The cell’s journey: from metaphoricalto literal factoryAndrew Reynolds

Department of Philosophy and Religious Studies, Cape Breton University, Sydney, Nova Scotia, Canada B1P 6L2

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The concept of the cell has been based on metaphorsince its inception, and the history of cell theory hascontinued to rely on metaphor and analogy. In the nine-teenth century, cells were most popularly conceivedeither as building stones or elementary autonomousorganisms from which larger organisms are composed.With advances in physiology and the rise of modernbiochemistry in the early twentieth century, the chemi-cal factory or laboratory became the dominant metaphorfor this biological unit. Today in the twenty-first century,the metaphorical imagery has become a reality, withcells acting as chemical factories for the synthesis ofcommercially valuable bio-products. The history of thecell shows how metaphors act as conceptual tools, withparticular strengths for facilitating different sorts ofquestions and experimental techniques.

In the beginningThe proposition that all living things are composed of smallfundamental vital units, otherwise known as cells, ranksnext to Darwin’s theory of evolution as one of the greatunifying thesesofbiological science.But likemost importantconcepts in the history of science the cell has undergone aninteresting evolution or development of its own. Today it isnot at all unusual to run across some version of the followingdescription of what scientists understand a cell to be:

‘All living things are made from cells, the chemicalfactories of life. Cells act as chemical factories, takingin materials from the environment, processing them,and producing ‘‘finished goods’’ to be used for the cell’sown maintenance and for that of the larger organismof which they may be part. In a complex cell,materials are taken in through specialized receptors(‘‘loading docks’’), processed by chemical reactionsgoverned by a central information system (‘‘the frontoffice’’), carried around to various locations (‘‘assem-bly lines’’) as the work progresses, and finally sentback via those same receptors into the larger organ-ism. Far from being a shapeless blob of protoplasm,the cell is a highly organized, busy place, whosemanydifferent parts must work together to keep the wholefunctioning’ [1].

It is tempting to dismiss such overt metaphoricallanguage as fulfilling a purely communicative or rhetoricalrole, existing only within the confines of the popular science

Corresponding author: Reynolds, A. (Andrew_Reynolds@capebretonu.ca).Available online 29 June 2007.

www.sciencedirect.com 0160-9327/$ – see front matter � 2007 Elsevier Ltd. All rights reserve

genre.But thiswould beamistake.Thehistory of cell theoryoffers a rich lesson in the use of metaphor and analogy inscientific thought.Thefirst account of the cell likened it toanempty room, but it has also been conceptualized through themetaphors of a building stone (Baustein), an elementaryorganism (Elementarorganismus), a chemical laboratory orfactory, amotor and amachine. Each of theseways of seeingthe cell helped to emphasize certain features under inves-tigation and served to promote particular methodologicalapproaches to further studies. Some metaphors are prim-arily morphological and concerned with structure (forinstance, the cell as empty chamber or building stone) whileothers are primarily physiological (the cell as chemicallaboratory or factory, electric motor or machine).

The elementary organismThe dominant metaphor in the second half of the nine-teenth century described the body as a ‘society’ or ‘state’ ofcells (Zellenstaat). Cells were ‘citizens’ arranged into sep-arate classes or professions according to their functions,together making up the ‘economy of the organism’. Thereare hints of this metaphor in the writings of MatthiasSchleiden (1804–1881) and Theodor Schwann (1810–1882), who are credited with founding the cell theory inthe 1830s (Figure 1). It was, however, the German anat-omist and pathologist Rudolf Virchow (1821–1902) whoexplicitly introduced such language (Figure 2). Using thephysiologist Ernst Brucke’s (1819–1892) proposal that cellsbe considered ‘elementary organisms’ (itself an analogy tothe way the chemical elements came together to form com-plex molecules), evolutionary zoologist Ernst Haeckel(1834–1919) gave the cell-statemetaphor aDarwinian spin:higher plants and animals, he argued, were evolved intocolonies of these elemental organisms and humans werelittlemore thana complex colony of protozoan-like cellswitha highly evolved division of labor [2]. This ‘theory of the cellstate’, as it was called, was of great significance to the fieldsof anatomy, embryology, phylogenetics and physiology [3].Early in the twentieth century, this notion was strength-ened still further, as tissue-culture techniques demon-strated that cells removed from the body of a livinganimal could continue to survive and reproduce in isolation.

Yet the thesis that the organism is merely the sum of itscellular parts did not go unchallenged. Criticisms fromprominent figures like Thomas H. Huxley (1825–1895),Anton de Bary (1831–1888), Julius Sachs (1832–1897),Charles Otis Whitman (1842–1910), Adam Sedgwick (anembryologist and grandson of the celebrated geologist;1854–1918) and Clifford Dobell (1886–1949) fell into two

d. doi:10.1016/j.endeavour.2007.05.005

Figure 1. Cells arranged according to their function. Plate 1 1of Matthias Schleiden’s Principles of Scientific Botany of 1849 (British Library).

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Figure 2. Title page of Rudolf Virchow’s Cellularpathologie of 1862 (British

Library).

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main categories [4]: first, embryological evidencesuggested that the growth and development of an organismcan occur without the formation of new cells throughdivision; second, the existence of protoplasmic connectionsbetween cells (‘plasmodesmata’) andmultinucleate massesof protoplasm (‘syncytia’) challenged the claim that organ-isms are aggregates of distinct, autonomous cells. Furtherevidence from embryology showed that the ‘fate’ of anembryonic cell could be influenced by its location andcontact with neighboring cells (a process called ‘induction’).For some, thismade it difficult to see how higher plants andanimals could bemerely complex cell colonies or ‘states’, andthey adopted a more ‘holistic’ interpretation of ontogeny.This holistic or ‘organismal’ perspective, as University ofChicago zoologist Charles O. Whitman dubbed it, becamefamously associated with the slogan of Anton De Bary, whosaid, with regard to plants, that it is the plant that makescells not the cells that make the plant [5].

Yet others, like William Emerson Ritter (1856–1944),an American zoologist and director of the Scripps Institu-tion for Biological Research at the University of California,La Jolla (now the Scripps Institute of Oceanography),

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objected to the evidence from cell-culture experiments,arguing that they were merely artificial manipulations.When it came to the ‘natural order of things’, suggestedRitter, the cell was typically subordinated to the organismas a whole. In The Unity of the Organism, or the Organis-mal Conception of Life (1919), he argued that in vitro tissuecultures were unnatural and should be thought of asuberlebende Gewebe (‘surviving tissues’) [6]. By contrast,American cytologist Edmund BeecherWilson (1856–1939),a firm defender of the elemental organism, preferred to seecultured cells as ‘emancipated’ [7].

The rise of the chemical factoryRitter insisted that biologists approach their studies fromthe perspective of the organism as a whole and that thecells should be regarded as ‘organs of the organism just asmuscles and glands and hearts and eyes and feet are soregarded’ [8]. Biochemical studies of the cell, he noted,suggested it should be regarded as an ‘organized labora-tory’ [9]. This appealed to Ritter since, unlike an elemen-tary organism, a laboratory does not run itself or exist forits own sake but is an instrument used by the total organ-ism for its own ends. And it is at this time – the earlytwentieth century – when biochemical investigations cameto dominate the attention of cytologists that the descriptionof the cell as a chemical factory began to rise in popularity.

This metaphor already had a distinguished pedigree. In1851, the Anglo-Belgian zoologist Henri Milne-Edwards(1800–1885) compared the body of a living organism to aworkshop (‘un atelier’) [10] and, in 1858, Virchow remarkedthat ‘starch is transformed into sugar in the plant andanimal just as it is in a factory’ [11]. This comparison musthave seemed rather natural in the wake of the laboratorysynthesis of urea by the German chemist Friedrich Wohler(1800–1882) in 1824.

At the time Wohler achieved this chemical feat, he wasworking with Justus Liebig (1803–1873), who subsequentlyexploited the technique to synthesize other organic com-pounds, such as dyes for the textile industry that helped tomake the German economy amongst the strongest of theperiod (Figure 3). The nineteenth-century historian Theo-dore Merz noted that ‘physiology and economics joinedhands’ in the Victorian period through the concepts of the‘autonomy of the cell’ and the ‘physiological division oflabour’, and did so chiefly through the influence of Liebig[12]. ‘Liebig lookeduponnatureon the largeandonthe smallas an economy’, wroteMerz. ‘Through Liebig’, he remarked,‘chemistry entered into closealliancewithpolitical economy’[13].

The French physiologist and biochemist Claude Ber-nard (1813–1878) also pressed the analogy with factories.In 1878, he described the structure and function of animalorgans, writing that they were ‘like the factories or theindustrial establishments in an advanced society whichprovide the variousmembers of this society with themeansof clothing, heating, feeding, and lighting’ [14]. The realmembers of this organic society, Bernard explained, werethe cells. ‘Organs and systems do not exist for themselves’,he noted, ‘they exist for the cells, for the innumerableanatomical elements that form the organic edifice’ [15].In 1885, the British physiologist Michael Foster (1836–

Figure 3. The floorplan and view into Justus Liebig’s analytical laboratory. Heck’s Pictorial Archive of Nature and Science; Heck, J.G. 1994. By permission of Dover Publications.

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1907) referred to ‘the chemical labour wrought in the manycellular laboratories of glands and membranes’ [16], and adecade later, in 1895, the German cytologist and compara-tive anatomist Oscar Hertwig (1849–1922) saw the cell as‘a small chemical laboratory, for themost varying chemicalprocesses are almost continually taking place in it, bymeans of which substances of complex molecular structureare on the one hand being formed, and on the other arebeing broken down again’ [17].

The metaphor of the cell factory or laboratory wasemployed chiefly when the topic of discussion was physi-ology, and in particular the problem of metabolism. Theterm ‘metabolism’ was introduced by Schwann in his land-mark cell paper of 1839 to denote the chemical changescarried out by the cells of living bodies [18]. The termderives from the Greek word for ‘change’ but can also mean‘exchange, barter, or traffic’, thereby providing the meta-phorical connection between cell activity and economics[19]. For those interested in metabolic activities, wantingto know how these little things worked rather than wherethey came from, the factory or laboratorymetaphor was farmore suggestive than the comparison to an elementaryorganism. This may explain why the metaphor of the cellfactory emerged as a serious competitor to the elementaryorganism metaphor in the early twentieth century. It wasthen that biologists began to turn away from the construc-tion of phylogenetic trees of the sort made popular byHaeckel towards more experimental investigations of cell

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activity guided by the mechanistic principles of chemistryand physics.

One of the early fruits of this experimental turn was theisolation and preservation of tissue cells outside of theanimal body. But despite this evidence for the elementalorganism some leading representatives of biochemistry,such as the Cambridge experimental zoologist James Gray(1891–1975), refused to regard the cell as primary to theorganism as a whole. Gray’s influential Text-book of Exper-imental Cytology was instrumental in diverting attentionaway from evolutionary comparative anatomy towards thefunctional analysis of cell activity [20]. In the openingpages, Gray declared that ‘Nearly every experimentalbiologist has declined to accept’ the view that ‘a metazoonis to be regarded as a colony of cells in which each cell is afundamental unit of function’ [21]. His objective was to putphysiology on a firmer chemical and physical footing andthe cell was merely a convenient unit of study to achievethis. The cellular organization of organisms was a meremechanical necessity, he argued, dictated by structuraland functional limitations on the size of a single unit ofprotoplasm. For Gray, cellular organization was thereforeof secondary importance to the more essential chemicaland physical properties of protoplasm. ‘There can be littledoubt’, he wrote in a tone reminiscent of earlier cell critics,‘that the most natural unit of life is the living organism,and when we find, in some cases, that its constituent cellsare united by intercellular processes it is impossible to

Figure 4. Schematic diagram of a ‘general’ bacterial cell. Reproduced, with

permission, from Karp, G. (2004) Cell and Molecular Biology.

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admit the validity of the cell unit without further enquiry’[22].

Gray complained that ‘The problems of classicalcytology are largely concerned with intracellular structureand not, primarily, with the parts which individual cellsplay in the economy of the whole organism’ [23]. The newexperimental approach promised to rectify this by‘attempting to dissemble the machinery of an organisminto its simplest component parts’ [24], while consideringthose parts as integral components of a larger organicwhole rather than as isolated and autonomous membersof a loose colony or society.

Yet even as late as 1960, as the British physiologistLeonard E. Bayliss (1900–1964) noted, some biologists stilldoubted the value of in vitro experiments on ‘tissue slices,minced tissues and extracts from tissues’ [25]. But, Baylissargued, if one insists that studies be carried out on theorganism as a whole, one is restricted to observing inputs(ingesta) and outputs (excreta) only. ‘The comparison of theorganism to a town’, he wrote, ‘where various occupationsare carried on, is often made. If we notice that a largequantity of milk goes into the town and that a correspond-ing amount of cheese comes out we conclude that the milkhas been used to make the cheese, but we learn nothingabout the method employed’ [25].

Likewise, being told that the cell is an ‘elementaryorganism’ was not very helpful to those interested inknowing how organisms work in the first place. Whatwas needed was a metaphor highlighting the activity ofthe cell and its inner workings. Sir William M. Bayliss(1860–1924) had earlier commented in his Principles ofGeneral Physiology on the need for a process philosophyview of organisms: ‘It is of the very greatest importance forthe understanding of the behaviour of organisms, to lookupon them chiefly as something dynamic – as processesrather than as structures. An animal is something thathappens’ [26]. The largely structural-morphological con-

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ception of the body as a community or state of elementaryorganisms ceased to be suggestive for physiologists inter-ested in understanding cell metabolism, and so it wasrather naturally replaced in popularity by the chemicalfactory metaphor (Figure 4).

With an increased understanding of the complexity ofthe cell and its role in what Gray called ‘the economy of thewhole organism’, thewaywas paved for attempts tomanip-ulate the efficiency of the cell’s operations, leading ulti-mately to the literalization of the cell factory metaphor bymodern biotechnology.

Cell factories in the age of biotechnologyIn 1999, the European Union launched a s400 millionresearch program called ‘the Cell Factory Key Action’[27]. A supporting document explained that

The concept of the ‘bio-product’ is as old as the knowl-edge involved in the making of bread, beer, wine orcheese. However, recent techniques and knowledgein molecular biology and genetics mean that livingcells – from bacteria to man – are now becoming real‘factories’. In vast fermentation vats, engineers candirect and control natural metabolism in order toproduce all sorts of substances with a high addedvalue: proteins, amino acids, alcohols, citric acid,solvents and even bio-plastics. This industrial mas-tery of the mechanisms of life opens up revolutionaryperspectives in the development of new kinds ofmedicines, foodstuffs with specific nutritional proper-ties, and biodegradable biochemical products [28].

Today there are professional journals specificallydevoted to research into cell factories. A recent articleappearing in one such publication explained further theopportunities for the engineered improvement of the cell’sinnate manufacturing ability:

Genome programs changed our view of bacteria as cellfactories, by making them amenable to systematicrational improvement. As a first step, isolated genes. . . or small gene clusters are improved and expressedin a variety of hosts. New techniques derived fromfunctional genomics . . . now allow users to shift fromthis single-gene approach to amore integrated view ofthe cell, where it is more and more considered as afactory.One canexpect in thenear future thatbacteriawill be entirely reprogrammed, and perhaps evencreated de novo from bits and pieces, to constituteman-made cell factories. This will require explorationof the landscape made of neighbourhoods of all thegenes in the cell. Present work is already paving theway for that futuristic viewof bacteria in industry [29].

We see then how the idea that the cell is a chemicalfactory ultimately has become a dead metaphor but a verylively and potentially lucrative economic enterprise, asbiotech engineers learn how to ‘rationally improve’ cellsby reprogramming them to produce ‘high value-addedcarotenoids’, ‘proVITamin A’ and other ‘cell factory crops’[30]. Wohler’s and Liebig’s early insights into the chemicalbasis of cell function are now in preparation for massiveindustrial application.

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ConclusionsTwo rationales can be identified for why the factory meta-phor of the cell came to be preferred over the elementaryorganism/cell-state metaphor: one is that the holist ororganismal conception favoured the view that cells arenot autonomous elementary organisms but ‘organs’ orcomponent parts of a larger whole organism. Second, therise of biochemistry placed a strong emphasis on what cellsdo and how they do it.

This brief history of the cell factory metaphor revealssomething crucial about the role of this heuristic device:metaphors can be far more than just simply convenientdevices to explain difficult scientific concepts to a popularaudience; they are also able to act as a form of ‘experimen-tal technology’, effecting real material change. It is not thatbacteria and other cells would not have become manipu-lated by bioengineers to becomemore efficient producers ofvarious bio-products without the metaphor. But it is clearthat the metaphor assisted this transition by making it arather natural project to pursue. Will there come a timewhen people stop recognizing the chemical factory meta-phor as a metaphor, that it will become a ‘dead’ metaphor?Perhaps not, but then again, people probably thought thesame for the very concept of the cell, which began itsjourney as ‘just’ a metaphor. And now look at it.

References1 Hazen, Robert M. and James Trefil. (1990) Science Matters: Achieving

Scientific Literacy, pp. 206–207, Doubleday2 Virchow, R. (1858) Die Cellularpathologie, Hirschwald, pp. 12–13;

Brucke, E. (1861) Die Elementarorganismen. Sitzungsberichte derkaiserlichen Akademie der Wissenschaften in Wien. 44, pp. 381–406.Haeckel, E. (1866) Generelle Morphologie der Organismen, (Vol. 1),p. 264.

3 See for instance Wilson, E.B. (1928) The Cell In Development andInheritance, 3rd edition revised and enlarged, MacMillan Company,pp. 5, 102–103 1st ed. 1896, 2nd ed.1900

4 Huxley, T.H. (1853) The cell theory. British and Foreign Medico-Chirurgical Review 12, 285–314;de Bary, A. (1879) Botanische Zeitung , pp. 221–223 Nr. 14, April4Sachs, J. (1887) Lectures on Physiology. Translated by H. MarshallWard, Clarendon Press, p. 73;Whitman, C.O. (1893) The inadequacy of the cell-theory ofdevelopment. Journal of Morphology 8, 639–658;Sedgwick, A. (1895) On the inadequacy of the cellular theory ofdevelopment, and on the early development of nerves, particularlyof the third nerve and of the sympathetic in elasmobranchii. QuarterlyJournal of Microscopical Science 37, 87–101;Dobell, C. (1911) Principles of protistology. Archiv fur Protistenkunde23 (3), 269–310

5 For a more detailed examination of these debates see Reynolds, A.(2007) The Theory of the cell state and the question of cell autonomy innineteenth and early twentieth-century biology. Science In Context 20(1), pp. 71–95

6 Ritter, W.E. (1919) The Unity of the Organism, or the OrganismalConception of Life, Gorham Press, p. 168

7 Wilson (op. cit. 2nd ed., p. 427)

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8 Ritter (loc. cit., p. 191. Italics in original)9 Ibid

10 Milne-Edwards, H. (1851) Introduction a la Zoologie Generaleconsiderations sur les tendances de la nature dans la constitution duregne animal, Victor Masson, p. 35;The French term for factory is ‘‘usine’’, but as Maxine Berg explains,there was a continuous development in the late-eighteenth tonineteenth centuries from workshop to factory systems of labourorganization;See Berg, M. (1985) The Age of Manufactures: 1700–1820, Barnes &Noble, pp. 41–42. Milne-Edwards may also have chosen ‘‘atelier’’ toemphasize the division of labour among the various organs within theliving body, which itself would be analogous to the factory (‘‘usine’’) as awhole. I am grateful to Mary Morgan for drawing my attention to therelevance of the history of the factory system

11 Virchow, R. (1958) Mechanistic interpretation of life. In Disease, Life,and Man: Selected Essays by Rudolf Virchow, translated and with anintroduction by Lelland J. Rather, p. 107, Stanford University Press

12 Merz, J.T. (1965) A History of European Thought in the NineteenthCentury (Vol. 2), Dover, pp. 395–396, 415;noted in Geison, G. (1978)Michael Foster and the Cambridge School ofPhysiology: The scientific enterprise in late Victorian society, PrincetonUniversity Press, p. 349

13 Ibid., p. 39514 Bernard, C. (1974) Lectures on the Phenomena of Life Common to

Animals and Plants (Vol. 1) (Hebbel E. Hoff, Roger Guillemin, andLucienne Guillemin, trans.), p. 259, Charles C. Thomas [originalpublication 1878]

15 Ibid., p. 25916 Foster, M. (1885) Encyclopedia Britannica (Vol. XIX, 9th edn. 1878–

1889), C. Scribner’s Sons, p. 917 Hertwig, O. (1895) The Cell: Outlines of General Anatomy and

Physiology (translated by M. Campbell and edited by HenryJohnstone Campbell M.D.), p. 126, Sonnenschein

18 Bayliss, L.E. (1960) Principles of General Physiology (Vol. 2, 5th edn),Longmans, p. 171

19 Liddel, H.G. and Scott, R. (1989) An Intermediate Greek-EnglishLexicon, Clarendon

20 Anonymous (1989). ‘‘Gray, Sir James’’ in Encyclopedia Britannica (Vol.5, 15th edn), p. 437, Encyclopedia Britannica

21 Gray, J. (1931) A Text-Book of Experimental Cytology, CambridgeUniversity Press, p. 2

22 Ibid., pp. 3–423 Ibid., p. 1. Italics added24 Ibid., p. 525 Bayliss, L.E. (1960) Principles of General Physiology (Vol. 2),

Longmans, p. 172. This is the fifth edition of Sir William MaddoxBayliss’s (1860–1924) original text of the same name, extensivelyrewritten by his son

26 Ibid., xii, from the original preface to the first edition reprinted in thefifth edition. This is a quotation from the American protozoologistHerbert Spencer Jennings (1868–1947)

27 http://europa.eu.int/comm/research/rtdinf21/en/key/03.html28 Aguilar, A. (1999) The key action cell factory, an initiative of the

European Union. International Microbiology 2, pp. 121–12429 Danchin, A. (2004) The bag or the spindle: the cell factory at the time of

systems’ biology. Microbial Cell Factories 3, p. 1330 Among the list of project objectives are included: ‘‘To transform the

tomato fruit into a cell factory for carotenoids: overproduction oflycopene, zeaxanthin, astaxanthin and lutein’’; and ‘‘To transformthe potato tuber into a cell factory for carotenoids: overproduction oflycopene and beta-carotene.’’ http://europa.eu.int/comm/research/quality-of-life/cell-factory/volume1/projects/qlk3-2000-00809_en.html