The Road Taken: Past and Future Review Foundations of Membrane Traffic (2000)

ironically, may have later proved to be incorrect. It would Establishing human biological autonomy has been thus be difficult to enumerate the many individuals reslow and is by no means completed. It began with ad- sponsible for bringing the field to its current state of vances in the physical sciences, notably the work of sophistication. Nevertheless, acknowledging a few peoCopernicus and Galileo, who helped to establish that ple and events is essential to illustrating some key obthe earth, and thus humankind, did not occupy a unique servations and discoveries. or privileged position at the center of the universe. De- Prescient Early Observations spite the obvious difference in scale, as important were The study of membrane traffic dates back to a time the contributions of the life sciences. Cell biology in before it was clear that membranes even existed. Unparticular provided the incontrovertible proof that hu- doubtedly the most widely known, if not necessarily mans as well as all other living beings consist of individ- the most important, observations were provided by the ual cells (utilizing the same genetic code) whose activi- great Italian histologist Camillo Golgi. Golgi developed ties, inheritance, and ability to assemble into organisms his silver nitrate‐based cytochemical stains to explore can be understood in logical, if not always straightfor- the organization of the central nervous system but, in ward, biochemical terms. This fact demonstrated that addition, revealed that neurons contain a distinctive inhowever miraculous the existence of life on earth might ternal reticular structure, which has borne his name ever be, it is not entirely mysterious. Life’s mechanisms can since (Golgi, 1898). Though the existence of this strucbe understood, regardless of whether one invokes spiri- ture in all eukaryotic cells was hotly debated for the next tual or quantum mechanical reasons for its existence. half century (Bentivoglio, 1998), the “Golgi apparatus” As we stand at the end of the millennium, we probably was in fact the first organelle of the secretory or endounderstand, albeit superficially, nearly all of the basic cytic pathways to be identified. Ironically, Golgi’s main principles that govern life, death, cognition, and repro- conclusion from his studies, namely that the brain conduction. We are not yet at the Golden Age predicted sisted of a continuous syncitial network, turned out to some years ago by Gunther Stent (Stent, 1969), but it be less influential in the long run (Henry, 1998). seems increasingly likely that the study of cells as inte- Another critical if less widely appreciated observation grated, functional units will be the vehicle that will finally of this era was provided by Elie Metchnikoff (Metchnibring us to a complete understanding of our physical koff, 1887). Born in 1845, just two years after Golgi (he existence. also won his Nobel Prize two years after Golgi), MetchniCell biology can be divided into a number of branches, koff’s discovery of cellular immunity provided a similar which, with every advance, are becoming progressively cell biological by-product. Whereas the Golgi apparatus intertwined. The study of biological membranes is the was an object without a clear function, the ability of branch most responsible for this confluence, largely be- individual cells to internalize extracellular particles by cause it is a cell’s system of membranes that provides “phagocytosis” suggested a functional intracellular dithe very boundaries within which life exists. A membrane gestive tract. This suggestion was highlighted by the separates the panoply of biochemical reactions that de- demonstration that ingested particles (e.g., blue litmus) fine a living cell from the extracellular world. Within the were exposed to acidic pH and presumably degraded cell, membranes also organize and separate these bio- following uptake. Metchnikoff provided the first demonchemical reactions from each other, generating the stration that cells have internal specializations that carry compositionally and morphologically distinct compart- out specific functions. ments characteristic of eukaryotes. Transfer of material Founding the Modern Era between many of these compartments (in particular, By the middle of the twentieth century, the advent of secretory or endocytic compartments) occurs by means electron microscopy (EM) combined with the developof small, membrane-bound vesicles. Although vesicular ment of fixatives (e.g., glutaraldehyde [Sabatini et al.,