The science of Parkinson’s In the Parkinson’s universe, how much do we really understand?

Dr Beckie Port  -  Research Communications Manager - Ex-researcher in oncology and virology.(UK)

February 5, 2018

Over a century ago, Albert Einstein dramatically shifted our concept of space and time. His work on general relativity, presented over the course of 4 lectures in 1915, still underpins much of our understanding of the wonders of the cosmos, and continues to impact on our life on earth.

While a ‘theory of everything’ still eludes even the greatest minds in physics, the combination of general relativity and quantum mechanics, along with the development of countless other theories, has seen an unprecedented acceleration in our understanding of the physics which governs our reality.

So, why am I starting a Parkinson’s post with these theories?

In some ways, our scientific understanding of Parkinson’s today resembles the understanding of the universe pre-1915. And, as the 20th century brought about a new framework for physics, connecting a multitude of concepts relating to space, time, mass, energy and gravity, the 21st century is bringing a dramatic shift in our understanding of Parkinson’s.

In Parkinson’s, progress is being made every day on many different fronts. While it may seem that these different lines of research are unconnected and unable to guide one other, there is a bigger picture at work built upon our combined understanding. Together small advancements being made around the world are bringing us closer to a treatment that will one day consign the condition to the history books.

While this post contains no such unified theory of Parkinson’s, the condition is in many ways as complex as the universe that physicists are still trying to understand, I hope that it will highlight some of the ways recent discoveries in seemingly unconnected Parkinson’s fields, and neuroscience more generally, influence and depend on each other. It is in these connections that I find hope for new and better treatments, and one day a cure.

Developments in the management of Parkinson’s symptoms have produced the most meaningful impact on the lives of people with Parkinson’s over the last few decades. Improvements have come in many forms — from different delivery mechanisms for Parkinson’s drugs and their combination with other compounds which extend their use and reduce their side effects, to advances in surgical techniques and better understanding of the role of exercise in symptom management. But, despite these developments, Parkinson’s remains a debilitating condition.

The main treatment at the heart of most Parkinson’s drug regimes is levodopa, which has been around for over 50 years. And, while current medications play an important role in managing symptoms, too often they fail in the later stages of the condition. Perhaps most surprising is that 200 years after it was first described we still have no therapy that is able to slow or halt the progression of Parkinson’s.

But we are on the brink of new and better treatments, driven by a dramatic improvement in our understanding of Parkinson’s over the last few decades. Today, we are starting to understand the universe that exists inside these brain cells and appreciate the complexities that have prevented a cure from being developed for so long, we can see the challenges and now science is helping us to overcome them.

Let’s start by delving deep inside the brain to look inside the cells affected by Parkinson’s — the dopamine producing cells of the substantia nigra . While it is generally recognised that Parkinson’s does not start in these cells, studies of the progression of the condition show its spread from further down the spinal cord and, in some cases, may even originate in the gut, it is their loss that causes the symptoms of the condition.

Over the past few decades, we have learnt a lot about how Parkinson’s impacts on the pathways and distinct parts of these brain cells, and have started to discover what goes wrong leading up to their loss. This is where the first challenge in Parkinson’s appears…

“Parkinson’s was once thought to be the easiest of the major neurological disorders to solve. The knowledge of the past 20 years, has been great, but it’s also made the field appreciate just how complex a disorder it is.”

 — Martin Taylor 

Unlike in other conditions where a single genetic change or faulty pathway can be identified as the root cause, what we have learnt is that the cause of brain cell loss in Parkinson’s is incredibly complex. Multiple parts of cell are disrupted — from the cellular power stations and waste disposal systems, to the way the cell copes with stress and responds to inflammation. To further complicate matters, these processes are linked and can impact on each other in a web like fashion, so establishing the faulty link that starts the downhill spiral towards cell loss becomes challenging.

Much of our understanding of what happens inside these cells has come from relatively rare genetic factors that predispose certain parts of the cell to malfunction. These associations have helped researchers develop studies and animal models to pick apart the problems at the root of Parkinson’s and find the commonalities that exist between both inherited and sporadic forms of the condition.

Through these studies, researchers are adding snippets of information to our global understanding — using their expertise to tease out previously unknown connections. At the same time other teams are bringing all the pieces of the puzzle together, translating biological discoveries into databases and producing a map of this complex web that allows researchers to see how their science interacts with the bigger picture.

It is with this understanding that we can now see how individual scientific discoveries are linked, and how, in Parkinson’s, a broken connection can rapidly snowball out of control. But this map also suggests ways to stop this snowball, which could be a game changer in a condition which we are currently unable to slow.

Better understanding is allowing us to develop new drugs that specifically target areas of the cell at the root of the problem, these drugs aim to correct or bypass disruptions protecting brain cells and preventing their loss. And with thousands of drugs already available on pharmacy shelves to treat different conditions that have yet to be tested in Parkinson’s, the answer may already be out there waiting to be found. This idea is called drug repurposing, and could help to deliver a better treatment for Parkinson’s in years, not decades.

Whether a wonder drug is already out there, or still needs to be developed, we’re ready with the Parkinson’s Virtual Biotech to invest in the best ideas and make sure the treatments with the most potential go forward toward clinical trials.

As we learn more about what is happening inside the brain cells of those with the condition, it is becoming clear that different things are at the root of Parkinson’s in different people and it is likely there are different types of the condition. This discovery helps to explain why no two people with Parkinson's are the same — everyone has different symptoms and responds differently to medications. 

Progress is being made towards identifying these different types of Parkinson’s, knowledge which will likely bear condition halting treatments for individual subsets of people. The speed at which these personalised treatments will be delivered will be based on the ease of identifying the underlying problem, and the ability to address and correct it in a manner that is both safe and effective. And when we consider that an effective treatment must be able to reach the brain cells that are lost in Parkinson’s, producing a new drug treatments that are safe and effective is no simple feat.

Developments are already being made on this front, advanced in part by science’s relatively new ability to take skin samples, turn the skin cells into brain cells and take a close look at what is going wrong inside them. This cell manipulation wizardry is also allowing researchers to test potential drugs that specifically target parts of the cell, such as broken down power stations or malfunctioning waste disposal centres, and better understand what treatments would work and in which people.

Advances in drug delivery systems may also facilitate in the production of safe and effective treatments for Parkinson’s. The groundbreaking GDNF clinical trial saw the development of an innovative drug delivery system specifically designed to help get the therapy into the brain where it is needed. And other researchers are investigating the potential of novel therapies such as vaccines and gene therapy for Parkinson’s. 

While the complexity of the condition may mean that we need to target multiple different parts of the cell in different individuals, some comfort can come from looking for similarities, areas of the cell that seem to fail more often than not.

It also means that some of the potential drug therapies for Parkinson’s that have reached, but then failed to show benefit in, late stage clinical trials may have failed simple because the drug was not tested in the right people. But it may soon be possible to ensure new treatments are tested in the right people, and this is one way in which our Critical Path for Parkinson’s project aims to make clinical trial for Parkinson’s faster, cheaper and more likely to succeed. 

If the need for personalised treatments in a complex condition wasn’t enough, there are still more challenges that Parkinson’s puts up.

Currently there is no simple way to measure Parkinson’s. In the lack of a simple test for Parkinson’s, the main way we measure Parkinson’s is using a scale called the Movement Disorders Society Unified Parkinson’s Disease Rating Scale (or MDS-UPDRS for short). But while this scale can quantify different symptoms, it cannot measure the progression of the condition — which is crucial to demonstrate that a new treatment can slow its course.

Scientists have been making headway in the search for a biomarker of Parkinson’s, something in the body that changes as Parkinson’s progresses. Ideally we would want to measure this change with a simple test such as a blood or urine test, or a brain scan, and here again advances in other areas of science may be our solution.

Today we have more highly sophisticated machines that can accurately detect minute changes in chemicals present on our skin and in our breath, which Parkinson’s researchers are looking to utilise. We also have imaging techniques that allow us to see inside the brain with greater clarity than ever before. 

These developments are bringing a simple test to measure Parkinson’s within reach.These developments may also mean that we are able to detect Parkinson’s in the very earliest stages, potentially many months or even years before diagnosis would currently be possible. In the hunt for new and better treatments, this ability to predict Parkinson’s could play an important role in finding drugs that truly slow or stop it, and one day prevent the condition all together.

A cure for Parkinson’s will look different for different people, for those in the early stages halting the condition and managing its symptoms without side effects may be the answer, while for those with more advanced symptoms researchers are looking for ways to encourage cells to grow back or to replace them.

Our capacity to direct the path of these naive cells, coaxing them to become any number of fully fledged functional adult cells, including dopamine producing brain cells, is progressing at a rapid rate. This means that while today’s Parkinson’s therapies focus on replacing and maintaining dopamine levels we could be soon able to replace much more.These developments have encouraged investment in cell banks, which could one day become the source of donor cells to treat a range of conditions — replacing old, malfunctioning or missing cells with new functioning cells able to turn back the hands of time in conditions like Parkinson’s.

While researchers are driving forward our knowledge of Parkinson’s and how to overcome its challenges, there is another voice needed to fully understand the Parkinson’s universe. Those with the condition, their family, friends and carers form the final vital piece of the big picture. As experts in the condition they can direct and inform research so that it addresses the needs of those affected, and undertake an essential role by taking part in research studies to continue to increase our understanding and test new drugs and therapies.

After all, the Parkinson’s universe is made up of more than just science and researchers, and if there is one thing that will drive us towards new and better treatments it is the Parkinson’s community

https://medium.com/parkinsons-uk/the-unified-theory-of-parkinsons-778a43e8cca6