it was difficult to
handle and susceptible to deterioration. But
it was its structural complexity that pre-
vented a simple reduction to models
derived from the cell theory. Nerve-cell
bodies, nervous prolongations and nervous
fibres were observed in the first half of the
nineteenth century. However, attempts at
reconstructing a three-dimensional struc-
ture of the nervous system were frustrated
by the impossibility of determining the
exact relationships between cell bodies
(somas), neuronal protoplasmic processes
(dendrites) and nervous fibres.
A book by Karl Deiters (1834–1863),
published posthumously in 1865, contains
beautiful descriptions and drawings of
nerve cells studied by using histological
methods and microdissections made with
thin needles under the microscope (see
photographs on next page)
19
. Deiters’s
nerve cells were characterized by a soma,
dendrites and a nerve prolongation (axon)
which showed no branching. Kölliker, in
the fifth edition of his important book on
histology, published in 1867, proposed that
sensory and motor cells of the right and left
halves of the spinal cord were linked “by
anastomoses” (direct fusion)
20
.
In 1872, the German histologist Joseph
Gerlach (1820–1896) expanded Kölliker’s
view and proposed that, in all of the central
nervous system, nerve cells established
anastomoses with each other through a net-
work formed by the minute branching of
their dendrites. According to this concept,
the network or reticulum was an essential
element of grey matter that provided a sys-
tem for anatomical and functional commu-
nications, a protoplasmic continuum from
which nerve fibres originated
21
.
The most important breakthrough in
neurocytology and neuroanatomy came in
1873 when Golgi developed the ‘black reac-
tion’
22
, which he announced to a friend with
these few words, “I am delighted that I have
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NATURE CELL BIOLOGY | VOL 1 | MAY 1999 | | cellbio.nature.com
E15
found a new reaction to demonstrate, even
to the blind, the structure of the interstitial
stroma of the cerebral cortex. I let the silver
nitrate react with pieces of brain hardened
in potassium dichromate. I have obtained
magnificent results and hope to do even
better in the future.” This reaction pro-
vided, for the first time, a full view of a sin-
gle nerve cell and its processes, which could
be followed and analysed even when they
were at a great distance from the cell body.
The great advantage of this technique is
that, for reasons that are still unknown, a
precipitate of silver chromate randomly
stains black only a few cells (usually from 1
to 5%), and completely spares the others,
allowing individual elements to emerge
from the nervous puzzle.
Aided by the black reaction, Golgi dis-
covered the branching of the axon and
found that, contrary to Gerlach’s theory,
dendrites are not fused in a network. Golgi,
however, failed to go beyond the ‘reticular-
istic paradigm’. He believed that the
branched axons stained by his black reac-
tion formed a gigantic continuous network
along which the nervous impulse propa-
gated. In fact, he was misled by an illusory
network created by the superimposition
and the interlocking of axons of separate
cells. Golgi’s network theory was, however,
a substantial step forward because it
emphasized, for the first time, the function
of branched axons in connecting nerve cells.
According to Gerlach and Golgi, the
nervous system represented an exception to
cell theory, being formed not by independ-
ent cells but rather by a gigantic syncytium.
Its unique structure and function could well
justify an infringement of the general rule.
Matters changed quickly in the second
half of the 1880s. In October 1886, the Swiss
embryologist Wilhelm His (1831–1904) put
forward the idea that the nerve-cell body
and its prolongations form an independent
unit
23,24
. In discussing how the axons termi-
nate at the motor plate and how sensory
fibres originate at peripheral receptors such
as the Pacinian corpuscles, he suggested
that a separation of cell units might be true
of the central nervous system. The nervous
system began to be considered, like any
other tissue, as a sum of anatomically and
functionally independent cells, which inter-
act by contiguity rather than by continuity.
Similar conclusions were reached, at the
beginning of 1887, by another Swiss scien-
tist, the psychiatrist August Forel (1848–
1931), and, in 1891, Waldeyer introduced
the term ‘‘neurons’’ to indicate independ-
ent nerve cells
25,26
. Thereafter, cell theory as
applied to the nervous system became
known as the ‘neuron theory’.
Ironically, it was by using Golgi’s black
reaction that the Spanish neuroanatomist
Santiago Ramón y Cajal (1852–1934) became
the main supporter and indefatigable cham-
pion of the neuron theory. His neuroanatom-
ical investigations contributed to the
foundations of the basic concepts of modern
neuroscience. However, definitive proof of
the neuron theory was obtained only after the
introduction of the electron microscope,
which allowed identification of synapses
between neurons
21
. When the nervous system
was also found to be made up of independent
units, cell theory obtained its final triumph.
The missing link
With the theory of evolution, the cell theory
is the most important generalization in
biology. There is, however, a missing link
between these theories that prevents an
even more general and unifying concept of
life. This link is the initial passage from
inorganic matter to the primordial cell and
its evolution — the origin of life. If it ever-
proves possible to recreate in the laboratory
the prebiotic physicochemical conditions
required for the spontaneous generation of
life, the link between these two generaliza-
tions will be finally at hand and a unifying
paradigm will explain all biological phe-
nomena. The theory of spontaneous gener-
ation would then be vindicated.
Paolo Mazzarello is in the Istituto di Genetica
Biochimica ed Evoluzionistica – CNR, Via
Abbiategrasso 207, 27100 Pavia, Italy.
e-mail: mazzarello@igbe.pv.cnr.it
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Left, drawing of an isolated neuron by Karl Deiters (reproduced from ref. 19). Right,
isolated neuron obtained with the Deiters microdissection technique, using thin needles
under the microscope (courtesy of G. Merico). The long axon in both cases does not
appear ramified because branchings were disrupted during the procedure.
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Flow cytometers are well-established tools with fundamental importance in biology and medicine to examine and identify cell populations, density, size distributions, compositions, and disease diagnosis and monitoring. Still, these devices are expensive with a low level of integration for sample preparation. Miniaturized microfluidic cytometers, i.e., microcytometers, for monitoring cells in a wide range of biological samples are currently being developed, providing more affordable and integrated solutions. Several detection methods have been developed and applied in microcytometers such as electrical, optical, and magnetic sensing techniques, which are integrated with microfluidic technology. Magnetic microcytometers present several advantages when compared to optical systems such as the fact that these devices provide more stable labeling by using magnetic nanoparticles (MNPs) or beads (MBs) instead of fluorophores. In this chapter, we explore the evolution of the automation of whole cell detection and enumeration that led to the development of microcytometers and particularly examine the anatomy of magnetic microcytometers applied to cancer research. We then give an overview of the challenges of Circulating Tumor Cells enrichment and enumeration, and the progress of magnetic microcytometers in this field.
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The grand challenge of engineering a minimal artificial cell provides a controllable framework for studying the biochemical principles of life. Artificial cells contribute to an increased understanding of complex synthetic systems with life-like properties and provide opportunities to create autonomous cell-like materials. Recent efforts to develop life-like artificial cells by bottom-up approaches involve mimicking the behavior of lipid membranes to recapitulate fundamental cellular processes. This review describes the recent progress in engineering biomimetic artificial minimal cells and recently developed chemical strategies to drive de novo membrane formation from simple synthetic precursors. In the end, we briefly point out the challenges and possible future directions in the development of artificial cells.
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Immunology and Cell Biology focuses on the general functioning of the immune system in its broadest sense, with a particular emphasis on its cell biology. Areas that are covered include but are not limited to: Cellular immunology, Innate and adaptive immunity, Immune responses to pathogens,Tumour immunology,Immunopathology, Immunotherapy, Immunogenetics, Immunological studies in humans and model organisms (including mouse, rat, Drosophila etc)
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The appearance of volume 16 of the Dictionary of Scientific Biography (DSB), the index, marks an important milestone in the life of the major reference tool in the history of science. Since the appearance of volume one in 1970, the DSB has become an indispensable tool for anyone seeking information about the lives and work of the scientists of the past. With over 6,000 sets sold it represents a major addition to the genre of multi-volumed biographical dictionaries.