Membranes to Molecular Machines: Active Matter and the Remaking of Life

Membranes to Molecular Machines: Active Matter and the Remaking of Life

by Mathias Grote

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Today's science tells us that our bodies are filled with molecular machinery that orchestrates all sorts of life processes. When we think, microscopic "channels" open and close in our brain cell membranes; when we run, tiny "motors" spin in our muscle cell membranes; and when we see, light operates "molecular switches" in our eyes and nerves. A molecular-mechanical vision of life has become commonplace in both the halls of philosophy and the offices of drug companies, where researchers are developing “proton pump inhibitors” or medicines similar to Prozac.
Membranes to Molecular Machines explores just how late twentieth-century science came to think of our cells and bodies this way. This story is told through the lens of membrane research, an unwritten history at the crossroads of molecular biology, biochemistry, physiology, and the neurosciences, that directly feeds into today's synthetic biology as well as nano- and biotechnology. Mathias Grote shows how these sciences not only have made us think differently about life, they have, by reworking what membranes and proteins represent in laboratories, allowed us to manipulate life as "active matter" in new ways. Covering the science of biological membranes in the United States and Europe from the mid-1960s to the 1990s, this book connects that history to contemporary work with optogenetics, a method for stimulating individual neurons using light, and will enlighten and provoke anyone interested in the intersection of chemical research and the life sciences—from practitioner to historian to philosopher.

Product Details

ISBN-13: 9780226625294
Publisher: University of Chicago Press
Publication date: 07/19/2019
Series: Synthesis
Sold by: Barnes & Noble
Format: NOOK Book
Pages: 304
File size: 5 MB

About the Author

Mathias Grote is assistant professor at Humboldt-University Berlin, Germany.

Read an Excerpt


What Membranes Can Tell a Historian and Philosopher of the Life Sciences

Just as chemistry could not have developed without test tubes to hold reacting substances, so organisms could not have evolved without relatively impermeable membranes to surround the cell constituents. [...] It can truly be said of living cells, that by their membranes ye shall know them.

E. Newton Harvey, foreword to Davson and Danielli, The Permeability of Natural Membranes, 1952.

Trivial but true — life takes place in containers. As much as multicellular organisms are surrounded by a skin, an integument, an epidermis, or other surface layers, every cell is surrounded by at least one layer of membrane, and often several of them. Thus, in most definitions of life, the container, or the boundary, seems the least controversial point, as compared to, for instance, metabolism or a system of heredity. The obviousness of a boundary required to separate cells from their environment, thereby creating a milieu, a space for metabolic reactions, and a compartment that harbors hereditary molecules, may have contributed to the neglect of what specifically biological membrane research has told us about life and what it has allowed us to do with it. However, without such membranes, cells would not be discernible, and we would be left with some ill-defined protoplasm, primordial soup, or surface in which metabolism and heredity take place. Stanislaw Lem's science fiction novel Solaris (1961) impressively shows how difficult a scenario of life without boundaries may be to imagine. Here, an ocean covering an entire planet seems to be "alive," in the sense that it somehow interacts with the humans that approach it in their spaceships; however, within the enlivened ocean, no boundaries of an organism-like structure are discernible, leaving the psychologists and cyberneticians in utter incomprehension regarding their counterpart.

In addition to their obviousness, another reason why membranes have been neglected by the history and philosophy of the life sciences, in spite of their indubitable relevance to science, may be the fact that research into them has been much less disciplined than, say, the study of heredity in genetics. Plant physiologists of the nineteenth century stumbled upon surfaces and interfaces of tissue when studying water transport, that is, the curious phenomena of osmosis (the tendency of water to flow across semipermeable boundaries from solutions of lower to higher concentrations of ions). Everybody has experienced osmotic effects, for instance, in the miraculous recovery of withered plants upon watering, or the swelling of a gummi bear in a glass of water. Osmosis illustrates another almost trivial necessity of living in a container: As much as a boundary is required for life, this boundary must be traversed in order for metabolism to occur. Water needs to flow into plant tissues, while cells need to take up nutrients and excrete waste products, etc.

Another important research field where membranes moved into the focus of early twentieth-century biology was the physiology of "excitable tissue," such as nerve or muscle. Just as in electrochemical devices (e.g., batteries, composed of two compartments filled with different ionic solutions, separated by a semipermeable membrane), nerve membranes were the site at which the electricity of the tissue was generated, which was a centerpiece of sensory physiology since the nineteenth century. Moreover, biological membranes seemed to be examples of an "active surface," similar to the artificial membranes used in, for example, filtration. Just as the thin layers of synthetics such as collodion, they were endowed with properties perceived as extraordinary: Surfaces behaved very differently than expected from the physics and chemistry of bulk matter, such as common gases, liquids, and solids. Thus biological research successfully cross-fertilized with other fields interested in what British colloid chemist Sir Frederic Donnan evoked as a "fourth state of matter" in the interwar period, among them even electrical engineering.

One major step of twentieth-century membrane biology was to distinguish the biological membrane proper from other surface layers of cells and tissues, such as the cell walls of plants, fungi, or bacteria. Whereas the latter are more or less inert sheaths rendering the cell with mechanical stability (e.g., against "explosion" due to the osmotic influx of water and swelling), the membrane was conceived of in the 1930s as a delicate double lipid, or fat layer, only several nanometers thick (fig. 2).

This lipid film, too thin to be visible under optical microscopes, but intriguing for its effects, actually led to a veritable membrane-craze in the 1930s and 1940s (not only amongst neurophysiologists), before molecular biology as we now know it had formed. Yet, the exact molecular architecture and the function of the thin double layers composed of lipids and proteins remained controversial even in the postwar age of the electron microscope, as the following section shows. How membranes achieved their remarkable effects — the generation of action potentials in nerve, the selective uptake of ions or nutrients in blood cells or bacteria, respiration, or photosynthesis (all of these centerpieces of twentieth-century life sciences) only became noncontroversial and properly addressed after 1970, in cases such as that described in this book.

Exploring these membrane histories does not just add a novel dimension to our picture of the life sciences. The way in which researchers have conceptualized and dealt with life in membrane research provides novel insight for a philosophy interested in the concrete, as it suggests viewpoints and questions that differ from those posed by genetics and evolutionary biology. Take heredity, for example: Cells "inherit" half of their membrane (as their metabolically produced and self-maintained boundary) when dividing. Obviously, this transfer of a material structure is a form of heredity radically different from that of DNA. Or, consider membranes' dynamic mode of existence; that is, their self-organization and the fact that they remain discernible entities in spite of continuous material exchanges with the environment, with which they form a dynamic equilibrium. Membrane research is of interest to study the interplay of the life sciences with physics and chemistry (thermodynamics, reaction catalysis, etc.), especially in regard to models for the emergence of larger structures, the formation of order, or the origin of cells. It is the material modeling of membranous objects and their dynamics — from mixing lipids and water for spontaneous membrane formation, to extractions, centrifugations, syntheses of "protocells" to the study of communication between cells and interactions with their environment — that has allowed membrane research to reformulate and re-cast many of the central issues of the life sciences. Stories from membrane research challenge distinctions such as those between the living and the unenlivened, or the "natural" and the "synthetic."

Bringing membranes into history and philosophy will not only highlight a realm in the life sciences that is quite different from the ones that have found more scholarly attention; insight into membrane sciences will also expose the extent to which the late twentieth-century life sciences have been an endeavor of chemical thinking and working; that is, of isolation, preparation, making, unmaking, and reassembling matter.

The cell's elusive boundaries and the molecular age

Excitement and disillusion were close counterparts when it came to membranes in the 1960s. Let us first examine excitement. Under the heading "Molecular biology — the next phase," Max Delbrück hit on the subject of membranes in 1968. Evoking physicist Richard Feynman's "There is plenty of room at the bottom" address, later taken as foundational charter of nanotechnology, Delbrück outlined membranes as a form of natural technology, as the cell's "chemical factories" in enzymology, or as its "surface structures" transmitting signals in the nerve fiber, which influence cellular behavior:

On the molecular level these [i.e., the membranes'] transducer mechanisms are not understood and will constitute the principal challenge for the next phase of molecular biology. The depth of our ignorance in this area may be compared with the depth of our ignorance with respect to the molecular basis of genetics 30 or 40 years ago.

Despite Delbrück's next frontier rhetoric, and his group's work on sensory physiology of simple organisms (somewhat unsuccessfully), he was not among the important membrane researchers of the time. Yet, if we take Delbrück's role as an interdisciplinary leader and community organizer with a nose for the vanguard of science seriously, his 1968 essay indicates that membranes were emerging as a novel subject of the molecular life sciences and drew attention in the later 1960s. Potentially similar in architecture and function, membranes from different cells or organisms were another candidate for a general principle of biological function at the level of physics and chemistry. At least for Delbrück, genetics cast its long shadow over this surmised next big thing of molecular biology — he framed the topic in a cybernetic discourse on information and technology that seems familiar from both the story of DNA, the genetic code, and later neurophysiology. Thus, we will again encounter Delbrück, as well as Feynman's promise of molecular technology, when it comes to 1960s "transducer physiology," and biological macromolecules as "switches" or other "devices" in the 1980s (see chapters 2 and 4).

So much for membrane enthusiasm — but what was the nitty-gritty of research at the time? In 1968, a lengthy review on "Current Models for the Structure of Biological Membranes" (note the generalizing expression, as opposed to particular membrane specimen) by Rockefeller University electron microscopist Walther Stoeckenius discussed almost 300 references, only to conclude that the most acceptable model, or at least the one with the fewest counterarguments, was the "Davson and Danielli bilayer model," which proposed two lipid films with proteins attached, and which dated back to 1930s research. Two years later, the first edition of a biochemistry textbook authored by American Albert L. Lehninger (known among biochemists as "the Lehninger" to this date) openly reflected this lack of consensus on membrane structure by depicting different models of how these were made up from their components, lipids and proteins (see fig. 2). The situation was no better regarding the investigation of membrane activities in neurophysiology or bioenergetics. Arthur B. Pardee, another molecular geneticist on the lookout for new subjects, stated in 1968 that the details of membrane activities such as transport of substances into cells were "completely mysterious" and that the existing "black-box approach" of physiology did not permit one to decide the central issue of mechanisms.

Another controversial and perhaps the best-known arena of inquiry into membranes at the time was bioenergetics, or the study of cellular energy generation, which had developed out of intermediary metabolism studies and photosynthesis in the postwar period. Membranes of mitochondria and the so-called thylakoid membranes of chloroplasts were known as the sites of production of the central energy metabolite adenosine-triphosphate (ATP), yet if and how the lipid-protein-film was involved in ATP synthesis remained a matter of controversy. Whereas many biochemists thought the membrane was of less importance, and looked for enzymes and intermediate reaction products, the so-called chemiosmotic model developed by British biochemist Peter Mitchell had put the membrane center stage. Similar to the semipermeable membranes used in batteries, which serve to create ionic gradients between two compartments and thereby electricity, Mitchell thought of the membrane and the ionic gradient as a general biological stratagem to catalyze and utilize surface processes, thereby revealing himself as a late acolyte of interwar chemistry in the age of molecular biology. So, conflicting evidence and clashing styles of biochemical working and thinking had turned bioenergetics in the second half of the 1960s into an acrimonious controversy. Efraim Racker, an Austrian-American biochemist from Cornell who was deeply entangled in the debates, put it thus: "Anyone who is not thoroughly confused just does not understand the situation."

From these contrasting assessments, membrane research emerges as an endeavor loaded with expectations for new general insights into life, but plagued by conceptual confusion and experimental stagnation since its first heyday in the interwar period. Membranes did not live up to their promises. To exaggerate, one could say that different membranes were researched by different communities in the 1960s: The relationship of the biochemists' membrane (a lipid fraction prepared from cells) to the physiologists' membrane (the electrical effects of which in living cells were recorded on paper slips and screens) to the electron microscopists' membrane (visualized as thin dark lines in stained specimens of cells and tissues) to that of physical chemists' (e.g., assembled synthetic thin films) remained unclear, with one participant of a 1967 conference speaking of different "tribes" inhabiting "membraneland."

In the remainder of this chapter, I will present this scattered landscape of 1960s membrane research, with its cornerstones such as the bilayer model reaching back into the 1930s. I will first venture into the problem of membrane structure, then on membranes as known by remaking them, and third, on their — to echo Pardee — mysterious dynamics. The bottom line of this story is that membranes have remained at one remove from providing uncontroversial models of structure and dynamics up to the late 1960s, different aspects of membrane research remained unconnected, and most importantly — the object itself materially elusive. Thus, this chapter, composed of somewhat disconnected threads, can also be read as a story of slow-moving, meandering research, which yet prepared the ground for the coming "membrane moment" of the 1970s.

Neglected dimensions: Membrane structure

Even if much remained controversial about membrane structure and assembly in the 1960s, it was accepted that these delicate films represented dynamic aggregates of relatively small lipid or fatty acids molecules. These latter comprised hydrophobic, i.e., water-adverse, tails and hydrophilic heads, thus often being depicted in a tadpole-like schematic (see fig. 2). In the cytoplasm, or watery solutions more generally, these molecules spontaneously assemble into spherical aggregates of microscopic size, not unlike soap bubbles. Whereas the lipids' water-loving head groups would face the outside solution, the water-adverse tails would spontaneously orient away from water for thermodynamic reasons. The analogy between such processes of membrane self-organization and the formation of cells, and thereby a major step in the origin of life, is easily made, and had in fact been drawn already in the early twentieth century by the Soviet chemist Alexander I. Oparin.

Lipid films as flat sheaths or the spherical liposomes and micellae everybody knows from turbid soap solutions, formed part of what German colloid chemist Wolfgang Ostwald (the son of physical chemist Wilhelm Ostwald) has famously called the "world of neglected dimensions" in the early twentieth century, i.e., a realm of aggregate structures the size of which ranged in between those of the organic molecules studied by biochemists and larger cellular structures visible in the microscope. This cosmos of colloidal substances and effects encompassed enzyme action and cell structure as much as it promised to explain the properties of paint or ketchup, all of which seemed to elude what was known from the ordinary chemistry of solutes. When crystallography and the ultracentrifuge revealed that protein enzymes were not organized as aggregates in the 1930s, but as macromolecules, colloidal chemistry as a biological research program largely collapsed, yet, membranes remained a stronghold of colloidal thinking and working. They formed if not a world, then at least an island, of neglected dimensions next to or within postwar molecular biology.


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Table of Contents

Introduction: The Molecular Mechanical Vision of Life Descartes among the X-ray machines? Mechanisms, molecular machines, and the epistemology of science
Life and matter—another history of the molecular life sciences after 1970
Constitutive and exemplary: Bacteriorhodopsin, membranes, and the rise of molecular machinery
A note on people and places, times and sources
Outline of the book
Part One: Taking Membranes Apart, Isolating a Molecular Pump
1. What Membranes Can Tell a Historian and Philosopher of the Life Sciences
2. Active Matter

Part Two: Remaking Membranes and Molecular Machines
3. Synthesizing Cells and Molecules—Mechanisms as “Plug-and-Play”
4. Biochip Fever: Life and Technology in the 1980s

Conclusion Matter, activity, and mechanisms at the interstice of the chemical and the life sciences
Molecular machinery in past, present, and beyond
The bigger picture—membranes and molecular machines in the history of the life and the chemical sciences
Beyond life? Places and scientists after molecular biology

List of Abbreviations

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