Interview to Prof Richard H Myers,PhD  Professor of Neurology,  Boston University, USA

Prof Myers,  in the biography at the site of your University (http://genetics.bumc.bu.edu/people/faculty/myers.htm) you say that your professional interests have focused upon the application of genetic research methods for the investigation of adult onset diseases with complex etiology, such as Parkinson's and  Alzheimer's disease and that you initiated a genome scan project in Parkinson's disease (PD), the "GenePD" study.  Please explain what this study is and what induced you to set up such a study, specifying why you chose PD.

Twenty years ago I was involved in research on another neurodegenerative disease, which was found to be due to a genetic defect - Huntington's disease.  Its causative gene was identified and I decided to extend my research to other neurodegenerative diseases with a more complex etiology. 

I was fascinated by PD, because I observed a number of contradictions in the hypotheses of the time regarding its etiology.  I had been taught in graduate school that it was not a genetic disease.  Epidemiological studies had identified a number of environmental factors associated with increased prevalence of the disease, such as pesticides, heavy metals and, subsequently, hydrocarbons.  However, the associations were weak and the only strong predictor of the disease was a positive family history.  Interestingly, affected family members were mostly siblings and not spouses, which suggested a genetic rather than an environmental etiology. 

This induced me to develop a different concept i.e. that maybe the disease is the result of an interaction between genetic and environmental factors, whereby only genetically susceptible individuals would develop the disease if they were exposed to key environmental factors.  In other words, genetic mutations alone or exposure to environmental factors alone would not suffice, only the concomitant presence of both kinds of factors would trigger development of the disease.

During my research on Huntington's disease I had met many people involved in research on other neurodegenerative diseases, including PD, and had been asked to serve as consultant on the Advisory Board of APDA, the American Parkinson' s Disease Association.  I expounded my hypothesis to neurologists who were members of the Advisory Board and the decision was taken to set up an international multi-institutional consortium, called the GenePD Project, in order to carry out a large study in patients with at least 2 family members affected by the same disease, with the aim of identifying any causative genes.  This occurred in 1997.

You say that the study involved an international collaboration of 20 clinical centers in PD.  One of the centres is the ICP Parkinson Institute with its DNA Bank sponsored by the Fondazione Grigioni and Telethon.  How has the cooperation with this centre been?

The co-operation has been excellent.

The ICP Parkinson Institute made the largest contribution of all, both in quantitative and qualitative terms.  The GenePD study managed to collect a total of 1,095 DNA samples from 487 families.  The ICP Parkinson Institute is one of our largest contributors to the GenePD study.  But even more important than the familial samples, is that we have studied an additional 500 PD DNA samples from the Italian centre.  These samples have been especially valuable to validate the findings from the GenePD Project.  Please thank all the patients who contributed to the DNA Bank donating a sample of their blood. 

Moreover, the patient population at the ICP Parkinson Institute includes a large number of samples of both patients and healthy subjects.  This enabled us to test preliminary findings: whenever interesting genetic variants were found, we could search for the variant in the DNA of both PD patients and healthy subjects in Italy and verify whether it was more common in PD Patients than in healthy subjects. 

We intend to continue the co-operation in the future on other projects.

I know that the GenePD study, which started at the turn of the century, has already provided a wealth of results.  Could you summarize the main findings of the study so far?

We have made a number of interesting findings. 

We found that a variant of the gene encoding the brain-derived neurotrophic factor (BDNF) is strongly associated with age at onset of PD, a finding that suggests that growth factors may be involved in the development of the disease.

Another interesting finding was the interaction between polymorphisms of the GSTP1 gene, which encodes a detoxification enzyme, and exposure to pesticides.  We analyzed the gene by means of the SNP  (single-nucleotide polymorphism) technology in order to establish which kind of GSTP1 gene the patient had out of 7 types, which differed only by one nucleotide (SNPs) and then assessed whether any of the 7 SNPs was related to age at onset within each of three strata: patients with no history of exposure to pesticides, patients with residential exposure (medium degree of exposure) and patients with occupational exposure (high degree of exposure).   We found that that 3 SNPs were associated with age at onset of PD amongst the patients with a history of occupational exposure. 

These findings support our initial hypothesis that PD is the result of an interaction between genetic and environmental factors.

I have heard that your latest initiative is to pool the database of the GenePD study with that of the PROGENI study.  Why have you decided to do this?  What do you hope to achieve?

In the last 2 to 3 years novel technology has come to fruition that enables us to analyse all the genes  i.e. the whole genome simultaneously.   Thus, we are now able to perform genome-wide association studies, searching for associations between 370,000  genetic combinations and PD at the same time, in other words to put 370,000 questions and get the relative answers at the same time - a mind boggling achievement.  

The problem is that the most questions you put, the greater the probability of getting what appear to be significant results by chance.  The only way to prevent this is to analyze very large numbers of samples, many more samples than we were able to collect in the GenePD study.  This is the reason why we decided to pool our data with the data of another similar study, the PROGENI study.  The data collected in this study are similar, with small differences.  For instance, they did not collect data on pesticides, preferring to collect data on symptoms.  The genetic data are identical, so the data of the two studies can be pooled without any qualms. 

All going well, we should be able to come up with a genetic "signature" of the disease,  i.e. a number of genetic features that make an individual susceptible to the disease.

We suspect that what we currently call PD in reality is a group of similar diseases and that we shall come up with more than one "fingerprint".

We have just completed the pooling and are analyzing the results.  We should be able to reach some conclusions soon.

I believe that SNP technology is already available to individuals who wish to find out more about their genetic make-up.  Do you recommend these tests?   Why?

Yes, SNP technology is available and anybody can ask to have their DNA analyzed.  At present the problem is that we do not really know what the results mean.  DNA is like a text in a foreign language that we are just learning to understand.  At the moment we are able to identify the letters of the alphabet and have begun to group them into words, but we do not know how to put the words together to make meaningful sentences.  Consequently, at present these tests are not worthwhile.

Is there any message you would like to give to patients with PD?

These are exciting times, as a lot is going on in research.  Personally I am involved not only in looking for the genetic "signature" of PD, but also in stem cell research.  I am co-operating with the American centre that published the results on the reprogramming of adult skin cells so that they were rejuvenated and transformed into stem cells.  We hope to be able to learn how to remove skin cells from a PD patient and transform them first into stem cells and then into dopaminergic neurons that could be transplanted into the brain without the risk of rejection as they would be the patient's own cells, with the same DNA. 

How successful have you been up to now ?

Sorry, it's too early.  I am not prepared to talk about our results at present.  Maybe next year.

Professor Myers, thank you for your time.  If it's OK with you, I should like to book another interview in one year's time then, to hear more about both the genetic "fingerprint" of PD and the skin cell rejuvenation project.

That's fine.  And please remember to thank the patients of the ICP Parkinson Institute of Milan.