The quiet pathway

For many years regarded as merely a cell biological process, autophagy is now implicated in many diseases. Thanks to progress made in the Signalling research programme this year autophagy – the mechanism cells use to recycle unwanted or damaged components to create molecules they need – is now understood in greater detail than ever before. We find out how research at the Institute could harness autophagy to help us age more healthily.

 

The more we learn about autophagy, the more fascinating, important and complex it becomes. Literally the process of ‘self-eating’, autophagy is the cell’s way of recycling itself to survive short-term starvation, as well as cleaning itself of unwanted and potentially harmful material. Although most of us know little about it, autophagy is vital from the moment we are born until we die.



“It’s a quiet pathway, but it’s super important,” says Dr Nicholas Ktistakis, group leader in the Signalling research programme. “It is an ancient pathway – all cells have it – but normally it works in the background.”



Despite its usually unsung role, the better we understand autophagy, the more we discover about its links with health and disease. As newborns, it is what tides us over the period immediately after birth when our cells are our only fuel. Boosting autophagy seems strongly linked with longevity. There is evidence that by cleaning our cells of potentially damaging material, autophagy could be involved in protecting against neurodegenerative diseases such as Alzheimer’s and Parkinson’s. We now know that cancer cells use autophagy to fuel their uncontrolled growth. And it is even linked to the health benefits of fasting, including the 5:2 diet.



First described in 1963, Ktistakis has found references to autophagy dating back to 1860. During the past 50 years we have learned that many steps, and more than 30 genes, are involved in autophagy, and that two protein complexes – mTOR and ULK – are pivotal to the process. We have also discovered that it can be turned on and off with remarkable rapidity, and that switching on autophagy by inactivating mTOR can increase lifespan in model organisms by an astonishing 30%.



Autophagy works by forming small membrane-bound sacs or autophagosomes to bag up material for clean up or for fuel. It’s likely that these two types of autophagy – the selective clean-up variety and the general nutrient-generating type – share the same machinery but rely on different signals.



Understanding these early signals is a key focus for Ktistakis’ group and other researchers at the Institute. “A lot of our work is trying to figure out the signal the cell uses to start the process. It happens very quickly – within 15 minutes of detecting a drop in nutrients – and must stop very fast when conditions improve, because you don’t want to be digesting yourself for any longer than necessary,” Ktistakis explains.



“We want to understand it at the molecular level – what happens when the signal arrives, how quickly mTOR is switched off and on, and what happens when ULK is activated and leads to formation of the autophagosome. I’m interested in this early part of the pathway – in identifying how dynamic it is and which are the important players controlling how it happens.”

But studying such a complex, finely-tuned and rapidly reactive system is a huge technical challenge – one recently solved by the expertise in biological chemistry and imaging technologies in the Institute’s core facilities and collaborating teams. With so many proteins involved, many of which are protein complexes rather than single proteins, developing ways to tag them with fluorescent markers in order to observe autophagy as it happens is a tall order.



And it’s not the only challenge. Studying events so early in the pathway, before the autophagosome is visible, means Ktistakis had to develop new ways of seeing. By teaming up with scientists at the Francis Crick Institute in London and the Zeiss Microscopy Labs in Munich, the Babraham group has successfully combined live imaging with other forms of microscopy. These new techniques reveal how the first autophagy structure forms and the protein and membrane associations that lead to it developing into a fully-fledged autophagosome.



According to Ktistakis: “We now know more about where the autophagosomes form, and how the autophagy machinery uses the cell’s membranes to generate these tiny sacs. We still don’t know how these regions are selected, but we are keen to find out, because it will give us the final level of understanding.”



Understanding is important, but it’s the impact this knowledge could have on our lives that matters. Once we understand the process fully, it could enable us to find ways of harnessing autophagy to tackle neurodegenerative diseases and cancers, helping us age more healthily.



“When autophagy is more active, it is likely to make cells healthier, so knowing more about the process increases our ability to find ways to manipulate or boost it for future therapeutic benefit. The idea ultimately is that if we understand autophagy enough we can change it in a way that benefits the cell and the organism,” Ktistakis concludes. “We think this is probably a very good idea.”





This feature was written by Becky Allen for the Annual Research Report 2016