What Is a Medical Superhero?

7. June 2016
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Medical superheroes are those who don't suffer from illness despite having the relevant mutations in their genetic tissue. Researchers have not come to a proper understanding of this phenomenon with respect to monogenic diseases as yet. It's reason enough to warn against making simplistic correlations between genotype and phenotype.

When Daniel MacArthur, a researcher at Massachusetts General Hospital, Boston, talks about “superheroes” he doesn’t have muscular flying powerhouses in mind. This super capability is concealed at the nanometer level in DNA molecules: some individuals don’t suffer ailments, although on the basis of their genome they would be expected to. For the first time accurate figures on this phenomenon are now at hand.

Healthy despite gene mutation

Rong Chen and Lisong Shi from the Icahn School of Medicine in Mount Sinai, New York, evaluated biomolecular data from 589,306 adult volunteers – the biggest database for the study of genetic resistance capabilities. In order to be able to work successfully, the Icahn Institute for Genomics at Mount Sinai, Sage Bionetworks, the genome service 23andMe, BGI Cognitive Genomics, the Ontario Institute for Cancer Research and other partners joined up together to form the Resilience Project. According to Anne Wojcicki some 400,000 of these units of data came from 23andMe projects. The CEO of 23andMe services also advocates for free records to advance research, as occurred with the current publication.

Chen and Shi’s valuable gem appeared in the form of 13 participants. These were apparently healthy, although on the basis of their genetic makeup they ought to have been suffering from various ailments.

  • These include cystic fibrosis due to a trinucleotide deletion within a gene on chromosome 7 which encodes a chloride transporter. Without osmotically effective chloride ions, secretions become highly viscous.
  • With Smith Lemli-Opitz Syndrome a mutation on chromosome 11 leads to the event that 7-dehydrocholesterol reductase activity in the body is drastically reduced.
  • Patients with familial dysautonomia suffer from various adverse effects of the autonomic nervous system – ranging from serious digestive problems and blood pressure fluctuations to the absence of tear fluid.
  • The term epidermolysis bullosa is used by doctors to denote differing genetically defined processes of the epidermis involving various causes.
  • Pfeiffer syndrome is associated with craniofacial malformations. Geneticists refer to mutations of the FGFR-1 and FGFR-2 genes (fibroblast growth factor receptors) in offering an explanation.
  • Polyendocrine autoimmune diseases were also mentioned in the study. This collective term covers a set of various genetic abnormalities.
  • Campomelic dysplasia is yet another monogenic ailment: this is a lethal skeletal dysplasia which runs its course due to mutations in the region of chromosome 17.
  • The list also includes atelosteogenesis, a lethal skeletal dysplasia with diverse genetic abnormalities.

 

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Image source: http://resilienceproject.com/

Judging by the large sample, 13 people seems at first glance to be something perhaps insignificant. However, only single cases have been reported in previous literature. The comparatively high number surprised geneticists, and also gives food for thought. According to Rong Chen and Lisong Shi, monogenic diseases can’t simply be reduced to known mutations. Phenotype and genotype correlate in many, but not in all cases. This point casts shadows of doubt over prenatal testing at least in part. With view to these resiliencies, the authors suggest that there are regions in the genome which unleash a protective effect. Details are however not yet at hand. Geneticists are particularly interested in individual cases, in order to decrypt disease processes. Here monogenic diseases are still considered relatively clear.

Many genes many puzzles

There is much more difficulty to be dealt with in cases of diseases involving polygenic background, as Hannah J. Jones, Bristol, shows for example with schizophrenia. For birth cohort purposes she along with colleagues recruited 14,062 children. Genetic data on 9912 adolescent subjects were also added to this. All previously known single nucleotide polymorphisms (SNPs) according to the study account for 30 to 50 percent of the genetic schizophrenia risk. Jones then worked with a risk score which takes into account both the number of alleles and the magnitude of the effect – without resounding success. She succeeded only in determining higher risks for anxiety disorders or for negative symptoms.

A similar controversy exists in relation to scientists’ discussions about therapeutic decisions in breast cancer cases: patients with HER2-negative early-stage breast cancer can safely forego adjuvant chemotherapy, should gene expression tests indicate low aggressiveness for the tumour. This was the conclusion which Oleg Gluz of the West German Study Group in Mönchengladbach came to. At the end of 2015 the Institute for Quality and Efficiency in Health Care (IQWiG) wrote that the benefit is unclear. In our genes there are just so many secrets still hidden away.

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