Everyone knows about Down's syndrome of genetic origin, yet there is not much scientific research dedicated to this condition. It is the paradox that an association of Mandello del Lario (Lecco, Italy) has decided to face.
“Vola con Martin oltre il 21” (Fly with Martin beyond the 21), this is the name of the non-profit organisation that has chosen to support as its first scientific research “Genoma 21” (Genome 21), an innovative project led by Professor Pierluigi Strippoli and Dr. Lorenza Vitale of the University of Bologna.
In this interview, Professor Strippoli explains the objectives of the path inspired by the research of Jérôme Lejeune, the French geneticist to whom we owe the demonstration that DS is due to the presence of a third pair in the pair of chromosome 21 instead of the normal two (since then it is also called Trisomy 21): the innovative approach is that of an integration of clinical, biochemical, genetic and bioinformatic data to identify new treatment possibilities for the intellectual disability associated with this form of trisomy.
Associate Professor of Applied Biology at the Alma Mater Studiorum, University of Bologna, where he teaches Genetics and leads the Genomics Laboratory of the Department of Experimental, Diagnostic and Specialty Medicine (DIMES), Strippoli has applied the use of molecular genetics and genomics techniques to the study of blood, colorectal cancer and trisomy 21 disorders. He designed and produced some original computational biology tools for the analysis of the human genome and published sixty articles in international scientific journals.
Professor, can you first summarise the symptoms of Down's syndrome?
“Beyond some physical characteristics, this syndrome features intellectual disability as a constant, while there are heart disease (in 30-40% of cases), hypothyroidism, infections, autoimmune diseases in variable ways: however, all these disorders are manageable. As for the intellectual deficit, it is a very specific disorder, which affects some intelligence areas and not others: it affects language, which develops but sometimes more slowly and with some difficulty; there is also a difficulty to speak that during growth can be a source of discomfort, i.e., the child understands much more than he or she can express; and again, there is a disorder of symbolic or abstract thinking. Other areas, however, are absolutely preserved, such as that of long-term memory, even socialisation and affection are highly developed: the ability of Down children to arouse around them a climate of affection more marked than the common is well known.
In short, this intellectual disability must be placed in a certain context, even gives some strengths to children and many parents tell us that 'they are wonderful as they are'. But it is also true that there is an objective limit to their capabilities and autonomy, a limit given by a specific alteration of DNA and specific actions of genes that if better known could be opposed at the gene level as in other therapies”.
How did your interest in this syndrome begin?
"After studying molecular genetics of blood disorders, when I was a researcher, my Professor Maria Zannotti - a pupil of Professor Lejeune, who brought the theme of research on Trisomy 21 to Bologna - encouraged me in this direction. And at the beginning I didn't want to deal with it, I thought it was a field of research already 'overcrowded', since Down's syndrome is absolutely the most frequent genetic alteration. Instead, I soon found out that studies were scarce. So for a few years we worked on identifying the genes involved in Trisomy 21 and, for example, it was my colleague, Lorenza Vitale, who identified one of the 250 genes involved.
In short, there is a great deal of basic genetic research still to be done at the level of the chromosome. In 2011, after a difficult phase also due to the lack of funds, at a conference I got to know the history of Lejeune, his family, I rediscovered his scientific work and our research was reborn, but with a much broader vision of Down's syndrome. At the suggestion of Lejeune's wife, I returned to the clinic as an observer, and thanks to the collaboration with Professor Guido Cocchi and Dr. Chiara Locatelli of Bologna, the idea was born to carry out together a large experimental clinical project, which starting from the observation of children and blood analysis led to a greater understanding of the mechanisms of this syndrome. In short, our research has become more focused on a cure for intellectual disability, which remains the main issue of children and adults with Down's syndrome.
What are the specific objectives of the Genome 21 project?
“In the last three years, we have achieved results that we believe to be significant, following a particular path indicated by Lejeune. That is, the hypothesis that Down's syndrome is mainly due to a metabolic problem: the extra chromosome would lead to a permanent intoxication of neurons that causes their slowdown. Another point taken from Lejeune: to be responsible for the syndrome would be only a portion of the third chromosome 21. Three years ago we published a study showing that there is actually a small 'region' of such a chromosome associated with Down's syndrome, and that if this region - a sequence present only in humans and chimpanzees - is absent, one can also have a third chromosome 21 but not have Down's syndrome”.
“We have identified a 'region' of the third chromosome 21 related to the syndrome and with a metabolomics analysis we have shown how the metabolism of children with Down's syndrome is altered. Now we must close the circle, connecting this 'critical' region and the precise metabolic alterations discovered”.
Which are your next goals?
“The identification of some genes of this 'region' of the third chromosome 21 will be the subject of a forthcoming publication so I cannot go into detail, but I can say that only a few months ago the automated maps have received signals of gene activation from this region of the chromosome. Then there is another open front. One year ago we published the results of metabolomics analysis that showed that the metabolism of children with Down's syndrome is altered: there are a number of substances detected with abnormal concentrations, and proportionally to the model predicted by geneticists when there is an extra chromosome. Now, then, we have to close the circle, connecting the 'region' of the chromosome mentioned above and the precise metabolic alterations identified: if we understood which is the most critical, i.e., which disturbs the brain the most, we could envisage a therapy aimed at correcting the metabolic imbalance.
To achieve this goal we would also like to use genetic engineering to remove the critical 'region' of the chromosome from cells in test tubes, not to apply such therapy to a patient but to understand with an effective demonstration how this would modify the metabolism. Our team, small and also composed of unstructured people, has managed to do all this thanks to many valuable collaborations, including international ones: the one with Professor Marzo Seri in charge of Medical Genetics at the S. Orsola Hospital in Bologna, with Professor Paola Turano of the University of Florence with whom we collaborate on metabolomics, with Professor Patrick Harrison of the University of Cork, Ireland, for the part of genetic engineering with the Crispr technique.
We also collaborate with professors Silvia Lanfranchi and Renzo Vianello of the University of Padua on their detailed studies on people with Down’s syndrome: this will allow us to correlate any precise metabolic imbalances with specific cognitive functions, and is currently the most systematic study conducted in Italy on Down’s syndrome”.
Since June 2018 your project has been supported by the Lombard association “Vola con Martin oltre il 21”...
“I've known them for just over a year, we're very few in Italy to do research on Trisomy 21 as a priority and they were positively impressed by our approach. Then when they discovered that 90% of our funds come from private entities, mostly from individuals, they wanted to be involved and we want to thank them for that. They decided to support us as a matter of priority, in particular for the purchase of a fluorescent microscope to perform experiments with the cells I was talking about”.
Why is there a lack of public funding for research into the currently most widespread genetic origin syndrome?
“In the current mentality of research funding, the idea of quite sure investments has prevailed, with an increasing tendency to ask for an enormous amount of preliminary data to support the hypotheses that are to be demonstrated. This way, however, research is financed when it is no longer truly innovative. Research is by definition high-risk, otherwise it would not really be so and we should rather talk about works 'confirming' hypotheses already considered.
Then there is another element to consider. Given the fact that today the majority of women who undergo prenatal diagnosis and receive a diagnosis of Trisomy 21 choose not to carry on with their pregnancy, there is the perception of a future progressive decline in the number of people with Down's syndrome. I oppose another fact, namely that there are still six million of them in the world. Moreover, the data also tell us that there is no significant decrease in births with Trisomy 21, also because of the constant increase in the age of women at childbirth, the factor that most affects the probability that the newborn has Down's syndrome”.