The history of cell and molecular biology displays an arms race between biological challenges and their technological solutions, regarding the detection and analysis of ever smaller structures and processes. For a long time, advancements in microscopy have kept pace with scientific motivations. But since fundamental physical laws cannot be simply overcome, appropriate instruments need to become more and more complex if modern biology does not simply want to stand still due to technical limitations. As a prominent example, the need to zoom further into biological matter in space and time recently sparked an explosion in sub-resolution techniques in microscopy. But is it actually always necessary to adapt our technology to the actual dimensions of biological matter if we want to understand fundamental processes? We know that biology works on many scales. So why not just try and upscale biological phenomena?

Blowing Up

In 1989, the movie Honey, I Shrunk the Kids was released, in which an unfortunate scientist develops a shrinking machine and accidentally shrinks his and the neighbor's children to the size of insects. In 1992, a sequel was released under the title Honey, I Blew Up the Kid. Justifiably, it eluded the success of the previous movie. Nevertheless, the idea behind the plot shall be of interest for us. This time, the unfortunate scientist - with the help of a new invention - inflates his 2-year old son to a 34 m-tall giant that starts to terrify Los Angeles in Godzilla manner.

Why not apply this concept to cell and molecular biology? If the structure or process of interest is too small to be observed with modern microscopy, why not just magnify the very phenomenon, instead of ever increasing optical magnification? Is this possible? Yes, under certain conditions, and the key to it seems to be an approach taken from synthetic biology.

Rafts and Membrane Domains

Just to give an example: In the past ten years, membrane rafts have received much attention in the cell biology community. Until the mid-nineties, the cell membrane was generally viewed as a homo-genous fluid, in which membrane proteins are embedded.

This view was challenged in 1997 by Simons and Ikonen [17], and by an avalanche of consecutive research work in the following years [7], [10].

According to this "raft hypothesis", lipids organize into domains within the plasma membrane, with physical properties that distinguishes the domains from the rest of the membrane (fig. 1a). These physical properties can be, for example, lateral fluidity, surface tension, and thickness of the double layer structure. These domains, or rafts, are thought to play a major role in recruiting membrane proteins and controlling their function.

The raft hypothesis is nowadays more or less accepted, with one blemish: no one has directly observed rafts in vivo so far. Many experiments point to their existence, but they could so far not be proven microscopically. Probably this will also not be possible for a long time, since rafts are assumed to organize on the nano­scale, and may have very fast turnover. Much effort is spent to make them "visible" by other means than optical microscopy, or just to indirectly prove their existence. An alternative to that would be to "blow up" these rafts so that they can be examined in a standard fluorescence microscope. This appears to be possible by leaving the in vivo-world and entering the field of synthetic biology of minimal systems [16]. When mimicking the cell membrane by artificial membranes containing specific raft-like lipid composition, phase separations of lipids appear as domains on the micrometer scale (fig. 1b).

These domains are supposed to be synthetic functional siblings of the assumed rafts in cells. Most importantly however, they distinguish themselves by their actual visibility in fluorescence microscopy. Such artificial membranes of appreciable size are achieved either as supported lipid bilayers by fusing small unilamellar vesicles (SUVs) with a hydrophilic support, such as glass or mica [18]. Another possibility is to rehydrate dehydrated lipid films in the presence of an alternating current, such that so-called giant unilamellar vesicles form (GUVs), which can be seen as a very crude in vitro approximation of the biological cell membrane: a membrane bilayer separates an inner volume from the environment and therefore provide the essential boundary conditions for organelle-like function [2], [19]. The ability to make domains visible in minimal cell membrane-like systems yielded deeper insight into the features and functions of the hypothetical rafts [3], [4], [6].

Min Proteins for the Division Site Selection

Is this application, blowing up molecular mechanisms from the nanoscopic to the microscopic scale by transformation of cellular processes into synthetic biology a singular example, or can this concept be transferred to other biological problems, e.g., fundamental ones such as structure and pattern formation?