Ecocentrism and Biosphere Life Extension.

The biosphere represents the global sum of all ecosystems. According to a prominent view in environmental ethics, ecocentrism, these ecosystems matter for their own sake, and not only because they contribute to human ends. As such, some ecocentrists are critical of the modern industrial civilization, and a few even argue that an irreversible collapse of the modern industrial civilization would be a good thing. However, taking a longer view and considering the eventual destruction of the biosphere by astronomical processes, we argue that humans, a species with considerable technological know-how and industrial capacity could intervene to extend the lifespan of Earth's biosphere, perhaps by several billion years. We argue that human civilization, despite its flaws and harmful impacts on many ecosystems, is the biosphere's best hope of avoiding premature destruction. We argue that proponents of ecocentrism, even those who wholly disregard anthropocentric values, have a strong moral reason preserve the modern industrial civilization, for as long as needed to ensure biosphere survival.

Information Hazards in Biotechnology.

With the advance of biotechnology, biological information, rather than biological materials, is increasingly the object of principal security concern. We argue that both in theory and in practice, existing security approaches in biology are poorly suited to manage hazardous biological information, and use the cases of Mousepox, H5N1 gain of function, and Botulinum toxin H to highlight these ongoing challenges. We suggest that mitigation of these hazards can be improved if one can: (1) anticipate hazard potential before scientific work is performed; (2) consider how much the new information would likely help both good and bad actors; and (3) aim to disclose information in the manner that maximally disadvantages bad actors versus good ones.

Brainjacking in deep brain stimulation and autonomy.

'Brainjacking' refers to the exercise of unauthorized control of another's electronic brain implant. Whilst the possibility of hacking a Brain-Computer Interface (BCI) has already been proven in both experimental and real-life settings, there is reason to believe that it will soon be possible to interfere with the software settings of the Implanted Pulse Generators (IPGs) that play a central role in Deep Brain Stimulation (DBS) systems. Whilst brainjacking raises ethical concerns pertaining to privacy and physical or psychological harm, we claim that the possibility of brainjacking DBS raises particularly profound concerns about individual autonomy, since the possibility of hacking such devices raises the prospect of third parties exerting influence over the neural circuits underpinning the subject's cognitive, emotional and motivational states. However, although it seems natural to assume that brainjacking represents a profound threat to individual autonomy, we suggest that the implications of brainjacking for individual autonomy are complicated by the fact that technologies targeted by brainjacking often serve to enhance certain aspects of the user's autonomy. The difficulty of ascertaining the implications of brainjacking DBS for individual autonomy is exacerbated by the varied understandings of autonomy in the neuroethical and philosophical literature. In this paper, we seek to bring some conceptual clarity to this area by mapping out some of the prominent views concerning the different dimension of autonomous agency, and the implications of brainjacking DBS for each dimension. Drawing on three hypothetical case studies, we show that there could plausibly be some circumstances in which brainjacking could potentially be carried out in ways that could serve to enhance certain dimensions of the target's autonomy. Our analysis raises further questions about the power, scope, and necessity of obtaining prior consent in seeking to protect patient autonomy when directly interfering with their neural states, in particular in the context of self-regulating closed-loop stimulation devices.

Euthanasia and cryothanasia.

In this article we discuss the moral and legal aspects of causing the death of a terminal patient in the hope of extending their life in the future. We call this theoretical procedure cryothanasia. We argue that administering cryothanasia is ethically different from administering euthanasia. Consequently, objections to euthanasia should not apply to cryothanasia, and cryothanasia could also be considered a legal option where euthanasia is illegal.

Modeling the Social Dynamics of Moral Enhancement: Social Strategies Sold Over the Counter and the Stability of Society.

How individuals tend to evaluate the combination of their own and other's payoffs-social value orientations-is likely to be a potential target of future moral enhancers. However, the stability of cooperation in human societies has been buttressed by evolved mildly prosocial orientations. If they could be changed, would this destabilize the cooperative structure of society? We simulate a model of moral enhancement in which agents play games with each other and can enhance their orientations based on maximizing personal satisfaction. We find that given the assumption that very low payoffs lead agents to be removed from the population, there is a broadly stable prosocial attractor state. However, the balance between prosociality and individual payoff-maximization is affected by different factors. Agents maximizing their own satisfaction can produce emergent shifts in society that reduce everybody's satisfaction. Moral enhancement considerations should take the issues of social emergence into account.

The Medicalization of Love.

In 2015, we published an article entitled "The Medicalization of Love," in which we argued that both good and bad consequences could be expected to follow from love's medicalization, depending on how the process unfolded. A flurry of commentaries followed; here we offer some preliminary thoughts in reply to the more substantial of the criticisms that were raised. We focus in particular on the nature of love itself as well as the role it plays (or should play) in our lives; we also touch on a number of practical issues concerning the likely effects of any plausible "real-life" love drugs and conclude with a call for careful regulation.

The medicalization of love.

Pharmaceuticals or other emerging technologies could be used to enhance (or diminish) feelings of lust, attraction, and attachment in adult romantic partnerships. Although such interventions could conceivably be used to promote individual (and couple) well-being, their widespread development and/or adoption might lead to the 'medicalization' of human love and heartache--for some, a source of a serious concern. In this essay, we argue that the medicalization of love need not necessarily be problematic, on balance, but could plausibly be expected to have either good or bad consequences depending upon how it unfolds. By anticipating some of the specific ways in which these technologies could yield unwanted outcomes, bioethicists and others can help to direct the course of love's medicalization--should it happen to occur--more toward the 'good' side than the 'bad.'

If I could just stop loving you: anti-love biotechnology and the ethics of a chemical breakup.

"Love hurts"-as the saying goes-and a certain amount of pain and difficulty in intimate relationships is unavoidable. Sometimes it may even be beneficial, since adversity can lead to personal growth, self-discovery, and a range of other components of a life well-lived. But other times, love can be downright dangerous. It may bind a spouse to her domestic abuser, draw an unscrupulous adult toward sexual involvement with a child, put someone under the insidious spell of a cult leader, and even inspire jealousy-fueled homicide. How might these perilous devotions be diminished? The ancients thought that treatments such as phlebotomy, exercise, or bloodletting could "cure" an individual of love. But modern neuroscience and emerging developments in psychopharmacology open up a range of possible interventions that might actually work. These developments raise profound moral questions about the potential uses-and misuses-of such anti-love biotechnology. In this article, we describe a number of prospective love-diminishing interventions, and offer a preliminary ethical framework for dealing with them responsibly should they arise.

Stabilization of neurotoxic Alzheimer amyloid-beta oligomers by protein engineering.

Soluble oligomeric aggregates of the amyloid-beta peptide (Abeta) have been implicated in the pathogenesis of Alzheimer's disease (AD). Although the conformation adopted by Abeta within these aggregates is not known, a beta-hairpin conformation is known to be accessible to monomeric Abeta. Here we show that this beta-hairpin is a building block of toxic Abeta oligomers by engineering a double-cysteine mutant (called Abetacc) in which the beta-hairpin is stabilized by an intramolecular disulfide bond. Abeta(40)cc and Abeta(42)cc both spontaneously form stable oligomeric species with distinct molecular weights and secondary-structure content, but both are unable to convert into amyloid fibrils. Biochemical and biophysical experiments and assays with conformation-specific antibodies used to detect Abeta aggregates in vivo indicate that the wild-type oligomer structure is preserved and stabilized in Abetacc oligomers. Stable oligomers are expected to become highly toxic and, accordingly, we find that beta-sheet-containing Abeta(42)cc oligomers or protofibrillar species formed by these oligomers are 50 times more potent inducers of neuronal apoptosis than amyloid fibrils or samples of monomeric wild-type Abeta(42), in which toxic aggregates are only transiently formed. The possibility of obtaining completely stable and physiologically relevant neurotoxic Abeta oligomer preparations will facilitate studies of their structure and role in the pathogenesis of AD. For example, here we show how kinetic partitioning into different aggregation pathways can explain why Abeta(42) is more toxic than the shorter Abeta(40), and why certain inherited mutations are linked to protofibril formation and early-onset AD.

A Safe Governance Space for Humanity: Necessary Conditions for the Governance of Global Catastrophic Risks.

The world faces a multiplicity of global catastrophic risks (GCRs), whose functionality as individual and collective complex adaptive networks (CANs) poses unique problems for governance in a world that itself comprises an intricately interlinked set of CANs. Here we examine necessary conditions for new approaches to governance that consider the known properties of CANs-especially that small changes in one part of the system can cascade and amplify throughout the system and that the system as a whole can also undergo rapid, dramatic, and often unpredictable change with little or no warning.

Aß42 oligomer-specific antibody ALZ-201 reduces the neurotoxicity of Alzheimer's disease brain extracts.

BACKGROUND: In Alzheimer's disease (AD), amyloid-ß 1-42 (Aß42) neurotoxicity stems mostly from its soluble oligomeric aggregates. Studies of such aggregates have been hampered by the lack of oligomer-specific research tools and their intrinsic instability and heterogeneity. Here, we developed a monoclonal antibody with a unique oligomer-specific binding profile (ALZ-201) using oligomer-stabilising technology. Subsequently, we assessed the etiological relevance of the Aß targeted by ALZ-201 on physiologically derived, toxic Aß using extracts from post-mortem brains of AD patients and controls in primary mouse neuron cultures. METHODS: Mice were immunised with stable oligomers derived from the Aß42 peptide with A21C/A30C mutations (AßCC), and ALZ-201 was developed using hybridoma technology. Specificity for the oligomeric form of the Aß42CC antigen and Aß42 was confirmed using ELISA, and non-reactivity against plaques by immunohistochemistry (IHC). The antibody's potential for cross-protective activity against pathological Aß was evaluated in brain tissue samples from 10 individuals confirmed as AD (n=7) and non-AD (n=3) with IHC staining for Aß and phosphorylated tau (p-Tau) aggregates. Brain extracts were prepared and immunodepleted using the positive control 4G8 antibody, ALZ-201 or an isotype control to ALZ-201. Fractions were biochemically characterised, and toxicity assays were performed in primary mouse neuronal cultures using automated high-content microscopy. RESULTS: AD brain extracts proved to be more toxic than controls as demonstrated by neuronal loss and morphological determinants (e.g. synapse density and measures of neurite complexity). Immunodepletion using 4G8 reduced Aß levels in both AD and control samples compared to ALZ-201 or the isotype control, which showed no significant difference. Importantly, despite the differential effect on the total Aß content, the neuroprotective effects of 4G8 and ALZ-201 immunodepletion were similar, whereas the isotype control showed no effect. CONCLUSIONS: ALZ-201 depletes a toxic species in post-mortem AD brain extracts causing a positive physiological and protective impact on the integrity and morphology of mouse neurons. Its unique specificity indicates that a low-abundant, soluble Aß42 oligomer may account for much of the neurotoxicity in AD. This critical attribute identifies the potential of ALZ-201 as a novel drug candidate for achieving a true, clinical therapeutic effect in AD.

The Timing of Evolutionary Transitions Suggests Intelligent Life is Rare.

It is unknown how abundant extraterrestrial life is, or whether such life might be complex or intelligent. On Earth, the emergence of complex intelligent life required a preceding series of evolutionary transitions such as abiogenesis, eukaryogenesis, and the evolution of sexual reproduction, multicellularity, and intelligence itself. Some of these transitions could have been extraordinarily improbable, even in conducive environments. The emergence of intelligent life late in Earth's lifetime is thought to be evidence for a handful of rare evolutionary transitions, but the timing of other evolutionary transitions in the fossil record is yet to be analyzed in a similar framework. Using a simplified Bayesian model that combines uninformative priors and the timing of evolutionary transitions, we demonstrate that expected evolutionary transition times likely exceed the lifetime of Earth, perhaps by many orders of magnitude. Our results corroborate the original argument suggested by Brandon Carter that intelligent life in the Universe is exceptionally rare, assuming that intelligent life elsewhere requires analogous evolutionary transitions. Arriving at the opposite conclusion would require exceptionally conservative priors, evidence for much earlier transitions, multiple instances of transitions, or an alternative model that can explain why evolutionary transitions took hundreds of millions of years without appealing to rare chance events. Although the model is simple, it provides an initial basis for evaluating how varying biological assumptions and fossil record data impact the probability of evolving intelligent life, and also provides a number of testable predictions, such as that some biological paradoxes will remain unresolved and that planets orbiting M dwarf stars are uninhabitable.

Anthropic shadow: observation selection effects and human extinction risks.

We describe a significant practical consequence of taking anthropic biases into account in deriving predictions for rare stochastic catastrophic events. The risks associated with catastrophes such as asteroidal/cometary impacts, supervolcanic episodes, and explosions of supernovae/gamma-ray bursts are based on their observed frequencies. As a result, the frequencies of catastrophes that destroy or are otherwise incompatible with the existence of observers are systematically underestimated. We describe the consequences of this anthropic bias for estimation of catastrophic risks, and suggest some directions for future work.

Who Should We Fear More: Biohackers, Disgruntled Postdocs, or Bad Governments? A Simple Risk Chain Model of Biorisk.

The biological risk landscape continues to evolve as developments in synthetic biology and biotechnology offer increasingly powerful tools to a widening pool of actors, including those who may consider carrying out a deliberate biological attack. However, it remains unclear whether it is the relatively large numbers of low-resourced actors or the small handful of high-powered actors who pose a greater biosecurity risk. To answer this question, this paper introduces a simple risk chain model of biorisk, from actor intent to a biological event, where the actor can successfully pass through each of N steps. Assuming that actor success probability at each independent step is sigmoidally distributed and actor power follows a power-law distribution, if a biorisk event were to occur, this model shows that the expected perpetrator would likely be highly powered, despite lower-powered actors being far more numerous. However, as the number of necessary steps leading to a biological release scenario decreases, lower-powered actors can quickly overtake more powerful actors as the likely source of a given event. If steps in the risk chain are of unequal difficulty, this model shows that actors are primarily limited by the most difficult step. These results have implications for biosecurity risk assessment and health security strengthening initiatives and highlight the need to consider actor power and ensure that the steps leading to a biorisk event are sufficiently difficult and not easily bypassed.

Defence in Depth Against Human Extinction: Prevention, Response, Resilience, and Why They All Matter.

We look at classifying extinction risks in three different ways, which affect how we can intervene to reduce risk. First, how does it start causing damage? Second, how does it reach the scale of a global catastrophe? Third, how does it reach everyone? In all of these three phases there is a defence layer that blocks most risks: First, we can prevent catastrophes from occurring. Second, we can respond to catastrophes before they reach a global scale. Third, humanity is resilient against extinction even in the face of global catastrophes. The largest probability of extinction is posed when all of these defences are weak, that is, by risks we are unlikely to prevent, unlikely to successfully respond to, and unlikely to be resilient against. We find that it's usually best to invest significantly into strengthening all three defence layers. We also suggest ways to do so tailored to the classes of risk we identify. Lastly, we discuss the importance of underlying risk factors - events or structural conditions that may weaken the defence layers even without posing a risk of immediate extinction themselves.

Protein autoproteolysis: conformational strain linked to the rate of peptide cleavage by the pH dependence of the N --> O acyl shift reaction.

Nucleophilic attack by a side chain nucleophile on the adjacent peptide bond followed by N --> O or N --> S acyl shift is the primary step in protein autoproteolysis. Precursor structures of autoproteolytic proteins reveal strained (or twisted) amides at the site of cleavage, and we previously showed that SEA domain autoproteolysis involves substrate destabilization by approximately 7 kcal/mol. However, the precise chemical mechanism by which conformational energy is converted into reaction rate acceleration has not been understood. Here we show that the pH dependence of autoproteolysis in a slow-cleaving mutant (1G) of the MUC1 SEA domain is consistent with a mechanism in which N --> O acyl shift proceeds after initial protonation of the amide nitrogen. Unstrained amides have pK(a) values of 0 with protonation on the oxygen, and autoproteolysis is therefore immeasurably slow at neutral pH. However, conformational strain forces the peptide nitrogen into a pyramidal conformation with a significantly increased pK(a) for protonation. We find that pK(a) values of approximately 4 and approximately 6, as in model compounds of twisted amides, reproduce the rate of autoproteolysis in the 1G and wild-type SEA domains, respectively. A mechanism involving strain, nitrogen protonation, and N --> O shift is also supported by quantum-chemical calculations. Such a reaction therefore constitutes an alternative to peptide cleavage that is utilized in autoproteolysis, as opposed to a classical mechanism involving a structurally conserved active site with a catalytic triad and an oxyanion hole, which are not present at the SEA domain cleavage site.

Cognitive enhancement: methods, ethics, regulatory challenges.

Cognitive enhancement takes many and diverse forms. Various methods of cognitive enhancement have implications for the near future. At the same time, these technologies raise a range of ethical issues. For example, they interact with notions of authenticity, the good life, and the role of medicine in our lives. Present and anticipated methods for cognitive enhancement also create challenges for public policy and regulation.

Hacking the Brain: Dimensions of Cognitive Enhancement.

In an increasingly complex information society, demands for cognitive functioning are growing steadily. In recent years, numerous strategies to augment brain function have been proposed. Evidence for their efficacy (or lack thereof) and side effects has prompted discussions about ethical, societal, and medical implications. In the public debate, cognitive enhancement is often seen as a monolithic phenomenon. On a closer look, however, cognitive enhancement turns out to be a multifaceted concept: There is not one cognitive enhancer that augments brain function per se, but a great variety of interventions that can be clustered into biochemical, physical, and behavioral enhancement strategies. These cognitive enhancers differ in their mode of action, the cognitive domain they target, the time scale they work on, their availability and side effects, and how they differentially affect different groups of subjects. Here we disentangle the dimensions of cognitive enhancement, review prominent examples of cognitive enhancers that differ across these dimensions, and thereby provide a framework for both theoretical discussions and empirical research.

Recombinant amyloid beta-peptide production by coexpression with an affibody ligand.

BACKGROUND: Oligomeric and fibrillar aggregates of the amyloid beta-peptide (Abeta) have been implicated in the pathogenesis of Alzheimer's disease (AD). The characterization of Abeta assemblies is essential for the elucidation of the mechanisms of Abeta neurotoxicity, but requires large quantities of pure peptide. Here we describe a novel approach to the recombinant production of Abeta. The method is based on the coexpression of the affibody protein ZAbeta3, a selected affinity ligand derived from the Z domain three-helix bundle scaffold. ZAbeta3 binds to the amyloidogenic central and C-terminal part of Abeta with nanomolar affinity and consequently inhibits aggregation. RESULTS: Coexpression of ZAbeta3 affords the overexpression of both major Abeta isoforms, Abeta(1-40) and Abeta(1-42), yielding 4 or 3 mg, respectively, of pure 15N-labeled peptide per liter of culture. The method does not rely on a protein-fusion or -tag and thus does not require a cleavage reaction. The purified peptides were characterized by NMR, circular dichroism, SDS-PAGE and size exclusion chromatography, and their aggregation propensities were assessed by thioflavin T fluorescence and electron microscopy. The data coincide with those reported previously for monomeric, largely unstructured Abeta. ZAbeta3 coexpression moreover permits the recombinant production of Abeta(1-42) carrying the Arctic (E22G) mutation, which causes early onset familial AD. Abeta(1-42)E22G is obtained in predominantly monomeric form and suitable, e.g., for NMR studies. CONCLUSION: The coexpression of an engineered aggregation-inhibiting binding protein offers a novel route to the recombinant production of amyloidogenic Abeta peptides that can be advantageously employed to study the molecular basis of AD. The presented expression system is the first for which expression and purification of the aggregation-prone Arctic variant (E22G) of Abeta(1-42) is reported.