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.

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.

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.

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.

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.

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.

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.

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 Unilateralist's Curse and the Case for a Principle of Conformity.

In some situations a number of agents each have the ability to undertake an initiative that would have significant effects on the others. Suppose that each of these agents is purely motivated by an altruistic concern for the common good. We show that if each agent acts on her own personal judgment as to whether the initiative should be undertaken, then the initiative will be undertaken more often than is optimal. We suggest that this phenomenon, which we call the unilateralist's curse, arises in many contexts, including some that are important for public policy. To lift the curse, we propose a principle of conformity, which would discourage unilateralist action. We consider three different models for how this principle could be implemented, and respond to an objection that could be raised against it.

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.'

Brave New Love: The Threat of High-Tech "Conversion" Therapy and the Bio-Oppression of Sexual Minorities.

Our understanding of the neurochemical bases of human love and attachment, as well as of the genetic, epigenetic, hormonal, and experiential factors that conspire to shape an individual's sexual orientation, is increasing exponentially. This research raises the vexing possibility that we may one day be equipped to modify such variables directly, allowing for the creation of "high-tech" conversion therapies or other suspect interventions. In this article, we discuss the ethics surrounding such a possibility, and call for the development of legal and procedural safeguards for protecting vulnerable children from the application of such technology. We also consider the more difficult case of voluntary, adult "conversion" and argue that in rare cases, such attempts might be permissible under strict conditions.

When is diminishment a form of enhancement? Rethinking the enhancement debate in biomedical ethics.

The enhancement debate in neuroscience and biomedical ethics tends to focus on the augmentation of certain capacities or functions: memory, learning, attention, and the like. Typically, the point of contention is whether these augmentative enhancements should be considered permissible for individuals with no particular "medical" disadvantage along any of the dimensions of interest. Less frequently addressed in the literature, however, is the fact that sometimes the diminishment of a capacity or function, under the right set of circumstances, could plausibly contribute to an individual's overall well-being: more is not always better, and sometimes less is more. Such cases may be especially likely, we suggest, when trade-offs in our modern environment have shifted since the environment of evolutionary adaptation. In this article, we introduce the notion of "diminishment as enhancement" and go on to defend a welfarist conception of enhancement. We show how this conception resolves a number of definitional ambiguities in the enhancement literature, and we suggest that it can provide a useful framework for thinking about the use of emerging neurotechnologies to promote human flourishing.

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.

Amyloid-ß protofibrils: size, morphology and synaptotoxicity of an engineered mimic.

Structural and biochemical studies of the aggregation of the amyloid-ß peptide (Aß) are important to understand the mechanisms of Alzheimer's disease, but research is complicated by aggregate inhomogeneity and instability. We previously engineered a hairpin form of Aß called Aßcc, which forms stable protofibrils that do not convert into amyloid fibrils. Here we provide a detailed characterization of Aß42cc protofibrils. Like wild type Aß they appear as smooth rod-like particles with a diameter of 3.1 (±0.2) nm and typical lengths in the range 60 to 220 nm when observed by atomic force microscopy. Non-perturbing analytical ultracentrifugation and nanoparticle tracking analyses are consistent with such rod-like protofibrils. Aß42cc protofibrils bind the ANS dye indicating that they, like other toxic protein aggregates, expose hydrophobic surface. Assays with the OC/A11 pair of oligomer specific antibodies put Aß42cc protofibrils into the same class of species as fibrillar oligomers of wild type Aß. Aß42cc protofibrils may be used to extract binding proteins in biological fluids and apolipoprotein E is readily detected as a binder in human serum. Finally, Aß42cc protofibrils act to attenuate spontaneous synaptic activity in mouse hippocampal neurons. The experiments indicate considerable structural and chemical similarities between protofibrils formed by Aß42cc and aggregates of wild type Aß42. We suggest that Aß42cc protofibrils may be used in research and applications that require stable preparations of protofibrillar Aß.