Understanding Parkinson’s Research – The Nature Of The Beast
The Parkinson’s research community now benefits from thousands of studies each year. The field of study is enormous, from fundamental research to clinical practice, across Neurology, Biochemistry, Genetics and Molecular Biology. In addition there is the possibility of insights from other fields of science and technology. Research happens in a complex world.
Research studies, for acceptance by the international community, must conform to a formal model. Firstly, a statement of the expected result of the investigation, the idea being tested; the research world refers to “the hypothesis”. Secondly, the criteria that will decide whether the hypothesis is valid or not; sometimes cut down to a simple pass mark. Thirdly, the method(s) used to test the criteria to show whether the hypothesis is valid, or not. The hypothesis, criteria and methods are all open to challenge by other studies. A fundamental principle of research requires replication before a hypothesis will be accepted. Many findings are straightforwardly confirmed in subsequent or parallel studies, or the reasons for an unlikely finding are identified, or a hypothesis thought to sound is fatally undermined. Studies of similar purpose are hoovered up by studies of studies (“meta-surveys”) looking for more knowledge from consolidation. We do not live in a perfect world, so this whole process is subject to honest endeavour, chance, mistakes and (occasionally) misrepresentation. In the quest for Parkinson’s treatments, a study may be a step forwards, sideways or (later turn out to be) a step backwards.
From studies flows a cascade of articles published in the trade journals of the many professions involved. The professions face a challenge in keeping up to date in their own their own field, let alone keeping track of others. There are 150+ journals in the field of Neurology alone, and over 2,000 covering Biochemistry, Genetics and Molecular Biology. The time from completion of the study to publication of results in an article varies from weeks to years to never, so a study may or may not be informed by the best information in its research field. Equally the importance of an article may not be clear at the outset. The research field is complex, the research topics are specialised both in their nature and in the skills involved. “Silos” of research activity are inevitable and communication between silos is problematic.
A study, notably in fundamental science, may rely on or generate “intellectual property”. This knowledge of data, a process, a material, etc. may be owned by an institution, company or individuals. Intellectual property, when expressed in a Patent, is a basis for commercial gain or the prevention of gain by others. A pharmaceutical business, a government agency, an academic institution, a charitable foundation, a philanthropist, has made a judgement about the outcome of providing facilities, technology and salaries. The judgement may be commercial, societal, entrepreneurial, personal or driven by circumstances. However, as the supply of money is finite, choices must be made. Choices can be influenced in many ways, “fair” or otherwise. The motive for a study or series of studies may be a corporation’s profit or a government agency calculation of the cost benefit of misery reduced. A commercial motive is never far behind a research study; they are rarely free.
The medical research and publishing worlds are closely interweaved. Most articles are first published in subscription journals, behind a “paywall”. Journals compete to capture articles with the potential for making an impact. The career progress of researchers is commonly measured by the number of mentions, “citations”, that they achieve. Research Institutions and clinical practitioners need both the knowledge embodied in articles and a system that filters articles. This heady commercial mix has led to the rise of prosperous publishing empires, and a level of interdependence that is seen to restrict the availability of knowledge. The Open Access movement is bringing an increasing amount of articles to free (to the reader) and to full availability straightaway. Open access publishing as a condition of funding is now a policy of some funding organisations. However, research publication is no more a free resource than any other part of the process, so the cost of publication in this model falls on the researcher. Research must be done, seen to be done and seen promptly. Availability of research findings to Parkinson’s researchers is of great importance. Obstacles to it are of practical and ethical concern.
However, availability does not change the fact that most articles are impenetrable to the layman. The media industry frequently steps forward with a translation into everyday language, with varying degrees of success. Most of us must rely on competent commentators to assess the importance of the information and express it in plain English. The nature of Parkinson’s and the slow progress towards new treatments means that the field of study now includes studies driven by personal and commercial agendas, to the extent that charlatans are at work. The other side of this coin is the relevance of the research work being done to the lived experience. The willingness and ability of People with Parkinson’s to contribute to research is much dependent on the connections made between what must be done by research professionals, and what can be done by the layman. The principal contribution from the people with Parkinson’s comes at the clinical phases of the research process, which is the focus of PenPRIG.
Parkinson’s was once thought not to have genetic causes. In 1997 mutations in a particular gene were shown to be responsible for a form of Parkinson’s in some families. Over the following 30 years some 20 genes have been identified in various inherited forms of Parkinson’s. Even so, inherited Parkinson’s remains in the minority. Estimates range from 15% to 25%, the balance being an Idiopathic Parkinson’s diagnosis. Idiopathic is best understood as the medical dictionary entry for “don’t know where you got that from”.
Whether Parkinson’s has been inherited or acquired from somewhere, the basic mechanism of the disease is the same, at least insofar as our movement problems (“motor deficits”) are concerned. The neuro-degeneration at the root of Parkinson’s is a result of the loss of signals between brain cells in a specific part of the brain. The identification of genetic cases, and therefore of individuals who can be investigated in depth is facilitating research into the mechanisms that are causing this loss of signal.
The Not bohemian, just ‘Rapsodi’ study is looking at people with the GBA gene risk factor and who also demonstrate the early signs of Parkinson’s. The GBA gene was the topic for Dr. Stephen Mullin’s talk at the inaugural PenPRiG Meet The Researcher events. The LRRK2 (“Lark two”) gene is another villain of the piece. The Michael J Fox Foundation brought together otherwise competing companies to demonstrate that drugs that (in essence) switched off this faulty gene were safe for human use. They are part-funding the Denali Phase 1b clincal trial.
Slow, stop, reverse
Outside the genetic sphere the causes of Parkinson’s are the subject of much speculation. What makes the brain susceptible is not at all clear, and until relatively recently our understanding of how Parkinson’s attacks the brain was limited to post-mortem examination of the brain. The root cause of degenerative diseases of the brain is, by definition, the death of cells. The differences between neurological diseases are marked out by which part or parts of the brain are affected and by the rate of progression of the disease. This damage can be identified in brain images of live subjects, but it is still the case that definitive diagnosis rests on examination after death. In a somewhat perverse twist of terminology, by “progression” the medical world means deterioration.
The research knowledge base has expanded through the development of animal models and advances in biotechnology. However, the detailed biological mechanisms of Parkinson’s are still the subject of much research effort and argument. A great deal of research activity is concerned with basic biology, where the opportunity for interaction with members of the general public is distinctly limited. From basic biology springs the development of drugs (“compounds”).
The objective of a compound may be to slow down, stop or reverse the progression of the disease. Examples include stem cell therapy and re-purposed drugs. Perhaps of more immediate relevance to People with Parkinson’s are treatments where the intention is to maintain or improve the lived experience. Examples are the so-called gold standard drug, Levodopa, surgical procedures such as Direct Brain Stimulation, and exercise programmes.
What are the mechanisms that cause the premature brain cell death that is symptomatic of Parkinson’s? The biology is complex and partially understood but is sufficient to support a simple model of what is happening, or not. All our conscious movements, and unconscious processes such as breathing are enabled by neurons (aka neurones) creating or responding to electrical signals between each other. Everything else in the brain can be regarded as members of the support crew.
Treatment addressed to the neurons, Nurturing The Neurons may for example be focused on the mechanism that charges the internal batteries of neurons that fire the signals. In the normal course of events cells die. Our skin cells are continuously shed. The same is true within the brain, amplified by the life cycle of the cells that service the electrical activity. The most widely held view at present of the cause of Parkinson’s is that by not Removing The Rubbish, the accumulation of dead material suffocates the neurons.
Stem cells are the most newsworthy treatment strategy, the beguilingly simple idea of replacing the neurons that we have lost with new ones. Simple, but already the graveyard of major studies, an ethical minefield until recently and technically very challenging. In certain parts of the brain new neurons are developed spontaneously, but there is no evidence of this in the parts of the brain concerned with Parkinson’s. Thus the stem cells injected must reliably develop into the correct type of neuron and in enough quantity to make a difference. An alternative treatment strategy of refreshing the support crew, the GDNF Trial shows the promise of new neuron growth in the places where it counts. These approaches may not bring a complete return of function since any collateral damage would not be repaired, but otherwise are arguably a Cure for Parkinson’s. Nevertheless this trial was adjudged clinically as a failure.
Several newly-created drugs have failed in clinical trials. The costs, timescales and processes for development of compounds are all increasing. As a result there has been a significant shift in the direction of research to the possibilities for using drugs already approved for other treatments. This is a July 2018 review of the safety and potential efficacy of the most promising candidate drugs in the advanced stages of clinical testing.
Clinical Trials Many of those some way down the road of understanding our condition will have considered taking part in a clinical trial. PenPRiG’s purpose is to promote local opportunities. We share knowledge about the clinical trial process as it is today and views as it perhaps should be tomorrow. Informed Consent” is central to participation in a trial. Introducing Clinical Trials Highlights explores the issues.