Till Entropy Do Us Apart

"It appears that you are all amazed, maybe you did not expect this..." such is the comment of Göran Hansson, the secretary of the Nobel Committee for Medicine to the audience of speechless journalists. We are at the Karolinska Instutute in Stockholm just after the announcement of the 2013 Nobel Prize for Medicine to Randy Schekman, Jim Rothman and Thomas Sudhof for discovering the vesicular transport system of cells. 

Why the surprise? Well, because this year many predicted a Nobel to the fathers of Epigenetics, a recently discovered process that regulates expression of genes, on which many researchers hope to build the medicine of the future. 

But no, this year's Nobel goes to discoverers of the way cell membranes fuse, an affair of  lipids, fat in science lingo, and proteins. 

This is a great Nobel, a long-awaited and thrilling one, especially because it rewards the great merit of basic research, the one not necessarily pursued for medical purposes (I'm biased since my laboratory focuses on basic research of vesicular trafficking). 

Below I explain briefly the history not of the research that led to this recognition, but rather of fascinating biology that stems from these discoveries, and that few have told in these day of Nobel celebrations. 

We start with the most obvious fact, brought to light primarily by Sudhof and widely mentioned, that the vesicular transport and its fine regulation are at the heart of synaptic transmission, the process of communication between neurons in the brain of all organisms that have one (regardless of how they decide to use it). The perceptions of themselves, of others and of the environment in sentient beings, and by extension their reactions and emotions, travel through neurons in the form of electrical impulses. These pulses are, however, passed from one neuron to another, or from one neuron to a muscle, using events of fusion and internalization of vesicles highly regulated on the surface of neurons. So in the brain, if we want to use a metaphor, the music is electronic but part of the its execution is analog and based on vesicular transport. 

Another key role of vesicular transport in each cell - not only in neurons - is to allow the preparation and packaging, literally in the form of the folding, sugar-coating and greasing - according not to taste but rather to necessity - of proteins and other molecules produced within the cell. These are then shipped to various cell districts including the surface, the border beyond which is the mare magnum of the rest of the body. This has to do with vesicular transport because a very large number of proteins are associated with or are included in membranes, the leaflets of lipids that form vesicles. The production process is generally called secretion or exocytosis, and is coupled with the opposite process, endocytosis, namely the internalization, from the outside of the cell or from its surface, of molecules destined to various places within the cell, or to degradation in the lysosome, the cell recycle bin. In the lysosome you don’t recycle plastic, but rather membrane proteins (for the recycling of water-soluble proteins there is a shredder, the proteasome). Thus, the vesicular transport rule all the life, literally from birth to death, of the proteins that are inserted or attached to a cell membrane. 

Endocytosis and exocytosis are based on the continuous production, trafficking and fusion of vesicles between organelles such as the Golgi apparatus, the endosome, and lysosomes, veritable assembly, sorting and recycling stations of the cell. That’s way people  usually compare vesicular transport to the cell highway system. However, the very integrity of the vesicular organelles in a cell like ours depends largely on the proper functioning of vesicular transport, a bit as if the size of the service stations on the highway depended on how many vehicles are stopping there. The vesicles emerge through an elaborate system of folding and cleavage of the membrane, which involves several systems of proteins in different places in the cell that have nothing to envy to the most elaborate origami. Then the vesicles travel after being loaded on molecular motors that literally walk on networks of tracks that constitute the cellular skeleton, or cytoskeleton. Once at the arrival station, vesicles are incorporated to the organelles for which they are intended, using a set of SNARE proteins that in fact snare vesicles that need to fuse with the membrane of the target organelle. Final fusion require SNAP proteins that, well, snap the SNARE to allow close contact and membrane mixing. If we are not tired of metaphors we can think of a orbiter that must be lassoed and attached to a space station. Metaphors aside, fusion is a delicate and complicate affair. The vesicles and organelles have membranes made of fats and are in a water-based environments, such as the cytoplasm of the cell. Water and oil, as all know, don’t mix, thus SNARE proteins on vesicle membranes and organelle target are needed to bring fats close enough to fuse. A little bit as it happens when two drops of oil in water come close. 

Out of a set of thirty or so SNARE proteins in the cell only certain combinations of three-four of them allow fusion events. This is good because it allows Golgi vesicles that fuse with the cell membrane to be different from vesicles that go to the endosome. In essence, the system identifies incoming packets on the basis of the SNARE and allows to reach only the right destination. Your carkey not only opens the right car, but it also identifies the bearer as the one with legitimate access rights (the rightful owner, most of the time). The more we study the more we discover complications to this paradigm, which is what emerged from genetic and biochemical studies of Rothman and Schekman. 

The events of fusion between membranes are suitable for a multitude of very creative uses in specialized cells of our body. One of the most amazing happens in the T-killer lymphocytes. The T-killer, aptly named, are to all intents and purposes the natural born killers of our immune system. They scavenge cells to be eliminated because infected or malfunctioning. Wen they find one, they literally attach to part of it, forming a specialized type of synapse, the immunological synapse. In microscopy images, it looks like a kiss, the kiss of the death, one would say. In fact, after pointing their lysosomes towards the synapse - bang! - they fuse them with the surface of the membrane unloading their lethal content to the cell to be killed. Why lethal? Well because, lysosomes, as any good recycling station, are stuffed with very caustic substances to chop and break down fats and proteins, and in these cells they are further loaded to do damage. A chilling fate, akin to dissolving your enemy in acid after a kiss on the cheek, capisc? 

Let's move from the merciless individualism (for our own good) of T-killer, to the selfless altruism of the cells forming the tissues in our bodies. To make an organ in a fetus, and to make it work after birth, cells in tissues must adhere to each other, communicate and move. As in any caring community, they are commuting, hugging, chatting and kissing among millions of other cells, following a highly dynamic and precisely regulated choreography that intensely uses the vesicular transport system. In fact, inserted in membranes are the receptors for the signals that tell the cell how to behave. Associated to membranes are the transducers that amplify and pass messages arrived from the outside and going to the nucleus, where the DNA will interpret them, putting in place the corresponding genetic programs. The birth of signals, receptors and adhesion molecules is in the secretory pathway, and their death follows the endo-lysosomal route, both events inextricably linked to vesicular transport. Given that many cancers arise from abnormalities of signaling between cells, it is not surprising after all that many mutations in proteins that regulate vesicular traffic are found in tumors. What do you say to that, Epigenetics?!

These stories, I hope fascinating to you as they are to me, are the result of the passion for the science of many researchers like me, who have read the discoveries of Schekman, Sudhof and Rothman. The ones told briefly here only constitute an minimal window on the landscape of diversity that evolved from the conquest of vesicular transport by cell of our ancestors. The vesicular transport is an ancient invention, but a most important one to allow the transition from simple cells, such as bacteria, to complex cells, such as our owns. Like all others, it is the result of chance and selection, the two pillars of Darwinian evolution. Lucky us... in fact without vesicular transport, we would arguably be a sad broth of a hundred billion cells considering that multicellular organisms like not only us, but also other animals like your pet or your annoying little brother, and all plants have emerged only after vesicular transport and organelle compartmentalization evolved. 

Essentially, the Nobel Prize this year speaks to us of how beautiful is the complex life of our cells. A life in which water - that permeates us and allows the chemical reactions inside our body, and oil, the fat of which cell membranes are made, are kept separate using energy - in infinitely more elaborate ways than in simple cells of bacteria thanks precisely to vesicular transport - in an eternal dance that separates order and life, from entropy and death.


Note: This piece was written initially in Italian (see post below) in October 2013, shortly after the announcement of the Nobel prize for Medicine. I finally found some time to translate it into English (with some mods to spice it up). Hope the reader will enjoy and comment.