The Evolution and Medicine Review

…bridging the gap.

Author: Neil Greenspan (Page 1 of 9)

Malaria-Specific Antibody Diversification via Interchromosomal Insertion of a Non-Immunoglobulin Gene Sequence

Identifying broadly neutralizing antibodies against infectious agents such as influenza A viruses, HIV, and Plasmodium falciparum that display impressive degrees of antigenic variation is a major focus of investigators developing therapeutics and vaccines for pathogens of importance in public health (Corti and Lanzavecchia, 2013).  In a previous post, I discussed one study (Klein et al., 2013) illustrating the sorts of unanticipated types of mutations found for broadly neutralizing antibodies against HIV.  Lanzavecchia and colleagues have now identified antibodies reactive with antigens encoded by different isolates of Plasmodium falciparum and expressed on infected erythrocytes (Nature, 2015).  They find an unexpected source for the heavy chain variable domain amino acid sequences that confer the broad anti-malarial reactivity against proteins in the RIFIN family.

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Tissue-Specific Stem Cell Mutation, Selection, and Evolution as a Cause of Aging

There is a mature literature on evolution and aging intended to explain how, despite selection for the morphological, metabolic, physiological, and behavioral prerequisites for survival and procreation, with the passage of time bodies deteriorate ultimately resulting in death. The focus of such explanations is typically on concepts such as age-related variation in the potency of selection and the related notion of antagonistic pleiotropy (Fabian and Flatt, 2011), by which suggests that genes able to promote survival and reproductive success in youth may increase loss of function with age. These concepts address selection on intact organisms. In contrast, a recent article in Science (Goodell and Rando, 2015) contains an article addressing the role of selection directly on somatic cells and in particular tissue-specific stem cells.

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Towards Xenografts in Clinical Transplantation: Multiplexed Negative Selection of Porcine Endogenous Retroviruses with CRISPR-Cas9

Clinical organ transplantation is now a large medical enterprise, with more than 29,000 organ transplants performed in 2014 in the United States alone (https://www.unos.org/data/transplant-trends/#transplants_by_organ_type+year+2014). Nevertheless, the number of organ donors is insufficient to meet the demand for new organs. For example, in the U.S. during 2014, there were 17,104 kidney transplants but 101,035 individuals on the waiting list for such transplants. Therefore, a recent study in Science (Yang et al., 2015) offers an important proof of principle for a necessary but not necessarily sufficient step on the path to safely using pig organs to substitute for failing human organs.

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Nietzsche Undone: An Infection that Doesn’t Kill You Can Make You Weaker

The German philosopher, Friedrich Nietzsche, is known for a number of ideas among which a particularly oft-quoted one is, “That which does not kill us makes us stronger” (https://www.goodreads.com/quotes/30-that-which-does-not-kill-us-makes-us-stronger). A recent report in Cell (Fonseca et al., 2015) offers evidence that in the context of infection and immunity, the above aphorism may not be a reliable guide to reality.

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Microbial Warfare and the Ecological Dynamics of Cystic Fibrosis Lung Disease

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.

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Fighting HIV Evolution with an Evolved Therapeutic Agent: Phase I Dose Escalation Clinical Trial of a Potent Broadly Neutralizing Human Antibody

In previous commentaries (https://evmedreview.com/?p=1863; https://evmedreview.com/?p=837; https://evmedreview.com/?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.

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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).

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A Functional Classification of Genomic Elements Informed by the Principles of Evolution

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.

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Chromosomal Catastrophe (Chromothripsis) Causing Curative Clonal Conquest

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.

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Altered Androgen Receptor Ligand Specificity in Prostate Cancer Cells Treated with an Androgen Biosynthesis Inhibitor

Carcinomas of the prostate are the most common cancers affecting men and a leading cause of male cancer deaths in the United States (CDC web site, Cancer Prevention and Control).  Given the unique association of the prostate with males, it makes sense that prosate carcinoma cells are often dependent for continued growth and proliferation on signaling by the androgen receptor, as andogens are primarily associated with physiological effects critical for male sexual development.  Therefore, therapies aimed at inhibiting either androgen synthesis or androgen receptor function make great sense. In a recent paper by Chen et al. (2014), Steven Balk and colleagues demonstrate that treatment of castration-resistant prostate cancer with a drug (abiraterone) that inhibits the production of androgens can select for mutant androgen receptors (AR) that more effectively recognize and get activated by a non-androgen.

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