There is a paradox in rare disease research. Financing it is still problematic yet, at the same time, research into rare diseases has enabled us to make significant advances in more common diseases. So the added value from this research goes far beyond rare diseases. If we analyze this purely objectively, we could say that we are missing out on huge economies of scale by funding rare disease research so little and so poorly.

Romain Alderweireldt and Ludivine Verboogen need only a few words to make clear the significance for society of their joint commitment to the 101 Genomes Foundation. Their ambition? To provide scientists with a bioinformatics platform to advance in the field of genomic research, one of the keys to better understanding rare diseases.


Life’s vagaries result in a magnificent drive for the public good

The story of the foundation actually began on 3 September 2015, with the birth of Ludivine and Romain’s son Aurélien.

The joy of the first few days soon gave way to concern. The doctors suspected Marfan syndrome, a rare disease that can severely affect the connective tissues, with consequences for the heart in particular.

On 4 August 2016, 11 months later, a genetic analysis confirmed the bad news, Aurélien carries a spontaneous mutation of the FBN1 gene. In fact, he suffers from a severe form of Marfan syndrome.


Late diagnosis and tools to invent

It’s a spontaneous and very rare variant of Marfan syndrome. That played a role in the 11-month delay in making the diagnosis. The reference center that was asked by the geneticist following Aurélien to carry out a genetic analysis was still using gene-by-gene analysis techniques, whereas genomic analysis did exist”, explains Ludivine. “And it was during the many discussions we had with this geneticist, Professor Guillaume Smits, that we realized that the clinic lacked the physical and bioinformatics tools to take advantage of the advances in genomic research, both in terms of diagnosis and the development of new treatments, explains Romain.

Six years later, it is possible to sequence the entire human genome and identify mutations in all our genes at an increasingly affordable cost. But the initial cost of the machines is still very high and genome sequencing has not yet become routine in research or clinical practice. A sequenced genome generates such a large volume of data that it is absolutely impossible to process it manually. One genome corresponds to nearly 300 gigabytes of data! You need algorithmic tools, artificial intelligence and a highly specialized team to get anything out of it. Moreover, this combination of ICT and biological research has a name: bioinformatics.

Feelings of helplessness transformed into positive energy

For these two lawyers, the realization of the need to invest in genomics and bioinformatics was a trigger. Ludivine and Romain transformed their feelings of helplessness into positive energy with a goal: to advance research and clinical practice and help bring about treatments that would help Aurélien and other children affected by rare diseases.


Search for a protective gene

Romain started devouring scientific studies. That’s how he came across the Resilient Project and its reanalysis of nearly 600,000 exomes (which are basically the coding part of the genome). It is important to know that many rare diseases, and in particular Marfan syndrome, are caused by pathogenic mutations or, if you prefer, anomalies in the genes, explains Ludivine.

By reanalyzing the data available to it, this study identified 13 adults who carry a genetic abnormality that should have made them very ill, or even killed them as children. Yet all 13 had reached adulthood”, continues Romain. “Why? One explanation might be the presence of other genes that have a protective effect against the disease. Studying these people’s genomes could therefore be the key to better understanding this protective mechanism. And understanding that could lead to the development of drugs or new treatments, based, for example, on the proteins produced by these genes.”

Ludivine: “Romain decided to replicate this approach in the specific context of Marfan syndrome. And the incredible happened. He succeeded in finding carriers of the pathogenic mutations in the global genomic reference database (gnomAD), who were supposed to be affected by a severe form of Marfan syndrome but were apparently not. It became clear to us that if a protective gene could be identified, its effects could be replicated to develop a treatment.


The 101 Genomes Foundation and its pilot project

In 2017, the 101 Genomes Foundation was created on the initiative of Ludivine and Romain.

The objective? To develop a bioinformatics platform to host genomic data and to cross-reference it with the medical records of rare disease patients and volunteers serving as ‘controls’, in order to get a better understanding of the interactions between genes in the genome.

A pilot project was soon launched: the 101 Marfan Genomes project, which involved setting up a cohort of 101 patients affected by Marfan syndrome as a basis for research work. It soon became clear that 101 genomes was only a start, and that it was crucial to surround themselves with knowledgeable scientists.

The scientific committee steering the Foundation is made up of world experts in genomics, Marfan syndrome and algorithms, several of whom are Belgian. These scientific luminaries are full of admiration for the work done by Ludivine and Romain, which they consider to be an unprecedented example of patient participation in scientific research.

Our work has focused on the creation of a cohort of patients with the same mutation, so as to limit confusing factors (GEMS project), and, in parallel, on the creation of an algorithm to confirm (or refute) the pathogenic nature of mutations of the FBN1 gene. Then, with this as a basis, we hope to explore the entire genome to identify the (protective or aggravating) modifier genes for Marfan syndrome. The first results are promising”, says Romain. “And Innoviris’ intervention has helped give this work a real boost.

GENOME4BRUSSELS, an ecosystem at the intersection of 3 disciplines

Innoviris’ call for projects ‘From therapeutic medicine to predictive medicine: Prediction, Prevention, Identification’ got 5/5 from Romain, Ludivine and the Foundation.

Scientific Advisor of Innoviris, Aiko Gryspeirt says: “There is still too little attention paid to rare diseases. And as a result, there is also a lack of funding for that type of research, whether it’s disease-specific or treatment research. Patients often spend months or years going from one specialist to another before getting a diagnosis. With GENOME4BRUSSELS, Ludivine and Romain have launched a fantastic initiative to better understand rare diseases, by collecting genetic data and sharing it with medical researchers and bioinformaticians in Brussels. This is an invaluable project that may have an important impact on the lives of people with rare diseases.

GENOME4BRUSSELS is a project funded by Innoviris, in which the Foundation is involved, as well as the Interuniversity Institute of Bioinformatics in Brussels, the Center of Human Genetics, and the Machine Learning Group, all three of which are part of the ULB [Université libre de Bruxelles]. The objective is to create an ecosystem, in Brussels, dedicated to medical, genomic and bioinformatics expertise. This support has enabled our pilot project to progress and to combine our expertise to identify the protective genes that will open the way to helping patients better, concludes Romain.

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