Interview with Jean-Louis Mandel, recipient of the 2022 Kavli Prize in Neuroscience
“Dialogue with the families of patients is essential to our research”
A physician and geneticist, Jean-Louis Mandel was director of the Institute of Genetics and Molecular and Cellular Biology (IGBMC) at the University of Strasbourg (CNRS/Inserm) from 2002 to 2006, where he dedicated his career to the study of the genetic origins of rare diseases. Holder of the Collège de France’s chair of Human Genetics from 2004 to 2016, he also holds the Chair of Human Genetics at the University of Strasbourg Institute for Advanced Study (USIAS) since 2012, where he is also member of the Governing Board. In 2022, he was awarded the Kavli Prize in Neuroscience for his discovery of the genetic mechanism responsible for fragile X syndrome.
Very early on in your life, you became interested in both art and science. After a few years spent at the Paris Conservatory studying the violin, you finally opted for scientific studies. What led you to make such a decision?
Jean-Louis Mandel: During the three years that I spent in Paris, I realised how much more talented than me some of my colleagues were. I am talking about people who went on to have brilliant musical careers, such as the great soloist Pierre Amoyal, who was a pupil of Jascha Heifetz; Emmanuel Krivine, who became director of the National Orchestra of France; or the renowned violinist Augustin Dumay. Besides that, I also suffered badly from stage fright. If you want to become a soloist or to play chamber music, your performance must be consistent – every second counts! – whereas, when doing research, you can hesitate or even make a mistake one day and do better the next. Error is part of the daily life of a scientist, it is constitutive of one’s work, I would say. The pressures are not the same. Moreover, the world of science had fascinated me since I was a child. My father, Paul Mandel, was a professor at the Faculty of Medicine in Strasbourg, and a researcher. He created a large laboratory of neurochemistry – a field, now part of the larger domain of neurosciences, of which he was one of the pioneers. I witnessed him being very enthusiastic about his work, and scientists, all very friendly, interesting and from various countries, would often come and visit him at our home. On the advice of my father, I therefore embarked on a double course in science and medicine at the University of Strasbourg, even though I must concede that I was not very diligent in the latter.
Since 1982, your work has revolved around the search for the genetic origins of rare diseases, although this was not your specialty during your thesis. How did this topic spark your interest?
It was very much the result of a series of coincidences. At the time, in medical school, we only had two hours of lessons on genetic diseases, so it was an area that I knew very little about. Then, I went to work on my thesis in biochemistry and molecular biology at Pierre Chambon’s laboratory. Once the thesis had been completed, my military service was imminent, which was just not my cup of tea. Fortunately, there was an alternative called “Cooperation”, which consisted of sending young doctors and teachers to the former French colonies, particularly in Africa, and I had heard that it was possible to go to Canada via this system. Pierre Chambon thus introduced me to Lou Siminovitch, the father of genetic research in Canada, who accepted me as a post-doc in the Department of Medical Genetics at the University of Toronto, where I was supposed to teach in French. I must admit that I never uttered a single word in the language of Molière while I was over there, except when it came to explaining the spoonerisms of “Le Canard Enchaîné” (a French weekly newspaper). It was during these two years that I attended some fascinating conferences on the topic of genetic diseases.
Were you able to explore this newfound interest as soon as you came back to Strasbourg?
Not immediately, no. First, I worked with Pierre Chambon on a very exciting project on egg white protein genes. Put that way, it may seem trivial, but we were using the very newest methods in genetic engineering. This led me to participate in a fundamental discovery: the structure of genes is fragmented, which means that the coding sequence, contained in what we now call exons*, is interrupted by non-coding sequences, called introns*, and therefore does not consistently match the structure of messenger RNAs, the molecules derived from DNA that are read for protein synthesis. During this work, I became aware of the genetic variability in the hen. At the same time, I began teaching biochemistry at the Faculty of Medicine, but realised that students were not interested in this field, unless it was associated with diseases. So, I started giving courses in which biochemistry and genetics were intertwined. I then recalled the notion of genetic variability, in particular because of its potential usefulness in the diagnosis and study of rare diseases. As a researcher, I believe teaching to be very enriching, because you can’t just talk about your own research topic to your students. You have to broaden your horizons, by taking an interest in other subjects. In my case, it allowed me to find the research subject that would go on to become the very basis of my whole scientific career. Besides, I thought it was time for me to strike out on my own, so I launched my first project that consisted of using the same technologies we had used with the hens, but on the human genome. I was motivated, but some obstacles had yet to be overcome.
What obstacles?
A few months after the initiation of this project, the quadrennial visit of the Chambon laboratory by the CNRS – the French National Centre for Scientific Research - took place, during which I was able to present my project. Unfortunately, the committee didn’t seem convinced, especially because I was interested in human genetics without having been trained in it. Nonetheless, Pierre Chambon supported me and I was able to continue. And, as early as 1983, we began to obtain very promising results. That’s when I started working on fragile X syndrome, which was a very little-known disease at the time. It was the subject of my very first publication in the field of medical genetics, in collaboration with Jean-François Mattei, who later became Minister of Health under Jacques Chirac’s presidency, and his wife, Marie-Geneviève. They were among the first geneticists to be interested in this disease in France.
You have been awarded the 2022 Kavli Prize in neuroscience for your work on this disease. What was the fundamental discovery that earned you this recognition?
Fragile X syndrome is characterised by behavioural problems and intellectual and cognitive difficulties, among other things. In the 1980s, virtually nothing was known about the causes of this disease, but we did know that it was associated with an anomaly – detectable in certain conditions – of the X chromosome, that seemed to break, hence the name “fragile X”. It took eight years for my team to map this region of the genome, which led us to discover a new and astonishing form of mutation in 1991, called “unstable expanded repeats”, which is characterised by the repetition of groups of nucleotides* in or around a given gene. In the case of fragile X, the cause is the unstable repeat of nucleotide triplets (CGG) in a specific location of the X chromosome. It was the very first time that such a mechanism was identified, and it was very quickly determined that it was also the source of other rare genetic diseases that had been clinically recognised for a long time, but whose causes remained unknown.
Such as?
In 1992, it was identified as the cause of myotonic dystrophy – or Steinert’s disease – one of the most common muscular diseases. In 1993, an American team found this mechanism to be the source of Huntington’s disease, a horrendous neurodegenerative and hereditary disease, which is better known because it only appears around the age of 35 or 40, and has therefore affected people who had achieved celebrity in show business prior to being ill – like the American folk singer Woody Guthrie or French actress Sophie Daumier. In the years just after our discovery, this mechanism was identified as being at the origin of an array of rare diseases, including three neurological disorders that affect balance and coordination by our laboratory, between 1996 and 1997. After that, nothing for a good while. In recent years, however, new genome sequencing technologies have unblocked the situation, in particular by making it possible to analyse large DNA fragments, a method called “long-range sequencing”. New computer analysis techniques that are faster and more efficient, have also made it easier to find these repetitions among the immense flow of information of the genome. It is due to these technologies that we were able to shed light on the origin of the most frequent genetic form of Charcot’s disease, or amyotrophic lateral sclerosis (ALS), which is called Lou Gehrig’s Disease in the United States, as a tribute to a great baseball player affected by it.
Has this discovery made it possible to develop treatments for fragile X syndrome?
To date, there is no specific treatment for fragile X syndrome. You need to understand that it is far more difficult to conduct clinical trials with patients with intellectual disabilities and behavioural disorders than it is with patients with other conditions. For diseases in general, everything is explained directly to the patient, who participates willingly in the trials. But if the patient is not autonomous enough to give their consent, the family must be involved. It is a cumbersome and difficult process. Some paths do exist; we have found potential therapeutic strategies, but the problem is to carry them out in these cases. Fortunately, these avenues continue to be explored, in particular by Hervé Moine’s team at the IGBMC. On the other hand, there is what we call “genetic counselling”. Fragile X syndrome can be transmitted by people who do not show signs of the disease, sometimes in distant branches of the same family. However, the discovery of the underlying mechanism has allowed the development of diagnostic tests through which one can identify the risk of transmitting the disease to one’s children. This way, people who are not carriers can be reassured, and those who are can be offered a prenatal diagnosis. However, in France we are still quite wary about extending this kind of preconception tests, supposedly for ethical reasons. One of my personal battles is to allow everyone who wants such tests the opportunity to do them, especially since it is a practice that has already been in place for 25 years applied to prenatal screening for trisomy 21.
You have been in contact with the families of patients for a long time. How important was this relationship in your research work?
To work on the genetic origins of such diseases, we need the collaboration of the families. From the beginning, it was obvious to me that we had to establish contact and get closer to these people. It is not possible to be interested in this subject from a purely scientific point of view, without taking the patients’ daily life into account. On this matter, I will always be crystal clear: collaboration and dialogue with patients and their families has been essential to my research on all the genetic diseases on which I have worked. I have been involved in the scientific councils of family associations, such as the French association of Fragile X where I was present for the recent celebration of its 30th anniversary. Moreover, from time to time, I would take the young researchers and students of the team with me to meet these families so that they could really see that their subject of work is more than just DNA contained in test tubes. It is motivating for them to realise that entire lives are involved but it does also generate a certain expectation which, as researchers, we wonder if we’ll be able to satisfy.
Have you had difficulties finding funding, since you are working on rare diseases?
I would tend to say no. Very early on, the French association against myopathies (AFM) understood the importance of genetic research. If France has a national “Rare Diseases” plan today, it is in particular thanks to the efforts of the AFM that has made decision-makers but also the general public and doctors aware of genetic diseases, through the telethon, and related sporting and cultural events. It is true, however, that research is more and more expensive and that it is more difficult to obtain sufficient funds for more innovative projects. For example, for my GenIDA project – a participatory initiative to collect information on patients with intellectual disabilities or autism spectrum disorders – all our funding requests fell through. It’s thanks to the University of Strasbourg Institute for Advanced Study (USIAS), where I hold the Chair of Human Genetics, that we were able to set up this project. More than finding the actual money, the real difficulty lies in finding it to test new things, to take risks or to initiate large-scale efforts…
How does being awarded the Kavli Prize impact your work?
I must admit that this is an unexpected recognition. I thought that the time of prizes had passed for me, especially for my fragile X discoveries, which date back from over 30 years! Today, it is becoming difficult for the current generation of young teams to find funding that enables them to be competitive. Moreover, in the field of genetics, machines are becoming more and more expensive that are obsolete more and more quickly, because technology is advancing rapidly. And, even if ideas are and will always remain central, access to technology can be decisive in the success of a study. I therefore want the funding associated with the prize to nurture the research of the teams of the neurogenetics department of the Institute of Genetics and Molecular and Cellular Biology (IGBMC), to make a real difference to some of their projects.
Interview conducted by William Rowe-Pirra, science journalist.
Glossary:
Intron: During transcription of DNA into RNA, introns are segments of the gene that are not conserved. They are cut and removed during the step called splicing.
Exon: Unlike introns, exons are segments of a gene that are retained in RNA after transcription and splicing.
Nucleotide: An organic molecule that constitutes the basic element of DNA, composed of a nucleic base – denoted by A, C, G or T depending on its structure – associated with a sugar and a phosphate group.
