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What is a mutation? And what are the consequences at the level of the organism?
Patrick Revy: Damages regularly appear in the DNA contained in our cells, following exposure to a dangerous substance - chemicals, UV products - even spontaneously. There are many repair systems responsible for eliminating these sequence modifications. However, sometimes they remain in the cells, we then talk about mutations.
Recent studies show that spontaneous mutations appear in our cells throughout our lifetime and that they accumulate with age. Most have no consequences (neutral) but some can lead to modifications in cell behavior. That is what allows the evolution of organisms over generations. On the other hand some can alter cell function. It is followed by the growth of cells that no longer fulfil their role, which disrupts the proper functioning of an organ for example, or uncontrollable cells like in cancers.
Are these mutations always associated with a negative effect?
PR: For a long time, these mutations have been associated with cancers, genetic diseases and ageing. However, little research has since highlighted the characteristic of these mutations that is sometimes beneficial. The most supported example concerns hereditary genetic diseases affecting the hematopoietic system (due to a mutation in a gene).
Before becoming red blood cells, white blood cells or platelets, cells go through a series of stages of differentiation and maturation from hematopoietic stem cell and progenitor cells. On average, 14 mutations appear each year in these cells, mother of all specialized cells in the blood.
When a spontaneous mutation occurs giving the cell an advantage, for example in relation to deficient cells, it can take over in a sense. This is what happened in a patient with a severe immunodeficiency in 1994: even though he did not produce any T lymphocytes from birth, a spontaneous mutation restored their production. From other examples, this isolated case was confirmed. However, up to now it was believed that this was an extremely rare phenomenon and only concerned very few genes. The development of sequencing techniques show that this phenomenon is not so anecdotal and can take different forms.
What is known about these beneficial mutations?
PR: They can have a very diverse nature: some correct the mutation of origin, others lead to the disappearance of the DNA fragment concerned and sometimes they indirectly restore the defective mechanism.
In addition, these mutations do not systematically lead to the replacement of all pathogenic cells. Sometimes they cause a mosaic of cells, some healthy, others defective, with a lessening of symptoms in some cases.
They are mainly described in hematopoietic diseases due to germline mutations, therefore present in all cells. Corrective mutations in the cell have been recorded in 33 hereditary hematological diseases. Even though these diseases seem particularly appropriate because of the high renewal rate of hematopoietic cells, this mechanism has also been highlighted in other tissues containing stores of stem cells, notably in skin diseases and Duchenne muscular dystrophy.
Which clinical perspectives uncover these discoveries?
PR: They pave the way for new forms of gene therapies, but also for new therapeutic strategies based on the repair of damage, either ex vivo in the T lymphocytes for example, or in vivo using CRISPR/Cas9.
The development of analysis techniques on the level of the single cell should see other diseases concerned by these “auto-repair” mechanisms emerge in the years to come, but also new tools to treat these defects in patients.