How we can collectively expand our assault on Parkinson's disease

A Patient’s Essay on a Modified Approach to Eradicating Parkinson’s Disease

Written by Bruce Davies B.A., B.D., M.B.A. (published November 2012)


This essay was written in SEPTEMBER 2012 - and some key items have obviously changed. 

The UPDATES subsequently inserted in RED in the text below are designed to draw your attention to these changes 

Parkinson’s Disease appears to have been around for a very long time.
Several early sources describe symptoms resembling those of PD. An Egyptian papyrus from the 12th century B.C. mentions a king drooling with age and the Bible contains a number of references to tremor. An Ayurvedic medical treatise from the 10th century B.C. describes a disease that evolves with tremor, lack of movement, drooling and other symptoms of PD.” 
“In 1817 James Parkinson published his essay reporting 6 cases of paralysis agitans. An Essay on the Shaking Palsy described the characteristic resting tremor, abnormal posture and gait, paralysis and diminished muscle strength, and the way that the disease progresses over time.”
The problem is that this was 195 years ago, and we still do not know what causes PD. Neither can we stop its progression. All we can do effectively, is to fiddle with alleviation of some symptoms, for a while until the disease overpowers these efforts as well.
On my score card, this constitutes an outright failing grade. In short, our progress has been pitiful, in spite of the efforts of huge numbers of really dedicated and extremely intelligent researchers and doctors.
So where have we gone wrong?
I can think of several areas immediately.
The first is what I call “believing your story”.
For example, if you come to think of PD as a problem in which the dopamine producing neurons in the substantia nigra die off, then your research for the next decade will probably all be focused around studies shaped by that belief. As a result you will not, for example, be looking for data which may prove that PD actually might begin in the spinal column and then work its way up to the brain and substantia nigra. Nor would you imagine that it shows up in the colon and numerous other body systems. In short, the blinders (blinkers) worn by the ‘belief’, guarantee a level of blindness in the research. Debunking the ‘belief’ removes the blinders, but we may have lost a decade in the process. The “story” may change from time to time, but the effect is the same.
For this reason alone we propose a different approach below, which represents both a challenge to and a change from, the traditional scientific model, simply because that by hypothesizing a set of assumptions prior to conducting any research, we automatically incur the risk of guaranteeing "blind-spots", while also spot-lighting the perils of deductive as opposed to inductive research. 

Currently the new story seems to be alpha-synuclein aggregation. It too, carries the threat of producing a lost decade. In theory, it also carries the possibility of solving the mystery. Whilst we now know that all PD patients show accumulations of alpha-synuclein in their brains (and elsewhere), I still have my doubts about this story. UPDATE inserted late 2013   ...  "all" PD patients develop Lewy Bodies. Historically, whenever researchers dissected the brain tissue of deceased PD patients, they all contained accumulations of a protein called alpha-synuclein. Astonishingly, in 2013, we discovered via new research that this was NOT true for PD patients who carried mutations on the PARK2 gene (a small % of PD patients often associated with "young onset" of PD (prior to 55 years), and do NOT develop dementia.) Alpha-synuclein is widely used in the brain, although its "normal" function is not known. These 'globs' or accumulations of alpha-synuclein are called "Lewy-Bodies". Alpha-synuclein aggregations have also been found in PD patient's spinal columns, and even the colon. Lewy bodies also contain another protein called ubiquitin, which has links to some other hereditary forms of PD. Ubiquitin seems to have a role in removing old proteins from inside neurons, so any mutations which impair a 'take out the rubbish function' would help explain these accumulations of old proteins. This 2013 discovery throws the central theory (that alpha-synuclein accumulations somehow kill of dopamine producing neurons) into question. Are we looking at two different diseases that present the same way ? Or, is our model so flawed that we are missing a key bit of information which prevents us from really understanding PD at all ? 


The problem is that, if mutations on the alpha-synuclein gene (known as the SNCA gene, with 18 known mutations so far) are responsible for these accumulations of alpha synuclein (Lewy Bodies), then the geographic dispersion of PD patients globally is way out of sync with the occurrence of mutations in the SNCA gene. These SNCA mutations are rather rare (mainly found in Italy and Greece), whereas the LRRK2 gene (for example only) is much more common and geographically dispersed, and remains the dominant possible PD “genetic marker”.

Fortunately for me I have a PD physician who is also an eminent PD researcher (Dr. Robert “Bob” Hauser), who can explain some of these subtle “conflicting” issues to me. In his words …
“The key is that more than just alpha-synuclein mutations can lead to abnormal aggregation of a-synuclein. There may be many causes: Decreased energy status (perhaps causing inadequate clearance of misfolded alpha-synuclein) – these might include mitochondrial mutations, and a bunch of environmental exposures. Inadequate clearance of misfolded alpha-synuclein …some of the other known PD mutations probably cause this. (There is also increased oxidation and inflammation in PD, but I don’t know how these might lead to alpha-synuclein aggregation). I also have the feeling that there are many subtle ways to tip the balance between normal alpha-synuclein and misfolded alpha-synuclein which exist in equilibrium favoring the normal. So, for example, slight variations in genetics may alter alpha-synuclein stickiness (but in a more subtle relationship than the known alpha-synuclein mutations, where if you have them you get PD). With these types of variations, it may only put one at slightly increased risk, and something else is required in combination. Also, I have a feeling that there could be a triggering event (perhaps even due to chance) and once some alpha-synuclein misfolds and aggregates, the process can then spread (this has been called a prion-like process) similar to what we saw with fetal transplants where 14 years after we transplanted fetal grafts into PD patients brains, the grafts developed the pathology of PD. Seems likely it “spread” from the PD brain into the “normal” fetal grafts, which presumably had “normal” genetics. So, one approach is to try to ferret out all the different causes of PD, and determine the cause in each individual, and correct that problem, OR, if PD is at its heart (final common pathway) an aggregation of alpha-synuclein, then perhaps treatments that prevent its aggregation might be useful in all PD, regardless of the cause."


So how can we go about things differently to finally eradicate PD after all these centuries ?

I suspect the answer is that the research needs to become more “data driven”, as opposed to “story driven”. This would mean having absolutely huge amounts of data from PD patients from all parts of the world, and then mathematically analysing all this data continuously with statistical tools (like multiple regression analysis, inter alia), to discern highly unpredictable correlations and relationships which will suggest promising new lines of research.

To me, Dr. Hauser’s comments illustrate the notion that once you subscribe to the idea that there are also “environmental inputs / triggers” to PD (and almost all researchers agree on this), the permutations rapidly become unmanageable.

It is like looking for a needle in a haystack.

This alone, drives me to the central proposal of a single huge database of patient information which can be mathematically analysed by statistics and computers.

This data driven approach in no way detracts from the current approach of hoping one or more of our many brilliant scientific researchers has an “aha” moment. Instead it just adds to this option, as well as enhancing the likelihood of generating a major increase in “aha” possibilities.

The problem we have is that this “massive data pool” does not exist on anything like this kind of scale.

Granted that an inductive approach (reasoning from the specific to the general) flies in the face of scientific theory, but this in no way detracts from its unique properties as a tool to find those key "leads" which defy current conventional logic. There are not many real-world examples of well deployed inductive strategies, but the obvious example would be the National Security Agency (NSA). It is worth noting that this example also works off a massive single database of targeted data, which is mathematically analysed by some of world's the fastest computers.

This brings me to my second suggestion as to why we have not made more progress with PD. 
We have stinted the growth of the medical data we need in a number of ways:
(a) We have largely only collected data through doctors and clinics, in the belief that this channel would sterilize that data and therefore render it "reliable" for research purposes;
(b) We have done little to combine patient data from different nations, especially those separated by language;
(c) We have not yet fully engaged the enhanced power of the internet in our fight against PD;
(d) We have, up until recently, been blocked on progressing individual genetic analyses by the exorbitant cost of these procedures;
(e) We have tended to see a bias amongst researchers to compete rather than collaborate openly in our common quest;
(f) The interface between researchers and patients is generally limited to participants in each particular study, and is only temporary as it is usually limited to the duration of the study;
(g) Most patient reported information lies “dead” in the paper files in the clinic’s or neurologist’s office, after being collected by sometimes poorly trained assistants asking closed questions;
(h) Our total collection of research studies (and this applies to all areas of human medicine) is distorted by "Research Bias". Over 100 studies show that about half of all authorized trials go "missing" (never get reported); and that any particular study is twice as likely to be published if the results are positive rather than negative. So, if I flipped a coin 100 times, then excluded the 50 times that it came up tails from my results, what would you predict future flips will render?  This is a complex problem and at first glance it appears that the only solution here is to require that all human trials which attain authorization, must be published by law ... and no weasel clauses to get around this. However such legislation could create a competitive disincentive for initiating and funding more aggressive research initiatives and / or "partial" or distorted reporting of findings to avoid giving competitors a research advantage. 

So how do we rectify this situation to benefit our research efforts and eradicate Parkinson's Disease? 

(1) We continue to collect data through doctors and clinics, but in addition we establish a website (which we have called or which collects data confidentially, directly from patients on an on-going basis, on a wide variety of subjects. We know from psychological research, especially in the areas of personality orientation, that “self-rating” questionnaires produce extremely accurate information. This is also borne out by the research conducted by the Rare Diseases Network ( which has a highly sophisticated patient database of 20,000+, split 50-50% between doctor/clinic originated data and direct-patient data, combined with the ability to compare the two groups. ClubPD gives automatic membership to anyone on the planet with PD, and urges all patients to “activate” that membership for research purposes, by registering. ClubPD also offers separate catagories of membership for PD researchers, PD doctors and primary caregivers of PD patients. The market research industry and psychological testing has already supplied us with all the tools for structuring effective questioning tools.

(2) ClubPD's website will switch between all major languages with one CLICK, on the national flag array or country name. Languages will include English, Spanish, French, German, Italian, Arabic, Hindi, Chinese (Mandarin), Korean and Japanese.ClubPD will embrace all opportunities offered by the internet, including a mobile compatible platform and secure login technology.

(3) Genome sequencing makes it possible for us to look at our individual gene structures. This means we can see the genetic mutations we each carry in our approximately 25,000 genes that make up our DNA. We can then tie these mutations to the other parts of our individual PD profile / history and identify new, common patterns, which could lead us to eradicate this disease. There is no doubt that the solution to PD will have a major “genetic” component. The problem has been that genetic sequencing has been prohibitively expensive. The cost of sequencing the first genome in 1997 was US $3 billion in the US government project and $300,000 in its competing private venture. But look at how these costs have fallen - partly due to new technologies, partly due to increased computing power (Moore’s Law).



We now (late 2012) have companies like DECODE in Iceland offering their disease analysis package for $1,100 per person. (Their 47 diseases analysis does not currently include PD). USA based analytical facilities include M.I.T. and Baylor inter alia. Recently (thanks to Anne Wojcicki and Sergey Brin), has taken an aggressive lead in this area amassing a database of over 9,000 PD patient’s partial genetic data … and the number of genes identified with PD now exceeds 20. These costs will continue to fall, which will enable many of us Patients to afford this new level of analysis. If we band together, we could negotiate a “global discount rate” for all PD patients worldwide, with genetic analyses focused on PD’s 20 or so suspect genes. It is conceivable that we could then see costs drop below $100 per Patient.

(4) ClubPD will provide selected data to PD researchers worldwide which is relevant to their studies. The intention is to accomplish this without charge, funding this work solely with donations. Those who are registered as approved Researchers may have their findings published (not exclusively) on the site for other researchers to study. Researchers will have the option of having specific questionnaires designed and transmitted to the global PD patient body for responses, or to solicit tests from patients who may have agreed to participate in that study. Researchers may request aid from ClubPD to utilize the database to identify certain patient profiles which fit their particular controlled study (similar to the Michael J. Fox Foundation’s “Trial Finder” service - which will also have access thereto. If credit is due anywhere in the PD community it has to go to MJF, the dude is amazing !)

(5) ClubPD will thus provide a dynamic, real-time, on-going, direct relationship between PD patients, PD researchers, PD doctors and PD primary caregivers. In short it will be a global community of those who are either impacted by, or are addressing Parkinson’s Disease.

(6) ClubPD will establish on-line “patient disease progression monitoring questionnaires” which doctors and clinics can provide to the patient to complete via iPads (or any other tablet devices) during office visits (subject to agreements which satisfy laws protecting patient's privacy). This will both standardize the collection of data, while appropriately updating the data collected, and also ensuring that it all comes back to the “data pool” in real time, to be subjected to mathematical analysis. There will also be on-line options for patients to take (and periodically re-take) symptom tracking tests like the Universal Parkinson's Disease Rating Scale (UPDRS) and / or the UPDRS - 8, an abbreviated version from Hauser R.A, Lyons K.E., Pahwa R.) to measure disease progression, and highlight changes over time via comparison of test results. If the patient's base-line PD data is properly collected at the outset, we have a scientific basis for profiling the many "flavors" of PD, as this disease manifests very differently in different individuals. This process then enables ClubPD to immediately provide its members with (a) information on which type of PD profile they fall into; (b) to what extent they fit or do not fit that profile; (c) information on what members in that profile find most beneficial with regard to medications, therapy etc., and well as (d) reporting results from this opportunity for ClubPD to mathematically analyse all the base-line (by 'profile') against any other imaginable variable. 

(7) When a research study is funded and executed it always involves PD patients because without access to the patient there is no source of data. Whilst this obvious, it needs reiterating because that Patient data can only come from two sources: firstly, by asking the patient “what is going on with you?” or; secondly, by performing tests on the Patient’s body and recording the results (for example movement observations or genetic testing for mutated genes). The problem is that each research study reports only the patient data collected which has a bearing on the research hypothesis. All the other patient data collected is lost in the sense that it never reaches other researchers, because it’s “relevance / irrelevance” was determined by the scope of the study in which it was collected. For this reason I propose a new idea which, in a sense, becomes an extension of the Trial Finder idea, where the ClubPD membership is used to find the patients for the study. The idea is what I call “BUILD BACK”. It works like this. The ClubPD database asks PD Patients who fit the Research Profile for that study if they would like to participate in the study. If the patient responds, and says “yes”, then we establish contact between that patient and the researcher(s). As part of this, the patient, who is already registered with ClubPD, and the registered researcher agrees to BUILD BACK. After completing and perhaps publishing the results of the study, the researcher provides ClubPD with all the non-utilized and utilized patient data, and ClubPD has people who “build back” this new data into each patient’s existing profile. This way, the next time we mine the data for clues, or the next research project, we literally “pass-on” the benefits of all this data, effectively eliminating all the duplication which goes on now, which is completely unmonitored. This “build back” work will be time consuming (expensive), but far cheaper that endless repeats. 

(8) Over time, as the registered global membership of ClubPD builds, the question of ownership of the massive amount of data will need to be addressed. My view is that all this data can never be owned or controlled by any commercial interest. I know that I can protect it, for now, but I also have PD, so a longer term plan must emerge sooner rather than later. This is a topic for global discussion amongst PD patients and serious PD research donors. At this time, not yet having had these discussions, my feeling is that ownership needs to be eventually passed to a Trust which is managed by an international Board. The membership of this Board should be partially elected by the registered patient members of, but balanced by the other stakeholders invested in eradicating Parkinson’s Disease.

Let us all come together right now and collectively make sure that 195 years does not soon become 200 years.