Physiology and Medicine – The Importance Of Autophagy
On the third of October, 2016 the Nobel committee announced that Yoshinori Ohsumi would win the Nobel Prize in Physiology and Medicine for his work on autophagy. Autophagy literally means ‘self-eating’, it’s the process of degrading cellular components that have worn-out. During periods of starvation the cell uses autophagy to degrade non-essential parts to produce fuel and building blocks for essential cellular processes.
In 1974 Christian de Duve was awarded the Nobel prize for the discovery of the lysosome. Lysosomes are little sacs of digestive enzymes that sit inside our cells. Fungi and plants do not have lysosomes but the function of lysosomes is for the most part taken over by the vacuole. They have been described as cellular incinerators. Old, worn-out cellular organelles, such as mitochondria, are engulfed by a membranous sac (the resulting structure is called the autophagosome) this sac then fuses with the lysosome and the degradation process starts. This process of destroying cellular organelles by engulfing them in membranes and fusion with lysosomes is called autophagy. It was in fact de Duve who coined this term in 1963.
Ohsumi started his pioneering work in the early 1990s. Despite the fact that autophagy had been discovered 30 years earlier, little was known about it. For example, the mechanisms were unknown and also the role of autophagy in disease was unknown. Due to the fact that nobody was aware of any role for autophagy in disease, the study of autophagy received little interest outside of the field of cell biology. However since it has become clear that autophagy plays an important role in many disease processes such as neurodegenerative diseases, cancer, and infectious diseases.
Ohsumi used yeast as a model organism and mutated many genes expected to be involved in autophagy in the hope of finding cells in which the autophagy process was disturbed. In 1993 Ohsumi and colleagues published a landmark paper in which they describe 15 genes that are needed for autophagy. He named these genes autophagy 1 to 15 (APG1 to APG15). Later a unified naming system was developed and the abbreviation changed from APG to ATG. In the years that followed Ohsumi started to work out the role of these genes in the autophagy process. Ohsumi found that under nutrient rich conditions, the Target of Rapamycin (TOR) protein modified the Atg13 protein to reduce autophagy. This piece of work links directly to aging because TOR is a well known regulator of the aging process. The life extension drug rapamycin inactivates TOR and hence stimulates autophagy and the clearing of aging damage.
One example of aging damage that is cleared by autophagy are the protein aggregates that characterize neurodegenerative diseases such as Alzheimer’s disease. Treatment with rapamycin, that activates autophagy, has been shown to lower the toxicity of such protein aggregates.
Chemistry – Designing Molecular Machines
On the fifth of October, 2016 the Nobel committee announced that the Nobel Prize for Chemistry would be shared by Jean-Pierre Sauvage, Sir J. Fraser Stoddart and Bernard L. Feringa “for the design and synthesis of molecular machines”.
Biology is really dependent on small molecular machines. This first sentence in David S. Goodsell’s book “Our molecular nature” is “Busily at work within each of us is the most complex array of machinery known on earth”. This fact is beautifully demonstrated in this incredible beautiful short animation to the right that was made a few years ago and shows the internal workings of the cell.
One can see how a vesicle is transported around by a ‘machine’ that walks on ‘cellular highways’ (at 3:41) or how a tiny ‘translating machine’ makes proteins based on instructions in the form of an RNA code (at 4:41). These machines are not only tiny (nanometer scale), but also operate at incredible speeds and with extreme accuracy. For example, the little machine that copy the DNA can operate at speeds of 1000 letters per second and have error rates of about one error per ten million letters!
Chemists have been inspired by these natural machines and tried to construct artificial ones. The famous physicist Richard Feynman suggested in a talk given for the American Physical Society in 1959 that there’s “plenty of room at the bottom”. He gives the example of the fact that the full 24 volumes of the Encyclopedia Brittanica can easily be written on a pin head (about 1.5 millimeters across).
The first major advance that the Nobel committee cites is that of ‘topological entanglement’. Topological entanglement is a difficult word to describe two molecules that are not directly bounded together but whose movement is restricted by some kind of physical limitation. A good example of such a system is the magic trick called ‘Chinese linking rings’. Everyone has probably watched this trick at least once in their lives. A magician takes metal rings and is able to just link them together into a chain. Similarly, in the 1960s chemists figured out a way to synthesize two ring-shaped molecules that interlocked like the Chinese linking ring trick. The first Nobel Laureate, the French chemist Jean-Pierre Sauvage, succeeded in 1983 to make a huge leap forward in the synthesis of such linked ring-like molecules. Since this breakthrough the Sauvage group has been successful in synthesizing ever more complicated interlinked molecules.
The next step was taken by the lab of Sir James Frases Stoddart at the University of Sheffield (UK). In 1991 his team was successful in demonstrating ‘translational isomerism’. This is a difficult word to describe that they basically were successful in making two interlocked molecules move in a specific way. Their first success consisted of a ring-shaped molecule that surrounded a rod-shaped molecule. Upon putting energy in the system they could make the ring-shaped molecule move along the rod. They were also able to induce rotational movement. In 2004 the Stoddart group was able to design a complicated ‘molecular elevator’ that was able to move between two ‘floors’ that are 0.7 nanometer apart. The work from this group with the biggest practical value in the short-term is likely the development of molecular logic gates and memories. Logic gates are logic devices that allow our computers to process information.
The last Nobel Laureate was the Dutch chemist Bernard L. Feringa. His lab produced the first real unidirectional rotation device (a real molecular motor) in 1999. The energy for this motor came under the form of light. By further optimization, the Feringa group was able to design a motor that rotate with a frequency of over 12 MHz in 2014. But probably the most evocative success of the Feringa group was the design of a small automobile in 2011. Feynman had in his famous lecture already proposed to build such a car but Feynman’s design was 1 millimeter across and would function like a classical car with all parts just scaled down. In contrast the Feringa lab car was a single molecule, around a million times smaller than Feynman’s proposal, and operated on completely different principles than regular cars. The car was made by coupling four of their molecular motors and a rod-shaped ‘molecular chassi’ together. The car was operated electrically and drove on a copper surface.
What would be the practical application of such small machines for health and longevity? Well here again Feynman was a bit of a pioneer with the suggestion that we could design small robotic surgeons that could be swallowed or injected into the bloodstream. Such molecular machines (or nanobots for short) are still quite a few decades away. What is already on the market are small ‘bubbles’ filled with medicine and similar types of small particles with medication or imaging agents in or on them.
Royal Swedish Academy of Sciences (2016). Scientific Background: Discoveries of mechanisms for autophagy. Available at: https://www.nobelprize.org/nobel_prizes/medicine/laureates/2016/advanced-medicineprize2016.pdf
Martin Enserink, Elizabeth Pennisi (2016). Nobel honors discoveries in how cells eat themselves. Science 354(6308): 20.
Feynman RP (1959). Plenty of room at the bottom. Available at: https://www.pa.msu.edu/~yang/RFeynman_plentySpace.pdf
Goodsell DS (1996). Our molecular nature: The body’s motors, machines and messengers. Springer-Verlag New York, Inc.
Watson JD et al. (2008). Molecular biology of the gene. Sixth edition. Pearson Education inc. (pages 207-209).
Royal Swedish Academy of Sciences (2016). Scientific Background on the Nobel Prize in Chemistry 2016: Molecular Machines. Available at: https://www.nobelprize.org/nobel_prizes/chemistry/laureates/2016/advanced-chemistryprize2016.pdf