Studies in History and Philosophy of Biological and Biomedical Sciences 41 (2010) 172–182 Contents lists available at ScienceDirect Studies in History and Philosophy of Biological and Biomedical Sciences journal homepage: www.elsevier.com/locate/shpsc The cell: locus or object of inquiry? William Bechtel Department of Philosophy, the Center for Chronobiology, and the Science Studies Program, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0119, USA article info abstract Keywords: Research in many fields of biology has been extremely successful in decomposing biological mechanisms Cell biology to discover their parts and operations. It often remains a significant challenge for scientists to recompose Cell theory these mechanisms to understand how they function as wholes and interact with the environments Circadian rhythms around them. This is true of the eukaryotic cell. Although initially identified in nineteenth-century cell Decomposing mechanisms Mechanistic explanation theory as the fundamental unit of organisms, researchers soon learned how to decompose it into its Recomposing mechanisms organelles and chemical constituents and have been highly successful in understanding how these carry out many operations important to life. The emphasis on decomposition is particularly evident in modern cell biology, which for the most part has viewed the cell as merely a locus of the mechanisms responsible for vital phenomena. The cell, however, is also an integrated system and for some explanatory purposes it is essential to recompose it and understand it as an organized whole. I illustrate both the virtues of decomposition (treating the cell as a locus) and recomposition (treating the cell as an object) with recent work on circadian rhythms. Circadian researchers have both identified critical intracellular operations that maintain endogenous oscillations and have also addressed the integration of cells into multicellular systems in which cells constitute units. Ó 2010 Elsevier Ltd. All rights reserved. When citing this paper, please use the full journal title Studies in History and Philosophy of Biological and Biomedical Sciences 1. Introduction parts and operations within mechanisms, but successful explana- tion of the original phenomenon often requires pairing decomposi- The cell has figured prominently in the highly successful project tion with recomposition into the whole mechanism (Bechtel, 2009; of mechanistic research in the life sciences over the past two cen- Bechtel & Abrahamsen, 2009). When the parts comprise an inte- turies. Indeed, cell biology is one of the most successful mechanis- grated whole which functions as a coherent unit and confronts tic sciences. But, ironically, the cell itself does not figure its environment as a unit, then the whole itself is an important ob- prominently as an explanatorily relevant entity in the field known ject of inquiry. This raises the question of whether the cell itself as cell biology. Rather, it is the locus of many of the mechanisms of may be such a unit—does it operate as an integrated whole and en- interest, not itself a functionally relevant object. In this paper I ex- gage its environment causally in ways that require that it be trea- plore whether this is its inevitable fate as mechanistic science stea- ted as an object of inquiry? dily advances to lower levels, or whether there are research In this paper I will describe the project of decomposition that projects in which the cell once again serves as the object of inquiry. has been so successful, focusing first on the legacies of the cell the- What is distinctive of mechanistic science is the project of iden- ory of the nineteenth century and cell biology as it developed in tifying a mechanism responsible for a phenomenon of interest and the middle of the twentieth century. At the outset of this history, then explaining how the mechanism produces the phenomenon by the cell itself was the focus of inquiry, but was soon eclipsed as decomposing it into its component parts and operations and show- researchers took it apart and explored its constituents. As a point ing how the coordinated functioning of these parts and operations of contrast, I will then present in Section 4 a theoretical perspective generates the phenomenon (Bechtel & Richardson, 1993). The tools developed in recent decades that focuses on the minimal proper- of mechanistic research have been extremely successful in finding ties of living systems. This perspective emphasizes the integration E-mail address: [email protected] 1369-8486/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.shpsc.2010.07.006 W. Bechtel / Studies in History and Philosophy of Biological and Biomedical Sciences 41 (2010) 172–182 173 of processes within the cell, rendering the cell as the integrated distinctive feature that united the variably appearing anatomical unit into the object of inquiry. To provide further substance to this structures in different tissues as cells. Schwann extended this ap- analysis, I turn in the last sections (5 and 6) to a contemporary proach to animals, where even greater variability in the appear- example. In the quest to understand circadian rhythms, research- ance of anatomical structures was observed. But as important as ers first identified cells that endogenously maintain daily oscilla- the visualization of the nucleus was for the development of the cell tions. Researchers then decomposed these cells, identifying the theory, more important was the account of the process by which genes that exhibit a daily cycle of expression due to feedback loops the nucleus formed and how the cell was formed from it. involving the proteins they generate. As successful as that pursuit Schleiden and Schwann differed on the question of whether the has been in the last fifteen years, however, researchers also came process took place within existing cells or in the intercellular flu- to realize that there is considerable variability in the oscillations ids, but for both cells formed like crystals through a process of of individual neurons, and that synchronizing a population of neu- accretion out of the fluid matrix. Basing their account of cell forma- rons is critical for generating circadian rhythms in organisms. The tion on an analogy with a known physical process was critical to very success of the enterprise of decomposing the mechanism both Schleiden and Schwann as they were part of a group of young within the cell into its parts and operations has brought renewed mechanist physiologists that developed around Johannes Müller focus on the cell itself as a functional entity within a larger mech- (who remained more sympathetic to a vitalist approach than his anism, which again renders it the object of inquiry. students). Schwann went on to argue that cells were the basic unit for all metabolic processes (he coined the term metabolism): ‘The 2. From cell theory to organelles in the nineteenth century cause of nutrition and growth resides not in the organism as a whole, but in the separate elementary parts—the cells’ (Schwann, The word cell entered scientific discourse as a result of the 1839, p. 192). This extended his earlier claim (Schwann, 1836) that development of microscopes. In examining cork through an early processes such as fermentation occurred only in living cells, a microscope, Robert Hooke (1665, p. 113) described pores that claim that had rankled other mechanists, especially investigators ‘had a very little solid substance, in comparison of the empty cavity such as Friedrich Wöhler, who sought chemical accounts of living that was contain’d between’. He designated them with the Latin processes and thought even acknowledging living units as the lo- word for little rooms, cellulae, and treated their walls as their defin- cus of such processes capitulated to ‘vitalism’ (Wöhler, 1839). ing characteristic. In the same period Antony van Leeuwenhoek Schwann insisted, however, that these processes occurred in cells (1674) reported on bacteria and sperm, and characterized these as a result of the specific composition of the matter deposited in cells that existed independently of a larger structure as animalcules them as cells formed. He thereby saw himself as extending the (little animals). Over the next 150 years, however, the spherical mechanistic perspective to physiology generally (Bechtel, 1984). and chromatic aberrations in microscopes with multiple lenses In subsequent years some investigators focused on the viscous generated considerable controversy. Van Leeuwenhoek and others liquid within cells that von Hugo von Mohl (1846) named proto- who employed microscopes with only a single lens avoided these plasm and viewed it as responsible for the activities of cells. For problems, but they confronted limitations in the amount of magni- some investigators, such as Max Schultze (1861), protoplasm was fication they could achieve. With compound microscopes, spheri- more important than the cell boundary in distinguishing cells. Oth- cal aberrations result from light rays that leave the lens at ers, however, continued to focus on the cell boundary. This was different distances from the axis, and chromatic aberrations result particularly true of researchers such as Mohl, Nägeli, and Virchow, from light of different wavelengths refracting to different degrees. who rejected Schleiden’s and Schwann’s accounts of cell formation, Even in the face of these limitations, some investigators em- and argued that new cells arose from the division of existing cells. braced the microscope and treated the units they saw as the funda- For them, the crucial activity was the cell boundary closing in to mental units within living organisms. Thus, Henri Milne Edwards separate two daughter cells. Whether focusing on metabolism or and René Joachim Henri Dutrochet (1824) spoke of seeing globules, cell division, however, these early researchers were focused on which they construed as the building blocks of organisms. Others, activities involving whole cells, rendering the cell as a basic phys- such as Xavier Bichat (1805), rejected the microscope and limited iological unit.