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Podcast Review: How to be a Superhero – The hidden powers within your genes

29 March 2021
Appeared in BioNews 1089

When you hear the word 'superhero', the image which springs to mind may be of a billionaire playboy philanthropist or an agile acrobat in unnecessary tight latex. In the latest episode of the Genetics Unzipped podcast, 'How to be a superhero: the hidden powers within your genes', Dr Kat Arney expanded this term to include those who are resilient against disease-causing mutations in their own genome. Inspired by an article in The Atlantic, the episode discusses genetic research unified by an atypical, yet refreshing, scientific question: why are these individuals healthy?

Scientific communication is clearly Dr Arney's superpower, with the episode encompassing several interesting epidemiological studies. The host concisely describes a 2016 paper, published in Nature Biotechnology, which reported the screening of almost 600,000 genomes for mutations in 874 genes known to cause early-onset Mendelian diseases. The research identified 13 individuals who, according to their medical records, had no clinical manifestations of their inherited disease. Unfortunately, the lack of recontact clauses in the original studies meant clinical reports couldn't be verified, prompting the researchers to continue searching for these genetic 'superheroes'.

Lead authors Professor Eric Schadt and Dr Stephen Friend of the Icahn School of Medicine at Mount Sinai, New York City, named the search for these rare individuals 'The Resilience Project' – likely because 'The Avengers Initiative' was already taken. Being trained to be a scientific sceptic, I appreciated the episode covering the caveats of the research which is essential for providing a laymen's audience with a balanced perspective. Dr Arney discussed the potential for human error in large genetic datasets, as well as the prospect of somatic mosaics – people with genetic variation throughout tissues in their body.

Despite the compelling nature of this research, the episode lacked dynamicity, likely because it did not follow the usual Genetics Unzipped format. There were no conversational excerpts from interviews or a co-host to grant a reprieve from the rehearsed script. The podcast format thus provided no added value compared to the transcript, however, the brevity of the segments managed to maintain my attention – a testament to the power of editing.

Speaking over what I assume is classical European folk music, Dr Arney continued to review genetic resilience within a Dutch cohort. The 2014 Nature Genetics study created a genetic baseline for the Netherlands by whole genome sequencing 250 Dutch families, which accidentally discovered genetic anomalies such as two sexagenarian superheroes. Both individuals carried two dysfunctional copies of the SERPINA1 gene, which should have induced α1 antitrypsin deficiency – a disease primarily affecting the lungs and liver. Remarkably, they had no breathing issues – even after six decades, suggesting they were somehow resilient to their genetic code. However, it may be premature to start fitting them for initial-emblazoned capes: disease-causing mutations can be nullified when extended to larger, more diverse genetic datasets.

The highlight of the episode, as dog-lovers will understand, was Ringo the Brazilian golden retriever who defied odds by living a long, healthy life, despite being bred to develop Duchenne's Muscular Dystrophy (DMD). As males only have one X chromosome, inheritance of a single faulty dystrophin gene leads to severe muscle-wasting which affects one in 3500 males worldwide. Interestingly, as noted in the Cell paper, Ringo demonstrated high expression of Jagged1 in skeletal muscle tissue – a protein involved in a signalling pathway which influences muscle regeneration. This expression profile was identical in his unaffected puppy Suflair, who had 48 other siblings (down, Ringo), and was replicated in a zebrafish model. Amazingly, this has led to a completely new therapeutic avenue for DMD, meaning these dogs are undeniably good boys.

Ringo isn't the only superhero whose personal genome has led to new treatments: the episode concludes with the tale of Sharlayne Tracy, a 40-year-old African American woman with genetics to be envied. In a country which advises cholesterol levels to be under 100mg/dL, Tracy averages at an astounding 14mg/dL. In their Cell article, researchers at UT Southwestern, Dallas, Texas, discovered that Tracy carried two rare versions of the PCSK9 gene, which essentially ablated the gene's function.

After considering how to inhibit my own PCSK9 gene, I was informed that it encodes for a protein which regulates low-density lipoprotein (LDL) receptors found on the surface of liver cells. Without PCSK9 production, an increase in LDL receptors promotes clearance of cholesterol from the circulation, reducing the risk of arteriosclerosis. Unsurprisingly, PCSK9 inhibitors were subsequently approved in the UK in 2016 and contribute towards reducing heart disease, showing the impact of genetic resilience research.

Throughout the episode, Dr Arney features compelling anecdotes of genetic superheroes, both human and canine, providing a wholesome relief from the majority of research which focuses on disease-affected individuals. Although I prefer a more personable element to podcasts and feel the medium didn't enhance the transcript, I would recommend the series as a whole. Similarly, I would advocate signing up to The Resilience Project, especially if you are unaffected with a familial history of disease. For now, if I can't have telekinesis, I'll settle for low cholesterol.

SOURCES & REFERENCES
How to be a superhero: the hidden powers within your genes
The Genetics Society Podcast |  11 March 2021
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