Reply to J.N. Perry et al

The authors of “The anglerfish deception” respond to the criticism of their article.EMBO reports (2012) advanced online publication; doi: 10.1038/embor.2012.70EMBO reports (2012) 13 2, 100–105; doi: 10.1038/embor.2011.254Our respondents, eight current or former members of the EFSA GMO panel, focus on defending the EFSA''s environmental risk assessment (ERA) procedures. In our article for EMBO reports, we actually focused on the proposed EU GMO legislative reform, especially the European Commission (EC) proposal''s false political inflation of science, which denies the normative commitments inevitable in risk assessment (RA). Unfortunately the respondents do not address this problem. Indeed, by insisting that Member States enjoy freedom over risk management (RM) decisions despite the EFSA''s central control over RA, they entirely miss the relevant point. This is the unacknowledged policy—normative commitments being made before, and during, not only after, scientific ERA. They therefore only highlight, and extend, the problem we identified.The respondents complain that we misunderstood the distinction between RA and RM. We did not. We challenged it as misconceived and fundamentally misleading—as though only objective science defined RA, with normative choices cleanly confined to RM. Our point was that (i) the processes of scientific RA are inevitably shaped by normative commitments, which (ii) as a matter of institutional, policy and scientific integrity must be acknowledged and inclusively deliberated. They seem unaware that many authorities [1,2,3,4] have recognized such normative choices as prior matters, of RA policy, which should be established in a broadly deliberative manner “in advance of risk assessment to ensure that [RA] is systematic, complete, unbiased and transparent” [1]. This was neither recognized nor permitted in the proposed EC reform—a central point that our respondents fail to recognize.In dismissing our criticism that comparative safety assessment appears as a ‘first step'' in defining ERA, according to the new EFSA ERA guidelines, which we correctly referred to in our text but incorrectly referenced in the bibliography [5], our respondents again ignore this widely accepted ‘framing'' or ‘problem formulation'' point for science. The choice of comparator has normative implications as it immediately commits to a definition of what is normal and, implicitly, acceptable. Therefore the specific form and purpose of the comparison(s) is part of the validity question. Their claim that we are against comparison as a scientific step is incorrect—of course comparison is necessary. This simply acts as a shield behind which to avoid our and others'' [6] challenge to their self-appointed discretion to define—or worse, allow applicants to define—what counts in the comparative frame. Denying these realities and their difficult but inevitable implications, our respondents instead try to justify their own particular choices as ‘science''. First, they deny the first-step status of comparative safety assessment, despite its clear appearance in their own ERA Guidance Document [5]—in both the representational figure (p.11) and the text “the outcome of the comparative safety assessment allows the determination of those ‘identified'' characteristics that need to be assessed [...] and will further structure the ERA” (p.13). Second, despite their claims to the contrary, ‘comparative safety assessment'', effectively a resurrection of substantial equivalence, is a concept taken from consumer health RA, controversially applied to the more open-ended processes of ERA, and one that has in fact been long-discredited if used as a bottleneck or endpoint for rigorous RA processes [7,8,9,10]. The key point is that normative commitments are being embodied, yet not acknowledged, in RA science. This occurs through a range of similar unaccountable RA steps introduced into the ERA Guidance, such as judgement of ‘biological relevance'', ‘ecological relevance'', or ‘familiarity''. We cannot address these here, but our basic point is that such endless ‘methodological'' elaborations of the kind that our EFSA colleagues perform, only obscure the institutional changes needed to properly address the normative questions for policy-engaged science.Our respondents deny our claim concerning the singular form of science the EC is attempting to impose on GM policy and debate, by citing formal EFSA procedures for consultations with Member States and non-governmental organizations. However, they directly refute themselves by emphasizing that all Member State GM cultivation bans, permitted only on scientific grounds, have been deemed invalid by EFSA. They cannot have it both ways. We have addressed the importance of unacknowledged normativity in quality assessments of science for policy in Europe elsewhere [11]. However, it is the ‘one door, one key'' policy framework for science, deriving from the Single Market logic, which forces such singularity. While this might be legitimate policy, it is not scientific. It is political economy.Our respondents conclude by saying that the paramount concern of the EFSA GMO panel is the quality of its science. We share this concern. However, they avoid our main point that the EC-proposed legislative reform would only exacerbate their problem. Ignoring the normative dimensions of regulatory science and siphoning-off scientific debate and its normative issues to a select expert panel—which despite claiming independence faces an EU Ombudsman challenge [12] and European Parliament refusal to discharge their 2010 budget, because of continuing questions over conflicts of interests [13,14]—will not achieve quality science. What is required are effective institutional mechanisms and cultural norms that identify, and deliberatively address, otherwise unnoticed normative choices shaping risk science and its interpretive judgements. It is not the EFSA''s sole responsibility to achieve this, but it does need to recognize and press the point, against resistance, to develop better EU science and policy.     

Of mice and men

Thomas Erren and colleagues point out that studies on light and circadian rhythmicity in humans have their own interesting pitfalls, of which all researchers should be mindful.We would like to compliment, and complement, the recent Opinion in EMBO reports by Stuart Peirson and Russell Foster (2011), which calls attention to the potential obstacles associated with linking observations on light and circadian rhythmicity made on nocturnal mice to diurnally active humans. Pitfalls to consider include that qualitative extrapolations from short-lived rodents to long-lived humans, quantitative extrapolations of very different doses (Gold et al, 1992), and the varying sensitivities of each species to experimental optical radiation as a circadian stimulus (Bullough et al, 2006) can all have a critical influence on an experiment. Thus, Peirson & Foster remind us that “humans are not big mice”. We certainly agree, but we also thought it worthwhile to point out that human studies have their own interesting pitfalls, of which all researchers should be mindful.Many investigations with humans—such as testing the effects of different light exposures on alertness, cognitive performance, well-being and depression—can suffer from what has been coined as the ‘Hawthorne effect''. The term is derived from a series of studies conducted at the Western Electric Company''s Hawthorne Works near Chicago, Illinois, between 1924 and 1932, to test whether the productivity of workers would change with changing illumination levels. One important punch line was that productivity increased with almost any change that was made at the workplaces. One prevailing interpretation of these findings is that humans who know that they are being studied—and in most investigations they cannot help but notice—might exhibit responses that have little or nothing to do with what was intended as the experiment. Those who conduct circadian biology studies in humans try hard to eliminate possible ‘Hawthorne effects'', but every so often, all they can do is to hope for the best and expect the Hawthorne effect to be insignificant.Even so, and despite the obstacles to circadian experiments with both mice and humans, the wealth of information from work in both species is indispensable. To exemplify, in the last handful of years alone, experimental research in mice has substantially contributed to our understanding of the retinal interface between visible light and circadian circuitry (Chen et al, 2011); has shown that disturbances of the circadian systems through manipulations of the light–dark cycles might accelerate carcinogenesis (Filipski et al, 2009); and has suggested that perinatal light exposure—through an imprinting of the stability of circadian systems (Ciarleglio et al, 2011)—might be related to a human''s susceptibility to mood disorders (Erren et al, 2011a) and internal cancer developments later in life (Erren et al, 2011b). Future studies in humans must now examine whether, and to what extent, what was found in mice is applicable to and relevant for humans.The bottom line is that we must be aware of, and first and foremost exploit, evolutionary legacies, such as the seemingly ubiquitous photoreceptive clockwork that marine and terrestrial vertebrates—including mammals such as mice and humans—share (Erren et al, 2008). Translating insights from studies in animals to humans (Erren et al, 2011a,b), and vice versa, into testable research can be a means to one end: to arrive at sensible answers to pressing questions about light and circadian clockworks that, no doubt, play key roles in human health and disease. Pitfalls, however, abound on either side, and we agree with Peirson & Foster that they have to be recognized and monitored.     

Sustainability, capitalism and evolution. Nature conservation is not a matter of maintaining human development and welfare in a healthy environment

Capitalism and sustainable development are mutually exclusive. To protect the environment we need to develop alternative economic systems, even if some predict the next man-made mass extinction is already inevitable.Humans are exploiting the Earth in an unsustainable manner, which is accelerating both environmental degradation and loss of biodiversity. Moreover, owing to global climate change, the rates of deterioration and extinction will probably increase in the near future. The scientific community has been highly sensitive to this alarming development and increased the number of baseline and ecological studies on the impact of humans on the biosphere and proposed various strategies to alleviate the environmental and biotic crisis. This has triggered vivid discussions about the potential risks and benefits of measures such as adaptation and/or mitigation actions, ecosystem restoration, the assisted migration of species or triage conservation (Mooney, 2010).One constant in these proposals is a sense of urgency, as the pace of change seems to outstrip our capacity to react to it. There are various crucial issues that limit said capacity: the incomplete inventory of biodiversity—we still do not know how many and which species live on Earth; our deficiency in understanding the relationships between biodiversity and ecosystem functioning; and the inertia of the planet itself—even if we immediately stopped using fossil fuels and reduced CO₂ emissions, global climate change would continue for decades or even centuries (Matthews & Weaver, 2010). Finally, but maybe most damaging, our social and economic systems are too recalcitrant to even acknowledge, let alone abandon or reduce their destructive practices.…our social and economic systems are too recalcitrant to even acknowledge, let alone abandon or reduce their destructive practicesA popular remedy for the deterioration of nature is ‘sustainability''—commonly defined as meeting “the needs of the present without compromising the ability of future generations to meet their own needs” (WCDE, 1987)—which would harmonize human development and the conservation of nature. This classical notion of sustainable development argues inexplicitly for caring for our natural environment, because it is the primary provider of resources to sustain human life. Elkington (2002) introduced a social element to this by recognizing that sustainable development involves “the simultaneous pursuit of economic prosperity, environmental quality and social equity”. Baumgärtner & Quaas (2010) define sustainability as “a matter of justice at three levels: between humans of the same generation, between humans of different generations, and between humans and nature”. Many other forms, definitions and interpretations of sustainability exist—strong, weak, technological, economical, social, environmental, ecological, and so on—but, in all cases, the ultimate objective of sustainability is to preserve biodiversity and ecological functions for the benefit of present and future human generations. In short, our concern for nature is essentially anthropocentric (Rull, 2010a).The concept of sustainability has become the paradigm for conservation and environmental studies, to the extent that many consumer products, technologies and developments now claim to be ‘sustainable'', whatever that means. The same happens at the popular level, as the term ‘sustainable'' is often considered a synonym of good whereas ‘unsustainable'' is used in a pejorative sense for what is considered intrinsically bad. Curiously, these notions are widespread in different societal sectors—politicians, economists, scientists, journalists, the general public—independent of their social condition and political and economic orientation. The terms ‘sustainable'' and ‘sustainability'' are in danger of losing their original meaning to become merely rhetorical elements or advertising slogans.Our understanding and definition of nature conservation is largely guided by our concept of ‘naturalness''. But nature has always been in flux; after billions of years of biological evolution and ecological change—with and without human involvement—it is impossible to define the ‘natural'' state of the environment. In addition, human actions have an impact on ecosystems; thus, the maintenance of a pristine state of the Earth—however one would define this—does not seem to be compatible with basic human needs. A more practical approach to sustainability and the preservation of a ‘natural'' state would be to require that any modifications of nature leave ecosystems as diverse and ‘healthy'' as possible. More pragmatically, the best we could hope to achieve, even from an ecocentric point of view, is to stop further ‘spoiling'' of nature and preserve the current ‘unnatural'' state.Our understanding and definition of nature conservation is largely guided by our concept of ‘naturalness''Given this inherent conflict between conservation and human needs, conservation organizations struggle to propose practices that “balance the needs of people with the needs of the planet that supports us” (IUCN, http://www.iucn.org), or “protect Earth''s most important natural places for you and future generations” (The Nature Conservancy, http://www.nature.org), in order to “build a future where people live in harmony with nature” (WWF, http://www.wwf.org). In other words, conservationists advocate sustainable development of human societies, but their activities can only be palliative. Sustainability will only be attained after drastic reorientation towards steady-state or de-growth economic models (Lawn, 2010; Schneider et al, 2010), which would involve profound changes not only for societies, but also for every individual.The main obstacles to such broad socioeconomic change towards sustainable development are the high number of environmental problems that clamour for attention (seeing trees but not the forest) and the intransigence of social and economic systems. It is naive to pretend that representatives of the dominant economic and political systems will renounce capitalism; this has been repeatedly demonstrated at Kyoto or Copenhagen, where the international community was unable to agree on even small changes to slow global climate change.Even worse, scientists and conservationists could become trapped in the very system that they are trying to change. A good example of this risk comes from attempts to assign monetary value to biodiversity and ecosystem services and use market rules to manage them (Rull, 2010a). A simple economic analysis is enough to demonstrate the fallacy of this economic approach to sustainability, even from a pragmatic perspective.The appeal of this concept is that any ecosystem service could be submitted to a cost–benefit analysis, that would incorporate natural capital into current economic models. It also makes possible a general definition of comprehensive wealth, which includes not only reproducible capital such as buildings, machinery, roads and so on, but also natural capital. In this context, sustainable development has been redefined as ‘the accumulation of comprehensive wealth'', which requires that each generation should bequeath the next one at least as large a productive base, including both reproducible and natural capital, as it has inherited (Dasgupta, 2010).However, submitting natural resources to economic analysis does not guarantee sustainable practices. The first thing to bear in mind is that comprehensive wealth is finite and limited by the carrying capacity of the Earth. If certain planetary systems—such as climate, ocean acidity, freshwater and biodiversity—change beyond a certain limit, it could trigger nonlinear and catastrophic consequences on a global scale (Rokström et al, 2009). Second, the components of comprehensive wealth depend on each other: for example, building a road through a forest is done at the expense of the forest, that is, natural capital. Building the road might increase comprehensive wealth but it has a price: natural degradation, including resource exhaustion, loss of biodiversity and increased pollution. If human growth continues, these costs could become so high that systems—both ecological and economic—collapse. Sustainable practices could therefore aim to minimize the loss of natural capital, but if human development continues unabated, the carrying capacity of the Earth will nonetheless be reached sooner or later.Rockström et al (2009) argue that humanity has already transgressed three of nine critical planetary boundaries, namely climate change, biodiversity loss and interference with the nitrogen cycle through industrial and agricultural fixation of atmospheric nitrogen, the combustion of fossil fuels and biomass and the pollution of waterways and coastal zones. This means that nature is subsidizing the capitalist mode of development. For a quantitative estimate of natural costs, the LPI (Living Planet Index) of global diversity has declined by nearly 35% in the past 30 years (WWF, 2008); hence, the cost during this period has been about 1.2% of species per year.Even if capitalism, as the dominant economic model, incorporates natural capital into its cost–benefit analysis, nature still loses out; unlimited human growth—the central tenet of capitalism—and sustainable development are incompatible (Rull, 2010b). Some alternative modes of human development exist (Costanza, 2009; Schneider et al, 2010), but these also rely on sustainability.…even if capitalism, as the dominant economic model, incorporates natural capital into its cost-benefit analysis, nature still loses out…How then would nature benefit from sustainability? In other words, how would sustainability guarantee nature conservation? To answer this question, we must realize what nature is, beyond its role in fulfilling human needs. Our planet has mostly existed without humans since the first forms of life appeared around 3.8 billion years ago. Homo sapiens appeared around 200,000 years ago (Tattersall & Schwartz, 2009), but it was only during the past 10,000 years that humans began to change their environment on an increasing scale. Before this time, biodiversity gains and losses were the results of natural evolution; extinction patterns were more stochastic and were not determined by the needs of one species. The key question is whether humankind will endure, or be just another chapter in the history of the Earth.Despite claims that cultural evolution has replaced biological evolution in humans, natural selection is still shaping our biology in response to environmental change. Humans in their current form are therefore not necessarily the last word in evolutionary terms, nor is there a guarantee that Homo will be around in the future (Rull, 2009). If we take a strictly anthropocentric view and only worry for future humans, the preservation of the planet beyond the next few generations should not be a matter of concern. However, if we worry for the fate of the biosphere in general, nature conservation would imply not only the preservation of the current status, but also its safe evolutionary continuity.From an evolutionary perspective, sustainability is therefore not enough, given its intrinsic anthropocentric focus. Still, it would be a significant improvement on the unfettered exploitation of natural resources. To progress from sustainability to nature conservation would require a less anthropocentric and more evolutionary perspective. This might look like renouncing our status as the assumedly superior species on Earth but, as intelligent creatures, we should be able to embrace conservation of nature. So far, we have used our intelligence to try to understand our own existence, prolong our lives and develop new technologies to rule the Earth. When it comes to environmental issues, however, we are just stupid (Meffe, 2009). We must realize that the ‘real world'' is not the transitory socioeconomic scenario in which we live, but the Earth that is evolving at a pace and magnitude that exceeds our capacity to understand and appreciate it. So far, proponents of sustainability have emphasized social equity and justice for future generations, whereas nature is still viewed as a service provider that should be maintained for practical reasons.From an evolutionary perspective, sustainability is therefore not enough, given its intrinsic anthropocentric focusTo make the argument more complicated, evolution does not seem to be a linear process. On the basis of the geological and palaeontological record, the palaeontologist Peter Ward (2009) has proposed the Medea hypothesis: life—rather than contributing to the habitable condition of the Earth as proposed by the Gaia hypothesis (Lovelock, 1979)—can become self-destructive and has caused nearly all the mass extinctions that have occurred since the origin of life. So far, there have been five mass extinctions in the history of life on Earth (Courtillot, 1999). The last one, 65 million years ago—the demise of the dinosaurs—was probably triggered, at least in part, by a meteorite impact and is the only exception to the actions of Medea.The other mass extinctions were probably the result of biology (Ward, 2009): the proliferation of methane-producing microbes in the early days, which poisoned the biosphere and triggered a significant temperature decrease; the oxygenation of the atmosphere, caused by the evolution of photosynthetic organisms; a global glaciation of the planet (the Snowball Earth hypothesis), probably caused by a decrease in atmospheric greenhouse gases; and the eutrophication of coastal waters.The sixth mass extinction might be in progress, manifested in the ongoing loss of biodiversity caused by human activities (Wake & Vredenburg, 2008). This time, we would be the executors of Medea. The geological record, however, shows that each mass extinction was followed by a spectacular burst of diversification, which created new species. It seems that Gaia takes over after each of Medea''s annihilations; evolution on our planet is therefore imagined as the result of a capricious game between the goddess of Earth (Gaia) and the killer enchantress Medea.The sixth mass extinction might be in progress, manifested in the ongoing loss of biodiversity caused by human activitiesIf Ward is right, there is little we can do to avoid the next catastrophic extinction and we can only delay it for the sake of a few generations. This could lead to a contemplative attitude, given the inevitability of the looming destruction, combined with some efforts to preserve certain species for the sake of temporary human needs and pleasure. After all, Gaia will take care of life again. If this cycle is the ‘natural'' state, more radical ecocentrists should accept it: we have no reason to prefer the current state of life to the future result of Gaia''s creativity after the inevitable extinction. To maintain the status quo would be, according to this view, an unnatural attitude.If Ward is right, there is little we can do to avoid the next catastrophic extinction and we can only delay it for the sake of a few generationsIn conclusion, any proposals aiming to achieve sustainability, owing to their intrinsic anthropocentric nature, can help to promote intra- and inter-generational social justice, but they are not sufficient to achieve real nature conservation. This goal would require even more profound societal change than is acknowledged. Replacing capitalism with a new economic system is necessary for sustainability, but real nature conservation also requires a less anthropocentric attitude and the adoption of an evolutionary perspective. Scientists would have a key role in triggering and guiding these changes, provided that they are able to analyse and communicate the appropriate knowledge and maintain their independence from political and economic influences. Scientists must also leave their laboratories and begin to interact with society on a larger scale (Johns, 2009). One relevant lesson is that natural systems have their dynamics, guided by evolution, so there is no single ‘natural'' state as a preferred conservation target. Naturalness, on the contrary, is constant change.In the light of the long-term cyclical nature of destruction and creation, it could become a frustrating exercise to argue for conservation, given that the next major extinction and subsequent rise of a different biosphere is unavoidable. However, much remains to be done. Even if the cataclysm is inevitable, a reasonable target for conservation is to delay it as much as possible by passing on the responsibility to forces and processes beyond human control, biotic or not. In other words: let the next major extinction event be a natural one.? Open in a separate windowValentí Rull     

Cellular promiscuity: explaining cellular fidelity in vivo against unrestrained pluripotency in vitro

The differentiation of pluripotent stem cells into various progeny is perplexing. In vivo, nature imposes strict fate constraints. In vitro, PSCs differentiate into almost any phenotype. Might the concept of ‘cellular promiscuity'' explain these surprising behaviours?John Gurdon''s [1] and Shinya Yamanaka''s [2] Nobel Prize involves discoveries that vex fundamental concepts about the stability of cellular identity [3,4], ageing as a rectified path and the differences between germ cells and somatic cells. The differentiation of pluripotent stem cells (PSCs) into progeny, including spermatids [5] and oocytes [6], is perplexing. In vivo, nature imposes strict fate constraints. Yet in vitro, reprogrammed PSCs liberated from the body government freely differentiate into any phenotype—except placenta—violating even somatic cell against germ cell segregations. Albeit that it is anthropomorphic, might the concept of ‘cellular promiscuity'' explain these surprising behaviours?Fidelity to one''s differentiated state is nearly universal in vivo—even cancers retain some allegiance. Appreciating the mechanisms in vitro that liberate reprogrammed cells from the numerous constraints governing development in vivo might provide new insights. Similarly to highway guiderails, a range of constraints preclude progeny cells within embryos and organisms from travelling too far away from the trajectory set by their ancestors. Restrictions are imposed externally—basement membranes and intercellular adhesions; internally—chromatin, cytoskeleton, endomembranes and mitochondria; and temporally by ageing.‘Cellular promiscuity'' was glimpsed previously during cloning; it was seen when somatic cells successfully ‘fertilized'' enucleated oocytes in amphibians [1] and later with ‘Dolly'' [7]. Embryonic stem cells (ESCs) corroborate this. The inner cell mass of the blastocyst cells develops faithfully, but liberation from the trophoectoderm generates pluripotent ESCs in vitro, which are freed from fate and polarity restrictions. These freedom-seeking ESCs still abide by three-dimensional rules as they conform to chimaera body patterning when injected into blastocysts. Yet if transplanted elsewhere, this results in chaotic teratomas or helter-skelter in vitro differentiation—that is, pluripotency.August Weismann''s germ plasm theory, 130 years ago, recognized that gametes produce somatic cells, never the reverse. Primordial germ cell migrations into fetal gonads, and parent-of-origin imprints, explain how germ cells are sequestered, retaining genomic and epigenomic purity. Left uncontaminated, these future gametes are held in pristine form to parent the next generation. However, the cracks separating germ and somatic lineages in vitro are widening [5,6]. Perhaps, they are restrained within gonads not for their purity but to prevent wild, uncontrolled misbehaviours resulting in germ cell tumours.The ‘cellular promiscuity'' concept regarding PSCs in vitro might explain why cells of nearly any desired lineage can be detected using monospecific markers. Are assays so sensitive that rare cells can be detected in heterogeneous cultures? Certainly population heterogeneity is considered for transplantable cells—dopaminergic neurons and islet cells—compared with applications needing few cells—sperm and oocytes. This dilemma of maintaining cellular identity in vitro after reprogramming is significant. If not addressed, the value of unrestrained induced PSCs (iPSCs) as reliable models for ‘diseases in a dish'', let alone for subsequent therapeutic transplantations, might be diminished. X-chromosome re-inactivation variants in differentiating human PSCs, epigenetic imprint errors and copy number variations are all indicators of in vitro infidelity. PSCs, which are held to be undifferentiated cells, are artefacts after all, as they undergo their programmed development in vivo.If correct, the hypothesis accounts for concerns raised about the inherent genomic and epigenomic unreliability of iPSCs; they are likely to be unfaithful to their in vivo differentiation trajectories due to both the freedom from in vivo developmental programmes, as well as poorly characterized modifications in culture conditions. ‘Memory'' of the PSC''s identity in vivo might need to be improved by using approaches that might not fully erase imprints. Regulatory authorities, including the Food & Drug Administration, require evidence that cultured PSCs do retain their original cellular identity. Notwithstanding fidelity lapses at the organismal level, the recognition that our cells have intrinsic freedom-loving tendencies in vitro might generate better approaches for only partly releasing somatic cells into probation, rather than full emancipation.     

Not too much and not too little

We tend to think in black and white terms of good versus bad alleles and their meaning for disease. However, in doing so, we ignore the potential importance of heterozygous alleles.The structure and function of any protein is determined by its amino acid sequence. Thus, the substitution of one amino acid for another can alter the activity of a protein or its function. Mutations—or rather, polymorphism, once they become fixed in the population—can be deleterious, such that the altered protein is no longer able to fulfil its role with potentially devastating effects on the cell. Rarely, they can improve protein function and cell performance. In either case, any changes in the amino acid sequence, whether they affect only one amino acid or larger parts of the protein, are encoded by polymorphisms in the nucleotide sequence of that protein''s gene. For any given polymorphism, diploid organisms with two sets of chromosomes can therefore exist in either a heterozygous state or one of two homozygous states. When the polymorphism is rare, most individuals are homozygous for the ‘wild-type'' state, some individuals are heterozygous and a few are homozygous for the rare polymorphic variant. Conversely, if the polymorphism occurs in 50% of the alleles, the heterozygous state is common.At first glance, the deleterious homozygous state seems to be something that organisms try to avoid: close relatives usually do not breed, probably to prevent the homozygous accumulation of deleterious alleles. Thus, human cultural norms, founded in our biology, actively select for heterozygosity as many civilizations and societies regard incest as a social taboo. The fields of animal husbandry and conservation biology are littered with information about the significant positive correlation between genetic diversity, evolutionary advantage and fitness [1]. In sexually reproducing organisms, heterozygosity is generally regarded as ‘better'' in terms of adaptability and evolutionary advantage.Why then do we seldom, if ever, regard allelic heterozygosity as an advantage when it comes to genes linked with health and disease? Perhaps it is because we tend to distinguish between the ‘good'' allele, the ‘bad'' allele and the ‘ugly'' heterozygote—since it is burdened with one ‘bad'' allele. Maybe this attitude is a remnant of the outdated ‘one gene, one disease'' model, or of the early studies on inheritable diseases that focused on monogenic or autosomal-dominant genetic disorders. Even modern genetics almost always assigns ‘risk'' to an allele that is associated with a health condition or disadvantaged phenotype; clearly, then, the one homozygous state must have an advantage—sometimes referred to as wild-type—but the heterozygote is often ignored altogether.Maybe we also shun heterozygosity because it is hard to prove, beyond a few examples, that it might offer advantage. A 2010 paper published in Cell claimed that heterozygosity of the lth4A locus conveys protection against tuberculosis [2]. There is a mechanistic basis for the claim: lth4A encodes leukotriene A4 hydrolase, which is the final catalyst to synthesize leukotriene B4, an efficient pro-inflammatory eicosanoid. However, an extensive case–control study could not confirm the association between heterozygosity and protection against tuberculosis [3]. Therefore, many in the field dismiss the prior claim to protection conferred by the heterozygous state.Yet, we know that most biochemical and physiological processes are highly complex systems that involve multiple, interlinked steps with extensive control and feedback mechanisms. Heterozygosity might be one strategy by which an organism maintains flexibility, as it provides more than one allele to fall back on, should conditions change. We may therefore hypothesize that heterozygosity can be either a risk or an advantage, depending on the penetrance or dominance of the alleles. Indeed, there are a few cases in which heterozygosity confers some advantage. For example, individuals who are homozygous for the CCR5 deletion polymorphism (D32/D32) are protected against HIV1 infection, whereas CCR5/D32 heterozygotes have a slower progression to acquired immunodeficiency syndrome (AIDS). In sickle-cell anaemia, heterozygotes have a protective advantage against malaria, whereas the homozygotes either lack protection or suffer health consequences. Thus, although heterozygosity might not create a general fitness advantage, it is advantageous under certain specific conditions, namely the presence of the malaria parasite.In most aspects of life, there are few absolutes and many shades of grey. The ‘normal'' range of parameters in medicine is a clear example of this: optimal functioning of the relevant physiological processes depends on levels that are ‘just right''. As molecular and genetic research tackles the causes and risk factors of complex diseases, we may perhaps find more examples of how heterozygosity at the genetic level conveys health advantages in humans. As the above example regarding tuberculosis indicates, it is difficult to demonstrate any advantage of the heterozygous state. We simply need to be receptive to such possibilities, and improve and reconcile our understanding of allelic diversity and heterozygosity. Researchers working on human disease could benefit from the insights of evolutionary biologists and breeders, who are more appreciative of the heterozygous state.     

Measuring the societal impact of research. Research is less and less assessed on scientific impact alone-we should aim to quantify the increasingly important contributions of science to society

The global financial crisis has changed how nations and agencies prioritize research investment. There has been a push towards science with expected benefits for society, yet devising reliable tools to predict and measure the social impact of research remains a major challenge.Even before the Second World War, governments had begun to invest public funds into scientific research with the expectation that military, economic, medical and other benefits would ensue. This trend continued during the war and throughout the Cold War period, with increasing levels of public money being invested in science. Nuclear physics was the main benefactor, but other fields were also supported as their military or commercial potential became apparent. Moreover, research came to be seen as a valuable enterprise in and of itself, given the value of the knowledge generated, even if advances in understanding could not be applied immediately. Vannevar Bush, science advisor to President Franklin D. Roosevelt during the Second World War, established the inherent value of basic research in his report to the President, Science, the endless frontier, and it has become the underlying rationale for public support and funding of science.However, the growth of scientific research during the past decades has outpaced the public resources available to fund it. This has led to a problem for funding agencies and politicians: how can limited resources be most efficiently and effectively distributed among researchers and research projects? This challenge—to identify promising research—spawned both the development of measures to assess the quality of scientific research itself, and to determine the societal impact of research. Although the first set of measures have been relatively successful and are widely used to determine the quality of journals, research projects and research groups, it has been much harder to develop reliable and meaningful measures to assess the societal impact of research. The impact of applied research, such as drug development, IT or engineering, is obvious but the benefits of basic research are less so, harder to assess and have been under increasing scrutiny since the 1990s [1]. In fact, there is no direct link between the scientific quality of a research project and its societal value. As Paul Nightingale and Alister Scott of the University of Sussex''s Science and Technology Policy Research centre have pointed out: “research that is highly cited or published in top journals may be good for the academic discipline but not for society” [2]. Moreover, it might take years, or even decades, until a particular body of knowledge yields new products or services that affect society. By way of example, in an editorial on the topic in the British Medical Journal, editor Richard Smith cites the original research into apoptosis as work that is of high quality, but that has had “no measurable impact on health” [3]. He contrasts this with, for example, research into “the cost effectiveness of different incontinence pads”, which is certainly not seen as high value by the scientific community, but which has had an immediate and important societal impact.…the growth of scientific research during the past decades has outpaced the public resources available to fund itThe problem actually begins with defining the ‘societal impact of research''. A series of different concepts has been introduced: ‘third-stream activities'' [4], ‘societal benefits'' or ‘societal quality'' [5], ‘usefulness'' [6], ‘public values'' [7], ‘knowledge transfer'' [8] and ‘societal relevance'' [9, 10]. Yet, each of these concepts is ultimately concerned with measuring the social, cultural, environmental and economic returns from publicly funded research, be they products or ideas.In this context, ‘societal benefits'' refers to the contribution of research to the social capital of a nation, in stimulating new approaches to social issues, or in informing public debate and policy-making. ‘Cultural benefits'' are those that add to the cultural capital of a nation, for example, by giving insight into how we relate to other societies and cultures, by providing a better understanding of our history and by contributing to cultural preservation and enrichment. ‘Environmental benefits'' benefit the natural capital of a nation, by reducing waste and pollution, and by increasing natural preserves or biodiversity. Finally, ‘economic benefits'' increase the economic capital of a nation by enhancing its skills base and by improving its productivity [11].Given the variability and the complexity of evaluating the societal impact of research, Barend van der Meulen at the Rathenau Institute for research and debate on science and technology in the Netherlands, and Arie Rip at the School of Management and Governance of the University of Twente, the Netherlands, have noted that “it is not clear how to evaluate societal quality, especially for basic and strategic research” [5]. There is no accepted framework with adequate datasets comparable to,for example, Thomson Reuters'' Web of Science, which enables the calculation of bibliometric values such as the h index [12] or journal impact factor [13]. There are also no criteria or methods that can be applied to the evaluation of societal impact, whilst conventional research and development (R&D) indicators have given little insight, with the exception of patent data. In fact, in many studies, the societal impact of research has been postulated rather than demonstrated [14]. For Benoît Godin at the Institut National de la Recherche Scientifique (INRS) in Quebec, Canada, and co-author Christian Doré, “systematic measurements and indicators [of the] impact on the social, cultural, political, and organizational dimensions are almost totally absent from the literature” [15]. Furthermore, they note, most research in this field is primarily concerned with economic impact.A presentation by Ben Martin from the Science and Technology Policy Research Unit at Sussex University, UK, cites four common problems that arise in the context of societal impact measurements [16]. The first is the causality problem—it is not clear which impact can be attributed to which cause. The second is the attribution problem, which arises because impact can be diffuse or complex and contingent, and it is not clear what should be attributed to research or to other inputs. The third is the internationality problem that arises as a result of the international nature of R&D and innovation, which makes attribution virtually impossible. Finally, the timescale problem arises because the premature measurement of impact might result in policies that emphasize research that yields only short-term benefits, ignoring potential long-term impact.…in many studies, the societal impact of research has been postulated rather than demonstratedIn addition, there are four other problems. First, it is hard to find experts to assess societal impact that is based on peer evaluation. As Robert Frodeman and James Britt Holbrook at the University of North Texas, USA, have noted, “[s]cientists generally dislike impacts considerations” and evaluating research in terms of its societal impact “takes scientists beyond the bounds of their disciplinary expertise” [10]. Second, given that the scientific work of an engineer has a different impact than the work of a sociologist or historian, it will hardly be possible to have a single assessment mechanism [4, 17]. Third, societal impact measurement should take into account that there is not just one model of a successful research institution. As such, assessment should be adapted to the institution''s specific strengths in teaching and research, the cultural context in which it exists and national standards. Finally, the societal impact of research is not always going to be desirable or positive. For example, Les Rymer, graduate education policy advisor to the Australian Group of Eight (Go8) network of university vice-chancellors, noted in a report for the Go8 that, “environmental research that leads to the closure of a fishery might have an immediate negative economic impact, even though in the much longer term it will preserve a resource that might again become available for use. The fishing industry and conservationists might have very different views as to the nature of the initial impact—some of which may depend on their view about the excellence of the research and its disinterested nature” [18].Unlike scientific impact measurement, for which there are numerous established methods that are continually refined, research into societal impact is still in the early stages: there is no distinct community with its own series of conferences, journals or awards for special accomplishments. Even so, governments already conduct budget-relevant measurements, or plan to do so. The best-known national evaluation system is the UK Research Assessment Exercise (RAE), which has evaluated research in the UK since the 1980s. Efforts are under way to set up the Research Excellence Framework (REF), which is set to replace the RAE in 2014 “to support the desire of modern research policy for promoting problem-solving research” [21]. In order to develop the new arrangements for the assessment and funding of research in the REF, the Higher Education Funding Council for England (HEFCE) commissioned RAND Europe to review approaches for evaluating the impact of research [20]. The recommendation from this consultation is that impact should be measured in a quantifiable way, and expert panels should review narrative evidence in case studies supported by appropriate indicators [19,21].…premature measurement of impact might result in policies that emphasize research that yields only short-term benefits, ignoring potential long-term impactMany of the studies that have carried out societal impact measurement chose to do so on the basis of case studies. Although this method is labour-intensive and a craft rather than a quantitative activity, it seems to be the best way of measuring the complex phenomenon that is societal impact. The HEFCE stipulates that “case studies may include any social, economic or cultural impact or benefit beyond academia that has taken place during the assessment period, and was underpinned by excellent research produced by the submitting institution within a given timeframe” [22]. Claire Donovan at Brunel University, London, UK, considers the preference for a case-study approach in the REF to be “the ‘state of the art'' [for providing] the necessary evidence-base for increased financial support of university research across all fields” [23]. According to Finn Hansson from the Department of Leadership, Policy and Philosophy at the Copenhagen Business School, Denmark, and co-author Erik Ernø-Kjølhede, the new REF is “a clear political signal that the traditional model for assessing research quality based on a discipline-oriented Mode 1 perception of research, first and foremost in the form of publication in international journals, was no longer considered sufficient by the policy-makers” [19]. ‘Mode 1'' describes research governed by the academic interests of a specific community, whereas ‘Mode 2'' is characterized by collaboration—both within the scientific realm and with other stakeholders—transdisciplinarity and basic research that is being conducted in the context of application [19].The new REF will also entail changes in budget allocations. The evaluation of a research unit for the purpose of allocations will determine 20% of the societal influence dimension [19]. The final REF guidance contains lists of examples for different types of societal impact [24].Societal impact is much harder to measure than scientific impact, and there are probably no indicators that can be used across all disciplines and institutions for collation in databases [17]. Societal impact often takes many years to become apparent, and “[t]he routes through which research can influence individual behaviour or inform social policy are often very diffuse” [18].Yet, the practitioners of societal impact measurement should not conduct this exercise alone; scientists should also take part. According to Steve Hanney at Brunel University, an expert in assessing payback or impacts from health research, and his co-authors, many scientists see societal impact measurement as a threat to their scientific freedom and often reject it [25]. If the allocation of funds is increasingly oriented towards societal impact issues, it challenges the long-standing reward system in science whereby scientists receive credits—not only citations and prizes but also funds—for their contributions to scientific advancement. However, given that societal impact measurement is already important for various national evaluations—and other countries will follow probably—scientists should become more concerned with this aspect of their research. In fact, scientists are often unaware that their research has a societal impact. “The case study at BRASS [Centre for Business Relationships, Accountability, Sustainability and Society] uncovered activities that were previously ‘under the radar'', that is, researchers have been involved in activities they realised now can be characterized as productive interactions” [26] between them and societal stakeholders. It is probable that research in many fields already has a direct societal impact, or induces productive interactions, but that it is not yet perceived as such by the scientists conducting the work.…research into societal impact is still in the early stages: there is no distinct community with its own series of conferences, journals or awards for special accomplishmentsThe involvement of scientists is also necessary in the development of mechanisms to collect accurate and comparable data [27]. Researchers in a particular discipline will be able to identify appropriate indicators to measure the impact of their kind of work. If the approach to establishing measurements is not sufficiently broad in scope, there is a danger that readily available indicators will be used for evaluations, even if they do not adequately measure societal impact [16]. There is also a risk that scientists might base their research projects and grant applications on readily available and ultimately misleading indicators. As Hansson and Ernø-Kjølhede point out, “the obvious danger is that researchers and universities intensify their efforts to participate in activities that can be directly documented rather than activities that are harder to document but in reality may be more useful to society” [19]. Numerous studies have documented that scientists already base their activities on the criteria and indicators that are applied in evaluations [19, 28, 29].Until reliable and robust methods to assess impact are developed, it makes sense to use expert panels to qualitatively assess the societal relevance of research in the first instance. Rymer has noted that, “just as peer review can be useful in assessing the quality of academic work in an academic context, expert panels with relevant experience in different areas of potential impact can be useful in assessing the difference that research has made” [18].Whether scientists like it or not, the societal impact of their research is an increasingly important factor in attracting the public funding and support of basic researchWhether scientists like it or not, the societal impact of their research is an increasingly important factor in attracting public funding and support of basic research. This has always been the case, but new research into measures that can assess the societal impact of research would provide better qualitative and quantitative data on which funding agencies and politicians could base decisions. At the same time, such measurement should not come at the expense of basic, blue-sky research, given that it is and will remain near-impossible to predict the impact of certain research projects years or decades down the line.     

Microbial rights?

Our ability to disrupt habitats and manipulate living organisms requires a discussion of the ethics of microbiology, even if we argue that microbes themselves have no rights.Synthetic biology and the increasing complexity of molecular biology have brought us to the stage at which we can synthesize new microorganisms. This has generated pressing questions about whether these new organisms have any place in our system of ethics and how we should treat them.The idea that microbes might have some moral claims on us beyond their practical uses or instrumental value is not a new question. Microbiologist Bernard Dixon (1976) presciently asked whether it was ethical to take the smallpox virus to extinction at the height of the attempts of the World Health Organization in the 1970s to eradicate it. There is no unambiguous answer. Today, we might still ask this question, but we might extend it to ask whether the destruction or extinction of a synthetic microbe that was made by humans is also ethically questionable or is such an entity—in that it is designed—more like a machine, which we have no compunction in terminating? Would two lethal pathogens, one of them synthetic and one of them natural, but otherwise identical, command the same moral claims?In a colloquial way, we might ask whether microbes have rights. In previous papers (Cockell, 2004) I have discussed the ‘rights'' of microbes and further explored some issues about the ethics we apply to them (Cockell, 2008). Julian Davies, in a recent opinion article in EMBO reports (Davies, 2010) described my assertion that they should have constitutional rights as ‘ridiculous''. Although I did suggest that environmental law could be changed to recognize the protection of microbial ecosystems—which would imply statutory rights or protection—nowhere have I claimed that microbes should have ‘constitutional'' rights. Nevertheless, this misattribution provides a useful demonstration of the confusion that exists about exactly how we should treat microbes.Few people are in any doubt that microbes should be conserved for their direct uses to humans, for example, in food and drug production, and their indirect uses such as the crucial role they have in the health of ecosystems. Indeed, these motivations can be used to prioritize microbial conservation and protection efforts (Cockell & Jones, 2009). The crucial question is whether microbes have ‘intrinsic value'' beyond their practical uses. If the answer is ‘no'', then we should have no guilt about deliberately driving microbes to extinction for our benefit. However, there are people who feel uneasy with this conclusion, a feeling that calls forth more complex ethical questions.The question is whether microbes have some sort of ‘interests'' that make demands on our treatment of them that go beyond a mere utilitarian calculation. These arguments themselves question what we define as ‘interests'' and whether interests make demands on us. A microbe has no future plans or thought processes; the sorts of interests that are accepted as being of sufficient scope to place demands on our treatment of other human beings, for instance. However, microbes do have biological interests. A halophilic microbe might eventually die if it is dropped into freshwater. Does our knowledge of what is in the biological interests of a microbe mean that we must show it any consideration beyond practical uses? The answer is not obviously negative (Taylor, 1981), but even if we decide that it is, this does not let us off the hook quite yet.There are other intrinsic value arguments that are more obscure, particularly those around the notion of ‘respect''; the idea that we should show empathy towards the trajectory, however deterministic, of other life forms. These unquantifiable and controversial arguments might, nevertheless, partly explain any unease that we have in watching a group of people smash up and destroy some exquisite microbial mats, just because they were bored.Clearly, human instrumental needs do trump microbes at some level. If they did not, we could not use bleach in our houses, an absurd end-point raised in a 1970s science fiction story that explored the futuristic ramifications of full microbial rights, in which household bleaches and deodorants are banned (Patrouch, 1977).However, we should not be so quick to ridicule ideas about microbial ethics and rights. Although it might be true that phages kill a large percentage of the bacterial population of the world every few days, as Julian Davies points out, human society has achieved an unprecedented capacity for destruction and creation. Our ability to poison and disrupt habitats has been unquantified, with respect to the loss of microbial species. Both synthetic biology and bioterrorism raise the spectre of creating new organisms, including pathogens, which we might need to control or deliberately pursue to extinction. Dixon''s dilemma about the smallpox virus, raised more than 30 years ago, has become an urgent point of discussion in the ethics of molecular biology and microbiology.     

The 'National' and the 'Cosmos'. The emergence of synthetic biology in China

How can grass-roots movements evolve into a national research strategy? The bottom-up emergence of synthetic biology in China could give some pointers.Given its potential to aid developments in renewable energy, biosensors, sustainable chemical industries, microbial drug factories and biomedical devices, synthetic biology has enormous implications for economic development. Many countries are therefore implementing strategies to promote progress in this field. Most notably, the USA is considered to be the leader in exploring the industrial potential of synthetic biology (Rodemeyer, 2009). Synthetic biology in Europe has benefited from several cross-border studies, such as the ‘New and Emerging Science and Technology'' programme (NEST, 2005) and the ‘Towards a European Strategy for Synthetic Biology'' project (TESSY; Gaisser et al, 2008). Yet, little is known in the West about Asia''s role in this ‘new industrial revolution'' (Kitney, 2009). In particular, China is investing heavily in scientific research for future developments, and is therefore likely to have an important role in the development of synthetic biology.Initial findings seem to indicate that the emergence of synthetic biology in China has been a bottom-up construction of a new scientific framework…In 2010, as part of a study of the international governance of synthetic biology, the author visited four leading research teams in three Chinese cities (Beijing, Tianjin and Hefei). The main aims of the visits were to understand perspectives in China on synthetic biology, to identify core themes among its scientific community, and to address questions such as ‘how did synthetic biology emerge in China?'', ‘what are the current funding conditions?'', ‘how is synthetic biology generally perceived?'' and ‘how is it regulated?''. Initial findings seem to indicate that the emergence of synthetic biology in China has been a bottom-up construction of a new scientific framework; one that is more dynamic and comprises more options than existing national or international research and development (R&D) strategies. Such findings might contribute to Western knowledge of Chinese R&D, but could also expose European and US policy-makers to alternative forms and patterns of research governance that have emerged from a grass-roots level.…the process of developing a framework is at least as important to research governance as the big question it might eventually addressA dominant narrative among the scientists interviewed is the prospect of a ‘big-question'' strategy to promote synthetic-biology research in China. This framework is at a consultation stage and key questions are still being discussed. Yet, fieldwork indicates that the process of developing a framework is at least as important to research governance as the big question it might eventually address. According to several interviewees, this approach aims to organize dispersed national R&D resources into one grand project that is essential to the technical development of the field, preferably focusing on an industry-related theme that is economically appealling to the Chinese public.Chinese scientists have a pragmatic vision for research; thinking of science in terms of its ‘instrumentality'' has long been regarded as characteristic of modern China (Schneider, 2003). However, for a country in which the scientific community is sometimes described as an “uncoordinated ‘bunch of loose ends''” (Cyranoski, 2001) “with limited synergies between them” (OECD, 2007), the envisaged big-question approach implies profound structural and organizational changes. Structurally, the approach proposes that the foundational (industry-related) research questions branch out into various streams of supporting research and more specific short-term research topics. Within such a framework, a variety of Chinese universities and research institutions can be recruited and coordinated at different levels towards solving the big question.It is important to note that although this big-question strategy is at a consultation stage and supervised by the Ministry of Science and Technology (MOST), the idea itself has emerged in a bottom-up manner. One academic who is involved in the ongoing ministerial consultation recounted that, “It [the big-question approach] was initially conversations among we scientists over the past couple of years. We saw this as an alternative way to keep up with international development and possibly lead to some scientific breakthrough. But we are happy to see that the Ministry is excited and wants to support such an idea as well.” As many technicalities remain to be addressed, there is no clear time-frame yet for when the project will be launched. Yet, this nationwide cooperation among scientists with an emerging commitment from MOST seems to be largely welcomed by researchers. Some interviewees described the excitement it generated among the Chinese scientific community as comparable with the establishment of “a new ‘moon-landing'' project”.Of greater significance than the time-frame is the development process that led to this proposition. On the one hand, the emergence of synthetic biology in China has a cosmopolitan feel: cross-border initiatives such as international student competitions, transnational funding opportunities and social debates in Western countries—for instance, about biosafety—all have an important role. On the other hand, the development of synthetic biology in China has some national particularities. Factors including geographical proximity, language, collegial familiarity and shared interests in economic development have all attracted Chinese scientists to the national strategy, to keep up with their international peers. Thus, to some extent, the development of synthetic biology in China is an advance not only in the material synthesis of the ‘cosmos''—the physical world—but also in the social synthesis of aligning national R&D resources and actors with the global scientific community.To comprehend how Chinese scientists have used national particularities and global research trends as mutually constructive influences, and to identify the implications of this for governance, this essay examines the emergence of synthetic biology in China from three perspectives: its initial activities, the evolution of funding opportunities, and the ongoing debates about research governance.China''s involvement in synthetic biology was largely promoted by the participation of students in the International Genetically Engineered Machine (iGEM) competition, an international contest for undergraduates initiated by the Massachusetts Institute of Technology (MIT) in the USA. Before the iGEM training workshop that was hosted by Tianjin University in the Spring of 2007, there were no research records and only two literature reviews on synthetic biology in Chinese scientific databases (Zhao & Wang, 2007). According to Chunting Zhang of Tianjin University—a leading figure in the promotion of synthetic biology in China—it was during these workshops that Chinese research institutions joined their efforts for the first time (Zhang, 2008). From the outset, the organization of the workshop had a national focus, while it engaged with international networks. Synthetic biologists, including Drew Endy from MIT and Christina Smolke from Stanford University, USA, were invited. Later that year, another training camp designed for iGEM tutors was organized in Tianjin and included delegates from Australia and Japan (Zhang, 2008).Through years of organizing iGEM-related conferences and workshops, Chinese universities have strengthened their presence at this international competition; in 2007, four teams from China participated. During the 2010 competition, 11 teams from nine universities in six provinces/municipalities took part. Meanwhile, recruiting, training and supervising iGEM teams has become an important institutional programme at an increasing number of universities.…training for iGEM has grown beyond winning the student awards and become a key component of exchanges between Chinese researchers and the international communityIt might be easy to interpret the enthusiasm for the iGEM as a passion for winning gold medals, as is conventionally the case with other international scientific competitions. This could be one motive for participating. Yet, training for iGEM has grown beyond winning the student awards and has become a key component of exchanges between Chinese researchers and the international community (Ding, 2010). Many of the Chinese scientists interviewed recounted the way in which their initial involvement in synthetic biology overlapped with their tutoring of iGEM teams. One associate professor at Tianjin University, who wrote the first undergraduate textbook on synthetic biology in China, half-jokingly said, “I mainly learnt [synthetic biology] through tutoring new iGEM teams every year.”Participation in such contests has not only helped to popularize synthetic biology in China, but has also influenced local research culture. One example of this is that the iGEM competition uses standard biological parts (BioBricks), and new BioBricks are submitted to an open registry for future sharing. A corresponding celebration of open-source can also be traced to within the Chinese synthetic-biology community. In contrast to the conventional perception that the Chinese scientific sector consists of a “very large number of ‘innovative islands''” (OECD, 2007; Zhang, 2010), communication between domestic teams is quite active. In addition to the formally organized national training camps and conferences, students themselves organize a nationwide, student-only workshop at which to informally test their ideas.More interestingly, when the author asked one team whether there are any plans to set up a ‘national bank'' for hosting designs from Chinese iGEM teams, in order to benefit domestic teams, both the tutor and team members thought this proposal a bit “strange”. The team leader responded, “But why? There is no need. With BioBricks, we can get any parts we want quite easily. Plus, it directly connects us with all the data produced by iGEM teams around the world, let alone in China. A national bank would just be a small-scale duplicate.”From the beginning, interest in the development of synthetic biology in China has been focused on collective efforts within and across national borders. In contrast to conventional critiques on the Chinese scientific community''s “inclination toward competition and secrecy, rather than openness” (Solo & Pressberg, 2007; OECD, 2007; Zhang, 2010), there seems to be a new outlook emerging from the participation of Chinese universities in the iGEM contest. Of course, that is not to say that the BioBricks model is without problems (Rai & Boyle, 2007), or to exclude inputs from other institutional channels. Yet, continuous grass-roots exchanges, such as the undergraduate-level competition, might be as instrumental as formal protocols in shaping research culture. The indifference of Chinese scientists to a ‘national bank'' seems to suggest that the distinction between the ‘national'' and ‘international'' scientific communities has become blurred, if not insignificant.However, frequent cross-institutional exchanges and the domestic organization of iGEM workshops seem to have nurtured the development of a national synthetic-biology community in China, in which grass-roots scientists are comfortable relying on institutions with a cosmopolitan character—such as the BioBricks Foundation—to facilitate local research. To some extent, one could argue that in the eyes of Chinese scientists, national and international resources are one accessible global pool. This grass-roots interest in incorporating local and global advantages is not limited to student training and education, but also exhibited in evolving funding and regulatory debates.In the development of research funding for synthetic biology, a similar bottom-up consolidation of national and global resources can also be observed. As noted earlier, synthetic-biology research in China is in its infancy. A popular view is that China has the potential to lead this field, as it has strong support from related disciplines. In terms of genome sequencing, DNA synthesis, genetic engineering, systems biology and bioinformatics, China is “almost at the same level as developed countries” (Pan, 2008), but synthetic-biology research has only been carried out “sporadically” (Pan, 2008; Huang, 2009). There are few nationally funded projects and there is no discernible industrial involvement (Yang, 2010). Most existing synthetic-biology research is led by universities or institutions that are affiliated with the Chinese Academy of Science (CAS). As one CAS academic commented, “there are many Chinese scientists who are keen on conducting synthetic-biology research. But no substantial research has been launched nor has long-term investment been committed.”The initial undertaking of academic research on synthetic biology in China has therefore benefited from transnational initiatives. The first synthetic-biology project in China, launched in October 2006, was part of the ‘Programmable Bacteria Catalyzing Research'' (PROBACTYS) project, funded by the Sixth Framework Programme of the European Union (Yang, 2010). A year later, another cross-border collaborative effort led to the establishment of the first synthetic-biology centre in China: the Edinburgh University–Tianjing University Joint Research Centre for Systems Biology and Synthetic Biology (Zhang, 2008).There is also a comparable commitment to national research coordination. A year after China''s first participation in iGEM, the 2008 Xiangshan conference focused on domestic progress. From 2007 to 2009, only five projects in China received national funding, all of which came from the National Natural Science Foundation of China (NSFC). This funding totalled ¥1,330,000 (approximately £133,000; www.nsfc.org), which is low in comparison to the £891,000 funding that was given in the UK for seven Networks in Synthetic Biology in 2007 alone (www.bbsrc.ac.uk).One of the primary challenges in obtaining funding identified by the interviewees is that, as an emerging science, synthetic biology is not yet appreciated by Chinese funding agencies. After the Xiangshan conference, the CAS invited scientists to a series of conferences in late 2009. According to the interviewees, one of the main outcomes was the founding of a ‘China Synthetic Biology Coordination Group''; an informal association of around 30 conference delegates from various research institutions. This group formulated a ‘regulatory suggestion'' that they submitted to MOST, which stated the necessity and implications of supporting synthetic-biology research. In addition, leading scientists such as Chunting Zhang and Huanming Yang—President of the Beijing Genomic Institute (BGI), who co-chaired the Beijing Institutes of Life Science (BILS) conferences—have been active in communicating with government institutions. The initial results of this can be seen in the MOST 2010 Application Guidelines for the National Basic Research Program, in which synthetic biology was included for the first time, among ‘key supporting areas'' (MOST, 2010). Meanwhile, in 2010, NSFC allocated ¥1,500,000 (approximately £150,000) to synthetic-biology research, which is more than the total funding the area had received in the past three years.The search for funding further demonstrates the dynamics between national and transnational resources. Chinese R&D initiatives have to deal with the fact that scientific venture-capital and non-governmental research charities are underdeveloped in China. In contrast to the EU or the USA, government institutions in China, such as the NSFC and MOST, are the main and sometimes only domestic sources of funding. Yet, transnational funding opportunities facilitate the development of synthetic biology by alleviating local structural and financial constraints, and further integrate the Chinese scientific community into international research.This is not a linear ‘going-global'' process; it is important for Chinese scientists to secure and promote national and regional support. In addition, this alignment of national funding schemes with global research progress is similar to the iGEM experience, as it is being initiated through informal bottom-up associations between scientists, rather than by top-down institutional channels.As more institutions have joined iGEM training camps and participated in related conferences, a shared interest among the Chinese scientific community in developing synthetic biology has become visible. In late 2009, at the conference that founded the informal ‘coordination group'', the proposition of integrating national expertise through a big-question approach emerged. According to one professor in Beijing—who was a key participant in the discussion at the time—this proposition of a nationwide synergy was not so much about ‘national pride'' or an aim to develop a ‘Chinese'' synthetic biology, it was about research practicality. She explained, “synthetic biology is at the convergence of many disciplines, computer modelling, nano-technology, bioengineering, genomic research etc. Individual researchers like me can only operate on part of the production chain. But I myself would like to see where my findings would fit in a bigger picture as well. It just makes sense for a country the size of China to set up some collective and coordinated framework so as to seek scientific breakthrough.”From the first participation in the iGEM contest to the later exploration of funding opportunities and collective research plans, scientists have been keen to invite and incorporate domestic and international resources, to keep up with global research. Yet, there are still regulatory challenges to be met.…with little social discontent and no imminent public threat, synthetic biology in China could be carried out in a ‘research-as-usual'' mannerThe reputation of “the ‘wild East'' of biology” (Dennis, 2002) is associated with China'' previous inattention to ethical concerns about the life sciences, especially in embryonic-stem-cell research. Similarly, synthetic biology creates few social concerns in China. Public debate is minimal and most media coverage has been positive. Synthetic biology is depicted as “a core in the fourth wave of scientific development” (Pan, 2008) or “another scientific revolution” (Huang, 2009). Whilst recognizing its possible risks, mainstream media believe that “more people would be attracted to doing good while making a profit than doing evil” (Fang & He, 2010). In addition, biosecurity and biosafety training in China are at an early stage, with few mandatory courses for students (Barr & Zhang, 2010). The four leading synthetic-biology teams I visited regarded the general biosafety regulations that apply to microbiology laboratories as sufficient for synthetic biology. In short, with little social discontent and no imminent public threat, synthetic biology in China could be carried out in a ‘research-as-usual'' manner.Yet, fieldwork suggests that, in contrast to this previous insensitivity to global ethical concerns, the synthetic-biology community in China has taken a more proactive approach to engaging with international debates. It is important to note that there are still no synthetic-biology-specific administrative guidelines or professional codes of conduct in China. However, Chinese stakeholders participate in building a ‘mutual inclusiveness'' between global and domestic discussions.One of the most recent examples of this is a national conference about the ethical and biosafety implications of synthetic biology, which was jointly hosted by the China Association for Science and Technology, the Chinese Society of Biotechnology and the Beijing Institutes of Life Science CAS, in Suzhou in June 2010. The discussion was open to the mainstream media. The debate was not simply a recapitulation of Western worries, such as playing god, potential dual-use or ecological containment. It also focused on the particular concerns of developing countries about how to avoid further widening the developmental gap with advanced countries (Liu, 2010).In addition to general discussions, there are also sustained transnational communications. For example, one of the first three projects funded by the NSFC was a three-year collaboration on biosafety and risk-assessment frameworks between the Institute of Botany at CAS and the Austrian Organization for International Dialogue and Conflict Management (IDC).Chinese scientists are also keen to increase their involvement in the formulation of international regulations. The CAS and the Chinese Academy of Engineering are engaged with their peer institutions in the UK and the USA to “design more robust frameworks for oversight, intellectual property and international cooperation” (Royal Society, 2009). It is too early to tell what influence China will achieve in this field. Yet, the changing image of the country from an unconcerned wild East to a partner in lively discussions signals a new dynamic in the global development of synthetic biology.Student contests, funding programmes, joint research centres and coordination groups are only a few of the means by which scientists can drive synthetic biology forward in ChinaFrom self-organized participation in iGEM to bottom-up funding and governance initiatives, two features are repeatedly exhibited in the emergence of synthetic biology in China: global resources and international perspectives complement national interests; and the national and cosmopolitan research strengths are mostly instigated at the grass-roots level. During the process of introducing, developing and reflecting on synthetic biology, many formal or informal, provisional or long-term alliances have been established from the bottom up. Student contests, funding programmes, joint research centres and coordination groups are only a few of the means by which scientists can drive synthetic biology forward in China.However, the inputs of different social actors has not led to disintegration of the field into an array of individualized pursuits, but has transformed it into collective synergies, or the big-question approach. Underlying the diverse efforts of Chinese scientists is a sense of ‘inclusiveness'', or the idea of bringing together previously detached research expertise. Thus, the big-question strategy cannot be interpreted as just another nationally organized agenda in response to global scientific advancements. Instead, it represents a more intricate development path corresponding to how contemporary research evolves on the ground.In comparison to the increasingly visible grass-roots efforts, the role of the Chinese government seems relatively small at this stageIn comparison to the increasingly visible grass-roots efforts, the role of the Chinese government seems relatively small at this stage. Government input—such as the potential stewardship of the MOST in directing a big-question approach or long-term funding—remain important; the scientists who were interviewed expend a great deal of effort to attract governmental participation. Yet, China'' experience highlights that the key to comprehending regional scientific capacity lies not so much in what the government can do, but rather in what is taking place in laboratories. It is important to remember that Chinese iGEM victories, collaborative synthetic-biology projects and ethical discussions all took place before the government became involved. Thus, to appreciate fully the dynamics of an emerging science, it might be necessary to focus on what is formulated from the bottom up.The experience of China in synthetic biology demonstrates the power of grass-roots, cross-border engagement to promote contemporary researchThe experience of China in synthetic biology demonstrates the power of grass-roots, cross-border engagement to promote contemporary research. More specifically, it is a result of the commitment of Chinese scientists to incorporating national and international resources, actors and social concerns. For practical reasons, the national organization of research, such as through the big-question approach, might still have an important role. However, synthetic biology might be not only a mosaic of national agendas, but also shaped by transnational activities and scientific resources. What Chinese scientists will collectively achieve remains to be seen. Yet, the emergence of synthetic biology in China might be indicative of a new paradigm for how research practices can be introduced, normalized and regulated.     

A ‘metaphising’ dung beetle

Humans and beetles both have a species-specific Umwelt circumscribed by their sensory equipment. However, Ladislav Kováč argues that humans, unlike beetles, have invented scientific instruments that are able to reach beyond the conceptual borders of our Umwelt.You may have seen the film Microcosmos, produced in 1996 by the French biologists Claude Nuridsany and Marie Perrenou. It does not star humans, but much smaller creatures, mostly insects. The filmmakers'' magnifying camera transposes the viewer into the world of these organisms. For me, Microcosmos is not an ordinary naturalist documentary; it is an exercise in metaphysics.One sequence in the film shows a dung beetle—with the ‘philosophical'' generic name Sisyphus—rolling a ball of horse manure twice its size that becomes stuck on a twig. As the creature struggles to free the dung, it gives the impression that it is both worried and obstinate. As we humans know, the ball represents a most valuable treasure for the beetle: it will lay its eggs into the manure that will later feed its offspring. The behaviour of the beetle is biologically meaningful; it serves its Darwinian fitness.Yet, the dung beetle knows nothing of the function of manure, nor of the horse that dropped the excrement, nor of the human who owned the horse. Sisyphus lives in a world that is circumscribed by its somatic sensors—a species-specific world that the German biologist and philosopher Jakob von Uexküll would have called the dung beetle''s ‘Umwelt''. The horse, too, has its own Umwelt, as does the human. Yet, the world of the horse, just like the world of the man, does not exist for the beetle.If a ‘scholar'' among dung beetles attempted to visualize the world ‘out there'', what would be the dung-beetles'' metaphysics—their image of a part of the world about which they have no data furnished by their sensors? What would be their religions, their truths, or the Truth—revealed, and thus indisputable?Beetles are most successful animals; one animal in every four is a beetle, leading the biologist J.B.S. Haldane to quip that the Creator must have “had an inordinate fondness for beetles”. Are we humans so different from dung beetles? By birth we are similar: inter faeces et urinas nascimur—we are born between faeces and urine—as Aurelius Augustine remarked 1,600 years ago. Humans also have a species-specific Umwelt that has been shaped by biological evolution. A richer one than is the Umwelt of beetles, as we have more sensors than have they. Relative to the body size, we also possess a much larger brain and with it the capacity to make versatile movements with our hands and to finely manipulate with our fingers.This manual dexterity has enabled humans to fabricate artefacts that are, in a sense, extensions and refinements of the human hand. The simplest one, a coarse-chipped stone, represents the evolutionary origins of artefacts. Step-by-step, by a ratchet-like process, artefacts have become ever more complicated: as an example, a Boeing 777 is assembled from more than three million parts. At each step, humans have just added a tiny improvement to the previously achieved state. Over time, the evolution of artefacts has become less dependent on human intention and may soon result in artefacts with the capacity for self-improvement and self-reproduction. In fact, it is by artefacts that humans transcend their biology; artefacts make humans different from beetles. Here is the essence of the difference: humans roll their artefactual balls, no less worried and obstinate than beetles, but, in contrast to the latter, humans often do it even if the action is biologically meaningless, at the expense of their Darwinian fitness. Humans are biologically less rational than are beetles.Artefacts have immensely enriched the human Umwelt. From among them, scientific instruments should be singled out, as they function as novel, extrasomatic sensors of the human species. They have substantially fine-grained human knowledge of the Umwelt. But they are also reaching out—both to a distance and at a rate that is exponentially increasing—behind the boundary of the human Umwelt, behind its conceptual confines that we call Kant''s barriers. Into the world that has long been a subject of human ‘dung-beetle-like'' metaphysics. Nevertheless, our theories about this world could now be substantiated by data coming from the extrasomatic sensors. These instruments, fumbling in the unknown, supply reliable and reproducible data such that their messages must be true. They supersede our arbitrary guesses and fancies, but their truth seems to be out of our conceptual grasp. Conceptually, our mind confines us to our species-specific Umwelt.We continue to share the common fate of our fellow dung beetles: There is undeniably a world outside the confinements of our species-specific Umwelt, but if the world of humans is too complex for the neural ganglia of beetles, the world beyond Kant''s barriers may similarly exceed the capacity of the human brain. The physicist Richard Feynman (1965) stated, perhaps resignedly, “I can safely say that nobody today understands quantum mechanics.” Frank Gannon (2007) likewise commented that biological research, similarly to research in quantum mechanics, might be approaching a state “too complex to comprehend”. New models of the human brain itself may turn out to be “true and effective—and beyond comprehension” (Kováč, 2009).The advances of science notwithstanding, the knowledge of the universe that we have gained on the planet Earth might yet be in its infancy. However, in contrast to the limited capacity of humans, the continuing evolution of artefacts may mean that they face no limits in their explorative potential. They might soon dispense with our conceptual assistance exploring the realms that will remain closed to the human mind forever.     

Sex,mutations and marketing

Runaway consumerism imposes social and ecological costs on humans in much the same way that runaway sexual ornamentation imposes survival costs and extinction risks on other animals.Sex and marketing have been coupled for a very long time. At the cultural level, their relationship has been appreciated since the 1960s ‘Mad Men'' era, when the sexual revolution coincided with the golden age of advertising, and marketers realized that ‘sex sells''. At the biological level, their interplay goes much further back to the Cambrian explosion around 530 million years ago. During this period of rapid evolutionary expansion, multicellular organisms began to evolve elaborate sexual ornaments to advertise their genetic quality to the most important consumers of all in the great mating market of life: the opposite sex.Maintaining the genetic quality of one''s offspring had already been a problem for billions of years. Ever since life originated around 3.7 billion years ago, RNA and DNA have been under selection to copy themselves as accurately as possible [1]. Yet perfect self-replication is biochemically impossible, and almost all replication errors are harmful rather than helpful [2]. Thus, mutations have been eroding the genomic stability of single-celled organisms for trillions of generations, and countless lineages of asexual organisms have suffered extinction through mutational meltdown—the runaway accumulation of copying errors [3]. Only through wildly profligate self-cloning could such organisms have any hope of leaving at least a few offspring with no new harmful mutations, so they could best survive and reproduce.Around 1.5 billion years ago, bacteria evolved the most basic form of sex to minimize mutation load: bacterial conjugation [4]. By swapping bits of DNA across the pilus (a tiny intercellular bridge) a bacterium can replace DNA sequences compromised by copying errors with intact sequences from its peers. Bacteria finally had some defence against mutational meltdown, and they thrived and diversified.Then, with the evolution of genuine sexual reproduction through meiosis, perhaps around 1.2 billion years ago, eukaryotes made a great advance in their ability to purge mutations. By combining their genes with a mate''s genes, they could produce progeny with huge genetic variety—and crucially with a wider range of mutation loads [5]. The unlucky offspring who happened to inherit an above-average number of harmful mutations from both parents would die young without reproducing, taking many mutations into oblivion with them. The lucky offspring who happened to inherit a below-average number of mutations from both parents would live long, prosper and produce offspring of higher genetic quality. Sexual recombination also made it easier to spread and combine the rare mutations that happened to be useful, opening the way for much faster evolutionary advances [6]. Sex became the foundation of almost all complex life because it was so good at both short-term damage limitation (purging bad mutations) and long-term innovation (spreading good mutations).Sex became the foundation of almost all complex life because it was so good at both short-term damage limitation […] and long-term innovation…Yet, single-celled organisms always had a problem with sex: they were not very good at choosing sexual partners with the best genes, that is, the lowest mutation loads. Given bacterial capabilities for chemical communication such as quorum-sensing [7], perhaps some prokaryotes and eukaryotes paid attention to short-range chemical cues of genetic quality before swapping genes. However, mating was mainly random before the evolution of longer-range senses and nervous systems.All of this changed profoundly with the Cambrian explosion, which saw organisms undergoing a genetic revolution that increased the complexity of gene regulatory networks, and a morphological revolution that increased the diversity of multicellular body plans. It was also a neurological and psychological revolution. As organisms became increasingly mobile, they evolved senses such as vision [8] and more complex nervous systems [9] to find food and evade predators. However, these new senses also empowered a sexual revolution, as they gave animals new tools for choosing sexual partners. Rather than hooking up randomly with the nearest mate, animals could now select mates based on visible cues of genetic quality such as body size, energy level, bright coloration and behavioural competence. By choosing the highest quality mates, they could produce higher quality offspring with lower mutation loads [10]. Such mate choice imposed selection on all of those quality cues to become larger, brighter and more conspicuous, amplifying them into true sexual ornaments: biological luxury goods such as the guppy''s tail and the peacock''s train that function mainly to impress and attract females [11]. These sexual ornaments evolved to have a complex genetic architecture, to capture a larger share of the genetic variation across individuals and to reveal mutation load more accurately [12].Ever since the Cambrian, the mating market for sexually reproducing animal species has been transformed to some degree into a consumerist fantasy world of conspicuous quality, status, fashion, beauty and romance. Individuals advertise their genetic quality and phenotypic condition through reliable, hard-to-fake signals or ‘fitness indicators'' such as pheromones, songs, ornaments and foreplay. Mates are chosen on the basis of who displays the largest, costliest, most precise, most popular and most salient fitness indicators. Mate choice for fitness indicators is not restricted to females choosing males, but often occurs in both sexes [13], especially in socially monogamous species with mutual mate choice such as humans [14].Thus, for 500 million years, animals have had to straddle two worlds in perpetual tension: natural selection and sexual selection. Each type of selection works through different evolutionary principles and dynamics, and each yields different types of adaptation and biodiversity. Neither fully dominates the other, because sexual attractiveness without survival is a short-lived vanity, whereas ecological competence without reproduction is a long-lived sterility. Natural selection shapes species to fit their geographical habitats and ecological niches, and favours efficiency in growth, foraging, parasite resistance, predator evasion and social competition. Sexual selection shapes each sex to fit the needs, desires and whims of the other sex, and favours conspicuous extravagance in all sorts of fitness indicators. Animal life walks a fine line between efficiency and opulence. More than 130,000 plant species also play the sexual ornamentation game, having evolved flowers to attract pollinators [15].The sexual selection world challenges the popular misconception that evolution is blind and dumb. In fact, as Darwin emphasized, sexual selection is often perceptive and clever, because animal senses and brains mediate mate choice. This makes sexual selection closer in spirit to artificial selection, which is governed by the senses and brains of human breeders. In so far as sexual selection shaped human bodies, minds and morals, we were also shaped by intelligent designers—who just happened to be romantic hominids rather than fictional gods [16].Thus, mate choice for genetic quality is analogous in many ways to consumer choice for brand quality [17]. Mate choice and consumer choice are both semi-conscious—partly instinctive, partly learned through trial and error and partly influenced by observing the choices made by others. Both are partly focused on the objective qualities and useful features of the available options, and partly focused on their arbitrary, aesthetic and fashionable aspects. Both create the demand that suppliers try to understand and fulfil, with each sex striving to learn the mating preferences of the other, and marketers striving to understand consumer preferences through surveys, focus groups and social media data mining.…single-celled organisms always had a problem with sex: they were not very good at choosing the sexual partners with the best genes…Mate choice and consumer choice can both yield absurdly wasteful outcomes: a huge diversity of useless, superficial variations in the biodiversity of species and the economic diversity of brands, products and packaging. Most biodiversity seems to be driven by sexual selection favouring whimsical differences across populations in the arbitrary details of fitness indicators, not just by naturally selected adaptation to different ecological niches [18]. The result is that within each genus, a species can be most easily identified by its distinct mating calls, sexual ornaments, courtship behaviours and genital morphologies [19], not by different foraging tactics or anti-predator defences. Similarly, much of the diversity in consumer products—such as shirts, cars, colleges or mutual funds—is at the level of arbitrary design details, branding, packaging and advertising, not at the level of objective product features and functionality.These analogies between sex and marketing run deep, because both depend on reliable signals of quality. Until recently, two traditions of signalling theory developed independently in the biological and social sciences. The first landmark in biological signalling theory was Charles Darwin''s analysis of mate choice for sexual ornaments as cues of good fitness and fertility in his book, The Descent of Man, and Selection in Relation to Sex (1871). Ronald Fisher analysed the evolution of mate preferences for fitness indicators in 1915 [20]. Amotz Zahavi proposed the ‘handicap principle'', arguing that only costly signals could be reliable, hard-to-fake indicators of genetic quality or phenotypic condition in 1975 [21]. Richard Dawkins and John Krebs applied game theory to analyse the reliability of animal signals, and the co-evolution of signallers and receivers in 1978 [22]. In 1990, Alan Grafen eventually proposed a formal model of the ‘handicap principle'' [23], and Richard Michod and Oren Hasson analysed ‘reliable indicators of fitness'' [24]. Since then, biological signalling theory has flourished and has informed research on sexual selection, animal communication and social behaviour.…new senses also empowered a sexual revolution […] Rather than hooking up randomly with the nearest mate, animals could now select mates based on visible cues of genetic quality…The parallel tradition of signalling theory in the social sciences and philosophy goes back to Aristotle, who argued that ethical and rational acts are reliable signals of underlying moral and cognitive virtues (ca 350–322 BC). Friedrich Nietzsche analysed beauty, creativity, morality and even cognition as expressions of biological vigour by using signalling logic (1872–1888). Thorstein Veblen proposed that conspicuous luxuries, quality workmanship and educational credentials act as reliable signals of wealth, effort and taste in The Theory of the Leisure Class (1899), The Instinct of Workmanship (1914) and The Higher Learning in America (1922). Vance Packard used signalling logic to analyse social class, runaway consumerism and corporate careerism in The Status Seekers (1959), The Waste Makers (1960) and The Pyramid Climbers (1962), and Ernst Gombrich analysed beauty in art as a reliable signal of the artist''s skill and effort in Art and Illusion (1977) and A Sense of Order (1979). Michael Spence developed formal models of educational credentials as reliable signals of capability and conscientiousness in Market Signalling (1974). Robert Frank used signalling logic to analyse job titles, emotions, career ambitions and consumer luxuries in Choosing the Right Pond (1985), Passions within Reason (1988), The Winner-Take-All-Society (1995) and Luxury Fever (2000).Evolutionary psychology and evolutionary anthropology have been integrating these two traditions to better understand many puzzles in human evolution that defy explanation in terms of natural selection for survival. For example, signalling theory has illuminated the origins and functions of facial beauty, female breasts and buttocks, body ornamentation, clothing, big game hunting, hand-axes, art, music, humour, poetry, story-telling, courtship gifts, charity, moral virtues, leadership, status-seeking, risk-taking, sports, religion, political ideologies, personality traits, adaptive self-deception and consumer behaviour [16,17,25,26,27,28,29].Building on signalling theory and sexual selection theory, the new science of evolutionary consumer psychology [30] has been making big advances in understanding consumer goods as reliable signals—not just signals of monetary wealth and elite taste, but signals of deeper traits such as intelligence, moral virtues, mating strategies and the ‘Big Five'' personality traits: openness, conscientiousness, agreeableness, extraversion and emotional stability [17]. These individual traits are deeper than wealth and taste in several ways: they are found in the other great apes, are heritable across generations, are stable across life, are important in all cultures and are naturally salient when interacting with mates, friends and kin [17,27,31]. For example, consumers seek elite university degrees as signals of intelligence; they buy organic fair-trade foods as signals of agreeableness; and they value foreign travel and avant-garde culture as signals of openness [17]. New molecular genetics research suggests that mutation load accounts for much of the heritable variation in human intelligence [32] and personality [33], so consumerist signals of these traits might be revealing genetic quality indirectly. If so, conspicuous consumption can be seen as just another ‘good-genes indicator'' favoured by mate choice.…sexual attractiveness without survival is a short-lived vanity, whereas ecological competence without reproduction is a long-lived sterilityIndeed, studies suggest that much conspicuous consumption, especially by young single people, functions as some form of mating effort. After men and women think about potential dates with attractive mates, men say they would spend more money on conspicuous luxury goods such as prestige watches, whereas women say they would spend more time doing conspicuous charity activities such as volunteering at a children''s hospital [34]. Conspicuous consumption by males reveals that they are pursuing a short-term mating strategy [35], and this activity is most attractive to women at peak fertility near ovulation [36]. Men give much higher tips to lap dancers who are ovulating [37]. Ovulating women choose sexier and more revealing clothes, shoes and fashion accessories [38]. Men living in towns with a scarcity of women compete harder to acquire luxuries and accumulate more consumer debt [39]. Romantic gift-giving is an important tactic in human courtship and mate retention, especially for men who might be signalling commitment [40]. Green consumerism—preferring eco-friendly products—is an effective form of conspicuous conservation, signalling both status and altruism [41].Findings such as these challenge traditional assumptions in economics. For example, ever since the Marginal Revolution—the development of economic theory during the 1870s—mainstream economics has made the ‘Rational Man'' assumption that consumers maximize their expected utility from their product choices, without reference to what other consumers are doing or desiring. This assumption was convenient both analytically—as it allowed easier mathematical modelling of markets and price equilibria—and ideologically in legitimizing free markets and luxury goods. However, new research from evolutionary consumer psychology and behavioural economics shows that consumers often desire ‘positional goods'' such as prestige-branded luxuries that signal social position and status through their relative cost, exclusivity and rarity. Positional goods create ‘positional externalities''—the harmful social side-effects of runaway status-seeking and consumption arms races [42].…biodiversity seems driven by sexual selection favouring whimsical differences […] Similarly […] diversity in consumer products […] is at the level of arbitrary design…These positional externalities are important because they undermine the most important theoretical justification for free markets—the first fundamental theorem of welfare economics, a formalization of Adam Smith''s ‘invisible hand'' argument, which says that competitive markets always lead to efficient distributions of resources. In the 1930s, the British Marxist biologists Julian Huxley and J.B.S. Haldane were already wary of such rationales for capitalism, and understood that runaway consumerism imposes social and ecological costs on humans in much the same way that runaway sexual ornamentation imposes survival costs and extinction risks on other animals [16]. Evidence shows that consumerist status-seeking leads to economic inefficiencies and costs to human welfare [42]. Runaway consumerism might be one predictable result of a human nature shaped by sexual selection, but we can display desirable traits in many other ways, such as green consumerism, conspicuous charity, ethical investment and through social media such as Facebook [17,43].Future work in evolutionary consumer psychology should give further insights into the links between sex, mutations, evolution and marketing. These links have been important for at least 500 million years and probably sparked the evolution of human intelligence, language, creativity, beauty, morality and ideology. A better understanding of these links could help us nudge global consumerist capitalism into a more sustainable form that imposes lower costs on the biosphere and yields higher benefits for future generations.? Open in a separate windowGeoffrey Miller     

The biochemistry of love: an oxytocin hypothesis

The old saying that ‘love heals'' has some truth to it. The intricate dance between two neuropeptides both regulates our ability to love and influences our health and well-being.Love is deeply biological. It pervades every aspect of our lives and has inspired countless works of art. Love also has a profound effect on our mental and physical state. A ‘broken heart'' or a failed relationship can have disastrous effects; bereavement disrupts human physiology and might even precipitate death. Without loving relationships, humans fail to flourish, even if all of their other basic needs are met.As such, love is clearly not ‘just'' an emotion; it is a biological process that is both dynamic and bidirectional in several dimensions. Social interactions between individuals, for example, trigger cognitive and physiological processes that influence emotional and mental states. In turn, these changes influence future social interactions. Similarly, the maintenance of loving relationships requires constant feedback through sensory and cognitive systems; the body seeks love and responds constantly to interaction with loved ones or to the absence of such interaction.Without loving relationships, humans fail to flourish, even if all of their other basic needs are metAlthough evidence exists for the healing power of love, it is only recently that science has turned its attention to providing a physiological explanation. The study of love, in this context, offers insight into many important topics including the biological basis of interpersonal relationships and why and how disruptions in social bonds have such pervasive consequences for behaviour and physiology. Some of the answers will be found in our growing knowledge of the neurobiological and endocrinological mechanisms of social behaviour and interpersonal engagement.Nothing in biology makes sense except in the light of evolution. Theodosius Dobzhansky''s famous dictum also holds true for explaining the evolution of love. Life on Earth is fundamentally social: the ability to interact dynamically with other living organisms to support mutual homeostasis, growth and reproduction evolved early. Social interactions are present in primitive invertebrates and even among prokaryotes: bacteria recognize and approach members of their own species. Bacteria also reproduce more successfully in the presence of their own kind and are able to form communities with physical and chemical characteristics that go far beyond the capabilities of the individual cell [1].As another example, insect species have evolved particularly complex social systems, known as ‘eusociality''. Characterized by a division of labour, eusociality seems to have evolved independently at least 11 times. Research in honey-bees indicates that a complex set of genes and their interactions regulate eusociality, and that these resulted from an “accelerated form of evolution” [2]. In other words, molecular mechanisms favouring high levels of sociality seem to be on an evolutionary fast track.The evolutionary pathways that led from reptiles to mammals allowed the emergence of the unique anatomical systems and biochemical mechanisms that enable social engagement and selectively reciprocal sociality. Reptiles show minimal parental investment in offspring and form non-selective relationships between individuals. Pet owners might become emotionally attached to their turtle or snake, but this relationship is not reciprocal. By contrast, many mammals show intense parental investment in offspring and form lasting bonds with the offspring. Several mammalian species—including humans, wolves and prairie voles—also develop long-lasting, reciprocal and selective relationships between adults, with several features of what humans experience as ‘love''. In turn, these reciprocal interactions trigger dynamic feedback mechanisms that foster growth and health.Of course, human love is more complex than simple feedback mechanisms. Love might create its own reality. The biology of love originates in the primitive parts of the brain—the emotional core of the human nervous system—that evolved long before the cerebral cortex. The brain of a human ‘in love'' is flooded with sensations, often transmitted by the vagus nerve, creating much of what we experience as emotion. The modern cortex struggles to interpret the primal messages of love, and weaves a narrative around incoming visceral experiences, potentially reacting to that narrative rather than reality.

Science & Society Series on Sex and Science

Sex is the greatest invention of all time: not only has sexual reproduction facilitated the evolution of higher life forms, it has had a profound influence on human history, culture and society. This series explores our attempts to understand the influence of sex in the natural world, and the biological, medical and cultural aspects of sexual reproduction, gender and sexual pleasure.It also is helpful to realize that mammalian social behaviour is supported by biological components that were repurposed or co-opted over the course of mammalian evolution, eventually allowing lasting relationships between adults. One element that repeatedly features in the biochemistry of love is the neuropeptide oxytocin. In large mammals, oxytocin adopts a central role in reproduction by helping to expel the big-brained baby from the uterus, ejecting milk and sealing a selective and lasting bond between mother and offspring [3]. Mammalian offspring crucially depend on their mother''s milk for some time after birth. Human mothers also form a strong and lasting bond with their newborns immediately after birth, in a time period that is essential for the nourishment and survival of the baby. However, women who give birth by caesarean section without going through labour, or who opt not to breast-feed, still form a strong emotional bond with their children. Furthermore, fathers, grandparents and adoptive parents also form lifelong attachments to children. Preliminary evidence suggests that simply the presence of an infant releases oxytocin in adults [4,5]. The baby virtually ‘forces'' us to love it (Fig 1).Open in a separate windowFigure 1As a one-year-old Mandrill infant solicits attention, she gains eye contact with her mother. © 2012 Jessie Williams.Emotional bonds can also form during periods of extreme duress, especially when the survival of one individual depends on the presence and support of another. There is also evidence that oxytocin is released in response to acutely stressful experiences, possibly serving as hormonal ‘insurance'' against overwhelming stress. Oxytocin might help to assure that parents and others will engage with and care for infants, to stabilize loving relationships and to ensure that, in times of need, we will seek and receive support from others.The case for a major role for oxytocin in love is strong, but until recently has been based largely on extrapolation from research on parental behaviour [4] or social behaviours in animals [5,6]. However, human experiments have shown that intranasal delivery of oxytocin can facilitate social behaviours, including eye contact and social cognition [7]—behaviours that are at the heart of love.Of course, oxytocin is not the molecular equivalent of love. It is just one important component of a complex neurochemical system that allows the body to adapt to highly emotive situations. The systems necessary for reciprocal social interactions involve extensive neural networks through the brain and autonomic nervous system that are dynamic and constantly changing during the lifespan of an individual. We also know that the properties of oxytocin are not predetermined or fixed. Oxytocin''s cellular receptors are regulated by other hormones and epigenetic factors. These receptors change and adapt on the basis of life experiences. Both oxytocin and the experience of love change over time. In spite of limitations, new knowledge of the properties of oxytocin has proven useful in explaining several enigmatic features of love.To dissect the anatomy and chemistry of love, scientists needed a biological equivalent of the Rosetta stone. Just as the actual stone helped linguists to decipher an archaic language by comparison to a known one, animal models are helping biologists draw parallels between ancient physiology and contemporary behaviours. Studies of socially monogamous mammals that form long-lasting social bonds, such as prairie voles, are helping scientists to understand the biology of human social behaviour.The modern cortex struggles to interpret the primal messages of love, and weaves a narrative around incoming visceral experiences, potentially reacting to that narrative rather than realityResearch in voles indicates that, as in humans, oxytocin has a major role in social interactions and parental behaviour [5,6,8]. Of course, oxytocin does not act alone. Its release and actions depend on many other neurochemicals, including endogenous opioids and dopamine [9]. Particularly important to social bonding are the interactions between oxytocin and a related peptide, vasopressin. The systems regulated by oxytocin and vasopressin are sometimes redundant. Both peptides are implicated in behaviours that require social engagement by either males or females, such as huddling over an infant [5]. It was necessary in voles, for example, to block both oxytocin and vasopressin receptors to induce a significant reduction in social engagement either among adults or between adults and infants. Blocking only one of these two receptors did not eliminate social approach or contact. However, antagonists for either the oxytocin or vasopressin receptor inhibited the selective sociality, which is essential for the expression of a social bond [10,11]. If we accept selective social bonds, parenting and mate protection as proxies for love in humans, research in animals supports the hypothesis that oxytocin and vasopressin interact to allow the dynamic behavioural states and behaviours necessary for love.Oxytocin and vasopressin have shared functions, but they are not identical in their actions. The specific behavioural roles of oxytocin and vasopressin are especially difficult to untangle because they are components of an integrated neural network with many points of intersection. Moreover, the genes that regulate the production of oxytocin and vasopressin are located on the same chromosome, possibly allowing a co-ordinated synthesis or release of these peptides. Both peptides can bind to, and have, antagonist or agonist effects on each other''s receptors. Furthermore, the pathways necessary for reciprocal social behaviour are constantly adapting: these peptides and the systems that they regulate are always in flux.In spite of these difficulties, some of the functions of oxytocin and vasopressin have been identified. Vasopressin is associated with physical and emotional mobilization, and supports vigilance and behaviours needed for guarding a partner or territory [6], as well as other forms of adaptive self-defence [12]. Vasopressin might also protect against ‘shutting down'' physiologically in the face of danger. In many mammalian species, mothers behave agonistically in defence of their young, possibly through the interactive actions of vasopressin and oxytocin [13]. Before mating, prairie voles are generally social, even towards strangers. However, within approximately one day of mating, they begin to show high levels of aggression towards intruders [14], possibly serving to protect or guard a mate, family or territory. This mating-induced aggression is especially obvious in males.By contrast, oxytocin is associated with immobility without fear. This includes relaxed physiological states and postures that allow birth, lactation and consensual sexual behaviour. Although not essential for parenting, the increase of oxytocin associated with birth and lactation might make it easier for a woman to be less anxious around her newborn and to experience and express loving feelings for her child [15]. In highly social species such as prairie voles, and presumably in humans, the intricate molecular dances of oxytocin and vasopressin fine-tune the coexistence of care-taking and protective aggression.The biology of fatherhood is less well studied. However, male care of offspring also seems to rely on both oxytocin and vasopressin [5]; even sexually naive male prairie voles show spontaneous parental behaviour in the presence of an infant [14]. However, the stimuli from infants or the nature of the social interactions that release oxytocin and vasopressin might differ between the sexes [4].Parental care and support in a safe environment are particularly important for mental health in social mammals, including humans and prairie voles. Studies of rodents and lactating women suggest that oxytocin has the capacity to modulate the behavioural and autonomic distress that typically follows separation from a mother, child or partner, reducing defensive behaviours and thereby supporting growth and health [6].During early life in particular, trauma or neglect might produce behaviours and emotional states in humans that are socially pathological. As the processes involved in creating social behaviours and social emotions are delicately balanced, they might be triggered in inappropriate contexts, leading to aggression towards friends or family. Alternatively, bonds might be formed with prospective partners who fail to provide social support or protection.Males seem to be especially vulnerable to the negative effects of early experiences, possibly explaining their increased sensitivity to developmental disorders. Autism spectrum disorders, for example, defined in part by atypical social behaviours, are estimated to be three to ten times more common in males than females. The implication of sex differences in the nervous system, and in response to stressful experiences for social behaviour, is only slowly becoming apparent [8]. Both males and females produce vasopressin and oxytocin and are capable of responding to both hormones. However, in brain regions that are involved in defensive aggression, such as the extended amygdala and lateral septum, the production of vasopressin is androgen-dependent. Thus, in the face of a threat, males might experience higher central levels of vasopressin.In highly social species […] the intricate molecular dances of oxytocin and vasopressin fine-tune the coexistence of care-taking and protective aggressionOxytocin and vasopressin pathways, including the peptides and their receptors, are regulated by coordinated genetic, hormonal and epigenetic factors that influence the adaptive and behavioural functions of these peptides across the animal''s lifespan. As a result, the endocrine and behavioural consequences of stress or a challenge might be different for males and females [16]. When unpaired prairie voles were exposed to an intense but brief stressor, such as a few minutes of swimming or injection of the adrenal hormone corticosterone, the males (but not females) quickly formed new pair bonds. These and other experiments suggest that males and females have different coping strategies, and possibly experience both stressful experiences and even love in ways that are gender-specific.Love is an epigenetic phenomenon: social behaviours, emotional attachment to others and long-lasting reciprocal relationships are plastic and adaptive and so is the biology on which they are based. Because of this and the influence on parental behaviour and physiology, the impact of an early experience can pass to the next generation [17]. Infants of traumatized or highly stressed parents might be chronically exposed to vasopressin, either through their own increased production of the peptide, or through higher levels of vasopressin in maternal milk. Such increased exposure could sensitize the infant to defensive behaviours or create a life-long tendency to overreact to threat. On the basis of research in rats, it seems, that in response to adverse early experiences or chronic isolation, the genes for vasopressin receptors can become upregulated [18], leading to an increased sensitivity to acute stressors or anxiety that might persist throughout life.…oxytocin exposure early in life not only regulates our ability to love and form social bonds, it also has an impact on our health and well-beingEpigenetic programming triggered by early life experiences is adaptive in allowing neuroendocrine systems to project and plan for future behavioural demands. However, epigenetic changes that are long-lasting can also create atypical social or emotional behaviours [17] that might be more likely to surface in later life, and in the face of social or emotional challenges. Exposure to exogenous hormones in early life might also be epigenetic. Prairie voles, for example, treated with vasopressin post-natally were more aggressive later in life, whereas those exposed to a vasopressin antagonist showed less aggression in adulthood. Conversely, the exposure of infants to slightly increased levels of oxytocin during development increased the tendency to show a pair bond in voles. However, these studies also showed that a single exposure to a higher level of oxytocin in early life could disrupt the later capacity to pair bond [8]. There is little doubt that either early social experiences or the effects of developmental exposure to these neuropeptides can potentially have long-lasting effects on behaviour. Both parental care and exposure to oxytocin in early life can permanently modify hormonal systems, altering the capacity to form relationships and influence the expression of love across the lifespan. Our preliminary findings in voles suggest further that early life experience affects the methylation of the oxytocin receptor gene and its expression [19]. Thus, we can plausibly argue that “love is epigenetic.”Given the power of positive social experiences, it is not surprising that a lack of social relationships might also lead to alterations in behaviour and concurrently changes in oxytocin and vasopressin pathways. We have found that social isolation reduced the expression of the gene for the oxytocin receptor, and at the same time increased the expression of genes for the vasopressin peptide (H.P. Nazarloo and C.S. Carter, unpublished data). In female prairie voles, isolation was also accompanied by an increase in blood levels of oxytocin, possibly as a coping mechanism. However, over time, isolated prairie voles of both sexes showed increases in measures of depression, anxiety and physiological arousal, and these changes were seen even when endogenous oxytocin was elevated. Thus, even the hormonal insurance provided by endogenous oxytocin in the face of the chronic stress of isolation was not sufficient to dampen the consequences of living alone. Predictably, when isolated voles were given additional exogenous oxytocin this treatment restored many of these functions to normal [20].On the basis of such encouraging findings, dozens of ongoing clinical trials are attempting to examine the therapeutic potential of oxytocin in disorders ranging from autism to heart disease (Clinicaltrials.gov). Of course, as in voles, the effects are likely to depend on the history of the individual and the context, and to be dose-dependent. With power comes responsibility, and the power of oxytocin needs to be respected.Although research has only begun to examine the physiological effects of these peptides beyond social behaviour, there is a wealth of new evidence indicating that oxytocin influences physiological responses to stress and injury. Thus, oxytocin exposure early in life not only regulates our ability to love and form social bonds, it also has an impact on our health and well-being. Oxytocin modulates the hypothalamic–pituitary adrenal (HPA) axis, especially in response to disruptions in homeostasis [6], and coordinates demands on the immune system and energy balance. Long-term secure relationships provide emotional support and downregulate reactivity of the HPA axis, whereas intense stressors, including birth, trigger activation of the HPA axis and sympathetic nervous system. The ability of oxytocin to regulate these systems probably explains the exceptional capacity of most women to cope with the challenges of child-birth and child-rearing. The same molecules that allow us to give and receive love, also link our need for others with health and well-being.The protective effects of positive sociality seem to rely on the same cocktail of hormones that carry a biological message of ‘love'' throughout the bodyOf course, love is not without danger. The behaviours and strong emotions triggered by love might leave us vulnerable. Failed relationships can have devastating, even deadly, effects. In ‘modern'' societies humans can survive, at least after childhood, with little or no human contact. Communication technology, social media, electronic parenting and many other technological advances of the past century might place both children and adults at risk for social isolation and disorders of the autonomic nervous system, including deficits in their capacity for social engagement and love [21].Social engagement actually helps us to cope with stress. The same hormones and areas of the brain that increase the capacity of the body to survive stress also enable us to better adapt to an ever-changing social and physical environment. Individuals with strong emotional support and relationships are more resilient in the face of stressors than those who feel isolated or lonely. Lesions in bodily tissues, including the brain, heal more quickly in animals that are living socially compared with those in isolation [22]. The protective effects of positive sociality seem to rely on the same cocktail of hormones that carry a biological message of ‘love'' throughout the body.As only one example, the molecules associated with love have restorative properties, including the ability to literally heal a ‘broken heart''. Oxytocin receptors are expressed in the heart, and precursors for oxytocin seem to be crucial for the development of the fetal heart [23]. Oxytocin exerts protective and restorative effects in part through its capacity to convert undifferentiated stem cells into cardiomyocytes. Oxytocin can facilitate adult neurogenesis and tissue repair, especially after a stressful experience. We know that oxytocin has direct anti-inflammatory and anti-oxidant properties in in vitro models of atherosclerosis [24]. The heart seems to rely on oxytocin as part of a normal process of protection and self-healing.A life without love is not a life fully lived. Although research into mechanisms through which love protects us against stress and disease is in its infancy, this knowledge will ultimately increase our understanding of the way that our emotions have an impact on health and disease. We have much to learn about love and much to learn from love.? Open in a separate windowC Sue CarterOpen in a separate windowStephen W Porges     

Why do we love medicines so much?

An evolutionary perspective on the human love of pills, potions and placeboHumans love medicinal drugs; we cannot get enough. Worldwide, the amount of money spent on medicines annually is growing exponentially and is expected to reach around US$1 trillion in 2012. So far, there has been no satisfactory explanation for human ‘pharmophilia'', our powerful tropism to medicines. Most studies that have attempted to provide an explanation have focused on classical supply–demand economics. Here, we suggest a different explanation: pharmophilia evolved as a means to cope with disease and sickness and is mediated through belief-induced neurological and immunological signalling pathways. Given that our love for drugs seems to be hard-wired into our biology, such an assertion has both social and economic repercussions. If public health policies do not take into account our strong pharmophilia, we will continue to overspend on and ‘over-value'' drugs at the expense of non-medicinal treatments and prevention strategies. Human pharmophilia is also a threat to biodiversity; one that has already brought many animal and plant species to the brink of extinction.If public health policies do not take into account our strong pharmophilia, we will continue to overspend on and ‘over-value'' drugs…The World Trade Organization estimates that global spending on pharmaceuticals reached US$427 billion in 2008 and, given an annual growth rate of 5.5%, projects a staggering US$929 billion in 2012. In many countries, expenditure on medicines now accounts for more than 1% of GDP (Hubbard & Love, 2004) and even were the human population to stabilize somewhere around 2050, we would still spend increasing amounts of money on medicines to improve and extend our lives. Today, most of the money spent comes from the 1.3 billion customers in the established market economies (EME), while most of the global population still rely on traditional medicines: 65% of the 6.5 billion humans on Earth depend on folk materia medica. This will change rapidly during the next 40 years. The populations of the EME—the current principal users of expensive pharmaceuticals—will ultimately account for only 11% of the global population by 2050 (UN Population Division, 2008), but the huge population expansion in middle-income countries—of up to 7.8–9 billion people—will massively increase demand for both pharmaceuticals and traditional folk medicine (Sivin, 1987). The ‘bottom billion'' in low-income countries will swell to nearly 2 billion by 2050, but will continue to rely almost entirely on folk medicine.…the huge population expansion in middle-income countries […] will massively increase demand for both pharmaceuticals and traditional folk medicine…This extraordinary expansion has significant implications for national health-care systems, the pharmaceutical industry and billions of patients. Although the EME spend the most on pharmaceuticals in absolute terms—USA, 46.7% of total expenditure; Europe, 24.8%; and Japan, 11.3%—compared with low- to middle-income countries—Sub-Saharan Africa, 1.3%; India, 1.8%—there is a huge difference in terms of out-of-pocket expenditure on medicines. Sub-Saharan Africa and India are leading the way with 65% and 81%, respectively, compared with a maximum of 40% in some EME countries (Davis, 1997).Rightly or wrongly, public health policies have focused on economic factors with little regard for the social, biological and cultural causes of pharmophilia—a phenomenon that has had a considerable impact beyond public health systems on both global biodiversity and traditional medicine. Intelligent public health policies and new policy frameworks that encompass traditional medicines, biodiversity and public health therefore need a better understanding of what drives our consumption of medicines. In this regard, our evolutionary past could provide an explanation to help understand our pharmophilia, as it combines an evolutionary perspective of health with the placebo effect and its underlying biology.The earliest evidence that our ancient ancestors actively sought to improve their health dates to the Middle Palaeolithic period, some 60,000 years ago, and is based on pollen found at a Neanderthal burial site, suggesting the use of medicinal plants (Solecki & Shanidar, 1975; Lietava, 1992). We do not know whether this behaviour extends further into the past, but the finding indicates that our ancient forbears probably used natural remedies to treat injuries and disease.In addition to the historical evidence of the use of medicinal plants, we have growing molecular and clinical knowledge of the placebo effect, which is key for explaining human pharmophilia. The word placebo actually comes from a mis-translation of the Bible by St Jerome, an Illyrian priest (Fig 1) who incorrectly translated the ninth line of Psalm 116, which should be “I will walk”, into “I will please”—placebo in Latin. The first use of placebo as a ‘dummy intervention'' has been credited to the efforts of progressive Catholics in the sixteenth century attempting to discredit right-wing exorcisms (Kaptchuk et al, 2009). The modern confusion and controversy about the placebo effect in modern medicine results from the use of the term ‘placebo'' to refer to an inert dummy medicine, whereas the placebo effect itself is now widely recognized as a real biological mechanism.Health-seeking behaviour is still found across the animal kingdom and ranges from hard-wired, genetically determined behaviours to learned strategiesOpen in a separate windowFigure 1St Jerome writing. Circa 1604 (oil on canvas), Michelangelo Merisi da Caravaggio (1571–1610). Galleria Borghese, Rome, Italy / Bridgeman, Berlin.Notwithstanding the confusion, cultural anthropology has recognized the positive effects of placebo for more than 70 years. It was first described by the anthropologist Melville Herskovits (1948), and latter codified into a seminal article, The Powerful Placebo, by Henry Beecher (1955). Further research by anthropologists and molecular biologists revealed a unique neuroimmunological signalling and regulatory pathway, which is activated by a belief in the healing power of treatment and depends on the interaction of the patient, the medicine man and the medicine—nearly all of which include verbal communication. As Ankrah Twumasi described the Ashanti traditional system, “the positive psychological value of the medicine man as a medicine, which makes it possible for the patient to believe that he has established rapport with the “god” that controls him and contributes to his feeling of health has long been recognized” (Twumasi, 1987).From a neurocognitive and psychophysiological stimulation perspective, the placebo effect is poorly understood. There have also been numerous claims about the efficiency of the placebo effect that have fallen foul of methodological issues and/or have wildly overestimated its potency (Hrobjartsson, 2002). However, recent evidence shows that placebo does produce changes in brain activity similar to agents that act directly on neurological pathways—such as fluoxetine to treat depression—and subsequent immunological pathways (Mayberg et al, 2002). The placebo effect thus seems to operate both by classical conditioning and through thought-induced mechanisms (Lieberman et al, 2004) in cortical areas that generate and maintain cognitive experience through dopaminergic reward pathways. Indeed, pharmacological and psychostimulation are both able to yield similar neuroimmune changes (Fig 2; Faria et al, 2008). This evidence from the neurological and cognitive sciences provides a plausible mechanism for our tropism towards medicines. Irrespective of the real potency of any ingested medicines, a sufficient ‘thought-induced'' belief in their efficiency activates pathways that, in turn, generate a demonstrable biological effect.…evidence from field and laboratory studies demonstrate that human tropism towards medicines is not a recent social phenomenon, but has old evolutionary rootsOpen in a separate windowFigure 2Neurobiology and immunobiology of the placebo effect. Adapted from Pacheco-Lopez et al (2006).From a systems perspective, the placebo effect is a highly flexible neuroimmunological system. Multiple integrating pathways coalesce into a common ‘mission-critical'' system—in this case the neuroimmunological axis, an evolutionarily conserved pathway that is essential for the functioning of the organism—that can be fired up in response to a noxious insult. This biological system fits with the anthropologists'' view that, “the value of medicines seems to be based on a perception of them as having an inherent power to heal” (van der Geest & Whyte, 1989).Indeed, if we look at the placebo effect from an evolutionary perspective, its evolution and impact on our species makes even more sense. First, humans did not evolve in the presence of highly efficient medicines—most were developed only within the past few decades. Second, our ancestors obviously ingested pharmacological agents, mostly from plants, which are much less potent than today''s drugs, but might still have had a mild effect. Finally, we know from a systems perspective that diversity builds resilience. Therefore, we suggest that evolution would have favoured a web of diverse signalling pathways, such as the neuroimmunological axis, to increase resilience and adaptability and help us to heal ourselves.Put another way, as Gustavo Pacheco-Lopez and colleagues eloquently summarize in their extensive review of the neurobiology of immunomodulatory placebo effects: “Placebo effects can, therefore, benefit end organ functioning and the overall health of the individual through the healing power of belief, positive expectations and conditioning processes” (Pacheco-Lopez et al, 2006). But how then has the placebo effect arisen? Or put another way, what is the ultimate causation of this proximate mechanism? (Tinbergen, 1972).To address this question we need to look at evidence from comparative biology to ascertain the evolutionary origins of pharmophilia. In fact, our species is not the only one that uses proto-medicines. Health-seeking behaviour is still found across the animal kingdom and ranges from hard-wired, genetically determined behaviours to learned strategies. At one end of the spectrum, eusocial organisms, such as wood ants, incorporate conifer resin into their nests, which inhibits the growth of a wide range of pathogenic organisms. Medicinal strategies such as geophagy—the consumption of soil and charcoal to detoxify poisonous substances (Struhsaker et al, 1997)—also appear in a wide range of species, from parrots and new-world monkeys to apes such as gorillas and humans. Some of these behaviours might actually be feeding strategies to eat plants with high levels of phenols, which would otherwise be poisonous, or they might be learned strategies to cope with gastric problems after the accidental ingestion of a toxin. Either way, geophagy has been observed across a broad range of taxa, including species that we do not usually consider highly ‘intelligent''. Indeed, there is now good experimental evidence that sheep actively medicate themselves with tannins to control parasites (Lisonbee et al, 2009). The point is that proto-medicine-seeking behaviour appears in two species—sheep and man—that shared a common ancestor around 100 million years ago.The supposed schism between prevention and treatment might simply be a reflection of our deep-seated pharmophiliaHowever, it is species with higher intelligence that provide the most compelling evidence for the evolutionary roots of pharmophilia. Over the past two decades, Michael Huffman and colleagues have investigated the use of plants with medicinal properties by other species, in particular non-human primates. Through field studies and the observation of captive primates, they found that bonobos and chimpanzees—our closest living relatives with whom we shared a common ancestor around 6–7 million years ago—use herbaceous leaves such as Desmodium gangeticum for their phytochemical properties, or rough hispid leaves as a mechanical device by which to rid themselves of parasitic infections such as the worm Oesophagostomum stephanostomum (Huffman & Hirata, 2004; Fowler et al, 2007; Dupain et al, 2002). A recent field study of bonobos in Wamba, Congo, observed febrile, clearly sick adults eating an unidentified species of Manniophyton, known locally as Lukosa (Fig 3); it is a plant that is used in many traditional medicines to control fever.Open in a separate windowFigure 3Bonobo (Pan paniscus) in the wild. The inset shows Manniophyton fulvum.These learned medicinal behaviours are not unique to higher primates. In South Africa, sick Knysa elephants seek out and eat specific types of medicinal mushroom known for their immunostimulatory effects. The fact that these bracket tree fungi are extremely bitter and are not part of the elephants'' normal diet suggests strongly that this is medicine-seeking behaviour (Patterson, 2004). Together, this evidence from field and laboratory studies demonstrates that human tropism towards medicines is not a recent social phenomenon, but has old evolutionary roots.Pharmophilia has profound implications for public policy. In fact, the understanding that the placebo effect probably developed from proto-medicine-seeking behaviour millions of years ago among a range of animal species provides a novel framework to understand why medicines are globally ‘over-valued''. So far, the medicalization of health has been seen almost exclusively as an issue of supply—that is, the promotion of medicines and the medicalization of disease by society and the pharmaceutical industry. Yet, ‘value'' is a complex multidimensional concept that incorporates sociocultural, political and economic parameters. From an evolutionary and psychological perspective, pharmophilia is therefore likely to contribute substantially to increased expenditures across most therapeutic categories of pharmaceutical products.Public health policy and the economic analysis of pharmaceuticals has largely explained our use of medicines to treat illness in terms of rational factors, such as medical needs, patterns of care, access to technology, marketing forces, pricing and costs. However, neither of the two standard views of rational behaviour—‘consistent choice'' or ‘self-interest maximization''—has been able to provide an adequate representation of rationality or of the actual situation, according to the Indian economist Amartya Sen (Sen, 2009). Perhaps the answer lies in pharmophilia, which operates through both the supply and demand side of medicines and creates the uncertainty that current rational behaviour models find so difficult to predict.The ongoing demand for TM […] is accelerating the loss of biodiversity and pushes many plant and animal species close to extinctionIf we include pharmophilia into the analysis, neither the consumer nor the supplier acts rationally—both are driven by our evolutionary desire to seek medicines. If this is really the case, unregulated supply and demand will continue to feed on each other to create an ever-increasing spiral of consumption and costs.Current public policy approaches should take pharmophilia into account. Regulation is therefore the only efficient method of controlling the use of medicines by attempting to reduce demand; perhaps by controlling direct-to-consumer advertising and accepting that people will not act rationally within the context of health and medication. The assumption that a rational, logical argument can lead to a down-valuation of medicines is, according to this view, wrong. The supposed schism between prevention and treatment might simply be a reflection of our deep-seated pharmophilia. As such, extensive public debate about the need to shift public health policies from treatment to prevention will change little.Pharmaceutical public policy should turn this view around and regard the placebo effect as an ally of the medicalization of health. As Peter Davis, a medical sociologist at the University of Auckland in New Zealand, has argued, the use of medicines is a “visible expression of concern”; it is the ‘total drug effect'' that helps to increase the well-being of the patient (Davis, 1997). Although this seems initially to be a rather weak argument, closer inspection reveals that interaction with a doctor and the giving and receiving of medicines clearly does increase well-being. The unfettered popularity of complementary and alternative medicine (CAM)—or rather integrative medicine, as it is now called—is a case in point. While orthodox medicine has been constantly rallying against CAM, all evidence suggests that this has been a Canute-like reaction, a tide we cannot hold back. Despite the pronouncements of eminent scientists and many clinical trials, most of which show modest or no effect, the uptake of such practices is increasing. Cultural arguments that this is filling a holistic lacunae might be partly true, but it does not explain why so many patients believe in the benefits of CAM. The concept of pharmophilia would comfortably explain this apparent mismatch between CAM and patients'' beliefs.However, in both cases—pharmaceuticals and CAM—the problem is not so much the concept as the cost and the potential for harm, both of which need to be managed from a public policy perspective. Surveys in developing and middle-income countries by the World Health Organization and Health Action International have shown that 90% of the population in these countries purchase drugs through out-of-pocket payments, which makes medicines the biggest family expenditure after food (Cameron et al, 2009). The mantra of prevention, public health, non-pharmaceutical interventions, and the doctrine of ‘global public good''—that is, health policy responding to the objectively greatest need—might be intellectually satisfying, but it clearly does not reflect reality and the future trajectory of the continuing ‘pharmaceuticalization'' of disease in these countries (Smith & Mackellar, 2007).The great gap between prevention and cure is not simply a matter of history but a fundamental aspect of our evolution. Public policy cannot expect a rational choice based on utility when our evolved psychologies have such a strong tropism for medicines (Sen, 2009). Recognition of this sheds new light on the issue of how we promote medicines and in particular how we regulate or accept direct-to-consumer advertising, one of the most contentious battlegrounds in market economies. By ‘over-valuing'' medicines, unconstrained public policies in favour of drugs and medicines will have two effects: first, they will further drive up expenditure beyond rational-use limits; second, they will under-value the contribution towards health and disease management of prevention and non-medicinal modalities, such as surgery. The nature of human pharmophilia suggests that continued stringent controls on advertising and more thoughtful rational approaches to cost-effectiveness analyses need to come from public policy as they are unlikely to arise through market forces.Pharmaceuticals represent one end of the spectrum in terms of human medicines. However, the most abundant usage of medicines by far, now and in the future, is traditional medicine (TM). This pharmacopoeia of folk medicine, as well as organized TM systems such as Ayurvedic and Chinese medicine, contains hundreds of thousands of plants, animal, mineral and other substances (Alves & Rosa, 2007). TM dominates health care outside high-income countries and has an increasing role in complementary and/or integrative systems in developed countries (Fig 4). The World Bank estimates that the ratio of those trained in Western medicine to TM practitioners in various African countries is between 1:1,639 in urban South Africa to 1:50,000 in Malawi and Mozambique (Cunningham, 1993). Higher resolution studies, for example in South Africa, estimate that about 5.6% of the national health budget is spent on TM; much more, however, comes from out-of-pocket payments.…any public policies to address the health situation in both affluent and developing countries can only be successful if they take into account the human factorOpen in a separate windowFigure 4The South African medical plants industry. Adapted from Mander et al (2007). GMP, good manufacturing process.It is not only the cost that is at issue here. The ongoing demand for TM, a product of both population growth and increasing per capita purchasing power, coupled with a loss of habitats through climate change, over-usage, deforestation and other factors, is accelerating the loss of biodiversity and pushes many plant and animal species close to extinction. For example, some 200 animal and 550 plant species are actively traded in KwaZulu-Natal (South Africa); 60% of these are now reported as scarce (Mander et al, 2007). Population increases in Asia and Africa with unconstrained demand for TM coupled to non-sustainable habitat loss is a massive threat to biodiversity. The focus of the Convention on International Trade in Endangered Species and other bodies on critical species represents only the tip of the iceberg and public policy has only recently realized the extent of the problem. While problems such as deforestation and habitat loss have attracted public notice and led to public policies to alleviate these, the issue of how to provide sustainable TM for populations in much of Africa and Asia has received scant attention. Integrating TM into public health systems with policy approaches centred on conservation is a huge challenge, in particular because TM remains a totally unregulated arena. However, it is essential that countries that are dependent on TM as a source of health care urgently address the problem. It is only within these nations that effective measures can be taken.More generally, though, any public policies to address the health situation in both affluent and developing countries can only be successful if they take into account the human factor. Our pharmophilia is a deeply engrained behaviour and an important aspect of our health and well-being. It needs to be better understood and incorporated into global health policy frameworks.? Open in a separate windowIsabel BehnckeOpen in a separate windowRichard SullivanOpen in a separate windowArnie Purushotham     

The basis of morality

Psychologists, anthropologists and biologists are uncovering the bigger picture behind the development of empathy and altruismMany philosophers and anthropologists might argue that among the attributes that make humans unique, it is our ability to reason morally that sets us apart from all other animals—perhaps in addition to our capacity for spirituality. From Ancient Greece and the Roman Republic, to sixth century China and the European Enlightenment; philosophers throughout the ages have pondered why humans can feel empathy or behave altruistically—and, indeed, why they even contemplate it. Only later, in the twentieth century, did the biological sciences join the quest for understanding by seeking genetic, neurological and evolutionary explanations of self-awareness and morality.The answer has so far been elusive, as biologists have neither been able to find the ‘moral'' gene—if such a thing exists—nor to identify a specific cluster of neurons or region of the brain that takes care of ethical decision making. Yet, some parts of the picture are emerging and they reveal a relationship between the complex emotional processes that enable empathy and altruism and the advanced cognitive abilities, such as mirror self-recognition (MSR), that emerged with the evolution of the more complex structural and functional components of the brain. In addition, these studies show that many more animal species than we had appreciated, including birds, display more or less primitive versions of these traits.These findings have led to a proliferation of research into ‘human-like'' social behaviour in animals. “Empathy research is really taking off, not only on adult humans in neuroscience or on children, but also animals,” commented Dutch primatologist Frans de Waal, now at Emory University in Atlanta, GA, USA, who analyses the behaviour of chimpanzees to gain insight into their emotional and cognitive abilities. “We have collected thousands of observations of so-called consolation behaviour in chimpanzees. As soon as one among them is distressed, for example losing a fight, falling from a tree, or encountering a snake, others will come over to provide reassurance. They embrace the distressed chimp or try to calm him or her with a kiss and grooming. This behaviour is typical of chimps and other apes, and is used in research on children as the main behavioural marker of ‘sympathetic concern'',” he explained.Clues about the cognitive functions and neurological features underlying ‘sympathetic concern'' can be elucidated by correlating the results from studies of children with those of higher animals that appear capable of feeling empathy and possibly altruism. “In children, MSR emerges between 18–24 months of age and its onset is concurrent with the emergence of empathic behaviour and other indices of the theory of mind,” commented Diana Reiss, a specialist in the evolution of intelligence at Hunter College of the City University of New York, USA. Reiss also pointed out that all species that exhibit MSR have large, complex brains relative to their body weight, with evidence of a developmental link between MSR and empathy, as in human children.Researchers are now working to identify the neurological basis for this link, why it evolved and how it develops with the growing individual. MSR, widely regarded as an important requirement for empathic or altruistic behaviour, has now been identified in several species beyond the great apes and humans. Although MSR is not itself interesting from the perspective of cognitive evolution—it confers no direct selective advantage—as de Waal pointed out, the importance of the mirror test resides in what it tells us about the ability of animals to analyse their relationship with their environment, especially with respect to their social partners. “The mirror test is interesting not because it shows that an animal has the capacity for self-recognition but because of the cognitive abilities that are associated with MSR,” he explained.…biologists have neither been able to find the ‘moral'' gene—if such a thing exists—nor to identify a specific cluster of neurons or region of the brain that takes care of ethical decision makingGordon Gallup originally demonstrated MSR in animals in 1970 (Gallup, 1970). He developed a test in which a visible coloured mark is made on a part of the animal''s body that it cannot see without using a mirror. The test determines whether the animal can use the reflection to locate the mark and then touch or rub it, thus revealing that it can tell the reflection is of itself and not of another individual. Since Gallup''s early experiments, MSR has been seen in a number of animals, most notably dolphins (Reiss & Marino, 2001), the Asian elephant (Plotnik et al, 2006) and, a first for birds, the magpie (Prior et al, 2008).Although MSR has now been demonstrated in several species, it is clearly confined to a small group with highly evolved social interactions. Most species in this group are also set apart from the rest of the animal kingdom because they have spindle neurons, which are believed to be a vital component of large brains capable of empathic social behaviour. These neurons tend to be larger and have a streamlined bipolar structure that is well-adapted for the rapid and coordinated transmission of signals. Also known as von Economo neurons (VEN), they occur in areas of the cortex that process a large number of input signals from other brain regions, in particular the fronto-insular cortex and anterior cingulate cortex. Functionally, the VEN architecture seems to be optimized for the parallel receipt and processing of a large amount of diverse information.“Recent research has reported that spindle neurons are found to occur only in the brains of a few species—humans, the great apes, whales, dolphins and elephants—leading to the speculation that they are a possible obligatory neuronal adaptation in very large brains, permitting fast information processing and transfer along highly specific projections and that evolved in relation to emerging social behaviours,” commented Reiss, who was the first to demonstrate MSR in dolphins along with her colleague Lori Marino, also at Emory University. “It has been further suggested that these specialized brain cells may be involved in processing emotions and underlie empathic behaviour.”Although MSR has now been demonstrated in several species, it is clearly confined to a small group with highly evolved social interactionsFurthermore, the absence of spindle neurons in all other primates suggests that these evolved independently among the great apes and other species that are capable of MSR. This finding leads to the question of whether the brains of higher social animals that have spindle neurons have further common structural or functional features that also evolved in parallel. A recent study suggests that this has happened, at least in the case of elephants and humans, both of which have similar extensive regions of neocortex, which is the neurological structure responsible for sensory perception, motor commands and higher level thought processes (Goodman et al, 2009). The study examined several mammalian species to record the number of nucleotide substitutions in genes that have a crucial role in the brain; the results showed that the most substitutions occur in humans and elephants. This suggests that elephant and human brains have both encountered strong selection for this particular group of genes, which the other animals included in the study clearly had not.However, any suggestion that specific neurological structures are essential, at least for MSR, has been challenged by the discovery of MSR in magpies, which do not even have a neocortex. Although the detailed structures are different, the forebrains of magpies, along with some other members of the crow family, are large and have high neuron densities that are more comparable with humans than other bird species. Although spindle neurons have not yet been observed in magpies, their existence in birds has not been ruled out. In any case, it might be that magpies evolved more complex brain functions without the help of spindle neurons to speed up communication.Nonetheless, there seems to be a clear correlation between the emergence of MSR and empathic behaviour. Magpies, for example, have been subject to extensive research precisely because their ecological conditions have driven the evolution of social intelligence (Prior et al, 2008). They steal and store food, but they also form stable partnerships based to some extent on trust, which requires discrimination between other individuals and judgments about their intentions.…the enhanced cognitive and social interactive abilities of dolphins and great apes have allowed these species to develop rudimentary levels of morality and altruismIn the case of dolphins, the selective pressures they face are associated with their social groups—known as pods—which are able to cooperate with neighbouring groups in times of danger or when there is an opportunity to hunt for food on a larger scale. Dolphins are carnivores and have developed highly skilled cooperative techniques for hunting prey, similar to a pack of wolves hunting, but in three dimensions. Dolphins also devote a large amount of time to training their offspring to hunt and survive, and they are the only non-human mammals that exhibit strong evidence of vocal mimicry and physical imitation (Reiss et al, 1997).Although they live in superficially different ecosystems, dolphins and the great apes have been subject to fundamentally similar selective pressures, according to Marino, who co-authored the seminal study of vocal mimicry in dolphins. “Despite the seemingly disparate environmental pressures that would shape cetacean—the mammalian group including dolphins, whales and porpoises—and primate cognitive evolution, these drivers were actually extremely similar,” she said. “Both evolved complex levels of social interaction, and, in that respect, dolphins and primates evolved in, conceptually, very similar environments.”According to Marino, dolphin brain enlargement occurred only when they began to develop the use of echolocation to coordinate hunting and other activities. But other animals have developed echolocation without enlarging their brains. In the case of cetaceans and especially dolphins, Marino believes the key evolutionary driver was the incorporation of this technique into a complex system of social interaction. She argues that the enhanced cognitive and social interactive abilities of dolphins and great apes have allowed these species to develop rudimentary levels of morality and altruism.“Ongoing findings from studies of both primate and cetacean behaviour provide support for the conclusion that social complexity involves the evolution of morality,” Marino explained. “This is true in a number of ways. From an ultimate evolutionarily point of view, complex group living requires ways to regulate interactions among individuals in order to keep the group intact. Frans de Waal has provided abundant evidence for this argument in primates and I would contend the same is true of cetaceans. On a proximate level, much of the morality we see in primate and cetacean groups is underwritten by empathy, which is enabled by the kind of awareness of self and other that dolphins and primates—particularly great apes and humans—demonstrate.”Such behaviour might have evolved partly because altruism enhanced individual survival chances—providing that the cost was not too great. But, according to Antonio Damasio, Director of the Brain and Creativity Institute at the University of Southern California in Los Angeles, CA, USA, the key driver might have been that altruism enabled individuals to make ‘wiser'' decisions. Humans might be unique in the degree to which we apply ethics and morality to rational decision-making, but the presence of empathy in animals provides important clues about the neurological underpinnings of these abilities. In particular, research with animals might help to settle the long-standing argument about whether morality and altruism can be regarded as independent of the brain''s hardware, or whether morality is hard-wired into the brain and is a product of our neurological evolution.…humans commonly appear to balance rational and emotional factors when making judgements, creating the impression that there are distinct neural systems competing with each otherSome studies seem to suggest that the latter is true. For example, an experiment at the University of Zurich, Switzerland, in which subjects were asked to divide up a sum of money on a supposedly fair basis, found that the disruption of cognition altered the moral behaviour of the participants. In the so-called Ultimatum Game, one of the two participants—who does not know how much money is available—is required to make an offer to the other, who does know the size of the pot. If the second player does not accept, neither player receives anything, so in a sense it can be seen as a test of indignation versus greed. If the pot is big, the second player might decide to swallow his or her pride and accept it. The first player, however, might decide to make a generous offer in order to be sure it would be accepted. During the game, the Swiss researchers applied low-frequency transcranial magnetic stimulation to disrupt either the right or left dorsolateral prefrontal cortex of their test subjects. Disruption of the right side made them more susceptible to ‘immoral'' decisions as they were more willing to make offers that they judged to be unfair to their partners. Yet, they retained their ability to determine fairness. The researchers concluded that the right side of the prefrontal cortex has an implicit role in determining how to apply moral or ethical standards to information made available by cognitive processes (Sanfey et al, 2003).This suggests that morality is hard-wired and does not exist independently of the brain''s complex biochemistry, at least according to Damasio. “Emotions and feelings, as we know them, are related to our ‘wet'' biology, to our flesh,” he said. “Formally you can construct them in robotic artefacts but there is no reason to believe [that] they would be the same.”In this regard, Michael Koenigs, from the Department of Psychiatry at the University of Wisconsin–Madison, USA, pointed out that humans commonly appear to balance rational and emotional factors when making judgements, creating the impression that there are distinct neural systems competing with each other. “From a psychological standpoint, in the midst of a sticky moral dilemma it can certainly feel like your mind is being pulled in two different directions,” he said. “And in terms of the brain, it is very clear that certain areas are more concerned with emotion and affect, while other areas are more associated with ‘cold'' cognitive processes. Both systems play a role in determining morality, but at the neural level the relationship between the systems is more of an integration than a competition.”Until recently there was very little direct observation of these neurological processes at work. However, recent research based on functional magnetic resonance imaging has revealed that ‘true'' and ‘false'' statements activate different regions of the prefrontal cortex. The researchers found that people tend to use separate processes to resolve the distinctions between true and false statements, unless the answer is blindingly obvious (Marques et al, 2009). They concluded that people accept statements as true initially and confirm this merely by a call to memory. However, if the initial check suggests that the statement might be false, further reasoning is required to confirm the rejection. “The idea supported by this paper and others is that when the statement to verify is true—and by default we assume [that] it is—the task is to find if we have or recognize that information in our memory,” explained Frederico Marques, one of the authors of the study from the University of Lisbon, Portugal. “When we do not find that information, or if we have doubts, we further process the information, more like problem solving.”Animals that are capable of MSR also possess primitive abilities to assess truth or falsehood. Magpies, for example, have to decide whether a particular individual can be trusted to not steal food. Of course, more research is needed to provide further insight into the neurological processes involved in such assessments and to illuminate the evolutionary history of such a skill. What is established, however, is that the roots of complex social behaviour and the capacity for abstract thought—as well as ethical judgment, perhaps—can be found predominantly in the more advanced warm-blooded and social vertebrates. The capacity for morality is perhaps not, after all, uniquely human.     

Molecules of choice?

Transmembrane proteins with seven helices, whether they are in the insect ‘nose'' or the mammalian eye, are the molecule of choice for detecting the world. No matter the kingdom, evolution seems to settle on the optimal solution time and time again.How best to describe evolution? A drunkard''s walk; a shambling billion-year spree punctuated with prat-falls, accompanied by a Beckettian mumbling? Or a sleek greyhound rippling with suppressed energy, racing along the narrow highways of the Darwinian landscape? “Mumble and shuffle” would be the answer of most biologists, but perhaps next time we open our Darwin we should also turn up The Ride of the Valkyries.When reviewing the evolution of eyes, Russell Fernald hit the nail on the head when he remarked how the opsins have “proven irresistible for use in eyes” [1]. Indeed they have; not only do they belong to the vast family of G-protein-coupled receptors (GPCRs), but it is no accident that, in ears and noses, related transmembrane proteins with the canonical seven helices are also poised to transduce noise and smells into electrical signals and ultimately awareness.There is a comforting congruity in all this. Just as our eyes register the world through the opsins, in the compound eyes of insects the same proteins wait in attendance. But let us turn to the insect ‘nose''. Here, despite a radically different anatomy replete with antennal and maxillary sensilla, the arrangement turns out to be strikingly convergent in terms of operation with the mammalian schnozzle [2], but when we look at the molecular machinery something curious seems to be going on. One component, concentrated in the coeloconic sensilla, is tasked with detecting molecules such as alcohol and ammonia. Here, the machinery depends on the ionotropic glutamate receptors. This appears to be a classic case of co-option because not only are these receptors ancient [3], they also show fascinating links to synaptic receptors [4]. However, the bulk of the olfactory capacity looks to a series of transmembrane proteins. At first glance, complete with their seven helices spanning the sensory membrane, they look reassuringly like the ever-reliable GPCRs. Except they aren''t! Blink twice and then notice that these proteins are back to front so that the amino-terminal is cytoplasmic and the carboxy-terminal extracellular. This is completely opposite to the GPCRs [5], but surely it represents a trivial difference? On the contrary. Lurking in the insect ‘nose'' is a ligand-gated cation channel that at first sight looks practically identical to a GPCR but is completely unrelated [6].Maybe I am a bear of little brain, but is this not all a little peculiar? Why throw away a perfectly acceptable GPCR—which after all other ecdysozoans such as nematodes use—and install what is effectively a near-perfect mimic? A little trick to keep us on our Darwinian toes? Maybe a clue comes from the choanoflagellates. Central to their life is nitrogen metabolism, but rather oddly the genes they employ have been recruited from algae. “If it ain''t broke, don''t fix it”, except that Aurora Nedelcu and colleagues [7] suggest these imports turned out to be a notch better than the incumbent machinery. Spitfire versus Messerschmitt if you like; both superb aircraft, but the former had the edge.Perhaps a parallel argument applies to the insects. Their ‘noses'' might be functionally equivalent to those of mammals but insects live in a different world, zooming through the air at high speed and encountering smells in the form of narrow odour plumes separated by ‘clear'' air. Rather different from the leisurely inhalations of a large mammal; on the insect scale of things, time is of the essence [8]. This might also explain why there are a variety of transduction cascades, some linked to tried and tested methods but others evidently novel. We should, however, not lose sight of the central point. Be it in terms of fundamental configurations of olfactory design or the molecular machinery behind it, insects do indeed replay the tape of life, but with end results that are very much the same. With respect to the receptor protein, frankly who cares if it is a GPCR or a ligand-gated ion channel protein? They are completely unrelated, but the far more remarkable fact is that, in terms of transduction, the system evidently has no alternative. The molecule must be a seven-helix transmembrane protein; this is the molecule of choice. Evolution meets design: Darwin and Plato embrace.Irresistibly, evolution will navigate to this solution. Rest assured that on Threga IX—that charming little planet just to the left of Arcturus—eyes will flicker and noses will swivel beneath an alien sun. We can save ourselves all the fuss of an extremely expensive extraterrestrial excursion. In those alien eyes and noses, we can be quite certain that a seven-helix transmembrane protein will be busy telling its owner that the sunset is red and dinner is almost ready. Gin and tonic anybody?