Why are there people who can die from infectious diseases that are apparently mild for most of us?

One of the promises of the Human Genome Project –which was published 25 years ago this year– was that our genome would allow us to predict what we are like and what we will get sick from. The predictions of the 1990s, when the project began, were very optimistic and perhaps to some extent naive, because genetic information is not linear or simple, but complex, with many levels of regulation and interaction. Furthermore, environmental factors must also be taken into account, including diet, exercise, stress, and also, very importantly, the history of diseases and infections throughout life, which impacts our long-term health.

Following the covid-19 pandemic, we are also aware that there are individual differences, because not all of us were equally susceptible to the severe consequences of infection by the SARS-CoV-2 virus. Until a large number of people were infected by the pathogen, we did not know which ones suffered a more severe illness that could take their lives and which ones responded by having the illness mildly or asymptomatically. The existence of chronic diseases in the elderly was a factor to consider, but also genetic differences in the response to the virus.

As an example, after many genetic studies and with a cohort of patients as large and well-studied as the European one, different genes were identified that determined the response of our immune system to the virus, among which there was a specific chromosomal fragment from the genome of our Neanderthal ancestors that caused an exacerbated response to SARS-CoV-2 infection in people who had inherited it.

It is likely that some of you have seen one of John Travolta's early films, in which he played a boy with a rare genetic disease that caused severe combined genetic immunodeficiency (the misnamed "bubble boys disease). In this disease, infants who have inherited mutations in the ADA gene from both parents suffer preferential death of white blood cells and cannot defend themselves against infections. In other families, very infrequent mutations in genes that encode interferons (one of our immune system's defenses against infection by viruses and other pathogens) determine that an infection by a microorganism considered opportunistic and causing mild infections in most of us, can cause multi-organ involvement and, very often, death.

Regarding the population as a whole, we must not forget that we are the result of hundreds of thousands of years of natural selection on our ancestors, when there was no surgery or medicine, nor always available drinking water. People died of diarrhea, tuberculosis, and infections from open wounds. The viruses, fungi, and bacteria in humid areas are not the same as those in the tropics. Our past determines our genetic present. Thus, different genetic variants that provide resistance to malaria were selected, such as mutations in the alpha and beta globin genes, which alter hemoglobin formation and which, when variants are inherited from both parents, cause diseases such as sickle cell anemia or alpha and beta thalassemias; genetic mutations that confer greater resistance to typhus, cholera, or salmonellosis, but which also, if inherited from both parents, cause cystic fibrosis; or like this chromosomal region from our Neanderthal ancestors that was selected to resist certain pathogens, but which, in the face of the SARS-CoV-2 virus, determines an unexpected inflammatory reaction that can cause death.

Moving towards precision medicine

voluntary pilot program for genetic screening and diagnosis of all newborns

In fact, in the United Kingdom, the public health system is implementing a voluntary pilot program for screening and genetic diagnosis of all newborns through whole-genome sequencing, which currently complements the heel prick test, but provides much more information about the rare genetic diseases that these infants may suffer from, some long before they manifest. It is worth remembering that around 6%-8% of all of us have a rare disease, and around 5% have unexpected – but genetically predictable – adverse reactions to medications. Differential immune response can also be predicted in many cases.

All this information will allow for the implementation of precision medicine according to the genetic combinations we have inherited – which we cannot choose, it is a genetic lottery – and to make preventive decisions to avoid or slow down their manifestation, with personalized measures that do depend on us.