Dr. Ziv Gan-Or completed his MD and PhD at Tel-Aviv University, with a major interest in lysosomal related genes and their role in the development and progression of Parkinson’s Disease. In his current work at the MNI, he utilizes advanced genotyping and next-generation sequencing technologies to further study the genetic background of Parkinson’s Disease. Dr. Gan-Or’s lab is also interested the genetics of a specific prodromal condition – REM sleep behavior disorder. Individuals who suffer from REM sleep behavior disorder will most likely develop a neurodegenerative disease: either Parkinson’s Disease, dementia with Lewy bodies or multiple system atrophy. By identifying the genetic background of REM sleep behavior disorder and its progression to one of these neurodegenerative disorders, Dr. Gan-Or aims to identify novel pathways and mechanisms that may help developing treatment. (Source: McGill)
The following has been paraphrased from an interview with Dr. Ziv Gan-Or on June 4th, 2018.
(Click above for the full audio version or here for a downloadable link)
What are the limitations of modern genetics given all the new tools available to it (whole genome sequencing, RNA sequencing, GWAS, etc.)?
Each tool has various limitations. For example, genome-wide association studies are relatively cheap and easy to analyze, but it just gives hints as to where there is a genetic effect, we don’t know the cause of the effect. When you combine methods the picture gets clearer, but then it becomes much more difficult and expensive because you need a large number of patients and controls. It also creates a huge amount of data, which we are still limited in our ability to analyze, we have some methods for doing this, but they still have a long way to go. We understand the areas of the genome that encode for proteins pretty well, but we don’t really understand the rest of it, which is about 97% of the genome.
If we collected all the data we need and did the full analysis, what would we learn that we don’t know today?
We would know more variations that increases risk of disease, but we still wouldn’t how they increase risk. If I had all the money needed, I would do whole genome sequencing and RNA sequencing and methylation studies and other epigenetic studies on all patients, but then I would have to combine it all and we still don’t know how to properly analyze and contextualize all that data.
For non-mendelian diseases (diseases caused by a mutation in a single gene), will we have to incorporate environmental or lifestyle factors to properly intervene, or might genetic based interventions be enough to treat them?
We geneticists always think that everything is genetics, but of course it is not, in fact environmental factors play a larger role than genetics in contributing to Parkinson’s disease. We have measured heritability and determined the overall contribution of all genetic risk factors, that number is around 30%, which means most factors are not genetic. So to fully understand the disease we would need to better understand environmental factors, which are much more difficult to study. In genetics you either have the variant or you don’t, but environmental exposures are difficult to measure and quantify. We probably would need to do large prospective studies over dozens of years to really understand environmental impact
Do we have any way of measuring how much a genetic variant is responsible for an individual’s disease?
We can assign a score called a genetic risk score, which is a combination of all the variants you have. But it can’t accurately predict who will develop a disease, let alone how much of a role a particular variant plays in the onset of an individual’s disease.
There is a method being developed using CRISPR that allows us to take cells from an individual, reverse the mutations in cell lines, and isolate the effects of single variants to see its impact on cell development. This still needs to be perfected, but I think it will be ready in the next few years.
How is it that two conditions that seem so different, like REM sleep behavior disorder (RBD) and PD, can have a common risk-factor?
They are both symptoms of synucleinopathy (diseases characterized by the abnormal accumulation of a protein called alpha-synuclein). If you have RBD it just means the area of the brain that controls REM sleep is affected. But it is the same underlying disease, just different symptoms of it. RBD is often an early symptom and if you have it then your chances of developing a synucleinopathy are more than 80%.
It also involves a genetic mutation associated with PD called GBA. How well characterized is the GBA pathway?
Luckily for us, GBA is well studies because it also causes Gaucher disease, which has been studied for a long time, though there is still a lot to learn. In particular, we don’t know why the mutation leads to the accumulation of alpha-synuclein. The GBA gene regulates different lipids in the lysosome, so it is probably related to that, though we don’t know enough about it to be sure.
Which current approach being tried to treat GBA-PD do you believe will be most successful?
What worries me is that we have a huge problem with the way we are doing clinical trials and as a result we have consistently failed to translate therapies from the lab to the clinic. It could be because of the models we have been using, but also because we have been treating PD as a single disease. Now we have trials, like the GBA trial, doing a better job of identifying the right type of patients for the right trial. However I am worried that these too will fail because we treat all GBA variants as if they are the same, but they are not. Plus there are a lot of other variables that should be considered.
In trials, we take the participants and randomly assign them to two groups, give one group the drug and the other the placebo, and then see which group does better. This could create a situation where by chance we have one group that would naturally advance in their disease faster than the other group, which would throw off our ability to measure the effects of the drug. Some companies are taking measures to ensure the two groups are more balanced, but I am not very optimistic that these trials will work, however we are slowly heading in the right direction.