If you are a fan of alternative superhero movies, you will remember the one directed by Michael Night Shyamalan, famous for his debut with that blockbuster that was The Sixth Sense . Titled Unbreakable (unbreakable), in Spain the production company changed it to El Protegido for completely unknown reasons. It tells the story of a man who never gets sick or suffers in front of another who lives in constant danger of breaking down having been born with a disease called osteogenesis imperfecta, more commonly known as “glass bones”. An avid consumer of superhero comics, he believes that somewhere there must be someone to balance his scales, someone with the strength that he lacks. His search ends the day he hears the news of a train derailment where everyone has died except for one man who got out of there without a single scratch.
Well, more or less that is the story of Project Resilience . His goal is to discover why some people are able to resist or recover from a disease, even though they are genetically predestined for it . Or put another way, the project run by the Icahn School of Medicine at Mount Sinai looks for people who carry a mutation that invariably causes a genetic disease and yet don’t have it.
To do this, they study DNA samples in search of mutations that cause certain pathologies, and for this they have chosen a list of 675 Mendelian diseases . That is, diseases caused by a mutation or alteration in the DNA of a single gene, which, when transmitted to offspring, causes the appearance of dysfunctions in the organism.
The underlying idea is to find a gene or an environmental factor that allows resistance to a disease and use it to find a therapy. In this way, in the event that the inhibition of a certain gene has a protective effect, a drug can be designed that inactivates it. An example is found in the PCSK9 gene which, when deactivated by a mutation, keeps cholesterol levels low.
Protective genes?
There are several genes whose relationship with resistance to certain diseases has already been proven. An example is that of the HLA-DRB1 gene associated with the risk of suffering from rheumatoid arthritis, but the international team led by Sarah Dunstan, from the Nossal Institute of Global Health attached to the University of Melbourne in Australia, has confirmed that those who harbor in their genome a particular form of this gene, show a natural resistance to typhoid fever .
Also in Spain, researchers from the Marqués de Valdecilla Research Institute in Santander described in 2014 a mechanism that acts as a natural shield for the skin by which cells with mutations in the p53 protein are expelled by desquamation, protecting the epidermis from solar radiation and avoiding the appearance of skin cancer.
The p53 protein is considered the guardian of the integrity of the genome , since it plays a key role in controlling DNA replication so that errors are not transmitted. It is, therefore, a tumor suppressor gene and its inactivation is the genetic alteration most frequently found in cancer cells of numerous types of tumors, especially in skin carcinoma, where it is present in 80% of cases.
Is longevity genetic?
If these genetic variants can be transmitted from parents to children, why not study the genome of families that have lived longer than others without showing symptoms of disease? This premise served to develop a project at the Faculty of Medicine of the Free University of Amsterdam, whose objective was to find the causes why dementia is more present in some people than in others. To do this, they analyzed the DNA of the blood cells of Hendrikje van Andel-Schippers, an elderly woman who died in 2005 at the age of 115 without showing a single sign of dementia and whose mother lived to be 100 under the same conditions, so it seemed safe that its genome included elements that protected it.
They decided to study the genetic material contained in the white blood cells of this elderly woman, because the changes that occur in her chromosomes throughout life are faster and more numerous than in neurons. The results, published in the Genome Research journal, revealed that the old woman’s blood hid no more and no less than 400 mutations in her leukocytes . What’s more, they discovered that the white blood cells that contained them were derived from just two hematopoietic stem cells (bear in mind that human bone marrow contains some 11,000 of these cells, of which 1,300 are actively dividing and renewing cells). our blood cells). According to the authors, “This suggests that as we age, the hematopoietic stem cell pool declines until all of our cells are clones of just a few parental cells.” Is this the path to longevity?
References:
Dunstan S.J. et al (2014) Variation in the HLA-DRB1 region is associated with susceptibility to enteric fever, Nature Genetics. Dec;46(12):1333-6 doi: 10.1038/ng.3143
Holstege H. et al (2014) Somatic mutations found in the healthy blood compartment of a 115-year-old woman demonstrate oligoclonal hematopoiesis, Genome Research. doi: 10.1101/gr.162131.113
