In this commentary of Koonin’s target paper, we defend an extended view of CRISPR-Cas immunity by arguing that CRISPR-Cas includes, but cannot be reduced to, defence against nonself. CRISPR-Cas systems can target endogenous elements and tolerate exogenous elements. We conclude that the vocabulary of “defence” and “nonself” might be misleading when describing CRISPR-Cas systems.

The CRISPR-Cas systems of bacterial and archaeal adaptive immunity have become a household name among biologists and even the general public thanks to the unprecedented success of the new generation of genome editing tools utilizing Cas proteins. However, the fundamental biological features of CRISPR-Cas are of no lesser interest and have major impacts on our understanding of the evolution of antivirus defense, host-parasite coevolution, self versus non-self discrimination and mechanisms of adaptation. CRISPR-Cas systems present the best known case in point (...) for Lamarckian evolution, i.e. generation of heritable, adaptive genomic changes in response to encounters with external factors, in this case, foreign nucleic acids. CRISPR-Cas systems employ multiple mechanisms of self versus non-self discrimination but, as is the case with immune systems in general, are nevertheless costly because autoimmunity cannot be eliminated completely. In addition to the autoimmunity, the fitness cost of CRISPR-Cas systems appears to be determined by their inhibitory effect on horizontal gene transfer, curtailing evolutionary innovation. Hence the dynamic evolution of CRISPR-Cas loci that are frequently lost and acquired by archaea and bacteria. Another fundamental biological feature of CRISPR-Cas is its intimate connection with programmed cell death and dormancy induction in microbes. In this and, possibly, other immune systems, active immune response appears to be coupled to a different form of defense, namely, “altruistic” shutdown of cellular functions resulting in protection of neighboring cells. Finally, analysis of the evolutionary connections of Cas proteins reveals multiple contributions of mobile genetic elements to the origin of various components of CRISPR-Cas systems, furthermore, different biological systems that function by genome manipulation appear to have evolved convergently from unrelated MGE. The shared features of adaptive defense systems and MGE, namely the ability to recognize and cleave unique sites in genomes, make them ideal candidates for genome editing and engineering tools. (shrink)

Targeted modifications of the human epigenome, epigenome editing (EE), are around the corner. For EE, techniques similar to genome editing (GE) techniques are used. While in GE the genetic information is changed by directly modifying DNA, intervening in the epigenome requires modifying the configuration of DNA, for example, how it is folded. This does not come with alterations in the base sequence (‘genetic code’). To date, there is almost no ethical debate about EE, whereas the discussions about GE are voluminous. (...) Our article introduces EE into bioethics by translating knowledge from science to ethics and by comparing the risks of EE with those of GE. We, first (I), make the case that a broader ethical debate on EE is due, provide scientific background on EE, compile potential use-cases and recap previous debates. We then (II) compare EE and GE and suggest that the severity of risks of novel gene technologies depends on three factors: (i) the choice of an ex vivo versus an in vivo editing approach, (ii) the time of intervention and intervention windows and (iii) the targeted diseases. Moreover, we show why germline EE is not effective and reject the position of strong epigenetic determinism. We conclude that EE is not always ethically preferable to GE in terms of risks, and end with suggestions for next steps in the current ethical debate on EE by briefly introducing ethical challenges of new areas of preventive applications of EE (III). (shrink)

In recent years, immune systems have sparked considerable interest within the philosophy of science. One issue that has received increased attention is whether other phyla besides vertebrates display an adaptive immune system. Particularly the discovery of CRISPR-Cas9-based systems has triggered a discussion about how to classify adaptive immune systems. One question that has not been addressed yet is the transgenerational aspect of the CRISPR-Cas9-based response. If immunity is acquired and inherited, how to distinguish evolutionary from immunological adaptation? To shed light (...) on this issue and obtain conceptual clarity, I will investigate the inheritance of small RNA responses to pathogens in the nematode C. elegans as a further potential instantiation of a transgenerational adaptive immune system. I will explore how to make sense of systems that lie at the crossroads between genetic, immunological, and evolutionary spheres and explore the consequences of a transgenerational perspective on immune systems for immunology and its philosophy. (shrink)

In this commentary of Koonin’s target paper, we defend an extended view of CRISPR-Cas immunity by arguing that CRISPR-Cas includes, but cannot be reduced to, defence against nonself. CRISPR-Cas systems can target endogenous elements and tolerate exogenous elements. We conclude that the vocabulary of “defence” and “nonself” might be misleading when describing CRISPR-Cas systems.