Jérôme Lejeune Foundation: Hello professor, could you please tell us who you are?
Yann Hérault: Hello, I am Yann Hérault. I am the research director of the French National Centre for Scientific Research (CNRS). I am a former student of the Ecole Normale of Lyon and Doctor of Science of the university in Lyon. I was trained as a biologist, specialized in mice embryology and genetics.
JLF: You have been working on mouse models for a long time, can you explain what your work consisted of at the beginning? What was the objective of your work and what difficulties did you encounter?
Yann Hérault: The work we started with my team 12 years ago aims at better understanding the mechanisms which are perturbed in Down Syndrome.
As you know, Down Syndrome occurs as a result of the presence of a third copy of the chromosome 21, which leads to the apparition of a number of alterations. The best known are those which affect the patients’ intellectual performances and morphology. Finding the origin of these alterations and identifying the genes of the chromosomes 21 which play a part in the alteration remains a challenge. Studies on man including a small number of patients whose chromosome 21 is partially duplicated has enabled us to get a better understanding of various regions of the chromosome 21 in some alterations.
To carry on these studies we developed genetic approaches in a model organism, a mouse, to observe the changes at a cellular level of the expression of the genes and molecules which are induces by the presence of a third copy of the genes of the chromosomes 21. Indeed, it has been known for a long time that mice and men present a great number of similar genes, called homologous genes.
When we started the work in the years 2000, the genome sequence in men and mice was not finished yet. The order of the genes on the chromosomes 21 and the similar regions in the mice’s genome had hardly been identified. We had to check and then validate a certain amount of data before we were able to engage in work that was going to take several years. We ambitioned to apply various methods that would enable us to change the chromosomes in the genomes of mice. We wanted to make the mice have Down Syndrome by inducing tandem copies of homologous regions of the chromosome 21. It took us several years with the contribution of several PhD students and many members of my team.
Together, we worked at creating these models. We began our work with embryonic stem cells and then tried to obtain mice which carried these modifications. We needed to generate at least 3 models to cover the whole of the homologous regions of the chromosome 21 in mice and complete the existing models. Certain models were ready earlier than other models which had been started before. Each region had its particularities, was more or less easy to target and chromosomal rearrangement was sometimes more difficult in some than others.
It took us 5 years to obtain our first model and start to study it and yet we lost no time. The others were then easier to make. We now have six different models and thanks to what we know we were able to put aside a certain number of difficulties, thus enabling us to reduce the time of their creation to two years. But the major difficulty lay ahead of us; carry out functional studies to look for similitudes between our models and Down Syndrome…. Very soon, we understood we would need even more time to study these models but, luckily, we found wonderful collaborators which helped us in this adventure.
JLF: You are carrying on with the genotype-phenotype mapping in correlation with the data you got from patients with Down Syndrome: Can you explain what it consists of?
Yann Hérault: The chromosome 21 (HSA21) has over 350 genes of which we still don’t know all the functions. We want to understand what the impact of certain genes in Down Syndrome is, i.e., determine the consequences of the changes of genotypes on phenotypes, on the expression of the alterations characteristic in Down Syndrome.
We have made a set of mice models for Down Syndrome for various regions of the chromosome 21 in order to see what traits are affected by each regions. Indeed, a great region of homology with the chromosome 21 (HSA21) is found on the mice’s chromosome 16 (MMU16). Other homologous regions of HSA21 are located on the mice’s chromosomes MMU17 and MMU16. Historically two MMU16 with partial Down Syndrome, carrying a region said to be critical, have been studied in detail. These cases of Down Syndrome lead to modifications less severe than those observed in men.
These results support the hypothesis that several genes of HSA21 located in other homologous regions of HSA21 in mice intervene and probably interact to induce the alterations observed in people with Down Syndrome. We have therefore studied the phenotypes of our various mice models which correspond to a set of genes of Hsa21 by developing standardized analysis to evaluate the cognitive performances of the animals. Thus, we were able to show that only some of the regions of the chromosome 21 are involved in mental disability, and that the genes in these regions interact with each other. They are capable of modifying the phenotypes, the alterations being induced by other genes of Hsa21. This hypothesis is supported by several mouse models that were created by other collaborators or by my team. The interactions between the genes is probably responsible for the very variable phenotypes that can be observed in people with Down Syndrome but also for the variability of intellectual disability.
JLF: You are trying to analyse genes responsible for the phenotypes observed in murine models: why work on murine models, and what does the work consist of?
Yann Hérault: We are carrying on with our work on model organisms such as mice to better understand the mechanisms of memory or cognition which are perturbed in Down Syndrome. Thanks to mouse models, we have access to brain tissues and structures which are very difficult to study in men. We can collect tissue samples that will enable us to study molecular and cellular mechanisms, while keeping all the regulations, ethics and well-being of the animal. What’s more, we control our mice’s environment with a lot of care in order to compare “normal” animals with the ones with Down Syndrome. Finally, the lines of laboratory mice are usually consanguineous. This is a very peculiar advantage as it enables us to compare individuals whose genetic heritage is identical at 99%.
JLF: You have been working on the cystathionine beta synthase (CBS) gene: could you explain what the role of the gene is: what are the perspectives for research?
Yann Hérault: The CBS gene is known to be involved in the methionine metabolism and in another disease in men, also associated to intellectual disability. We have analysed a mouse with Down Syndrome which includes the CBS gene and have observed a decrease in recognition and memory performances in this model. Thanks to complementary studies mainly based on experiences in genetics we have accumulated many elements proving the role of this gene in Down Syndrome. We are now convinced that this CBS genes has a major role in Down Syndrome even though we still don’t know all the underlying mechanisms. We are in the middle of decrypting them in order to determine what the best means of actions are to counteract the presence of these 3 copies of the CBS in patients with Down Syndrome. We have already contributed to two studies on drug candidates, targeting another pathway perturbed in our models in the first and another gene candidate in the second. These are promising leads and with this new lead on CBS we have several means of actions to counteract the effects of Down Syndrome on cognitive performances.
JLF: The heart of your research is therefore based on therapeutics but what are the next steps?
Yann Hérault : The next steps will be finding active molecules which will enables us to compensate or re-establish intellectual performances, first of all in our mouse models. For example, with molecules which would cause the activity of the CBS to decrease back to a normal level we could re-establish our models’ performances in recognition or memory tests. We could also check whether these molecules don’t have side effect worse than the benefit they bring. This is a crucial step that, unfortunately, leads us to stop using more than half the molecules being developed. Then, after these preclinical trials, trials on human beings would be needed to check whether any ameliorations appear.
JLF: What are the next murine models going to be used for: other rare diseases can also serve as a basis for research can’t they?
Yann Hérault: We are working in two major directions: the first is to study and understand other rare diseases, which induce intellectual disabilities, in order to understand the mechanisms which are at stake and suggest courses of action; the second, even more ambitious, is to decrypt the function of the genes in mammals through the international mouse phenotyping initiative in order to give research new leads for discovery. Thanks to this international effort, we are hoping to deliver information on genes which have been identified but whose functions are still unknown, and they still represent 2/3 of our genome.
JLF: Your ambition in your research?
Yann Hérault: Work in order for our research to serve knowledge, other researchers and society.