"Tame the genome to advance research by 10 years" by Romain Alderweireldt

2018 /Thursday, October 18th, 2018

It is with pleasure that my wife and I responded to Véronique Vrinds ' invitation to prepare a special issue of the newspaper " The heart & the hand "dedicated to" Project 101 genomes Marfan "(hereinafter P101GM) of the" Fondation 101 Génomes (hereinafter F101G).

The P101GM derives from the action of ABSM and certainly would not exist in its present form without the support notably of Léon, Rémi, Yvonne, Lauriane and Véronique.

The crucial role of patient associations

Like many parents of children with a rare disease, we wanted to do something following the announcement of our son's diagnosis. We first turned to the ABSM which welcomed us with open arms and allowed us to discover the Belgian and then European Marfan community through VASCERN.

In this context, we have gradually been interested in research dedicated to Marfan syndrome. We found that in addition to patient and family support, patient associations play a key role in the advancement of research. A communication and funding role such as that played by the American Marfan Organization (www.marfan.org) but also a direct support role for research such as that assumed by the French Association of Marfan syndrome (www.assomarfans.fr).

The contribution of the French Association to the establishment of the UMD-FBN1 database has particularly challenged us. UMD-FBN1 is a free access database launched in 2003 which allows researchers from all over the world to consult online (at www.umd.be/FBN1/) an inventory of 3044 pathogenic mutations of the FBN1 gene encoding fibrillin 1 protein on chromosome 15, identified as causing Marfan syndrome.

This unique database feeds the work of hundreds of scientists around the world and is regularly quoted in the scientific literature dedicated to Marfan syndrome. This is a very important tool that has been accompanying research for many years.

Beyond the sometimes somewhat agreed speeches, UMD-FBN1 has appeared to us as one of the concrete proofs of the crucial role played by patient associations in scientific advances.

Continuing our research with the invaluable help of Dr Guillaume Smits, we then took the measure of the limits of UMD-FBN1 and quickly identified a gap - or a void as Cecile Chabot calls it. – that the scientific community wished to be able to fill as quickly as possible: access to the genome.

The genomic revolution

It is thus apparent that the specialists of the Marfan syndrome call for their wishes access to a version in some way " Upgraded ' of the UMD-FBN1 database which does not contain only the information on the pathogenic mutations observed on the only FBN1 gene with chromosome 15 but which would contain the information observed on all the genes on all 23 chromosome pairs that comprise the genome of patients with Marfan syndrome.

This implies that for each patient, the database would go from a "letter"[1] pathogenic mutated to... 3 billion letters that represent the DNA of an entire genome!

While this increase of 3 trillion% in the amount of information available on the database was unthinkable until 2014, it is no longer present since technological and bio-informatics advances now allow to obtain genomic information at a sequencing cost of around 1,000 euros and a volume of data in the order of 300 gigabytes.

To use the metaphor of the observation of galaxies made by the Doctor Guillaume Smits in the interview you will read below, with the technological and bioinformatics evolution of the last few years, scientists have somehow gone from Galileo's observation telescope to the Hubble telescopes! This allowed the passage of Genetics – the individual study of genes – to genomics – the study of all genes and their interactions.

It is this evolution that the Professor Paul Coucke qualifies as " technological revolution ».

And it is the benefits of this "genomic revolution" that we want to make available to scientists who study Marfan's syndrome to help them better understand the disease. With the ambition that therapists can then " better inform and treat "the patients as explained by Professor Julie De Backer....

Taming the genome

The genome's evocation feeds on many fantasies that are cumulating with those related to Algorithmics that necessarily intervene to deal with the extraordinary volume of data that the genome represents.

While some fears are perfectly legitimate, however, it is important to unravel the prejudices of the facts. And the P101GM participates in this attempt to "tame" the genome.

As Dr Michel Verboogen mentions, several initiatives in this sense are now flourishing around the world. These include Iceland, Finland, France, Estonia, Canada, China, the United States, Dubai and Great Britain. One of the most ambitious initiatives is the " 100,000 Genomes project » a British Government that mobilizes State budgets to serve many rare diseases – including Marfan syndrome – to use the genome for diagnostic and research purposes[2].

While the British project served as a source of inspiration for the establishment of the Fondation 101 Génomes, it differs in that at the present stage, its action is focused on research on Marfan's only syndrome (P101GM) and that it relies only on private financing.

In Belgium, on the institutional side, the Federal Centre of health care expertise (KCE) published a report at the beginning of the year 2018 advocating the introduction of a pilot project to better understand the technology, its costs and its implications before following the example of the Nations that are progressing in the study of the genome[3]. At this stage, we understand that the KCE suggests that an intermediate technology[4] be retained and that resources be released as a priority for Oncology in the care phase[5] and to participate in the diagnosis of rare diseases in General. The aspect of participation in the advancement of research is, according to our current understanding, not yet fully taken into account at this stage.

Nevertheless, reflection in relation to the genome is intense in Belgium and the Minister of Health has instructed the King Baudouin Foundation to sound out the opinion of citizens in relation to the genome. It is in this context that the King Baudouin Foundation welcomed our initiative, as explained by Mrs. Patricia Lanssiers And Mr. Gerrit Rauws.

It is on the strength of its knowledge in the field of genomics in Belgium that the King Baudouin Foundation suggested that we structure our action in such a way that it can be replicated for other rare diseases. This is what we have done by creating the pair Fonds 101 Génomes and Fondation 101 Génomes which allows us to set up genomic projects for other rare diseases by building on the experience gained with the P101GM as explained in the Professor Anne De Paepe.

All concerned

Also within the framework of the mission entrusted by the Minister of health, the King Baudouin Foundation has recently published a very interesting brochure entitled " My DNA, all concerned? »[6].

As its title indicates, this brochure addresses the question of everyone's responsibility for the genome and the resulting citizenship at the level of humanity. This question, also raised by Master Bruno Fonteyn, is particularly interesting.

Indeed, each individual whose genome is sequentially participates in a better understanding of the human genome and how the genes that compose it interact with each other.

This raises questions about the responsibility of everyone to participate in a better understanding of humanity in order to be treated oneself but also, eventually, to heal others.

For example, we can cite the history of Stephen Lyon Crohn who, being a carrier of a mutation of the gene CCR5, was genetically immunized against most forms of the AIDS virus[7]. The fortuitous discovery of this mutation and its effects has enabled the development of new medicines[8].

The genomic revolution allows today to multiply the possibilities of discovering " superhero genes "and to extend it to the field of rare diseases, as explained by Mr. Peter O'Donnell and Ms. Alisa Herero. That is to say, to discover modifying genes whose action thwarts (or Contrast amplifies) the pathogenic effect of a mutated gene that causes a genetic disease[9].

In this context, taking part in the genome adventure is a bit like giving blood: it can save someone's life and it can also save ours.

The couple genomic data/phenotypic data

Remains an essential point: in itself the consultation of the 3 billion bases (letters) that make up the genomic data is practically useless in the perspective that interests us[10].

To be really useful and to make it possible to establish connections scientifically, the genomic data must be coupled with data that describe in the most accurate, objective and complete way the observable biological traits of the person whose genome is collected: this is the phenotypic data.

Concretely, in the case of P101GM, it is only by having the "genomic data/phenotypic data" couple at their disposal that researchers will be able to try to discover what precisely corresponds to each gene and/or each mutation and their interactions. And that they will then be able to hope to understand the great variability in the spectrum of damage in the context of Marfan syndrome - even from an identical mutation - which cannot be explained at present, as is currently observed, in particular, researcher Aline Verstraeten.

This knowledge will enable better monitoring and treatment of patients as explained in the Professor Catherine Boileau and will respond to a concern of the families of patients as evidenced by the President of the ABSM, Mrs Véronique Vrinds.

Securing and anonymization of personal data

The 3 billion of letters that compose the genomic data are unintelligible to any human being without a suitable interface. This data is, moreover, practically identical – to almost 99% – for all individuals who are human beings. For the most part, it is therefore difficult to consider that this data shared by all is a personal data in the strict sense. There is no doubt that the balance, drowned in an ocean of letters, is peculiar to the point of being simply unique to every human being. Access to this balance – and all of which it can be isolated – must therefore be anonymized and secured.

Phenotypic data are also tricky to treat since they are personal data that actually correspond to the complete medical record of individuals. This phenotypic data must therefore be treated with the same care as the medical record of a person who would be made available to researchers.

While ensuring that coupling with genomic data is protected.

We have surrounded ourselves with a team of lawyers specialising in personal data protection issues in order to set up a legal framework that guarantees the secure processing of patient data in full compliance with the legislation in force. You will read below the interventions of several members of our team such as : Michael Lognoul, Assistant at the University of Namur (CRIDS) Bruno Fonteyn, Lawyer at the Brussels Bar specialising in life sciences issues and Cécile Chabot, lawyer in charge of the transposition of the "General Regulation on Data Protection" (RGPD) in companies.

What you do and what you do not do

To understand the issue of secure access to the genomic/phenotypic cross-database that the P101GM is intended to put in place, it is essential to understand beforehand what one does and what is not done.

As part of the P101GM, the Fondation 101 Génomes has given itself the task of financing:

  • The complete genome sequencing of 101 genetically diagnosed patients as being suffering from Marfan syndrome using the standard Golden market (currently it is the Illumina technology in 60 blankets (WGS 60x));
  • Storing this information in three formats (FastQ, BAM and VCF) for 10 years;
  • The establishment of a Bioinformatics platform to cross genomic data with corresponding phenotypic data;
  • The work of integrating phenotypic data from 101 patients on the platform;
  • Management of platform access and possible links to other platforms.

In the same spirit as UMD-FBN1, the Foundation does not fund the work of a particular team of researchers, but provides all research teams around the world with a resource that allows them to substantially reduce their research costs and to carry out their own investigations into Marfan syndrome more quickly.

To write it simply, scientific research will be carried out downstream of the bio-informatics platform set up in the framework of the P101GM. And it's already a that's a big push! " to research as explained Mrs Lauriane Janssens, researcher and President of the European Marfan network.


The different levels of access provided will be managed by a specific access Committee.

On the GnomAD model, it will be possible to perform a free access search on the genomic data in the raw format without any link to the phenotypic data.

Cross-data access will be accessible on a reasoned request to all research centres that study Marfan syndrome.

Any requests to recontact the members of the cohort will be transferred by the access Committee.

To encourage the pharmaceutical industry to invest in the development of new drugs for people with Marfan syndrome, a form of secure access under license will also be put in place and contribute to the financing of development of the tool.

Parallel searches

The investigations related to the implementation of the P101GM have already allowed to highlight some interesting elements on which the team of Dr. Guillaume Smits at theInteruniversity Institute of bioinformatics in Brussels ((IB) ²) is working and we look forward to the success.

Questions related to the harmonisation and objectification of phenotypic data to feed the database led us to contact Grégoire Vincke of the company Cytomine to examine the possibilities that algorithmic could offer for the measurement of the aorta of patients and their evolution.

We have discovered that the most widely used genetic technique currently in Belgium does not allow in all cases to pose a genetic diagnosis of Marfan and that the use of complete Genomic sequencing (whole genome sequencing – WGS) could to put an end to the diagnostic Odyssey of the patients affected by this problem. In General, our own experience and the encounter of several families lead us to think that the use of WGS technology could significantly shorten the diagnostic Odyssey[11] In addition to supplying research programs. From this perspective, we hope to be able to carry out the P101GM and make available to the competent public authorities what we have learned to feed their reflections in relation to the use of the genome.

The time has come...

When we discovered the genome and the needs of the researchers, we wondered why the model we were looking to put in place with the P101GM did not yet exist. When we present the P101GM, this question comes almost systematically. And we still do not have a satisfactory response at the moment.

One of the few answers we have has been provided to us by one of the (many) doctors who follow our little boy when he explained to us that there were so many obstacles[12] that the only real advances were those worn by patient associations.

Our destiny and that of our children is in our hands. If we do not fight for them and help the doctors who are trying to heal them, no one will.

That's what Professor Guillaume Jondeau has, it seems to us, translated very well by evoking transformation." of a drama into a creative force ». And that's also what Ms Stéphanie DelaunayPresident of the French Marfans Association, seems to have understood very well when she explained that the P101GM is "...". a unifying project for patient associations "Marfan.

In his commentary to Dessie and Laurens' article, Professor Bart Loeys confirms that he's looking forward to it because: " Genetics has undergone a real technological revolution in recent years and "that according to him" The time has come to use this technology to discover genetic explanations for clinical variations among Marfan patients. ".

The goal of F101G through the P101GM is to help researchers like Professor Bart Loeys advance 10 years in their work by Taming the genome to serve patients with rare diseases.

« The future remains uncertain and exciting as Dessie concludes, Sam's MOM.

Romain Alderweireldt
Fondation 101 Génomes


[1]       The "letters" in question are the famous nucleic bases A (adenine), C (cytosine), G (guanine) and T (thymine) with which the genome is written.

[2]       Former British Prime Minister David Cameron, whose little boy, Ivan, was suffering from a rare disease was one of the people behind this project.

[3]       KCE, " The use of whole genome sequencing in clinical practice: challenges and organisational considerations for Belgium available on the KCE website at https://kce.fgov.be/en/the-use-of-whole-genome-sequencing-in-clinical-practice-challenges-and-organisational-considerations

[4]       This is not a whole genome sequencing but a DNA-limited sequencing (whole Exome sequencing). It is certainly an interesting resource, but unfortunately it does not correspond to the Golden standard modern.

[5]       That is to help identify the most suitable therapy to put in place to treat patients.

[6]      Available at: https://www.kbs-frb.be/fr/Activities/Publications/2018/20180704PP

[7]      We will read the story of Stephen Lyon Crohn in " The Lancet » : https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(13)62279-5/fulltext.

[8]      Such as the "Maraviroc".

[9]      We will consult with interest the conclusions of the "resilience project" which identified 13 apparently healthy adult individuals while carrying pathogenic mutations that should have caused severe rare diseases in them that develop normally from childhood (CHEN R. et al., " Analysis of 589.306 genomes identified individuals resilient to severe Mendelian childhood diseases "Nature Biotechnology, 34, 531-538 (2016) doi:10.1038/nbt.3514, Received 29 July 2015 Accepted 12 February 2016 Published online 11 April 2016. Available at https://www.nature.com/nbt/journal/v34/n5/pdf/nbt.3514.pdf ).

[10]      However, genomic information without phenotypes may be useful in other areas, such as when studying, for example, the frequencies of mutations in the population (control database), the history of migrations, the analysis of evolution, etc.

[11]      This is the fact that the Swiss Stiftung für Menschen MIT seltenen Krankheiten | Foundation for people with rare diseases » in Zurich, which now systematically uses WGS sequencing to make a reliable diagnosis as quickly as possible.

[12]      And the complexity of the institutional system of our country would not fix anything according to this practitioner.

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