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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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. READ MORE »
Iron is a critical metal for essential cellular processes, such as respiration, in both human and microbial cells. Thus, in the context of infection, iron is a high-value cellular commodity and an evolutionist might reasonably expect a metallic tug-of-war between host and pathogen iron-binding proteins or other iron-binding molecules (siderophores). This speculation is impressively supported in a paper published this month (Barber and Elde, 2014). These authors provide strong evidence for positive selection affecting several sites in host (transferrin, Tf) and pathogen (transferrin binding protein A) iron-binding proteins based on a combination of genetic, structural, and functional experimental methods. READ MORE »
Epistasis refers to the influence of one genomic mutation or variant on the phenotypic effects of another mutation or variant. Based on available evidence and theory, this phenomenon has a major influence on evolutionary trajectories for organisms of all sorts. The role of epistasis has been studied primarily in the context of adaptive evolutionary change. In a recent paper (2014), Gong and Bloom attempt to determine the relative frequencies of epistatic interactions in adaptive versus stochastic evolution, i.e. evolution driven by selection as opposed to evolution resulting from random processes without a significant selective ‘pressure.’ Gong and Bloom perform this comparison by analyzing homologous nucleoprotein (NP) genes in human and swine influenza A viruses. The authors argue that the human viruses are subject to substantially more intense selection than the swine viruses since domestic swine are much shorter lived and their viruses are not as likely to be subjected to immune memory responses. READ MORE »
Geneticists have recognized for some time that many genes exhibit pleiotropy, meaning that one mutation can manifest in two or more distinguishable phenotypic effects. In a fascinating study recently published in Science [2014 Jan 10;343(6167):152-7. doi:10.1126/science.1246886], Joseph et al. offer evidence for an example of pleiotropy in which the distinct phenotypic effects associated with mutation of the POLR3A gene, which encodes a subunit (RPC1) of RNA polymerase III, are associated with two different diseases: one or another form of cancer and an autoimmune disease (scleroderma). READ MORE »
A careful reading of the review of fever in “Fever: Friend or Foe?”, reveals the embarrassing deficiency in medical science’s understanding of how fever, much less anorexia, functions in infection. Since fever (as well as anorexia and other components of the acute-phase response) is induced by our own cytokines, it is virtually axiomatic that fever has been more beneficial than harmful on an evolutionary scale (since otherwise the response would have been deleted). As a “fan” of fever, I’ve compiled a list of six potential benefits of fever, each of which is found in the literature and has a reasonable experimental or theoretical basis (and each likely has some degree of correctness). Note that the first four are based on fever being a heat stressor. Have a look and then see my take on it.
Fever may work by:
1) directly harming pathogens,*
2) inducing apoptosis of infected cells (and neoplastic cells),
3) inducing host’s heat shock proteins to protect host cells during infection,
4) inducing heat shock proteins in pathogens—extracellular heat shock proteins activate immune responses as “danger signals”,
5) increasing efficacy of immune responses since they work better at slightly elevated temperatures,*
6) turning down the immune response by causing apoptosis of neutrophils and lymphocytes. READ MORE »
Last month, I completed teaching a graduate course for the tenth time. After several years (in the early 1990’s) of thinking about launching a new alternate-year seminar course and then planning it, I began teaching PATH 480 in the fall of 1994. The original name of the course, maintained through the first seven times I taught it, was: “Immunology, Evolution and Logic.” Beginning in 2009, another faculty member, Derek Abbott, joined me in teaching the course, and the title was revised to: “Logical Dissection of Biomedical Investigations.” In my portion of the course, I retained an emphasis on the relevance of logic and evolutionary principles to thinking about immune recognition and immune functioning more generally. I focused class sessions on concepts and underlying assumptions critical to experimental investigations as well as on experimental design and data interpretation in articles reporting studies pertaining to immune recognition. Dr. Abbott has focused his portion of the course on the practical cognitive skills involved in reviewing papers and grant proposals pertaining primarily to innate immune signaling. READ MORE »
A central focus of recent research aimed at developing a vaccine for HIV-1 is the identification of potent broadly-neutralizing antibodies (bNAbs). Due to work from several laboratories, many such antibodies have now been identified, produced in quantity as monoclonal antibodies, and characterized with respect to key properties such as epitope specificity, affinity for the corresponding HIV-1 epitope, and neutralizing activity against many strains of varying susceptibility to antibody-mediated inactivation (important examples of these publications are: Scheid et al., 2009; Walker et al., 2009; Wu et al., 2010; Walker et al., 2011; Huang et al., 2012). These successes notwithstanding, the scale of the challenge facing the vaccine developers is clarified by the following facts: 1) potent bNAbs only develop in 10-30% of infected individuals, 2) it typically takes between two and three or four years after initial infection for these antibodies to appear in the blood of these individuals, and 3) antibodies with the desired attributes often have extraordinary numbers of somatic mutations in the variable domains that mediate binding to the HIV-1 antigen (Klein et al., 2013a). A study (Klein et al., 2013b) published earlier this year from the laboratory of Michel Nussenzweig both illuminates one possible factor accounting for the impressive length of time and number of mutations associated with the generation of potent bNAbs and provides an extraordinary example of the power of intense selection to confound expectations arising from previously observed associations. In this instance, the undermined expectations related to the well-established functional correlates of hypervariable and framework regions within antibody variable domains. READ MORE »
Currently, I am on vacation near the beach in South Carolina. Consequently, I have opted for a topic that is bit different than the majority of my monthly commentaries in that it focuses not on a recent original report but instead on a conceptual point made in a book over thirty years ago. Nevertheless, after a somewhat less strictly scientific diversion I will come to the central idea at issue, which is arguably the premier exemplar of the relevance of evolutionary principles to the operation of the immune system on short time scales, by which I refer to the concept of clonal selection. But first, we make a foray into the world of magazine publishing and the niche within that domain focusing on the arguably more intellectual readers. READ MORE »
The consortium of investigators known as ENCODE (ENCyclopedia Of DNA Elements) published, with much publicity, a series of about thirty papers last fall purporting to “identify all functional elements in the human genome sequence” (https://www.genome.gov/ENCODE/). Dan Graur, an evolutionary geneticist at the University of Houston, and his associates have published a paper in Genome Biology and Evolution (2013; online) challenging the assertion by the ENCODE investigators that 80.4% of the human genome can be considered functional (Nature, 2012). Graur’s critique of the ENCODE claim is grounded in evolutionary principles. READ MORE »
In 1996, Dean et al. (Science), demonstrated that a loss-of-function allele (CCR5Δ32) encoding a version of the chemokine receptor, CCR5, confers very substantial resistance to infection with HIV-1 in the homozygous state and slows progression in the heterozygous state. Given the relatively recent origin of HIV-1, this finding raised the question of what source of selection could account for the frequency, approximately 0.08 among Caucasians according to Dean et al., of this allele. A recent paper (Alonzo et al., 2013) offers new information on a relationship between CCR5 and a different pathogen that might offer insight into the evolutionary trajectory of CCR5Δ32.
The new study presents compelling evidence that leukotoxin ED (LukED), one of a family of bi-component exotoxins produced by Staphylococcus aureus, can bind to CCR5 and thereby cause cell death. LukED consistently produces substantially more cytotoxicity for CCR5+ than CCR5– cell lines of several types. Ligands for CCR5, including the drug, maraviroc, which is approved for clinical treatment of HIV-1 infection, significantly inhibit both the binding of LukED to cells and the magnitude of associated cytotoxicity. LukED also binds to and kills CCR5+ primarycells, such as human memory T cells, macrophages, and dendritic cells. READ MORE »
Influenza A viruses continue to be of enormous interest to biomedical researchers and clinicians alike. In addition to the annual influenza epidemics, which have been inferred to cause substantial excess mortality, there is the ever-present threat of a global pandemic due to several features of influenza virus biology. A high mutation rate associated with a segmented negative-sense RNA genome that facilitates recombination confers on these orthomyxoviruses a prodigious ability to evolve in ways that confound and evade the human immune system. The ability of influenza viruses to infect domesticated mammals, such as pigs, as well as birds, both wild and domesticated, provides additional opportunities for the virus to try out new genetic combinations and to disseminate around the globe by means both dependent and independent of human travel.
A recent paper by Jagger et al. (Science 2012) reveals that influenza A viruses are also, not surprisingly, capable of exploiting rather subtle and ingenious genetic “tricks” to maximize the value of every base pair in a total of a mere 13.5 kilobases of genome. These authors have discovered a new influenza gene product, PA-X, that represents a fusion protein incorporating 191 amino-terminal amino acids of the well-known RNA-dependent RNA polymerase (PA) protein and another carboxy-terminal 61 amino acids of a protein from a reading frame shifted by one nucleotide downstream. They present evidence from multiple experiments suggesting that the frameshift is related to a highly conserved codon that is rarely employed in mammalian and avian genomes and therefore interacts with a cognate tRNA of relatively low concentration in the cytosol. The longer-than-average wait for this tRNA to be recruited to the ribosome makes a frameshift mutation more probable. READ MORE »
There have been claims that variations in the composition of the intestinal flora influence individual health going back at least to the early years of the 1900s. Late in his career, Ilya Mechnikov, co-receipient of the Nobel Prize for Physiology or Medicine in 1908 (along with Paul Ehrlich) and a pioneer in the study of what we now call innate immune mechanisms, promoted a diet based on fermented milk containing live bacterial cultures of lactobacilli (i.e., yogurt) (1). Mechnikov apparently believed that the bacteria in the yogurt would compete with bacterial species that he thought were, on balance, harmful to human health. In other words, Mechnikov recognized the potential relevance of gastrointestinal ecology to human health a century ago. READ MORE »
Among the most pressing global public health problems at present is the AIDS epidemic. While it is clear that chemotherapy and behavioral interventions have much to offer in limiting the spread of infections by the causative virus, HIV-1, interest in developing a vaccine remains strong. Immunization would potentially provide a relatively cost-effective and scalable approach to minimizing the incidence of new infections on a global scale.
However, HIV-1 presents numerous challenges to would-be vaccine developers. There are many different lineages of HIV-1 viruses with different clades dominating in different geographic regions of the world. Even in a single infected patient, HIV-1 continues to generate many variants. Astonishingly, according to Korber et al. (2001), “The diversity of influenza sequences world-wide in any given year appears to be roughly comparable to the diversity of HIV sequences found within a single infected individual at one time point ….” The virion surface protein, gp120, which is critically involved in infecting host cells and is a major target for protective antibodies, contains regions that are especially variable in amino acid sequence.
In addition to the serious challenge of eliciting an immune response, of whatever sort, that can effectively provide immunity to the many viral variants in circulation, it remains unclear what types of immune responses are essential for providing a high level of protection against infection or disease. Some investigators are focsed on eliciting strong cell-mediated immune response. Others are devoting their efforts to generating humoral responses including potent and broadly-neutralizing antibodies. There are several recent and interesting reports pertaining to this latter effort. READ MORE »
In his essay (2011) on the history of Darwinian (or evolutionary) medicine, Jonathan Fuller describes potentially relevant interests and insights that preceded the famous paper by Nesse and Williams (1991) that is widely regarded as having catalyzed the resurgence of interest in applying evolutionary concepts and principles to medicine. For example, the author describes aspects of Aristotle’s biological thinking as well as elements of the medical concepts of Hippocrates that anticipated some features of evolutionary medicine while possibly also impeding full acceptance of the evolutionary perspective on medical phenomena. Fuller also mentions the writings of individuals such as A. C. Allison and Paul Ewald relating to infectious disease as relevant examples of pre-1991 applications of evolutionary thinking to medically-relevant problems.
There is, however, another medical field with a relatively long history (going back at least a century) of applying evolutionary principles and concepts to understanding phenomena of interest, immunology (Silverstein, 2003), which Fuller mentions only in passing. READ MORE »
Among human pathogens, Streptococcus pneumoniae holds an especially prominent place in the history of biomedical investigation. Griffith (1928) described the transforming principle, a soluble substance released by dead, virulent pneumococci that could render living avirulent pneumococci able to effectively kill a mouse. Oswald Avery’s commitment to curing pneumococcal pneumonia (http://profiles.nlm.nih.gov/ps/retrieve/Narrative/CC/p-nid/37) led him and his collaborators to determine that the pneumococcal transforming principle was DNA (Avery et al., 1944). It was also Avery’s and his collaborators’ work on pneumococci that provided some of the first insights into the chemical nature of most bacterial capsules. READ MORE »