First look at the genome sequence of Greenland shark to find possible clues that could explain their mind-boggling extreme lifespan of up to 400 years. - 70% of the genome is repetitive elements - many uniquely duplicated genes, many related to DNA repair pathway - p53 is not duplicated, but the authors find some unique insertion mutation in the p53 sequence Sahm et al. bioRxiv biorxiv.org/content/10.1101/…

Remarkable discovery of two human knockouts for Tumor Necrosis Factor alpha (TNF α) gene, who were found to be surprisingly healthy except for specific susceptibility to recurrent pulmonary tuberculosis infection. One aspect of this discovery that stands out for me is its therapeutic relevance. Infliximab is a TNF α monoclonal antibody, developed in the early 1990s, and approved for the treatment of Crohn's disease and rheumatoid arthritis in the late 1990s. In the phase III trial published in Lancet in 1999, the authors reported that one of the participants developed disseminated treatment-resistant tuberculosis and died. That was the first clue into possible links between TNF α deficiency and TB susceptibility in humans (thelancet.com/journals/lance…). There was a follow-up study of a larger trial data published two years later in NEJM that confirmed that indeed one of the rare adverse effects of infliximab is tuberculosis risk, and the report recommended physicians to screen patients for latent tuberculosis infection before initiating infliximab therapy. (nejm.org/doi/full/10.1056/NE…). More than 20 years later, now scientists are encountering humans naturally lacking TNF α and provide genetic evidence that TNF α deficiency indeed increase the risk for TB. But the most important thing is the authors also show that TNF α deficiency is not that dangerous as one might expect from animal studies. Except for the TB infection, the patients seem to be healthy. How amazing is that? This is another great example of how rare disease patients can inform drug development. Arias et al. Nature nature.com/articles/s41586-0…