In a previous EMR post from December 30 of 2014 (see link below), I discussed a study (Science, 2014) that offered evidence for reciprocal selection of host and pathogen iron-binding proteins arising out the competition for their shared ligand, which is critical to the metabolisms of both parties to the conflict. A recent paper (J. Bacteriol., 2015) by Filkins et al. demonstrates another sort of competition focused on the acquisition of iron that can affect human health. This conflict occurs between two species of bacterial pathogen associated with lung disease in cystic fibrosis (CF) patients. (more…)
Fighting HIV Evolution with an Evolved Therapeutic Agent: Phase I Dose Escalation Clinical Trial of a Potent Broadly Neutralizing Human Antibody
In previous commentaries (http://dev-evmedreview.pantheonsite.io/?p=1863; http://dev-evmedreview.pantheonsite.io/?p=837; http://dev-evmedreview.pantheonsite.io/?p=385), I have discussed the critical role of extensive B-cell and immunoglobulin gene evolution in generating broadly neutralizing antibodies for HIV-1. Of course, the unprecedented magnitude of antibody evolution necessary to achieve potent neutralization of a high percentage of HIV strains reflects the unprecedented evolutionary plasticity of HIV that originates in both high mutation and recombination rates for the HIV genome (Korber et al., 2001). A new study by Caskey et al. (Nature, 2015) from the Nussenzweig Laboratory reports results for a first-in-human dose escalation phase I clinical trial of a human monoclonal antibody (mAb) specific for the HIV envelope (env) protein. (more…)
Extent of Tumor Evolution as Assessed by Numbers of Nonsynonymous Somatic Mutations Correlates with the Effectiveness of Anti-Checkpoint Therapy
It would be hard to identify an approach to cancer treatment that has received more attention recently than anti-checkpoint therapy (Pollack, 2015). This strategy for eliminating tumor cells is based on interfering with one or another pathway that inhibits the initial activation or functions of T cells, such as CD8+ cytotoxic T cells (CTL). Activated tumor-specific CTL can directly kill their targets. However, if copies of the T-cell surface molecule, PD-1, are bound by their physiological ligands on tumor cells, either PD-L1 or PD-L2, or other cells the ability of the T cell to perform its functions is substantially reduced. A report published in Science (2015) by Rizvi et al. last month addresses the question of whether tumor mutation burden correlates with response to anti-checkpoint therapy for non-small cell lung cancer (NSCLC).
In an EMR commentary (http://evomed.org/?p=1644) from March two years ago, I discussed issues related to the functional classification of genomic DNA sequences that arose in the context of claims from the ENCODE (ENCyclopedia Of DNA Elements) consortium. A particular focus of that piece was an article by Graur and colleagues (2013) that offered an often humorous but rather stinging critique of the definition of “function” applied by the ENCODE authors to genomic DNA sequences. Graur and two of his associates have now published (2015) an interesting and valuable functional classification of genomic sequences that is critically informed by their understanding of evolution. (more…)
Last month, Murphy and colleagues (Cell, 2015) published a fascinating report about a patient with an immunodeficiency syndrome that underwent spontaneous resolution. The mechanism for this remarkable outcome points to the importance of somatic cell selection and evolution in the origins, pathogenesis, and most dramatically in this case, elimination of disease. (more…)