Research Articles

Understanding Parkinson’s Research

Introduction

For those unfamiliar with the world of research, this page gives a brief review of the principles and how it is conducted. We move on to introduce the principal topics of current research using some of their specialist words.

Parkinson’s research today draws on the sciences of neurology, biochemistry, genetics and molecular biology. Research and treatment processes are increasingly reliant on technologies. Complex, rapidly changing – but are they beyond the understanding of ordinary mortals?

Maybe yes, insofar as research is advanced by the work and insights of many scientific practitioners whose technical dictionaries are way beyond a layman’s understanding. But no, insofar as research depends ultimately on those who pay for it and on the people who help advance it by, for example, volunteering for trials. The research community must use a shared language. Furthermore, plain English is quite sufficient to explain how the research world functions and you do not need to understand how gravity works to contribute to a study of its effects.

We begin at the beginning; the hypothesis.

The Hypothesis

A hypothesis is a proposed explanation for something observed to be happening. A research study of a hypothesis must conform to a formal structure that declares, up-front:

  • The expected outcome of the investigation and the whys and wherefores.
  • The criteria to be met for the hypothesis to be vindicated; in clinical trials called the “primary outcome”.
  • The methods used.

A fundamental principle of research requires the results to be replicated before a hypothesis can be accepted. Support for a hypothesis may also come from a survey of multiple studies searching for knowledge through comparison and consolidation. Before the study is published, the “Article” describing it must be “peer-reviewed” by a suitably qualified independent person.

So far so straightforward, until you consider the scale of this enterprise. Parkinson’s research is generating thousands of articles per year in more than 150 Journals for the Neurology profession and over 2,000 journals covering biochemistry, genetics and molecular biology. Also, and as in real life, research is subject to the availability of money, to honest endeavour, chance, mistakes and occasionally to misrepresentation.

Publication

Just the number of Journals tells us that researchers face a challenge in keeping up to date in their own field, let alone keeping track of others. “Silos” of specific research activity have developed and communication between silos is problematic. They also face a challenge to get their work published, share their knowledge and be recognised as the contributor. Numerous as the trade journals are, the demand for publication space now far exceeds the space available. As a further complication,, a researcher’s career progress is commonly measured by the number of publications and mentions – “citations” – that they achieve.

Traditionally articles have been published first in the trade journals, behind a subscription “paywall”. To drive their readership up, journals compete to capture articles with the potential for making an impact. On the readership side Research Institutions and clinical practitioners need both the knowledge contained in articles and a quality control system – Peer Review – to filter articles. This combination of supply and demand factors has led to the rise of prosperous publishing empires, and a level of interdependence that arguably creates an unhealthy climate for the integrity of research.

The Open Access movement is bringing an increasing number of articles to free (to the reader) and full availability straightaway. It is now a condition of funding with some funding organisations. However, research publication is not a free resource, so the cost of publishing falls on the researcher.

Funding

A proposed study must already have or be able to attract the funds to make it happen. A great deal of a researcher’s time is taken up securing funds from government, charitable and commercial sources. Notably in molecular biology the research aim is to discover “intellectual property”, meaning the ownership of specific knowledge about a process or a material. Intellectual property is expressed in Patents. The owner may be seeking financial benefit (a pharmaceutical business, a government agency, an academic institution, the individuals conducting the research) or for the common good (national government, a charitable foundation, a philanthropist).

Timescale

The time from completion of a study to publication varies from weeks to years – and sometimes never – so someone else’s study plan may not be best informed. Furthermore the importance of a study may not be clear immediately, or it may later turn out to have misdirected subsequent studies.

Involvement of PwPs – People with Parkinson’s

Most of the articles published are impenetrable to the layman. So forward steps the Media industry with translations into everyday language, with varying degrees of reliability and sensationalism. The nature of Parkinson’s and the slow progress towards new treatments means that charlatans are at work, notably in the stem cell field.. The PwP community must be alert to this fallout from the research world.

Many institutions in the research community have historically viewed Parkinson’s as a disease to be studied in the laboratory. However, the last ten years or so has seen repeated failures in clinical trials to find new treatments – “therapies” – across the spectrum of neurological disease. This and the increasing concern about the rising incidence of Parkinson’s worldwide has motivated the research community to look much more closely at the lived experience. PwPs are engaged in influencing opinions and policies advocating change, but the two principal contributions that an individual can make are firstly to this quest for understandable information, and secondly to the trials of potential treatments. These are the topics in which PenPRIG is active.

Research directions

Until relatively recently our understanding of how Parkinson’s attacks the brain was limited to post-mortem examination. Degenerative diseases of the brain are the outcome of premature death of cells, but the clinical diagnoses of neurological diseases are only loosely informed about the cells in question. Why? Because it is very hard to get the evidence. Some types of damage can now be identified by brain imaging and biological samples, but it is still the case that definitive clinical diagnosis of Parkinson’s rests on examination of the brain after death. Arguably this is a self-fulfilling prophecy.

The focus of Parkinson’s research can be described with a simple model of what is happening (or not). All our conscious movements and unconscious processes such as breathing are enabled by a specialised class of cells – “neurons” – deep inside the brain. They initiate movement by firing electrical signals. To do that they create a specific chemical and rely on a biological battery cell. The neurons are surrounded by a multi-purpose support crew. Parkinson’s is one, some or all of these events:

  • 1. Progressive neuron death, howsoever caused.
  • 2. Reduction in output of the specific chemical, “dopamine”.
  • 3. Failure of the battery cells – the “mitochondria”.
  • 4. Failure of members of the support crew; they die on the job or collectively cannot cope with the situation.

As time passes, Parkinson’s reveals itself as a condition in which:

  • 5. There are no reliable biological indicators for onset or characteristics for progression.
  • 6. The progression of symptoms is an increasingly challenge for PwPs and those around them to manage.

Research so far has been overwhelmingly concentrated on Disease Modification therapies (1 through 4) and has recently expanded into the field of biomarkers and other diagnostic tools (5). Everything we have right now are Symptomatic therapies (5), most of them based on discoveries made over 30 years ago.

Disease Modification Therapies

Research knowledge has increasing rapidly using animal models and through advances in biotechnology. A great deal of activity is concerned with basic biology, from which springs the development of “compounds” for disease modification, meaning to slow down, stop or reverse the progression of the disease. Notice that the research community is now very wary of the word “cure”. Examples include stem cell therapy and re-purposed drugs.

For Genetic Factors. Although it was long suspected by some that heredity had a role in Parkinson’s, this was not a widely shared view. The investigative tools became available in the late 1990s and were used in a study of an Italian family over to show mutations in a gene were responsible for a heritable form of Parkinson’s. Since that time some 20 genes have been identified in various inherited forms of Parkinson’s.

Can the neurons that we are losing be replaced? This is already the graveyard of major studies, an ethical minefield until recently and technically incredibly challenging. The “Stem” cells injected must reliably develop into the correct type of neuron and in enough quantity to make a difference. There is a considerable amount of activity in gene-specific therapies, notably for the GBA and LRRK (pronounced “Lark”) defects. This presents a precise target for research.

Idiopathic Parkinson’s. Idiopathic means “I don’t know where you got that from”. Inherited Parkinson’s is in the minority, and having a genetic defect is by no means a prediction that the individual will develop it. Estimates for genetic origins range from 15% to 25% of the PwP population, the balance of diagnoses being idiopathic.

As a matter of course our skin cells die and are easily shed. Cell death is also true in the brain, but removal of the debris is rather more complicated. The most extensively researched hypothesis to date holds that Parkinson’s is the consequence of an accumulation of a type of debris that suffocates the neurons because the support crew does not recognise the problem or cannot cope. This is the protein called “alphasynuclein”; to be precise a deviant “mis-folded” variety. Several trials have been conducted with drugs that aim to remove it. A similar hypothesis with another type of debris has prevailed until recently regarding Alzheimers.

Other research activity is addressed “mitochondria” mechanism that charges each neuron’s battery and to other ways of protecting and protecting the support crew are being explored, with the aim of at least stopping the rot and hopefully stimulating re-growth of neurons.

Drug Re-purposing. Several new – “novel” – drugs have failed in clinical trials. The costs, timescales for the development of new compounds are increasing. This is driving a significant shift in the direction of research to the possibilities for using drugs already approved for other treatments.

Symptomatic Therapies

Of more immediate relevance to the daily lives of PwPs are therapies that alleviate the symptoms and thereby improve the lived experience. Examples of reserarch in this field are:

    • More responsive delivery methods for the so-called gold standard drug Levodopa
    • improved techniques and technology for surgical procedures such as “DBS” – Direct Brain Stimulation
    • Studies to establish exercise programmes as being of proven benefit.

Not enough, you may think. And you would be right.