Dr Paracchini, you work in genetics. What exactly do you research?
I'm interested in the genetics of neurodevelopmental traits. My main interest is dyslexia and the goal of my research program is to map the genes that contribute to dyslexia.
And, what is dyslexia?
It's a specific difficulty in learning to read which cannot be explainable with factors such as a lack of opportunities or other neurological conditions. For example, most children with dyslexia have a perfectly normal iQ but they are specifically struggling with reading.
Is dyslexia just the reading?
You said you try to map genes that contribute to dyslexia. Usually, gene mapping is done by creating so-called knock-out mice, meaning mice without the genes researchers you are interested in. But that wouldn't work with dyslexia.
No, it wouldn't. We start off by recruiting lots and lots of children. For that we collaborate with a team of clinicians. These children are assessed using many different cognitive tests, all aimed at measuring reading abilities. We then perform genetic screenings where we look for genetic variants that are associated with lower performance in some of these cognitive tests. The genetic variants can lead us to particular genes. That's when it starts to become really interesting – we start studying gene function. At this stage, when strong susceptibility genes are identify, we can start to model their function in mice, which is a strategy taken by some of our collaborators.
Does that mean, they teach mice how to read?
No no, they are not trying to teach mice how to read (Chuckle). They are rather looking at how these genes contribute to neural development in mice and the development of a healthy brain in particular.
In my lab, however, we are modeling the function of these genes in neural cells, to see which processes might be affected by knocking out these specific genes. We also use zebrafish. Again, we of course don't expect zebrafish to be able to read. But we are trying to find out at which stages these genes are active.
Having said that, there is even more to it: I am involved in a collaboration aimed at identifying genes contributing to mathematical abilities, which requires training zebrafish at counting. But the project is still at the very beginning.
If you now find genes that seem to be related to dyslexia, how can you be sure it wasn't just coincidence?
The way to start with gene discovery is to look for statistical associations. Very rarely one finds genetic variances that are actually disrupting genes. But in most cases the variants are located near genes and regulate their expression. It's a bit of a fine tuning process.
The key to making sure one did not just identify artifacts is replicating the same results in an independent sample. You run the same analysis looking at the same phenotype but in a separate cohort of individuals with dyslexia.
Do you then look at the same patterns in a healthy group of people to confirm your results?
Interesting that you mention that. One specific part of my research actually is looking for these genetic variances at population level. My question is: What happens in the general population when you have these genetic variances? We found that the same genetic variants associated with dyslexia also influence reading abilities in the general population. We assessed a large cohort of over 7,000 individuals, representative of the general population In the cohort, we found that the same variants associated with dyslexia also influence reading abilities in the normal range. These people usually do not have dyslexia but tend to have lower reading scores.
What medical use can doctors draw from these conclusions?
We are doing basic research, or better call it 'discovery research'. This type of research does not have an immediate translational effect. There for example won't be any targets for drugs. But in the short-term, we will start to understand the mechanisms underlying brain development.
Our work is more long-term: If we can understand how the brain develops and what leads to dyslexia, we will provide invaluable information to doctors so that more effective intervention strategies can be developed.
There have also been studies showing a relation between handedness and dyslexia. Is there such a thing as "If you are right- or left-handed, you are more likely to be dyslexic"?
There have been many studies looking at the frequency of left-handedness in psychiatric conditions, including dyslexia. At the origin of these studies is the observation that atypical brain asymmetries have been observed for these disorders. Handedness partially correlates with brain asymmetries. However, it is not easy to see clear patterns. Some studies indicate that it is also important to consider the mixed-handed who do not have a clear hand dominance.
Is hand preference reflected in the genes?
So far no genes have been published, yet, that are associated with hand preference. To me this is a sign that there are no strong genetic factors for being either left or right handed. Instead, we measured handedness along a continuum. So, we tested how much one individual is lateralized with one hand versus the other.
What did you find?
We found the very first gene being linked to a measure of handedness. Very interestingly, this gene is exactly the same as the one that initiates the process of setting up our left-right-body-symmetry. From the outside, our body looks symmetric but our internal organs are asymmetric.
Why is that important for dyslexia?
The association appears to be specific to individuals with dyslexia – I argue that the same pathways contributing to structural asymmetries and brain asymmetries are relevant for behavioural asymmetries like handedness. We know that individuals with dyslexia show atypical asymmetries in their brain, so there certainly is a link between brain symmetries and dyslexia. But these links cannot be reduced to simply looking at the frequencies of left-handers among patient groups. I believe there is a link but it's at a biological level and it is likely to be very complex. Handedness for us is just a way to tap into the process that contributes to the establishing of brain asymmetries.
So, no simple rule such as dyslexia is down to using one hand?
We like simple ideas but if it was simple it would have been there. The more we study the human genome and the human brain the more we understand that things are more complicated than anticipated.
Thank you, Professor Paracchini.
English interview and German version by Sonja Klein (© AcademiaNet)