With all the excitement surrounding the discovery of a particle that might be the elusive Higgs Boson this week, it set DrugBaron wondering what might be the equivalent in biology. The Higgs particle suffuses the entire universe, giving mass to all the other particles. Is there anything so ubiquitous, so central to everything else, in biology?
DNA makes RNA makes protein is the central dogma of molecular biology, so that must be in with a shout. But making proteins is only half the story. For some proteins, at least, getting rid of them at the end of their useful life is harder than making them in the first place.
The process of removing misfolded and damaged proteins is called “autophagy” (pronounced ‘or-tof-ogy’), from the Greek meaning ‘eating yourself’. Like the Higgs particle, autophagy was first described in 1964 and has taken decades to rise to the prominence it deserves. Today, the process of autophagy plausibly contributes to every chronic degenerative disease of middle and old age and the discovery of drugs that can control this central process could revolutionize medicine in much the same way that finding the Higgs Boson could revolutionize physics.
Proteins are the stuff of life – responsible for every key process in every living cell. Nucleic acids, in all their diversity from DNA in chromosomes to regulatory microRNAs, exits only to create the right proteins in the right place at the right time.
These proteins are incredibly diverse, and incredibly clever – fulfilling roles as different as scaffolding and enzymes to interconvert a dizzying array of metabolites with exquisite sensitivity. All these functions depend on the precise three-dimensional structure of the polypeptide chain, presenting the twenty different amino acid side-chains in a carefully chosen arrangement.
But, robust as amide bonds are, the three dimensional folded structure is susceptible to disruption by external stressors: chemicals, heat and UV light all damage proteins. Even quite minor damage can render the protein useless for its intended function, and in most cases the changes cannot be readily undone. Once damaged, the protein is useless and needs to be replaced.
For many prevalent degenerative diseases – such as Alzheimer’s or autoimmunity – there is a common safety valve: the autophagy pathway
However, disrupting the fine folded structure of the protein leads not just to loss of microscopic activity but also to macroscopic changes in properties. Most obviously, when proteins become denatured their solubility is decreased. Look at egg whites used to make a meringue – egg white is a solution of dissolved protein that is clear and almost colourless, but after whipping for several minutes to denature the protein, it changes into a stiff, white suspension. Cooking eggs achieves a similar conversion.
This turns out to be a headache for cells. Once the protein comes out of solution it is difficult, if not impossible to handle. The enzymes responsible for degrading proteins, called proteases, struggle to get a handle on the precipitated mass of denatured protein. Without “special measures”, these nodules of denatured protein would accumulate and eventually kill the cell.
For proliferating cells, this problem is relatively straightforward to solve: the accumulated debris made up of denatured proteins and damaged or dysfunctional organelles such as mitochondria, is jettisoned. The cell undergoes an assymetric division, shunting all the debris into just one the daughter cells, which is sacrificed – allowing the other daughter cell, free of damaged components, to proliferate healthily. The debris-laden daughter undergoes apoptosis and its components are resorbed through phagocytosis.
But denatured proteins and damaged organelles are a much bigger problem for quiescent cells, and in particular post-mitotic cells (those that can no longer undergo cell division, as a result of their specialized differentiation) such as neurons and muscle cells. These cells, which often have very long lifetimes (some post-mitotic cells in the human body last for your whole lifetime), have lost the option to jettison debris by assymetric division. They need a new solution.
That solution is autophagy.
Drugs that stimulate autophagy will do for common degenerative diseases what the recent crop of drugs have done for so many orphan diseases
The aberrant proteins and organelles are surrounded by a double membrane to form an autophagosome, in a process regulated by PI3Kinase and several “atg” proteins first discovered in yeast. The autophagosome then matures into a lysosome where the contents are crudely degraded by acid hydrolases.
Controlling the rate of this process is critical to lifespan, not only of the cell but – of greater interest to all of us – the whole organism. Those who efficiently deal with debris, keep their cells, their tissues, their organs in good shape for longer. Those who have less efficient debris clearance mechanisms succumb to degenerative diseases earlier and with greater severity – as soon as the amount of accumulated debris reaches an intolerable level.
Fortunately, the rate cell debris clearance has not been left to chance: nature has cleverly coupled the rate of cell debris clearance to the amount of debris waiting to be cleared. The number of litter-pickers goes up and down with the amount of litter lying on the ground. This mechanism works well – and indeed you can exploit it to your considerable benefit. When you take exercise, you cause damage to some of the muscle fibre proteins in your muscles, and this gentle stimulus elicits a spring-clean not just for your muscles but for all your organs from pancreas to brain. Increasingly this is being recognized as a key mechanism by which exercise improves health and longevity.
It isn’t just exercise that can boost your cell debris clearance. The ultraviolet component of sunlight is particularly damaging to skin proteins – again providing a steady prod for the clearance mechanisms. It is no coincidence then that individuals from sunny climes live longer, and suffer less degenerative diseases (with the exception of skin cancer) than those from northern latitudes where sunlight is rationed.
Or else, you can starve yourself back to health. Autophagy and cell proliferation are inversely coupled – dividing cells don’t need autophagy to ditch their damaged components. And your cells have a powerful, ancient mechanism that links cell proliferation to nutrient availability; a mechanism that operates as powerfully in your body as in a broth of primitive unicellular yeast. If nutrients are scarce, proliferation is toned down and autophagy is increased. Severe calorie restriction, then, is another way to spring clean your tissues. In diabetes, of course, where (at the cellular level) nutrients are never scarce, the reverse is true and cell debris clearance is downregulated in people whose proteins are under particularly intense assault from advanced glycation end-products.
If you don’t keep those tissues clean and tidy, eventually a crisis will occur. That crisis is triggered by the protective feedback circuit that increases the army of cleaners when debris levels rise. But what happens to the cleaners? Unfortunately, they are not immortal, and when they die they create – yes, you guessed it – debris. More debris, more cleaners. More dead cleaners, more debris. Positive feedback. Crisis.
These mechanisms are almost ubiquitous. Every disease you can imagine from Alzheimer’s Disease to diabetes, depression to osteoporosis, schizophrenia to autoimmunity has misregulation of these ancient pathways that control the disposal of damaged and unwanted cellular components at their core.
What about cancer? The ultimate degeneration of normal tissue structure and function – where does autophagy fit in the story of malignancy? Inefficient clearance of damaged proteins plausibly contributes to malignant transformation in the first place – there is much talk of “genomic instability” in cancer, but all the instability may not lie in the DNA. Increasingly, we are becoming aware of “proteome instability” in cancer, where accumulated damage to key proteins – particularly those such as p53 that regulates the DNA repair circuitry – is the first environmental “hit” in the transformation cascade.
But from a therapeutic perspective, perhaps the most interesting role for autophagy in cancer is the dependency of the rapidly proliferating tumour cell on the autophagosome. At first sight that’s contradictory to much of the earlier story – dividing cells don’t need autophagy. But cancer cells proliferate rapidly and in a very disordered way, with not the slightest chance of orchestrating an asymmetric division to jettison debris. Moreover, the hypoxic environment of the tumour microenvironment triggers its own kind of protein denaturation. Cancer cells, it seems, are paradoxically more dependent on autophagy than normal cells (even post-mitotic ones). Your heart, muscle and neurons can survive without tidying up for some considerable while, but cancer cells cannot. Without autophagy, the only option is honourable apoptosis.
Autophagy, then, is everywhere.
In physics, it is the mystical Higgs particle that ties together the ultimate Theory of Everything. Autophagy comes closest to fulfilling that same role in biology and medicine.
Gaining control of this critical process, then, promises a new wave of medical breakthroughs. Too many supposedly innovative therapeutics in the last decade have flattered to deceive. Each newly discovered pathway, touted as the cause of one disease or another, has been the target for drug hunters. And each pathway in turn has turned out to be less critical than expected – at least in the majority of patients. And as a result the incremental benefit of these expensive new therapeutic options has been marginal at best.
One of the few bright spots in the pharmaceutical landscape has been in orphan diseases. Drugs that successfully treat an array of rare diseases, many unheard of even to most doctors, have dramatically improved the lives of the minority who suffer them. The contrast between “big indications” and orphan diseases could not be more striking: in the rare conditions, typically caused by genetic defects in a single gene or pathway, the cause of the disease is consistent and drugs that hit that pathway offer real benefit. In common diseases, by contrast, an bewildering array of genetic and environmental factors act as triggers and drugs that treat these triggering pathways have marginal benefit, simply because there are so many triggers acting in parallel.
But for many of these diseases, there is a common safety valve: the autophagy pathway. Multiple triggers lead to disruption of tissue architecture. Autophagy attempts to set matters straight. And if you have a strong cell debris clearance mechanism you may never succumb to the degenerative diseases that typify middle and old age for so many people.
Stimulating autophagy, then, ought to protect against many different diseases – and against many different genetic and environmental triggers for the same disease. These stimulators of cell debris clearance should, in theory, offer the step change in treatment of these diseases that has eluded that generation of drugs targeting the parallel triggers.
Like the Higgs particle, autophagy was first described in 1964 and has taken decades to rise to the prominence it deserves.
And the evidence is gathering to support that proposition. Exercise protects against many different diseases, and some (at least) of that protection is mediated through stimulation of debris clearance. Drugs that modulate clearance (such as mTOR inhibitors and sirtuin activators) actual extend life – at least in laboratory animals. And the gene encoding apoE, a critical regulator of debris clearance, remains the only gene in the genome associated with longevity in man.
DrugBaron has already examined how a number of companies are now targeting this apoE protein to develop exciting new therapeutics. But the opportunities are much wider still. Our understanding of the regulation of autophagy is as incomplete as our understanding of the Higgs boson. We will see an explosion in drugs that modulate autophagy – both stimulators and inhibitors – over the next few years. And there is every reason to be confident that these drugs will do for common degenerative diseases what the recent crop of drugs have done for so many orphan diseases. Place your bets – the race is on!
RxCelerate Ltd is an outsourced drug development platform based near Cambridge, UK. We specialize in delivering an entire road map of drug development services from discovery and medicinal chemistry through to formal preclinical development and clinical up to Phase IIa. In the last five years, we have witnessed dramatic changes in the drug development …