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{{Short description|Biology of cells}}
{{pp|small=yes}}
[[File:HeLa cells stained with Hoechst 33258.jpg|thumb|right|Human [[cancer cell]]s with nuclei (specifically the DNA) stained blue. The central and rightmost cell are in [[interphase]], so the entire nuclei are labeled. The cell on the left is going through [[mitosis]] and its DNA has condensed.]]

In [[biology]], '''cell theory''' is a [[scientific theory]] first formulated in the mid-nineteenth century, that living [[organism]]s are made up of [[Cell (biology)|cell]]s, that they are the basic structural/organizational unit of all organisms, and that all cells come from pre-existing cells. Cells are the basic unit of structure in all living organisms and also the basic unit of [[reproduction]].

Cell theory has traditionally been accepted as the governing theory of all [[life]],<ref name=":0">{{Cite book |last1=Schaefer |first1=G. Bradley |title=Medical Genetics: An Integrated Approach |last2=Thompson, Jr. |first2=James N. |publisher=McGraw Hill |year=2017 |isbn=978-1259095191 |language=English |chapter=Chapter 1: Genetics: Unity and Diversity |type=Digital}}</ref> but some biologists consider [[non-cellular life|non-cellular entities]] such as [[virus]]es living organisms<ref>{{Cite journal |last1=Koonin |first1=Eugene V. |last2=Starokadomskyy |first2=Petro |date=November 2016 |title=Are viruses alive? The replicator paradigm sheds decisive light on an old but misguided question |journal=Studies in History and Philosophy of Science Part C: Studies in History and Philosophy of Biological and Biomedical Sciences |language=en |volume=59 |pages=125–134 |doi=10.1016/j.shpsc.2016.02.016 |pmc=5406846 |pmid=26965225}}</ref> and thus disagree with the universal application of cell theory to all forms of life.

==History==

With continual improvements made to [[microscope]]s over time, magnification technology became advanced enough to discover cells. This discovery is largely attributed to [[Robert Hooke]], and began the scientific study of cells, known as [[cell biology]]. When observing a piece of cork under the scope, he was able to see pores. This was shocking at the time as it was believed no one else had seen these. To further support his theory, [[Matthias Schleiden]] and [[Theodor Schwann]] both also studied cells of both animal and plants. What they discovered were significant differences between the two types of cells. This put forth the idea that cells were not only fundamental to plants, but animals as well.<ref>National Geographic Society. (2019, May 22). "[https://education.nationalgeographic.org/resource/history-cell-discovering-cell/ History of the Cell: Discovering the Cell]". Retrieved November 16, 2024.</ref>

== Microscopes==

{{Further|Microscope#Rise of modern light microscopes}}

The discovery of the cell was made possible through the invention of the microscope. In the first century BC, Romans were able to make glass. They discovered that objects appeared to be larger under the [[glass]]. The expanded use of lenses in [[eyeglasses]] in the 13th century probably led to wider spread use of [[Optical microscope#Simple microscope|simple microscopes]] ([[magnifying glass]]es) with limited magnification. [[Optical microscope#Compound microscope|Compound microscopes]], which combine an [[Objective (optics)|objective lens]] with an [[eyepiece]] to view a [[real image]] achieving much higher magnification, first appeared in Europe around 1620. In 1665, Robert Hooke used a microscope about six inches long with two convex lenses inside and examined specimens under reflected light for the observations in his book ''[[Micrographia]]''. Hooke also used a simpler microscope with a single lens for examining specimens with directly transmitted light, because this allowed for a clearer image.<ref name=Gest/>

An extensive microscopic study was done by [[Anton van Leeuwenhoek]], a draper who took the interest in microscopes after seeing one while on an apprenticeship in Amsterdam in 1648. At some point in his life before 1668, he was able to learn how to grind lenses. This eventually led to Leeuwenhoek making his own unique microscope. He made one with a single lens. He was able to use a single lens that was a small glass sphere but allowed for a magnification of 270x. This was a large progression since the magnification before was only a maximum of 50x. After Leeuwenhoek, there was not much progress in microscope technology until the 1850s, two hundred years later. [[Carl Zeiss]], a German engineer who manufactured microscopes, began to make changes to the lenses used. But the optical quality did not improve until the 1880s when he hired [[Otto Schott]] and eventually [[Ernst Abbe]].<ref name="Unifying Concept"/>

Optical microscopes can focus on objects the size of a [[wavelength]] or larger, giving restrictions still to advancement in discoveries with objects smaller than the wavelengths of [[visible light]]. The development of the [[electron microscope]] in the 1920s made it possible to view objects that are smaller than optical wavelengths, once again opening up new possibilities in science.<ref name="Unifying Concept"/>

<gallery mode=packed widths=150px heights=200px>
File:Leeuwenhoek Microscope.png|A reproduction of Anton van Leeuwenhoek's 17th century microscope with magnification of up to 300x<ref name=funsci>{{cite web |url=http://www.funsci.com/fun3_en/usph/usph.htm |title=A glass-sphere microscope |publisher=Funsci.com |access-date=13 June 2010 |archive-url=https://web.archive.org/web/20100611200259/http://www.funsci.com/fun3_en/usph/usph.htm |archive-date=11 June 2010 |url-status=dead }}</ref>
File:Hooke-microscope.png|Robert Hooke's microscope setup, as depicted in ''Micrographia''
</gallery>

== Discovery of cells ==

[[File:Cork Micrographia Hooke.png|thumb|upright|Drawing of the structure of [[Cork cambium|cork]] by [[Robert Hooke]] that appeared in ''[[Micrographia]]'']]

The cell was first discovered by [[Robert Hooke]] in 1665, which can be found to be described in his book ''[[Micrographia]]''. In this book, he gave 60 observations in detail of various objects under a coarse, compound microscope. One observation was from very thin slices of bottle [[Cork cambium|cork]]. Hooke discovered a multitude of tiny pores that he named "cells". This came from the Latin word ''Cella'', meaning ‘a small room’ like monks lived in, and also ''Cellulae'', which meant the six-sided cell of a honeycomb. However, Hooke did not know their real structure or function. What Hooke had thought were cells, were actually empty cell walls of plant tissues. With microscopes during this time having a low magnification, Hooke was unable to see that there were other internal components to the cells he was observing. Therefore, he did not think the "cellulae" were alive. His cell observations gave no indication of the [[Cell nucleus|nucleus]] and other [[organelle]]s found in most living cells. In ''Micrographia'', Hooke also observed mould, bluish in color, found on leather. After studying it under his microscope, he was unable to observe "seeds" that would have indicated how the mould was multiplying in quantity. This led to Hooke suggesting that spontaneous generation, from either natural or artificial heat, was the cause. Since this was an old [[Aristotelian physics|Aristotelian theory]] still accepted at the time, others did not reject it and was not disproved until [[Anton van Leeuwenhoek|Leeuwenhoek]] later discovered that generation was achieved otherwise.<ref name="Gest">{{Cite journal |last1=Gest |first1=H. |year=2004 |title=The discovery of microorganisms by Robert Hooke and Antoni Van Leeuwenhoek, fellows of the Royal Society |journal=Notes and Records of the Royal Society of London |volume=58 |issue=2 |pages=187–201 |doi=10.1098/rsnr.2004.0055 |pmid=15209075 |s2cid=8297229}}</ref>

[[Anton van Leeuwenhoek]] is another scientist who saw these cells soon after Hooke did. He made use of a microscope containing improved lenses that could magnify objects 270-fold. Under these microscopes, Leeuwenhoek found motile objects. In a letter to [[The Royal Society]] on October 9, 1676, he states that [[motility]] is a quality of life therefore these were living organisms. Over time, he wrote many more papers which described many specific forms of [[microorganisms]]. Leeuwenhoek named these "[[animalcules]]," which included [[protozoa]] and other unicellular organisms, like [[bacteria]]. Though he did not have much formal education, he was able to identify the first accurate description of red blood cells and discovered bacteria after gaining interest in the sense of taste that resulted in Leeuwenhoek to observe the tongue of an ox, then leading him to study "pepper water" in 1676. He also found for the first time the [[sperm cells]] of animals and humans. Once discovering these types of cells, Leeuwenhoek saw that the fertilization process requires the sperm cell to enter the [[egg cell]]. This put an end to the previous theory of [[spontaneous generation]]. After reading letters by Leeuwenhoek, Hooke was the first to confirm his observations that were thought to be unlikely by other contemporaries.<ref name="Gest" />

Cells in animal tissues were observed later than those in plants because their [[Tissue (biology)|tissues]] are fragile and difficult to study. Biologists believed that there was a fundamental unit to life, but until [[Henri Dutrochet]] were unclear what it was. Besides stating “the cell is the fundamental element of organization”, Dutrochet claimed that cells were also a physiological unit.<ref>Dutrochet, Henri (1824) [https://books.google.com/books?id=KwQOAAAAQAAJ "Recherches anatomiques et physiologiques sur la structure intime des animaux et des vegetaux, et sur leur motilite, par M.H. Dutrochet, avec deux planches"]</ref>

In 1804, [[Karl Rudolphi]] and [[Johann Heinrich Friedrich Link|J. H. F. Link]] were awarded the prize for "solving the problem of the nature of cells", meaning they were the first to prove that cells had independent [[cell walls]] by the [[University of Göttingen|Königliche Societät der Wissenschaft]] (Royal Society of Science), Göttingen.<ref>[http://www.mathnat.uni-rostock.de/geschichte/kalenderblatt/kalenderblatt-dezember-2013/ Kalenderblatt Dezember 2013 – Mathematisch-Naturwissenschaftliche Fakultät – Universität Rostock]. Mathnat.uni-rostock.de (2013-11-28). Retrieved on 2015-10-15.</ref> Before, it had been thought that cells shared walls and the fluid passed between them this way.

== Cell theory ==

[[File:PSM V22 D156 Matthias Jacob Schleiden.jpg|thumb|[[Matthias Jakob Schleiden]] (1804–1881)]]

[[File:Schwann Theodore.jpg|thumb|upright|[[Theodor Schwann]] (1810–1882)]]

Credit for developing cell theory is usually given to two scientists: [[Theodor Schwann]] and [[Matthias Jakob Schleiden]].<ref>{{cite book |last=Sharp |first=L. W. |year=1921 |url=https://archive.org/details/introductiontocy032473mbp |title=Introduction To Cytology |location=New York |publisher=McGraw Hill Book Company Inc.}}</ref> While [[Rudolf Virchow]] contributed to the theory, he is not as credited for his attributions toward it. In 1839, Schleiden suggested that every structural part of a plant was made up of cells or the result of cells. He also suggested that cells were made by a crystallization process either within other cells or from the outside.<ref>{{cite journal|author=Schleiden, M. J. |year=1839|title= Beiträge zur Phytogenesis|journal=Archiv für Anatomie, Physiologie und wissenschaftliche Medicin|volume=1838|pages=137–176|url=https://www.biodiversitylibrary.org/item/49861#page/347/mode/1up}}</ref> However, this was not an original idea of Schleiden. He claimed this theory as his own, though [[Barthelemy Charles Joseph Dumortier|Barthelemy Dumortier]] had stated it years before him. This crystallization process is no longer accepted with [[#Modern interpretation|modern cell theory]]. In 1839, [[Theodor Schwann]] states that along with plants, animals are composed of cells or the product of cells in their structures.<ref>{{cite book |last=Schwann |first=T. |year=1839 |title=Mikroskopische Untersuchungen über die Uebereinstimmung in der Struktur und dem Wachsthum der Thiere und Pflanzen |publisher=Sander |place=Berlin |url=http://www.deutschestextarchiv.de/book/show/schwann_mikroskopische_1839}}</ref> This was a major advance in the field of biology since little was known about animal structure up to this point compared to plants. From these conclusions about plants and animals, two of the three tenets of cell theory were postulated.

:1. All living organisms are composed of one or more cells
:2. The cell is the most basic unit of life

Schleiden's theory of free cell formation through crystallization was refuted in the 1850s by [[Robert Remak]], [[Rudolf Virchow]], and [[Albert Kolliker]].<ref name="Unifying Concept">{{Cite journal| doi=10.1038/8964| pmid=10559875| year=1999| last1=Mazzarello| first1=P.| journal=Nature Cell Biology| volume=1| issue=1| url=http://newburyparkhighschool.net/barra/classes/bio_cp/handout_cell%20theory%20reading_students.doc| pages=E13–5| title=A unifying concept: the history of cell theory| s2cid=7338204| url-status=dead| archive-url=https://web.archive.org/web/20150603062810/http://newburyparkhighschool.net/barra/classes/bio_cp/handout_cell%20theory%20reading_students.doc| archive-date=2015-06-03| url-access=subscription}}</ref> In 1855, Rudolf Virchow added the third tenet to cell theory. In Latin, this tenet states ''Omnis cellula e cellula''. This translated to:

:3. All cells arise only from pre-existing cells

However, the idea that all cells come from pre-existing cells had already been proposed by Robert Remak; it has been suggested that Virchow plagiarized Remak.<ref>{{cite journal |last=Silver |first=G. A. |title=Virchow, the heroic model in medicine: health policy by accolade |journal=[[American Journal of Public Health]] |year=1987 |volume=77 |issue=1 |pmid=3538915 |pmc=1646803 |doi=10.2105/AJPH.77.1.82 |pages=82–88}}</ref> Remak published observations in 1852 on cell division, claiming Schleiden and Schawnn were incorrect about generation schemes. He instead said that [[binary fission]], which was first introduced by Dumortier, was how reproduction of new animal cells were made. Once this tenet was added, classical cell theory was complete.

== Modern interpretation ==

The generally accepted parts of modern cell theory include:

# All known living things are made up of one or more cells<ref>Wolfe</ref>
# All living cells arise from pre-existing cells by division. 
# The cell is the fundamental unit of structure and function in all living organisms.<ref>Wolfe, p. 5</ref>
# The activity of an organism depends on the total activity of independent cells.<ref name="Müller-Wille2010">{{cite journal|last1=Müller-Wille|first1=Staffan|title=Cell theory, specificity, and reproduction, 1837–1870|journal=Studies in History and Philosophy of Science Part C: Studies in History and Philosophy of Biological and Biomedical Sciences|volume=41|issue=3|year=2010|pages=225–231|issn=1369-8486|doi=10.1016/j.shpsc.2010.07.008|pmid=20934643|pmc=4353839}}</ref>
# Energy flow ([[metabolism]] and [[biochemistry]]) occurs within cells.
# Cells contain [[DNA]] which is found specifically in the chromosome and [[RNA]] found in the cell nucleus and cytoplasm.<ref>Wolfe, p. 8</ref>
# All cells are basically the same in chemical composition in organisms of similar species.

== Opposing concepts ==

The cell was  first discovered by Robert Hooke in 1665 using a microscope. The first cell theory is credited to the work of [[Theodor Schwann]] and [[Matthias Jakob Schleiden]] in the 1830s. In this theory the internal contents of cells were called [[protoplasm]] and described as a jelly-like substance, sometimes called living jelly. At about the same time, [[colloidal chemistry]] began its development, and the concepts of [[bound water]] emerged. A [[colloid]] being something between a [[Solution (chemistry)|solution]] and a [[Suspension (chemistry)|suspension]], where [[Brownian motion]] is sufficient to prevent [[sedimentation]].{{citation needed|date=September 2023}}
The idea of a [[semipermeable membrane]], a barrier that is permeable to [[solvent]] but impermeable to solute [[molecules]] was developed at about the same time. The term [[osmosis]] originated in 1827 and its importance to [[physiological]] phenomena realized, but it wasn’t until 1877, when the [[botanist]] [[Pfeffer]] proposed the [[History of cell membrane theory|membrane theory]] of [[cell physiology]]. In this view, the cell was seen to be enclosed by a thin surface, the [[plasma membrane]], and cell water and solutes such as a [[potassium]] [[ion]] existed in a physical state like that of a [[dilute solution]]. In 1889 Hamburger used [[hemolysis]] of [[erythrocytes]] to determine the permeability of various solutes. By measuring the time required for the cells to swell past their elastic limit, the rate at which solutes entered the cells could be estimated by the accompanying change in cell volume. He also found that there was an apparent nonsolvent volume of about 50% in red blood cells and later showed that this includes water of hydration in addition to the protein and other nonsolvent components of the cells.{{citation needed|date=September 2023}}

=== Membrane and bulk phase theories ===

Two opposing concepts developed within the context of studies on [[osmosis]], permeability, and electrical properties of cells.<ref>{{cite book|last=Ling|first=Gilbert N.|title=In search of the physical basis of life|date=1984|publisher=Plenum Press|location=New York|isbn=0306414090}}</ref> The first held that these properties all belonged to the plasma membrane whereas the other predominant view was that the [[protoplasm]] was responsible for these properties. The [[History of cell membrane theory|membrane theory]] developed as a succession of ad-hoc additions and changes to the theory to overcome experimental hurdles. Overton (a distant cousin of [[Charles Darwin]]) first proposed the concept of a lipid (oil) plasma membrane in 1899. The major weakness of the [[lipid membrane]] was the lack of an explanation of the high permeability to water, so Nathansohn (1904) proposed the mosaic theory. In this view, the membrane is not a pure lipid layer, but a mosaic of areas with lipid and areas with semipermeable gel. Ruhland refined the mosaic theory to include pores to allow additional passage of small molecules. Since membranes are generally less permeable to [[anions]], [[Leonor Michaelis]] concluded that [[ions]] are [[adsorbed]] to the walls of the pores, changing the permeability of the pores to ions by [[electrostatic repulsion]]. Michaelis demonstrated the [[membrane potential]] (1926) and proposed that it was related to the distribution of ions across the membrane.<ref>{{Cite journal|last1=Michaelis|first1=L.|title=Contribution to the Theory of Permeability of Membranes for Electrolytes|journal=The Journal of General Physiology|volume=8|issue=2 |pages=33–59|year=1925|pmid=19872189|pmc=2140746|doi=10.1085/jgp.8.2.33}}</ref>

Harvey and Danielli (1939) proposed a [[lipid bilayer]] membrane covered on each side with a layer of protein to account for measurements of surface tension. In 1941 Boyle and Conway showed that the membrane of frog muscle was permeable to both {{chem|K|+}} and {{chem|Cl|-}}, but apparently not to {{chem|Na|+}}, so the idea of electrical charges in the pores was unnecessary since a single critical pore size would explain the permeability to {{chem|K|+}}, {{chem|H|+}}, and {{chem|Cl|-}} as well as the impermeability to {{chem|Na|+}}, {{chem|Ca|+}}, and {{chem|Mg|2+}}.
Over the same time period, it was shown (Procter and Wilson, 1916) that gels, which do not have a semipermeable membrane, would swell in dilute solutions.{{citation needed|date=September 2023}}

[[Jacques Loeb]] (1920) also studied [[gelatin]] extensively, with and without a membrane, showing that more of the properties attributed to the plasma membrane could be duplicated in [[gels]] without a membrane. In particular, he found that an electrical potential difference between the gelatin and the outside medium could be developed, based on the {{chem|H|+}} concentration. Some criticisms of the membrane theory developed in the 1930s, based on observations such as the ability of some cells to swell and increase their surface area by a factor of 1000. A lipid layer cannot stretch to that extent without becoming a patchwork (thereby losing its barrier properties). Such criticisms stimulated continued studies on protoplasm as the principal agent determining cell permeability properties.{{citation needed|date=September 2023}}

In 1938, Fischer and Suer proposed that water in the protoplasm is not free but in a chemically combined form—the protoplasm represents a combination of protein, salt and water—and demonstrated the basic similarity between swelling in living tissues and the swelling of gelatin and [[fibrin]] gels. Dimitri Nasonov (1944) viewed proteins as the central components responsible for many properties of the cell, including electrical properties.
By the 1940s, the bulk phase theories were not as well developed as the membrane theories. In 1941, Brooks and Brooks published a monograph, "The Permeability of Living Cells", which rejects the bulk phase theories.{{citation needed|date=September 2023}}

===Steady-state membrane pump concept ===

With the development of [[radioactive tracers]], it was shown that cells are not impermeable to {{chem|Na|+}}. This was difficult to explain with the membrane barrier theory, so the sodium pump was proposed to continually remove {{chem|Na|+}} as it permeates cells. This drove the concept that cells are in a state of [[dynamic equilibrium]], constantly using energy to maintain [[ion gradient]]s. In 1935, {{ill|Karl Lohmann (chemist)|de|Karl Lohmann (Biochemiker)|lt=Karl Lohmann}} discovered [[Adenosine triphosphate|ATP]] and its role as a source of energy for cells, so the concept of a metabolically-driven [[sodium pump]] was proposed.{{citation needed|date=September 2023}}
The success of [[Alan Lloyd Hodgkin|Hodgkin]], [[Andrew Huxley|Huxley]], and [[Bernard Katz|Katz]] in the development of the membrane theory of cellular membrane potentials, with differential equations that modeled the phenomena correctly, provided further support for the membrane pump hypothesis.{{citation needed|date=September 2023}}
 
The modern view of the plasma membrane is of a fluid lipid bilayer that has protein components embedded within it. The structure of the membrane is now known in great detail, including 3D models of many of the hundreds of different proteins that are bound to the membrane.
These major developments in cell physiology placed the membrane theory in a position of dominance and stimulated the imagination of most physiologists, who now apparently accept the theory as fact—there are, however, a few dissenters.{{citation needed|date=March 2020}}

=== Reemergence of bulk phase theories ===

In 1956, Afanasy S. Troshin published a book, ''The Problems of Cell Permeability'', in Russian, in which he showed that permeability was of secondary importance in determining the patterns of equilibrium between the cell and its environment. Troshin showed that cell water decreased in solutions of galactose or urea although these compounds did slowly permeate cells. Since the membrane theory requires an impermanent solute to sustain cell shrinkage, these experiments cast doubt on the theory. Others questioned whether the cell has enough energy to sustain the sodium/potassium pump. Such questions became even more urgent as dozens of new metabolic pumps were added as new chemical gradients were discovered.{{citation needed|date=September 2023}}

In 1962, [[Gilbert Ling]] became the champion of the bulk phase theories and proposed his association-induction hypothesis of living cells.<ref>{{Cite journal |last=Ling |first=Gilbert |date=2007 |title=Nano-protoplasm: the ultimate unit of life |journal=Physiological Chemistry and Physics and Medical NMR |volume=39 |issue=2 |pages=111–234 |issn=0748-6642 |pmid=19256352}}</ref><ref>{{Cite journal |last1=Ling |first1=G. N. |last2=Ochsenfeld |first2=M. M. |date=1965 |title=Studies on the ionic permeability of muscle cells and their models |journal=Biophysical Journal |volume=5 |issue=6 |pages=777–807 |doi=10.1016/S0006-3495(65)86752-2 |issn=0006-3495 |pmc=1367903 |pmid=5884012}}</ref><ref>{{Cite book |last=Ling |first=Gilbert Ning |url=https://books.google.com/books?id=nr3PAAAAMAAJ |title=A Physical Theory of the Living State: The Association-induction Hypothesis |publisher=Blaisdell Publishing Company |year=1962 |language=en}}</ref>

== See also ==

* [[Cell adhesion]]
* [[Cytoskeleton]]
* [[Cell biology]]
* [[Cellular differentiation]]
* [[Germ theory of disease]]
* [[Membrane models]]

== References ==

{{Reflist}}

== Bibliography ==

* {{cite journal |last=Tavassoli |first=M. |title=The cell theory: a foundation to the edifice of biology |journal=American Journal of Pathology |volume=98 |issue=1 |page=44 |date=1980 |pmid=6985772 |pmc=1903404 }}
* {{cite journal |last=Turner |first=W. |title=The Cell Theory Past and Present |journal=Journal of Anatomy and Physiology |volume=24 |issue=Pt 2 |pages=253–87 |date=January 1890 |pmid=17231856 |pmc=1328050 }}
* {{cite book |last=Wolfe |first=Stephen L. |title=Biology of the cell |url=https://books.google.com/books?id=gRo2AAAAMAAJ|year=1972|publisher=Wadsworth Pub. Co.|isbn=978-0-534-00106-3}}

== External links ==

* {{cite web |last=Mallery |first=C. |url=http://fig.cox.miami.edu/~cmallery/150/unity/cell.text.htm |title=Cell Theory |date=2008-02-11 |access-date=2008-11-25 |archive-date=2018-12-25 |archive-url=https://web.archive.org/web/20181225105148/http://fig.cox.miami.edu/~cmallery/150/unity/cell.text.htm%20 |url-status=dead }}
* {{cite web |url=http://www.biology.arizona.edu/cell_bio/tutorials/cells/cells3.html |title=Studying Cells Tutorial |year=2004 |access-date=2008-11-25}}

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